WM Medical Practice Guidelines & Research Articles

Download PDF

Efficacy and safety of bendamustine, rituximab and bortezomib treatment in relapsed/refractory Waldenstrom Macroglobulinaemia: results of phase 2 single-arm FIL-BRB trial. Benevolo G, Drandi D, Villivà N, et al. Br J Haematol. Published online November 27, 2024. DOI:10.1111/bjh.19920This multicenter phase II study Fondazione Italiana Linfomi (FIL)-bortezomib plus rituximab plus bendamustine (BRB) tested a combination of bendamustine (90mg/m2 on days 1–2), rituximab (375mg/m2 intravenously on day 1) and bortezomib (1.3mg/m2 sc on days 1, 8, 15, 22) every 28days for six cycles in 38 symptomatic patients with relapsed/refractory Waldenstrom macroglobulinemia (RR-WM). Moreover, MYD88L265P and CXCR4S338X mutations were tested by droplet digital polymerase chain reaction (ddPCR) both at baseline and at the end of treatment in 21 patients. Overall response rate at the end of therapy was 84.6%, including 4 (11%) complete remission, 15 (39%) very good partial response, 12 (32%) partial responses according to IWWM response criteria. At 18, 24 and 30months, progression-free survival was 84.2%, 81.5%, and 78.8% respectively. At 18months, the overall survival was 92.1%. Overall, 19 patients (50%) experienced grade 3–4 hematological toxicity, mainly thrombocytopenia, and grade 1–3 neuropathy rate was about 10% and required bortezomib dose reduction but did not result in treatment interruption. Moreover, BRB treatment induced the high rates of undetectable molecular minimal residual disease (MRD) at the end of the therapy. BRB regimen used as second line is an effective and well-tolerated salvage treatment for relapsed refractory WM patients. MRD monitoring showed promising efficacy in clearing the residual disease.

Download PDF

A comparative analysis of transformed indolent lymphomas and de novo diffuse large B-cell lymphoma: a population-based cohort study. Vaughn, J.L., Ramdhanny, A., Munir, M. et al.  Blood Cancer J. 14, 212 (2024). https://doi.org/10.1038/s41408-024-01194-5 Histologic transformation (HT) of indolent non-Hodgkin lymphoma (iNHL) to diffuse large B-cell lymphoma (DLBCL) carries a poor prognosis. Using the Surveillance, Epidemiology, and End Results-17 database, the authors conducted a population-based study of adult patients with transformed follicular lymphoma (t-FL), marginal zone lymphoma (t-MZL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (t-LPL/WM), and de novo DLBCL. Primary outcome was relative survival (RS), and secondary outcomes included overall survival (OS) and lymphoma-specific survival (LSS). Outcomes were modeled using flexible parametric survival models, while multivariable modeling was used to compare RS, OS, and LSS. The incidence of HT was highest in splenic MZL (SMZL, 6.78%) and lowest in extranodal MZL (EMZL, 1.62%). Median follow-up times were similar for patients with de novo DLBCL and transformed indolent lymphomas. The 5-year RS and OS were longer in de novo DLBCL compared to all other transformed iNHL subtypes (68 versus 59%, respectively). For t-FL, early transformation (within 2 years of diagnosis, Hazard ratio [HR] = 1.34) and prior treatment (HR = 1.89) were associated with inferior survival. This association was not observed in other transformed lymphoma subtypes. This is the first comparative study to show that the outcomes of t-LPL/WM were inferior compared to de novo DLBCL and highlights the need to incorporate early experimental therapies in patients with t-FL with early transformation and receipt of prior chemotherapy.

Download PDF

Determination of MYD88 and CXCR4 Mutations for Clinical Detection and Their Significance in Waldenstrom Macroglobulinemia. Yuting Yan, Ying Yu, Wenjie Xiong, Jun Wang, Yao Yao, Yujiao Jia, Yanshan Huang, Yuxi Li, Tingyu Wang, Rui Lyu, Hao Sun, Haoxu Wang, Qi Wang, Wei Liu, Gang An, Weiwei Sui, Yan Xu, Wenyang Huang, Zhen Yu, Dehui Zou, Mu Hao, Zhijian Xiao, Jianxiang Wang, Lugui Qiu, Shuhua Yi; Clin Cancer Res 1 December 2024; 30 (23): 5483–5493. https://doi.org/10.1158/1078-0432.CCR-23-3939 This study concludes that both AS-PCR and ddPCR are highly effective for detecting MYD88 mutations in unsorted samples, providing high sensitivity suitable for routine clinical use. For CXCR4 mutations, NGS showed the highest sensitivity. In the context of non-BTKi treatments, neither MYD88 nor CXCR4 mutation emerged as independent prognostic factors when considering the IPSSWM clinical staging. However, in the era of BTKi treatment, the prognostic relevance of both MYD88 and CXCR4 mutations becomes significant, independent of the IPSSWM score. This indicates that testing for these mutations is crucial for predicting survival outcomes in patients receiving BTKi therapy. Our findings highlight the importance of understanding how disease risk factors can vary depending on the treatment context.

Download PDF

Peripheral Neuropathy in the Phase 3 ASPEN Study of Bruton Tyrosine Kinase Inhibitors for Waldenstrom Macroglobulinemia. Heyman BM, Opat SS, Wahlin BE, et al. Blood Adv. Published online December 3, 2024. DOI:10.1182/bloodadvances.2024014115 Peripheral neuropathy (PN) is a significant cause of morbidity associated with Waldenstrom macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of zanubrutinib with ibrutinib in patients with WM. This ad hoc analysis examined treatment outcomes with zanubrutinib or ibrutinib on PN symptoms associated with WM in patients enrolled in ASPEN. Logistic regression was performed between PN symptom resolution and several predictors. Health-related quality of life (HRQOL) was assessed using the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. Forty-nine patients with PN symptoms were included (zanubrutinib treated, n=27; ibrutinib treated, n=22). Overall, 35 patients (71.4%) experienced resolution of PN symptoms, with a median time to resolution of 10.1 months (range, 1-46.8). In cohort 1 (MYD88 mutation), the median time to PN symptom resolution was 4.6 months (range, 1.1-46.8) with zanubrutinib and 14.1 months (range, 1-44) with ibrutinib. Logistic regression demonstrated a significant relationship between PN symptom resolution and both major response (hazard ratio [HR], 10.67 [95% CI,2.20-51.81]; P=.0033) and lower baseline anti-MAG antibody levels (HR, 0.72 [95% CI, 0.52-1.00]; P=.0486). Patients with PN symptom resolution had greater improvement in HRQOL. Physical functioning improved in patients with PN symptom resolution and was unchanged in patients without resolution. Improvements observed in PN symptoms may be in response to a reduction in IgM. While further investigation is required, this analysis supports the potential use and further exploration of Bruton tyrosine kinase inhibitors to treat PN symptoms in patients with WM.

Download PDF

Six-year follow-up of phase II study exploring chemo-free treatment association with idelalisib and obinutuzumab in symptomatic relapsed/ refractory patients with Waldenstrom’s macroglobulinemia. Tomowiak C, Poulain S, Nudel M, et al. Ann Hematol. Published online November 5, 2024. DOI: 10.1007/s00277-024-06076-1 A  six-year follow-up period allows the authors’ prospective study to demonstrate, for the first time, the impact of TP53 mutations in patients treated with a fixed-duration, chemo-free regimen, which leads to a significantly shorter overall survival in TP53-mutated patients. In contrast to what is observed with ibrutinib, CXCR4 mutations did not affect progression free survival nor overall survival. Nevertheless, given the potential efficacy of this class of agents, next-generation Pi3Kδ inhibitors in combination with obinutuzumab may limit the toxicity issues observed in this phase II trial and may prove an effective treatment option, particularly in WM patients who have previously undergone treatment with both BTKi and BCL2 inhibitors.

Download PDF

*Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia. Castillo JJ, Branagan AR, Sermer D, Flynn CA, Meid K, Little M, et al. Blood. (2024) 143:582–91.https://doi.org/10.1182/blood.2023022420In this important study the authors concluded that the combination of ibrutinib and venetoclax induced deep and durable responses in treatment-naïve patients with Waldenström macroglobulinemia. Planned study therapy was stopped early due to a higher-than-expected occurrence of ventricular arrhythmia in 4 of the 45 participants.

Download PDF

Review of BCL2 inhibitors for the treatment of Waldenstrom’s macroglobulinemia and non-IgM lymphoplasmacytic lymphoma. Tomkins O, D’Sa S. Front. Oncol., November 2024 Sec. Hematologic Malignancies Volume 14 – 2024 | https://doi.org/10.3389/fonc.2024.1490202In this mini review the authors cite five studies that have examined the use of BCL2 inhibitors in WM/LPL: one oblimersen sodium, three venetoclax, and one sonrotoclax. Three pivotal trials are currently in progress, with the potential to alter practice in the treatment of LPL/WM. Fixed-duration venetoclax monotherapy for 24 months resulted in high-response rates but significant progression within 12 months of completion. This suggests that either continuous or combination therapy is required for the use of BCL2i in this condition. The combination of a BTKi ibrutinib and BCL2i venetoclax in LPL/WM, unfortunately, resulted in unacceptably high rates of ventricular events and death, essentially excluding this drug combination from further evaluation in WM/LPL. A cautious interpretation of the rapid responses and high rates of VGPR with this combination suggests that BCL2i in combination with other covalent- and non-covalent BTKis, with less cardiotoxic side effect profiles and in selected patients, may be of interest. The combination may particularly have a role in the context of heavy bone marrow infiltration, given the high rates of bone marrow clearance seen. This combination is currently being evaluated in two studies, one using sonrotoclax-zanubrutinib frontline and another using venetoclax-pirtobrutinib for R/R WM. The combination of a BCL2i with an anti-CD20 antibody, such as rituximab, may also prove efficacious.

Download PDF

Extramedullary disease in Waldenstrom macroglobulinemia: A population-based observational study. Østergaard S, Munksgaard L, Nielsen TH, Hammer T, Pedersen LM, Ølgod Pedersen M, et al.  eJHaem. 2024; 1–5. https://doi.org/10.1002/jha2.1037Extramedullary disease (EMD) is a rare manifestation of Waldenstrom macroglobulinemia (WM), and its clinical and prognostic implications are poorly understood. In this single-center study, they investigated the clinical significance of EMD in a cohort of 469 WM patients. EMD was identified in 30 (6.4%) patients, with the central nervous system, kidneys, and lungs being the most frequently affected sites. The cumulative incidence of EMD was 12.6% at 15 years. Median overall survival rates for 5 and 10 years for patients with EMD were 63% and 37%, respectively. Their findings indicate a persistent risk of EMD throughout the disease course, with no significant impact on long-term survival.

Download PDF

Prognostic impact of nodal involvement in Waldenstrom Macroglobulinaemia. Østergaard S, Munksgaard L, Hammer T, Pedersen MØ, Nielsen TH, Gjerdrum LMR. Br J Haematol. 2024; 00: 1–5.https://doi.org/10.1111/bjh.19809The clinical and prognostic implications of nodal involvement (NI) in WM are largely unknown. In this study, the authors explored the impact of NI on clinical presentation and outcome in a population-based cohort of 469 patients with WM, consecutively diagnosed between 2000 and 2022. NI was detected in 34% of patients and was associated with symptomatic disease, adverse prognostic factors, an increased risk of transformation, and lymphoma-related death. Their findings indicate that NI is of prognostic significance in WM, suggesting a need for enhanced surveillance in these patients.

Download PDF

Determination of MYD88 and CXCR4 mutation for clinical detection and their significance in Waldenström macroglobulinemia. Yan Y, Yu Y, Xiong W, et al. Clin Cancer Res. Published online October 7, 2024.https://doi.org/10.1158/1078-0432.CCR-23-3939This study aimed to explore the incidence and clinical features of MYD88 and CXCR4 mutations in patients with WM and determine the optimal method for routine clinical practice. Additionally, they sought to evaluate the prognostic significance of these features across various therapeutic backgrounds [cytotoxic group, the Rituximab/Bortezomib-based group, and the Bruton’s tyrosine kinase inhibitor (BTKi) group]. They found that testing for MYD88 mutations using AS-PCR or ddPCR in unsorted samples is viable for routine clinical practice. They also found that under BTKi treatment, MYD88 and CXCR4 mutations hold greater prognostic importance than IPSSWM staging in WM.

Download PDF

Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 1.2025, NCCN Clinical Practice Guidelines in Oncology. Kumar, S. K., Callander, N. S., Adekola, K., Anderson, L. D., Jr, Baljevic, M., Baz, R., Campagnaro, E., Costello, C., D’Angelo, C., Derman, B., Devarakonda, S., Elsedawy, N., Godara, A., Godby, K., Hillengass, J., Holmberg, L., Htut, M., Huff, C. A., Hultcrantz, M., Kang, Y., Larson, S., Lee, H., Liedtke, M., Martin, T., Omel, J., Robinson, T., Rosenberg, A., Schroeder, M. A., Sherbenou, D., Suvannasankha, A., Valent, J., Varshavsky-Yanovsky, A. N., Vogl D., Kovach E. & Kumar, R. (2025). Journal of the National Comprehensive Cancer Network.  The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel during the NCCN Guidelines update have been included in this 2025 version of the discussion section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion. The complete details of the development and updates of the NCCN Guidelines are available at NCCN.org.

Download PDF

New approaches to active monitoring: Patient-reported outcomes and wearables utilization in Waldenstrom macroglobulinemia. Summers K, Agrippa O,  D’Sa S. JCO 42, 168-168(2024). DOI:10.1200/JCO.2024.42.23_suppl.168This report supports the enrichment of knowledge around baseline physiological and quality of life metrics for patients with WM, demonstrating the feasibility of a digital ecosystem of wearable-captured and ePRO metrics at a high data completeness level.

Download PDF

Clinician Perspective on Once-Daily Zanubrutinib Dosing for B-Cell Malignancies at a Single Center. Narang M, Horn C, Lee E. Clinical Medicine Insights:Oncology. 2024;18. doi:10.1177/11795549241275665.This article provides perspectives on zanubrutinib dosing through interviews with 2 clinical care professionals at the Maryland Oncology Hematology Center, based on their experiences treating patients with WM or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Zanubrutinib QD (once daily) is the preferred regimen for some physicians and pharmacists, as it may improve treatment adherence within weeks after initiation compared with BID (twice daily) dosing. According to the clinician interviews provided in this report, patients have reported positive experiences with QD dosing, including a reduced administration burden in those with complicated polypharmacy. Thus, observations from this single center indicate that the zanubrutinib QD regimen may offer benefits to both patients with WM or CLL/SLL and their clinical care teams and should be considered in patients receiving zanubrutinib.

Download PDF

IgM-Associated Cryoglobulinemia. Khwaja J, Salter SJ, D’Sa S. Hemato. 2023; 4(3):240-249.https://doi.org/10.3390/hemato4030019. Cryoglobulinemia is characterized by serum immunoglobulins that precipitate at temperatures below 37 °C and redissolve on warming. Monoclonal IgM immunoglobulin can be associated with type I and II cryoglobulinemia with underlying WM, monoclonal gammopathy of undetermined significance, or another non-Hodgkin lymphoma. In this research, the authors review the clinical characteristics of monoclonal IgM-associated cryoglobulinemia and suggest a management approach for addressing them. Laboratory testing is critical as even a minimal amount of measurable cryoglobulin may result in symptoms. Accurate detection of cryoglobulins may be challenging, care must be taken with preanalytical variables, and repeated testing of monoclonal protein and cryoglobulins is indicated if clinical suspicion is high. Presentations range from asymptomatic to showing multisystem involvement, meaning that careful evaluation of the features and a thorough interrogation of organ systems and the underlying clone are critical. Immediate management is required for clinical red-flag features. Due to their rarity, data to inform treatment decisions are scant and collaborative research is imperative and must be conducted to aid researchers in efforts to define optimal treatment strategies.

Download PDF

Waldenstrom macroglobulinemia lymphoma patients have impaired platelet and coagulation function.  Brysland SA,  Talaulikar D,  Hicks SM,  Hearn JI,  Ali SA,   Maqbool MG, Mokoonlall M, Bhoopalan V, Kaur A, Thong YL, Andrews RK,  Whisstock JC, Crispin PJ, Gardiner EE; Blood Adv 2024; bloodadvances.2024014190. doi: https://doi.org/10.1182/bloodadvances.2024014190 Therapeutics such as Bruton’s tyrosine kinase inhibitors (BTKis) exacerbate bleeding risk. Abnormal hemostasis arising from platelet dysfunction, altered coagulation or vascular impairment have not been investigated in WM patients. To evaluate hemostatic dysfunction in samples from WM patients whole blood samples were collected from 14 WM patients not receiving therapy, 5 patients receiving BTKis and 15 healthy donors (HDs). Platelet receptor levels and reticulation were measured by flow cytometry, plasma thrombin generation ± platelets by FRET assay, WB clotting potential by rotational thromboelastometry (ROTEM), and plasma soluble glycoprotein VI (sGPVI) and serum thrombopoietin (TPO) by ELISA. Donor platelet spreading, aggregation and ability to accelerate thrombin generation in the presence of WM-derived IgM were assessed. WM platelet receptor levels, responses to physiological agonists and plasma sGPVI were within normal ranges. WM platelets had reduced reticulation (p=0.0012) while serum TPO levels were increased (p=0.0040). WM plasma displayed slower thrombin generation (p=0.0080) and WM platelets contributed less to endogenous thrombin potential (ETP, p=0.0312). HD plasma or platelets incubated with IgM (50-60 mg/mL) displayed reduced spreading (p=0.0002), aggregation (p<0.0001) and ETP (p=0.0081). Alterations to thrombin potential and WB coagulation were detected in WM samples. WM IgM significantly impaired hemostasis in vitro. Platelet and coagulation properties are disturbed in well-managed WM patients.

Download PDF

PembroWM: A phase II trial to investigate the safety and efficacy of rituximab and pembrolizumab in relapsed/refractory Waldenstrom’s Macroglobulinemia. Kothari J, Eyre T, Rismani A, Ediriwickrema K, Edwards D, Galani S, et al.Br J Haematol. 2024; 00: 1–9. https://doi.org/10.1111/bjh.19706 PembroWM is the first study to evaluate the feasibility of PD-1 axis modulation in WM and has shown that in combination with Rituximab the combination is safe and deliverable.

Download PDF

Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial. Szymura, S.J., Wang, L., Zhang, T. et al.  Nat Commun 15, 6874 (2024). https://doi.org/10.1038/s41467-024-50880-2Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities. All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.

Download PDF

A Mystery in a Case: Unraveling the Complexity of Bing-Neel Syndrome. Kotlarz P N, Garcia G, Rosario M, et al. (July 21, 2024) Cureus 16(7): e65042. DOI: 10.7759/cureus.65042 Bing-Neel syndrome (BNS) is a rare complication of WM that results in the infiltration of the central nervous system (CNS) with IgM-secreting lymphoplasmacytic cells. This case study presents a 75-year-old Caucasian male with a history of WM and Agent Orange exposure who was diagnosed with BNS. This patient posed unique diagnostic challenges as the patient experienced clinical symptoms despite the absence of MRI abnormalities and therapeutic challenges. Consequently, it is crucial to maintain a high index of suspicion for BNS in patients with a history of WM who present with neurological symptoms. Several lessons from this case can help to improve the early detection of BNS. These lessons include performing detailed and repeated neurological examinations, using targeted and sequenced MRIs, utilizing early genetic testing, and employing a multidisciplinary care team. Such an approach is essential for preventing diagnostic oversights and improving the quality of life for affected patients.

Download PDF

P1679: Health-Related Quality of Life in Patients (PTS) with Waldenstrom Macroglobulinemia (WM) Treated with Zanubrutinib (ZANU) VS Ibrutinib (IBR): Results from the Phase 3 Aspen Trial Long-Term Follow-Up. Tedeschi A, Tam C, Owen R, Buske C, Leblond V, Dimopoulos MA, García-Sanz R, Castillo J, Trotman J, Treon S, Yang K, Tang B, Allewelt H, Patel S, Chan W, Cohen A, Schneider JY, Barnes G. Hemasphere. 2023 Aug 8;7(Suppl ):e27391ea.https://www.tandfonline.com/doi/epdf/10.1080/14796694.2024.2355079?needAccess=true. In addition to the better efficacy observed with zanubrutinib vs. ibrutinib, zanubrutinib provides a higher quality of life to patients with WM.

Download PDF

*New insights into the mechanisms regulating plasma cell survival and longevity. Khamyath M, Melhem H, Balabanian K, Espéli M. Curr Opin Immunol. Published online July 3, 2024. DOI: 10.1016/j.coi.2024.102442 . The authors review recent literature highlighting new findings pertaining to plasma cell survival rate, intrinsic regulation of plasma cell persistence and function, as well as the plasma cell/niche dialogue. Moreover, the now well-recognized heterogeneity observed among plasma cells is also discussed.

Download PDF

Waldenstrom Macroglobulinemia – A State-of-the-Art Review: Part 1: Epidemiology, pathogenesis, clinicopathologic characteristics, differential diagnosis, risk stratification, and clinical problems. Bibas M., Sarosiek S., Castillo J.J., Mediterr J Hematol Infect Dis 2024, 16(1): e2024061, DOI: http://dx.doi.org/10.4084/MJHID.2024.061 This state-of-the-art review presents a comprehensive description of the pathophysiology, clinicopathologic features, differential diagnosis, risk stratification, and clinical difficulties associated with WM. 

Download PDF

Strategies for overcoming resistance to Bruton’s tyrosine kinase inhibitor zanubrutinib. Dostálová H, Kryštof V.  Hematol Oncol. 2024;e3294.  https://doi.org/10.1002/hon.3294 The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. 

Download PDF

Ethnic diversity in presentation and outcome of Waldenstrom macroglobulinemia and IgM monoclonal gammopathy of clinical significance in the United Kingdom. Khwaja J, Japzon N, Gabriel M, Tomkins O, Lindsay J, Kyriakou C, Wechalekar A, D’Sa S. Haematologica. 2024 Jun 6. DOI: 10.3324/haematol.2024.285420 The aim of this study was to analyze baseline characteristics and outcomes of patients with WM, IgM monoclonal gammopathies of clinical significance (MGCS) and IgM-associated disorders across different ethnic groups in the United Kingdom (UK). They analyzed 1168 patients from the UK, demonstrating that ethnic minorities presented with WM at a younger age, a lower monoclonal protein (M protein) and with a higher proportion of MYD88WT which may suggest different disease biology than white patients. Black patients had a shorter treatment-free survival independent of baseline characteristics.

Download PDF

Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Javid J. Moslehi JJ, Furman RR, Tam CS, Salem JE, Flowers CR, Cohen A, Zhang M, Zhang J, Chen L, Ma H, Brown JR; Blood Adv 2024; 8 (10): 2478–2490. doi: https://doi.org/10.1182/bloodadvances.2023011641 This retrospective analysis, funded by BeiGene Co., demonstrated that the rates of atrial fibrillation, symptomatic ventricular arrhythmias, and hypertension with zanubrutinib were low and generally occurred less frequently than with ibrutinib. These data support the use of zanubrutinib as a treatment option with an improved cardiovascular events profile for patients with B-cell malignancies.

Download PDF

Simplified Risk Stratification Model for Patients With Waldenström Macroglobulinemia.  Zanwar S, Le-Rademacher J, Durot E, D’Sa S, Abeykoon JP, Mondello P, Kumar SK,  Sarosiek SR, Paludo J, Chhabra S, Cook J, Parrondo R, Dispenzieri A, Gonsalves WI, Muchtar E, Ailawadhi S, Kyle R, Rajkumar V, Delmer AJ, Fonseca R, Gertz MA, Treon SP, Ansell SM, Castillo JJ, Kapoor P; Blood 2023; 142 (Supplement 1): 3030. doi: https://doi.org/10.1182/blood-2023-179940 The authors reviewed 889 medical records of treatment-naïve patients with active WM 01/01/1996 and 12/31/2017. By assigning a score of 1 point each to albumin <3.5 g/dL, age 66-75 years, and 2 points for age >75 years or elevated LDH,four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups. They concluded that age (66-75 years and >75 years), serum albumin, and serum lactate dehydrogenase at diagnosis can reliably risk-stratify patients with active WM into four risk groups with distinct outcomes.

Download PDF

When Waldenstrom macroglobulinemia hits the kidney: Description of a case series and management of a “rare in rare” scenario. Danesin N, Scapinello G, Del Prete D, et al.  Cancer Reports. 2024; 7(4):e2062. doi:10.1002/cnr2.2062 Renal injury related to Waldenstrom macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non-amyloidotic), tubulo-interstitial and non-paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored. The authors collected clinical, genetic and laboratory data of seven cases of biopsy-proven renal involvement by WM managed at their academic center and focused on three cases they judged paradigmatic discussing their histopathological patterns, clinical features, and therapeutic options.

Download PDF

A phase 2, open-label study of ibrutinib plus rituximab in Japanese patients with Waldenstrom’s macroglobulinemia. Izutsu K, Kato H, Sekiguchi N, Fujisaki T, Kawakita T, Obara N, Matsue K, Nishimoto M, Hatayama T, Inagaki M, Fujikawa E. Int J Hematol. 2024 Apr 10. doi:10.1007/s12185-024-03761-9 Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenstrom macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.

Download PDF

Optimizing BTK inhibition in Waldenstrom macroglobulinemia. Sarosiek, S., Castillo JJ.   J Natl Compr Canc Netw. 2024 May;22(4):e247007. doi: 10.6004/jnccn.2024.7007 The authors propose a genomic-driven approach to selecting patients with WM who are more likely to experience fast, deep, and durable responses to BTK inhibitors, and provide practical strategies for managing adverse effects, including BTK inhibitor dose reductions, switching to other BTK inhibitors, and abandoning BTK inhibitor therapy. Ongoing clinical trials are evaluating covalent and noncovalent BTK inhibitors alone and in combination, as well as BTK degraders, with exciting results.

Download PDF

The landscape of rare genetic variants in familial Waldenstrom macroglobulinemia. Alexander Pemov, Jung Kim, Wen Luo, Jia Liu, Cole Graham, Kristine Jones, Delphine DeMangel, Neal D. Freedman, Charles Dumontet, Bin Zhu, Mary L. McMaster, Douglas R. Stewart; Blood Neoplasia 2024; 100013. doi: https://doi.org/10.1016/j.bneo.2024.100013 Risk for WM is elevated 20-fold among first-degree relatives of WM patients. However, the list of variants and genes that cause WM remains incomplete. The authors analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. They determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among WM patients; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. They identified pathogenic variants in TREX1 and SAMHD1 (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in WM patients from two pedigrees. There were additional P/LP variants in cancer-predisposing genes, e.g., POT1, RECQL4, PTPN11, PMS2. In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, they observed involvement of genes that play role in telomere maintenance, regulation of innate immune response, and DNA repair. Affected members of each pedigree shared multiple deleterious variants (median n=18) but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants, each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.

Immunoglobulin replacement vs prophylactic antibiotics for hypogammaglobulinemia secondary to hematological malignancy. McQuilten ZK, Weinkove R, Thao LTP, Crispin P, Degelia A, Dendle C, Gilbertson M, Johnston A, Keegan A, Pepperell D, Pullon H, Reynolds J, van Tonder T, Trotman J, Waters N, Wellard C, Weston H, Morrissey CO, Wood EM. Blood Adv. 2024 Apr 9;8(7):1787-1795. DOI: 10.1182/bloodadvances.2023011231 Immunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, they enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. The proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm. The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm. Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections.

Bruton Tyrosine Kinase Inhibition: an Effective Strategy to Manage Waldenström Macroglobulinemia. Tawfiq, R.K., Abeykoon, J.P. & Kapoor, P. Curr Hematol Malig Rep (2024). https://doi.org/10.1007/s11899-024-00731-0 The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. The next-generation BTKi’s demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi’s are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi’s serve as alternative agents in the event of acquired resistance. The authors review the current and emerging BTKi‘s and the evidence for their use in WM.

Impact of the presence and number of chromosomal abnormalities on the clinical outcome in Waldenstrom Macroglobulinemia: a monocentric experience. Danesin, N., Bonaldi, L., Martines, A. et al.  Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05770-4 The authors report their experience in a cohort of WM patients across 23 years. Based on their retrospective study, they found that abnormal karyotype was more represented in older patients and maintained a statistically significant independence from other molecular, clinical, and biological features related to WM. The presence and number of cytogenetic aberrations correlated with inferior overall and progression-free survival outcomes regardless of the type of single chromosome aberration. Their data suggests that the role of the altered karyotype deserves to be further clarified especially in elderly WM patients, in whom cytogenetic abnormalities and disease biology appear to be characterized by a higher degree of complexity.

Circulating tumor cells in Waldenstrom macroglobulinemia. Boccon-Gibod, C., Sourdeau, E., Morel, P. et al.  Leukemia (2024). https://doi.org/10.1038/s41375-024-02156-3. The authors aimed in a large cohort of WM patients (n=187) to evaluate the presence of detectable circulating tumor cells (CTCs) or lymphoplasmacytes by flow cytometry of peripheral blood (PB) at diagnosis, their potential correlation with cytogenic and molecular features and outcomes. They found that most patients (73%) at diagnosis harbor detectable CTCs. In most cases, low counts were observed, in line with the absence of absolute lymphocytosis generally observed in WM. This data suggests that CTCs are very frequent in WM at diagnosis and could therefore allow phenotypic description of the tumor population in peripheral blood for the vast majority of patients. However, they state it should not replace BM biopsy for diagnosis. They also showed that the proportion of patients with detectable CTCs was significantly higher in symptomatic WM patients and that CTC levels were associated with a shorter time to first treatment  in asymptomatic patients. The presence of increasing levels of CTCs was associated with other specific features, notably the presence of splenomegaly and elevated LDH, which could represent a gray zone group of patients between SMZL and WM, with cytogenetic and molecular features similar to other WM patients, but a clinical presentation more closely resembling SMZL. With regards to correlation with intrinsic biology, they identified a striking association between the presence of CXCR4 S338X mutation and significantly lower rate of CTCs, not observed with other CXCR4 variants. This is consistent with recent in vitro studies showing that there is a genotype- phenotype correlation among CXCR4 variants, with CXCR4 S338X associated with the strongest chemotaxis impairment. These data could also partly explain the poorer response and PFS on ibrutinib observed in this group of patients, in whom the BM niche may play a protective role, counteracting ibrutinib activity. Although the levels of CTCs did not impact PFS and OS in this cohort treated with chemoimmunotherapy, this might be explored in prospective studies with BTK inhibitors.

Long-term results of Waldenstrom macroglobulinemia treatment by bendamustine and rituximab: A study on behalf of the French Innovative Leukemia Organization (FILO). Laribi K, Poulain S, Willems L, Merabet F, Herbaux C, Roos-Weil D, et al.  Br J Haematol. 2024; 00: 1–4. https://doi.org/10.1111/bjh.19409 The bendamustine–rituximab (BR) combination is an efficient first-line therapy in Waldenstrom macroglobulinemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression-free (PFS) and overall survival (OS). With a median follow-up of 76.1 months, the 5-year outcome is still excellent at 66.63% for PFS and 80.01%) for OS. The rate of secondary cancers is 17.66% at 66 months. Relapsed patients who received ibrutinib as second-line clearly benefited from this combination. This confirms current recommendations suggesting BR long-term efficacy as first-line option in WM.

Lymphoplasmacytic lymphoma and multiple myeloma coexisting in the same patient: a case series and literature review. Itchaki G, Jarhovsky O, Castillo JJ, Hassan H, Gatt ML, Leiba M, Raanani P, Gertz MA, Vaxman I. Leuk Lymphoma. 2024 Mar 19:1-7. DOI: 10.1080/10428194.2024.2332499 . Epub ahead of print. The simultaneous occurrence of Waldenstrom macroglobulinemia and multiple myeloma in the same patient has been published as case reports. Patients with Waldenstrom macroglobulinemia often have a small clone of plasma cells. However, the concurrent occurrence of symptomatic myeloma with lytic bone lesions is rare. The diagnosis of this ‘hybrid’ entity is challenging, and there are no standard therapies. The authors present six patients from five centers (three in Israel and two in the United States). They describe these patients’ unique clinical course and treatment approaches.

Waldenstrom macroglobulinaemia with AA amyloidosis reveals a B-cell-restricted NLRP2 variant. Terré A, Buob D, Cez A, Rodero MP and Georgin-Lavialle S. (2024), Br J Haematol. https://doi-org.pitt.idm.oclc.org/10.1111/bjh.19383 describe the case of a patient with amyloid A (AA) amyloidosis

complicating WM. Whole exome sequencing (WES) revealed a somatic mutation of NLRP2 restricted to the B cells. The authors explored the consequences of this mutation.

Mutational landscape in Waldenstrom macroglobulinemia evaluated using a next-generation sequencing lymphoma panel in routine clinical practice. Østergaard S, Schejbel L, Breinholt MF, Pedersen MØ, Hammer T, Munksgaard L, Nørgaard P, Høgdall E, Gjerdrum LMR, Nielsen TH. Leuk Lymphoma. 2024 Feb 10:1-10. https://doi.org/10.1080/10428194.2024.2313623. Epub ahead of print. Next-generation sequencing (NGS) affords comprehensive insights into the genomic landscape of lymphomas. The authors examined the mutational pattern in patients with Waldenstrom macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL) as well as the diagnostic and clinical utility of a tailored NGS lymphoma panel. A consecutive series of 45 patients was reviewed and NGS analysis was performed as part of a routine diagnostic setup. The custom designed NGS panel assayed all coding sequences of 59 genes of known clinical significance in lymphoid neoplasms. The most frequently mutated genes were MYD88, CXCR4, BIRC3, CD79B, and ARID1A. Additional somatic mutations were detected in 17 genes with four mutations categorized as pathogenic or likely pathogenic. BIRC3 and TP53 mutations were associated with adverse clinical phenotypes. NGS performance for the MYD88^L265P variant was 96% when compared to qPCR. In conclusion, targeted NGS provided important diagnostic and prognostic information in a routine clinical setting.

A phase II study of ibrutinib in combination with ixazomib in patients with Waldenstrom macroglobulinemia. Parrondo RD, Dutta N, LaPlant BR, Elliott J, Fernandez A, Zimmerman A, et al. Br J Haematol. 2024; 00: 1–5. https://doi.org/10.1111/bjh.19320  This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenstrom macroglobulinemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow-up time of 25.7 months, the median progression-free survival (PFS) was 22.9 months. While the primary end-point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton’s tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM

A 74-Year-Old Man with Waldenstrom Macroglobulinemia and Progressive Dyspnea. Tzilas V, Nicholson AG, Gavriatopoulou M, Ntanasis-Stathopoulos I, Dimopoulos MA, Bouros D. Chest. 2024 Feb;165(2):e39-e43. DOI: 10.1016/j.chest.2023.08.004 Extramedullary involvement is rare in WM, occurring in approximately 5% of cases. Thus, clinical experience is extremely limited and is based mostly on small case series and case reports. Extramedullary involvement is defined by the presence of a clonal lymphoplasmacytic infiltrate at anatomic sites distant from the bone marrow, excluding circulating tumor cells. Most frequent sites of extramedullary disease are the lungs, soft tissue, cerebrospinal fluid, renal, and bone. Clinical Course: Because of the history of WM and in the absence of signs and symptoms in favor of infection or other obvious diagnoses, they elected to perform a surgical lung biopsy. The results of the biopsy confirmed lung involvement in the context of his lymphoproliferative disease. Therapy was initiated that included six cycles of rituximab, cyclophosphamide, and dexamethasone (DRC regimen). Treatment was well-tolerated, whereas IgM levels fell to 821 mg/dL from 1650 at the time of treatment initiation (partial response). The patient remains stable after 1 year of treatment and reports improvement of his dyspnea. Imaging is stable while there is functional improvement. Clinical Pearls: 1. In patients with respiratory manifestations, elevated levels of IgM should raise suspicion of an underlying lymphoproliferative disease that could provide a unifying diagnosis. 2. In patients with WM and respiratory manifestations, include lung involvement by the lymphoproliferative disease in the differential diagnosis. It can mimic interstitial lung disease. 3. In these cases biopsy-proven diagnosis by a specialized hemopathologist is essential because it secures diagnosis and guides appropriate treatment according to current guidelines for treatment of WM.

Biomarker analysis of the ASPEN study comparing zanubrutinib to ibrutinib in patients with Waldenstrom Macroglobulinemia. Tam CS, Opat S, D’Sa SP, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan SP, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby EN, Matous JV, Motta M MD, Siddiqi T, Tani M, Trněný M, Minnema MC, Buske C, Leblond V, Treon SP, Trotman J, Wu B, Yu Y, Shen Z Dr, Chan WY, Schneider J, Allewelt H, Cohen A, Dimopoulos MA. Blood Adv. 2024 Feb 5:bloodadvances.2023010906.  DOI: 10.1182/bloodadvances.2023010906

Epub ahead of print. The phase 3 ASPEN trial compared Bruton tyrosine kinase inhibitors (BTKi), zanubrutinib and ibrutinib, in patients with Waldenstrom macroglobulinemia (WM). Biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 zanubrutinib-treated and 92 ibrutinib-treated patients with mutated (MUT) MYD88 and 20 zanubrutinib-treated patients with wild-type (WT) MYD88. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P<0.05). Patients with CXCR4MUT (frameshift [FS] or nonsense [NS] mutations) had lower very good partial response and complete response rate (VGPR+CR) (17.0% vs 37.2%) and longer time to response (11.1 vs 8.4 months) than CXCR4WT BTKi-treated patients. CXCR4NS was associated with inferior progression-free survival (PFS; HR=3.39) in ibrutinib-treated, but not zanubrutinib-treated patients (HR=0.67), but VGPR+CR rates were similar between treatment groups (14.3% vs 15.4%). Compared to ibrutinib, zanubrutinib-treated patients with CXCR4NS had a favorable major response rate (MRR; 85.7% vs 53.8%) and PFS (HR=0.30,). In patients with TP53MUT, significantly lower MRR was observed in ibrutinib- (63.6% vs 85.7%) but not zanubrutinib-treated patients (80.8% vs 81.9%). In TP53MUT, compared to ibrutinib, zanubrutinib-treated patients had higher VGPR+CR (34.6% vs 13.6%), numerically improved MRR (80.8% vs 63.6%,), and longer PFS (not reached vs 44.2 months, HR=0.66). Collectively, WM patients with CXCR4MUT or TP53MUT had worse prognosis compared to patients with WT alleles and zanubrutinib led to better clinical outcomes.

Incidence and Risk of Secondary Malignancy in Patients with Waldenström Macroglobulinemia: A Population-Based Analysis. Rehman MEU, Hameed M, Shah Z & Ashruf O, Ali R, Faraz F, Basit J, Khan I, Fazal F Iftikhar A, Nashwan A, Faisal MS, Answer F. (2024). Clinical Hematology International. DOI:10.46989/001c.90436 The Surveillance, Epidemiology, and End Results (SEER) database is a comprehensive registry of cancer patients in the United States reporting on a wide set of demographic variables. Using the SEER-18 dataset, analyzing patients from 2000 to 2018, the authors aimed to assess the incidence of secondary malignancies (SMs) in WM patients. Patient characteristics such as gender, age, race, and latency were identified, and respective standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated to compare to the general population. Of the 4,112 eligible WM patients identified, SMs were reported in 699 (17%) patients. The overall risk of developing SM, second primary malignancy, and secondary hematological malignancy was significantly higher in WM patients compared to the general population. Our findings show that WM patients had a 53% higher risk of SMs relative to the general population, and an AER of 102.69 per 10,000. Although the exact mechanism is unclear, the risk of SM development may be due to genetic predisposition, immune dysregulation, or treatment-induced immune suppression.

Long-term survival in a patient with transformation of Waldenstrom’s macroglobulinemia into DLBCL. Solia E, Ntanasis-Stathopoulos I, Kastritis E, Terpos E, Dimopoulos MA, Gavriatopoulou M. January 2024, Cancer Diagnosis & Prognosis 4(1):77-80 DOI:10.21873/cdp.10289  In 5-10% of patients, WM undergoes transformation into diffuse large B-cell lymphoma (DLBCL), which is more aggressive, with poor prognosis and a low survival rate. The authors present a woman with DLBCL, which developed following WM, who has remained disease-free over the past 10 years after completion of chemotherapy.

Bing-Neel syndrome: a rare neurological complication of Waldenstrom macroglobulinemia. Alzghoul H, Haider A, Mukhtar F, et al. BMJ Case Rep 2024;17: e255268. DOI: 10.1136/bcr-2023-255268 Bing-Neel syndrome (BNS) is a very rare manifestation of WM, in which lymphoplasmacytic cells invade the central nervous system. The clinical presentation includes symptoms of headaches, visual floaters, neuropathy, seizures, and gait abnormalities. The authors describe an elderly woman, who presented with complaints of visual floaters, progressive neuropathy and cognitive changes. The workup including a bone marrow biopsy confirmed the diagnosis of WM. Shortly afterwards, the patient experienced a seizure leading to hospitalization, which revealed a right frontal lobe lesion on brain MRI. A biopsy of the lesion showed a small B cell lymphoma positive for an MYD88 mutation, confirming BNS. The patient was initially treated with ibrutinib, before transitioning to zanubrutinib. However, she developed disease progression necessitating radiotherapy with lenalidomide and rituximab maintenance therapy, which achieved remission. This case sheds light on the diagnosis and management of a very rare complication of a rare disease.

Sequential treatment escalation improves survival in patients with Waldenstrom macroglobulinemia. Yu Y, Xiong W, Wang T, Yan Y, Lyu R, Wang Q, Liu W, An G, Sui W, Xu Y, Huang W, Zou D, Wang J, Qiu L, Yi S.  Blood Science 6(1): p e00179, January 2024. http://dx.doi.org/10.1097/BS9.0000000000000179 The researchers analyzed the outcomes of the first- and second-line therapies in 377 patients with WM to illustrate the optimal choices for second-line therapy. After a median follow-up of 45.4 months, 89 patients received second-line therapy, and 53 patients were evaluated for response. The major response rates (MRR) of first- and second-line treatment were 65.1% and 67.9%. The median progression-free survival (PFS) for the second-line therapy (PFS2) was shorter than that for the first-line therapy (PFS1) 56.3 vs 40.7 months. However, PFS2 in targeted drugs group (R-/V-/BTKi-based regimens) was comparable to PFS1 (60.7 months vs 44.7 months, respectively. Regarding second-line therapy, patients who underwent sequential treatment escalation—such as transitioning from cytotoxic drugs to R-/V-/BTKi-based regimens or from R-/V-based to BTKi-based regimens (escalation group) —had higher MRR (80.6% vs 47.1%, respectively and longer PFS2 (50.4 vs 23.5 months, respectively, compared to the non-escalation group. Patients in the escalation group also had longer post-relapse overall survival compared with the non-escalation group (median, 50.4 vs 23.5months, respectively. Their findings indicate that sequential treatment escalation may improve the survival of patients with WM.

Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. Kumar, S. K., Callander, N. S., Adekola, K., Anderson, L. D., Jr, Baljevic, M., Baz, R., Campagnaro, E., Castillo, J. J., Costello, C., D’Angelo, C., Derman, B., Devarakonda, S., Elsedawy, N., Garfall, A., Godby, K., Hillengass, J., Holmberg, L., Htut, M., Huff, C. A., Hultcrantz, M., Kang, Y., Larson, S., Lee, H., Liedtke, M., Martin, T., Omel, J., Robinson, T., Rosenberg, A., Sborov, D., Schroeder, M. A., Sherbenou, D., Suvannasankha, A., Valent, J., Varshavsky-Yanovsky, A. N., Snedeker, J., & Kumar, R. (2024). Journal of the National Comprehensive Cancer Network, 22(1D), 1-19. Retrieved Feb 4, 2024, from https://doi.org/10.6004/jnccn.2024.0001 The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel during the NCCN Guidelines update have been included in this 2024 version of the discussion section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion. The complete details of the development and updates of the NCCN Guidelines are available at NCCN.org.

*Identification of robust predictors for ibrutinib response by multi-omics in MYD88 mutated Waldenstrom Macroglobulinemia. Richardson K, Castillo JJ, Sarosiek S, Branagan AR, Flynn C, Meid KE , Gutine J, Liu X, Kofides A, Liu S,  Wolf JL, Kacena KA, Patterson CJ, Guerrera ML, Tsakmaklis N, Treon SP, Hunter ZR; Blood Adv 2024; doi: https://doi.org/10.1182/bloodadvances.2023012111 While presence of CXCR4^Mut can predict inferior outcomes with BTK-inhibitors, many wild-type CXCR4 (CXCR4^WT) patients can also have inferior outcomes. Conversely, some patients with CXCR4^Mut disease can have robust responses to BTK-inhibitors. Thus, this research group sought to identify more robust biomarker(s) to better predict BTK-inhibitor response activity using a multi-omic approach. Such biomarkers may help position BTK-inhibitors relative to other available therapeutics such as bendamustine or proteasome-inhibitor based regimens. For these studies, they focused on ibrutinib utilizing bone marrow samples obtained in a prospective clinical trial with long-term follow-up in symptomatic, treatment-naïve WM patients. They identified putative biomarkers for clinical investigation to predict ibrutinib major responders at 6 months, TTR and PFS outcomes in MYD88^Mut WM patients. Low baseline expression of GPR18, as well as high levels of WNK2 showed the strongest associations with major response attainment at 6 months, shorter TTR and longer PFS in this study. In addition, differential gene expression of CHST15, KIF21A, PRDM15, DUSP22, S100A6 and KIF21A were also associated with major response attainment at 6 months and TTR but showed more marginal association with predicting PFS outcomes to ibrutinib. Many of these biomarkers including GPR18 and WNK2 are known modulators of ERK1/2 signaling. Further validation of these findings in a larger cohort will be required, as well as their potential use as predictors with other covalent and non-covalent BTK-inhibitors. The applied use of such validated biomarkers may better BTK-inhibitors over other available treatment options in WM. The findings may also be relevant for other B-cell malignancies in which BTK-inhibitors are used. Their studies provide a framework for the clinical investigation of novel, multi-omic identified genes as predictive biomarkers for BTK-inhibitors in WM.

How we use Genomics and BTK-Inhibitors in the Treatment of Waldenstrom Macroglobulinemia. https://doi.org/10.1182/blood.2022017235 Mutations in MYD88 (95-97%) and CXCR4 (30-40%) are common in Waldenstrom macroglobulinemia (WM). TP53 is also altered in 20-30% of WM patients, particularly those previously treated. Mutated MYD88 upregulates and activates HCK that drives BTK pro-survival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants such as CXCR4S338X show greater resistance to BTK inhibitors. Covalent BTK-inhibitors (cBTK-i) produce major responses in 70-80% of WM patients. MYD88 and CXCR4 mutation status can impact time to major response, depth of response and/or progression-free survival (PFS) in WM patients treated with cBTK-i. The cBTK-i zanubrutinib shows greater response activity and/or improved PFS in wild-type MYD88, mutated CXCR4, or altered TP53 patients. Marked differences in adverse events have been observed between BTK-inhibitors in WM patients, including atrial fibrillation, bleeding diathesis and neutropenia. Intolerance is also common with c-BTKi, and dose reduction or switchover to another c-BTKi can be considered. For patients with acquired resistance to c-BTKi, newer options include the non-covalent BTK-inhibitor pirtobrutinib or the BCL2 antagonist venetoclax. Combinations of BTK-inhibitors with chemoimmunotherapy, CXCR4 and BCL2 antagonists have advanced and are discussed. Algorithms for positioning BTK-inhibitors in treatment-naïve and previously treated WM patients based on genomics, disease characteristics, and co-morbidities are presented.

* Genome-scale functional genomics identify genes preferentially essential for multiple myeloma cells compared to other neoplasias. de Matos Simoes R, Shirasaki R, Downey-Kopyscinski SL, Matthews GM, Barwick BG, Gupta VA, Dupere-Richer D, Yamano S, Hu Y, Sheffer M, Dhimolea E, Dashevsky O, Gandolfi S, Ishiguro K, Meyers RM, Bryan JG, Dharia NV, Hengeveld PJ, Bruggenthies JB, Tang H, Aguirre AJ, Sievers QL, Ebert BL, Glassner BJ, Ott CJ, Bradner JE, Kwiatkowski NP, Auclair D, Levy J, Keats JJ, Groen RWJ, Gray NS, Culhane AC, McFarland JM, Dempster JM, Licht JD, Boise LH, Hahn WC, Vazquez F, Tsherniak A, Mitsiades CS. Nat Cancer. 2023;4:754-773. https://doi.org/10.1038/s43018-023-00550-x As outlined in this IWMF funded study, MM-preferential dependencies are not exclusively important for multiple myeloma (MM): several are recurrently essential in other neoplasias, primarily neoplasia related at least in part to the plasma cell (PC) lineage, including WM. Collectively, though, the patterns of essentiality for these genes are distinct for MM vs. other neoplasias (including other blood cancers). The study highlights the specific example of WM, and namely the fact that 68 of the identified MM-preferential dependencies are not essential in their in vitro CRISPR screens in either or both WM cell lines that they have examined.

Waldenstrom Macroglobulinemia: Targeted Agents Taking Center Stage.  Sarosiek S, Castillo JJ. 2023 Dec 6. DOI: 10.1007/s40265-023-01974-6. This review discusses the biological and clinical data supporting current and up-and-coming targeted agents in WM. Bruton tyrosine kinase inhibitors induce fast, deep, and durable responses in patients with WM, comparable to chemoimmunotherapy; however, there is a glaring absence of comparative studies between these regimens. The high response and progression-free survival rate and the ease of administration of BTK inhibitors must be balanced against their specific adverse-event profile with unique toxicity (e.g., bleeding and cardiac arrhythmia) and the indefinite duration of the therapy. Novel targeted agents of interest include BCL2 antagonists (e.g., venetoclax and sonrotoclax) and non-covalent BTK inhibitors (e.g., pirtobrutinib and nemtabrutinib), among others.

New developments in the diagnosis and characterization of Waldenstrom’s macroglobulinemia. García-Sanz R, Hunter ZR, Poulain S, Varettoni M & Owen RG(31 Oct 2023): Expert Review of Hematology, https://doi.org/10.1080/17474086.2023.2270779 This excellent review provides an overview of the diagnosis of WM, with a particular focus on the role of immunophenotyping and genotyping. Demonstration of LPL with a bone marrow biopsy is essential to reach a definitive diagnosis of WM. However, MYD88L265P and a typical WM immunophenotypic profile are valuable for the differential diagnosis of WM and related diseases, such as marginal zone lymphoma, multiple myeloma, and chronic lymphocytic leukemia. These methodologies must be utilized across centers and with appropriate standards followed in the evaluation and reporting of sensitivities and specificities. The diagnostic and/or prognostic value of mutations in genes such as CXCR4 and TP53 that are currently not routinely evaluated in the diagnosis of WM should be explored.

Song, Y., Wu, SJ., Shen, Z. et al.  Exp Hematol Oncol 12, 92 (2023). https://doi.org/10.1186/s40164-023-00448-5 Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidence on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors.

MYD88 Wild Type in IgM Monoclonal Gammopathies: From Molecular Mechanisms to Clinical Challenges.Bagratuni T, Papadimou A, Taouxi K, Dimopoulos MA, Kastritis E.  Hemato. 2023; 4(3):259-272. https://doi.org/10.3390/hemato4030021 The absence of the MYD88 mutation in patients with IgM monoclonal gammopathies has been associated with a higher risk of transformation to aggressive lymphomas, resistance to several therapies, and shorter overall survival. The present review focuses on the molecular mechanisms that shape the signaling pattern in MYD88 wild type cells, as well as on the clinical implications and therapeutic challenges of WM patients that harbor the MYD88 wild type genotype.

*Molecular Clusters and Tumor-Immune Drivers of IgM Monoclonal Gammopathies. Mondello P, Paludo J, Novak JP, Wenzl K, Yang ZZ, Jalali S, Krull JE, Braggio E, Dasari S, Manske MK, Abeykoon JA, Sarangi V, Kapoor P, Paulus A, Reeder CB, Ailawadhi S, Chanan-Khan AA, Kyle RA, Gertz MA, Novak AJ, Ansell SM. Clin Cancer Res. 2023 Mar 1;29(5):957-970. https://doi.org/10.1158/1078-0432.CCR-22-2215

The authors identified three clusters with distinct pathway activation, immune content, metabolomic, and clinical features. Cluster 1 included only patients with WM and was characterized by transcriptional silencing of genes involved in cell cycle and immune response, enrichment of mitochondrial metabolism, infiltration of senescent T effector memory cells, and aggressive clinical behavior. Genetic/structural alterations of TNFAIP3 were distinct events of this cluster. Cluster 2 comprised both MGUS and WM patients with upregulation of inflammatory response, senescence and glycolysis signatures, increased activated T follicular helper and T regulatory cells, and indolent clinical behavior. Cluster 3 also included both MGUS and WM patients and exhibited intermediate features, including proliferative and inflammatory signaling, as well as glycolysis and mitochondrial metabolism.

Impact of circulating lymphoma cells at diagnosis on outcomes in patients with Waldenstrom macroglobulinemia.  Nalin A, Zhao Q, Voorhees T, Bond D, Sawalha Y, Hanel W, Sigmund A, Annunzio K, Alinari L, Baiocchi R, Maddocks K, Jones D, Christian B, Epperla N. Front. Oncol. September 2023 13-2023    

https://DOI.org/10.3389/fonc.2023.1264387  In this study (largest-to-date) evaluating the impact of circulating lymphoma on outcomes in patients with newly diagnosed WM, the authors did not find the prognostic utility of circulating lymphoma in WM. Future studies should explore the correlation of circulating lymphoma with other biological factors that impact the outcomes in WM patients.

Bendamustine plus rituximab for the treatment of Waldenstrom Macroglobulinemia: Patient outcomes and impact of bendamustine dosing.  Arulogun SO, Brian D, Goradia H, Cooney A, Menne T, Koo R, O’Neill AT, Vos JMI, Pratt G, Turner D, Marshall K, Manos K, Anderson C, Gavriatopoulou M, Kyriakou C, Kersten MJ, Minnema MC, Koutoumanou E, El-Sharkawi D, Linton K, Talaulikar D, McCarthy H, Bishton M, Follows G, Wechalekar A, D’Sa SP. Am J Hematol. 2023 May;98(5):750-759. https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.26895 Bendamustine and rituximab (BR) therapy is commonly used in the treatment of WM. The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. The authors aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m² compared with those receiving 800-999 mg/m² (p = 0.04). In the relapsed cohort, those who received doses of <600 mg/m² had poorer PFS outcomes compared with those who received ≥600 mg/m² (p = 0.02). Attaining CR/VGPR following BR results in superior survival, and total bendamustine dose significantly impacts response and survival outcomes, in both frontline and relapsed settings.

Zanubrutinib: past, present, and future. Tam CS, Muñoz JL, Seymour JF, Opat S. Blood Cancer J. 2023 Sep 11;13(1):141. https://www.nature.com/articles/s41408-023-00902-x In this article, the authors review the development of zanubrutinib, a next-generation BTK inhibitor, from molecular design to patient-related outcomes.

Current approach to Waldenström Macroglobulinemia. Ravi G, Kapoor P. Cancer Treat Res Commun. 2022;31:100527 https://www.sciencedirect.com/science/article/abs/pii/S0268960X23000905

WM is a unique CD20+, B-cell non-Hodgkin lymphoma, characterized by lymphoplasmacytic infiltration of the bone marrow and circulating monoclonal immunoglobulin M. The clinical manifestations and outcomes of patients are highly variable. High-level evidence supports integration of monoclonal anti-CD20 antibody, rituximab, to the chemotherapy backbone to treat WM. However, its contemporary management has become more nuanced, with deeper understanding of the pathophysiology and incorporation of Bruton’s tyrosine kinase (BTK) inhibitors to the treatment paradigm. Prior knowledge of the patients’ MYD88L265P and CXCR4 mutation status may aid in the treatment decision-making. Currently, the two frequently utilized approaches include fixed-duration chemoimmunotherapy and BTK inhibitor-based continuous treatment until progression. Randomized trials comparing these two vastly divergent approaches are lacking. Recent studies demonstrating efficacy of B cell lymphoma-2 (BCL2) inhibitors and non-covalent BTK inhibitors in patients, previously exposed to a covalent BTK inhibitor, are a testament to the rapidly expanding options against WM.

Management of Waldenstrom Macroglobulinemia in Limited-Resource Settings. Riva E, Tietsche de Moraes Hungría V, Chiattone C, and Martínez-Cordero H. Hematol Oncol Clin N Am 37 (2023) 801-806 https://doi.org/10.1016/j.hoc.2023.04.010 WM is a rare, indolent, and currently incurable B-cell neoplasm characterized by monoclonal immunoglobulin M gammopathy, frequent nodal involvement, and lymphoplasmacytic infiltration of the bone marrow. The clinical pattern at diagnosis is similar to that reported in developed countries but, unfortunately, the tools for a complete diagnosis and access to novel therapies are suboptimal. Older drugs such as bendamustine, cyclophosphamide, and chlorambucil may still play a role in treating WM. Prospective studies in resource-limited regions are required to further evaluate these essential aspects of the disease. In this paper, the authors issue recommendations based on their local reality.

Evaluation and Management of Disease Transformation in Waldenstrom Macroglobulinemia. Talaulikar D, Tomowiak C, Toussaint E, Morel P, Kapoor P, Castillo JJ, Delmer A, and Durot E, Hematol Oncol Clin N Am 37 (2023) 787- 800 https://doi.org/10.1016/j.hoc.2023.04.009 Histologic transformation (HT) to diffuse large B-cell lymphoma occurs rarely in WM, with higher incidence in MYD88 wild-type patients. HT is suspected clinically when rapidly enlarging lymph nodes, elevated lactate dehydrogenase levels, or extranodal disease occur. Histologic assessment is required for diagnosis. HT carries a worse prognosis compared with non-transformed WM. A validated prognostic score based on three adverse risk factors stratifies three risk groups. The most common frontline treatment is chemoimmunotherapy, such as R-CHOP. Central nervous system prophylaxis should be considered if feasible and consolidation with autologous transplant should be discussed in fit patients responding to chemoimmunotherapy.

Evaluation and Management of Bing–Neel Syndrome. Schep SJ, Vos JMI, and Minnema MC, Hematol Oncol Clin N Am 37 (2023) 777-786  https://doi.org/10.1016/j.hoc.2023.04.008 Bing–Neel syndrome is a rare manifestation of WM, which is caused by infiltration of the malignant lymphoplasmacytic cells in the central nervous system. Patients can present with a diverse range of neurologic symptoms, and differentiation with other comorbidities seen in WM, such as immunoglobulin M-related polyneuropathy, can be challenging. Both the rarity of this disorder and the heterogeneity of the clinical presentation often cause a significant diagnostic delay with the risk of permanent neurologic damage. This review summarizes current knowledge regarding diagnosis, treatment, and prognosis of Bing-Neel syndrome.

Investigation and Management of Immunoglobulin M– and Waldenstrom Associated Peripheral Neuropathies. Tomkins O, Leblond V, Lunn MP, Viala K, Roos-Weil D, and D’Sa S. Hematol Oncol Clin N Am 37 (2023) 761-776  https://doi.org/10.1016/j.hoc.2023.04.007 The immunoglobulin M (IgM)-associated peripheral neuropathies (PN) are a heterogeneous group of disorders representing most paraproteinemic neuropathy cases. They are associated with IgM monoclonal gammopathy of undetermined significance (MGUS) or WM. Establishing a causal link between a paraprotein and neuropathy can be challenging but is necessary to adopt an appropriate therapeutic approach. The most common type of IgM-PN is anti-myelin-associated-glycoprotein neuropathy, but half of the cases are of other causes. Progressive functional impairment is an indication for treatment, even when the underlying disorder is IgM MGUS, involving either rituximab monotherapy or combination chemotherapy to achieve clinical stabilization.

Novel Agents in Waldenstrom Macroglobulinemia. Sarosiek S and Castillo JJ, Hematol Oncol Clin N Am 37 (2023) 751-760 https://doi.org/10.1016/j.hoc.2023.04.001 Owing to the indolent nature of WM, most patients experience a prolonged life expectancy, although many lines of therapy will likely be required to maintain disease control. Despite the currently available therapies, most patients will develop intolerance or resistance to multiple treatments. Therefore, new therapeutic options are being developed with a focus on targeted agents, such as novel Bruton tyrosine kinase (BTK) inhibitors and BTK degraders, as well as C-X-C chemokine receptor type 4, mucosa-associated lymphoid tissue translocation protein 1, and interleukin-1 receptor-associated kinase 4.

The Management of Relapsed or Refractory Waldenstrom’s Macroglobulinemia. García-Sanz R and Tedeschi A, Hematol Oncol Clin N Am 37 (2023) 727-750 https://doi.org/10.1016/j.hoc.2023.04.006

WM is an immunoglobulin M monoclonal gammopathy produced by a bone marrow lymphoplasmacytic lymphoma, an indolent non-Hodgkin lymphoma in which the cure is still an unmet challenge. Combinations with alkylating agents, purine analogs, and monoclonal antibodies, Bruton tyrosine kinase, and proteasome inhibitors are used for the treatment of relapsed and refractory patients. Moreover, new additional agents can be seen on the horizon as potential effective therapies. No consensus on a preferred treatment in the relapsed setting is available yet.

Future Directions in the Frontline Management of Waldenstrom Macroglobulinemia.  Buske C and Palomba ML, Hematol Oncol Clin N Am 37 (2023) 719-726 https://doi.org/10.1016/j.hoc.2023.05.001 Despite substantial progress in the clinical management of WM and the emergence of chemotherapy-free approaches such as BTK inhibitors, WM is still a disease in which current treatments fail to cure and are in part associated with significant toxicities, compromising treatment outcome and quality of life. Thus, the vision for future front-line therapy should be to develop regimens which combine improved efficacy and excellent applicability with a low toxicity profile. Conventional immunochemotherapy such as bendamustine-rituximab is highly active but limited by hematotoxicity and long-lasting immunosuppression. Thus, further intensification of this treatment concept will most likely not be successful. Chemotherapy-free approaches such as BTK inhibitors have already changed the treatment landscape in WM, but still have major limitations such as the need for non-fixed duration treatment. Most probably, the combination of non-chemotherapy based, targeted approaches with different modes of action will ensure that we at least come closer to our vision of achieving functional cure in WM in the near future.

BTK Inhibitors in the Frontline Management of Waldenstrom Macroglobulinemia. Varettoni M and Matous JV, Hematol Oncol Clin N Am 37 (2023) 707-718  https://doi.org/10.1016/j.hoc.2023.04.005

The discovery of MYD88 (L265P) mutation led to investigating BTK inhibitors WM. Ibrutinib, the first-in-class agent, was approved based on a phase II trial in relapsed/refractory patients. In the phase III iNNOVATE study, the combination of rituximab and ibrutinib was compared with rituximab and placebo in treatment-naive and relapsed/refractory patients. Second-generation BTK inhibitor, zanubrutinib, was compared with Ibrutinib in MYD88-mutated WM patients in the phase III ASPEN trial, whereas acalabrutinib was investigated in a phase II trial. Here, the authors discuss the role of BTK inhibitors in treatment-naive patients with WM based on currently available evidence.

Proteasome Inhibitor-Based Regimens in the Frontline Management of Waldenstrom Macroglobulinemia. Solia E , Dimopoulos MA, and Kastritis E, Hematol Oncol Clin N Am 37 (2023) 689-706 https://doi.org/10.1016/j.hoc.2023.04.004 Proteasome inhibitors (PIs) have long been used in myeloma therapy but also for WM. Their use has been successful and has also been investigated for the frontline management of the disease. Bortezomib was effective either as a single agent or in combination with other regimens with high response rates observed in most studies, despite its adverse effects, especially neurotoxicity, which remains a major concern. Clinical trials with second-generation PIs such as carfilzomib and ixazomib have also been conducted, always in combination with immunotherapy in previously untreated patients. They have been shown to be active and neuropathy-sparing treatment options.
 

Frontline Management of Waldenstrom Macroglobulinemia with Chemoimmunotherapy. Kapoor P, Paludo J, and Abeykoon JP, Hematol Oncol Clin N Am 37 (2023) 671-688 https://doi.org/10.1016/j.hoc.2023.04.003 Despite the introduction of effective novel agents, chemoimmunotherapy (CIT), with its widespread use, retains relevance and is one of the 2 vastly disparate strategies to treat WM, the alternative being the Bruton tyrosine kinase inhibitor (BTKi)-based approach. Considerable evidence over the past decades supports the integration of the monoclonal anti-CD20 antibody, rituximab, to the CIT backbone in WM, a CD201 malignancy. Besides substantial efficacy, the finite duration of the treatment, coupled with lower rates of cumulative and long-term, clinically significant adverse effects and greater affordability, make CIT appealing, notwithstanding the lack of quality-of-life data with such an approach in WM. Purine analog-based CIT has been extensively evaluated in WM, although its use has waned, even in the multiply relapsed patient population, as effective and safer alternatives emerge.

Biomarkers of Progression and Risk Stratification in Asymptomatic Waldenstrom Macroglobulinemia. Bustoros M, Gribbin C, Castillo JJ, Furman R. Hematol Oncol Clin North Am.  37 (2023) https://doi.org/10.1016/j.hoc.2023.06.012 The authors provide valuable insights into managing patients with smoldering WM, focusing on a novel scoring system for patients with asymptomatic WM. These insights are: WM is preceded by a heterogeneous asymptomatic stage that can be divided into risk-groups with different progression rates.  Risk models were developed based on specific biomarkers, such as serum IgM, monoclonal protein, albumin, beta2-microglobulin, and bone marrow infiltration.  Risk stratification models with discrete cutoffs or continuous variables provide reliable risk assessment for asymptomatic patients.  Genomic alterations in MYD88 or CXCR4 genes and other molecular biomarkers are emerging as promising biomarkers to be included in future risk models.  To date, the standard of care for asymptomatic patients is observation.

Clinical Implications of Genomic Profile in Waldenstrom Macroglobulinemia. Moreno DF and Fernandez de Larrea C, Hematol Oncol Clin N Am 37 (2023) 659-670 https://doi.org/10.1016/j.hoc.2023.04.002 With the increasing availability of sequencing techniques and new polymerase chain reaction-based methods, data regarding the genomic profile of WM are being continuously analyzed and reproduced. MYD88 and CXCR4 mutations are highly prevalent in all the stages of WM, including the early IgM monoclonal gammopathy of undetermined significance or a more advanced stage, such as smoldering WM. Thus, there is a need to define genotypes before starting either standard treatment regimens or clinical trials. Here, the authors review the genomic profile of WM and its clinical implications while focusing on recent advances.

Clonal architecture and evolutionary history of Waldenstrom’s macroglobulinemia at the single-cell level. García-Sanz R, García-Álvarez M, Medina A, Askari E, González-Calle V, Casanova M, de la Torre-Loizaga I, Escalante-Barrigón F, Bastos-Boente M, Bárez A, Vidaña-Bedera N, Alonso JM, Sarasquete ME, González M, Chillón MC, Alcoceba M, Jiménez C. Dis Model Mech. 2023 Jul 26:dmm.050227. https://doi.org/10.1242/dmm.050227. Epub ahead of print. To provide insight into the subclonal architecture and codependency patterns of the alterations in Waldenström’s macroglobulinemia (WM), the authors performed single-cell Disease Models & Mechanisms. Results showed that in asymptomatic WM at diagnosis, MYD88L265P was the predominant clonal alteration, while other events, if present, were secondary and subclonal to MYD88L265P. In symptomatic WM, clonal diversity was more evident, uncovering combinations of alterations that synergized to promote clonal expansion and dominance. At disease progression, a dominant clone was observed, sometimes accompanied by other less complex minor clones, which could be consistent with a clonal selection process. Clonal diversity was also reduced, probably due to the effect of treatment. Finally, they combined protein expression with mutational analysis to map somatic genotype with the immunophenotype. Their findings provide a comprehensive view of the clonality of tumor populations in WM and how clonal complexity can evolve and impact disease progression.

Zanubrutinib Versus Ibrutinib in Symptomatic Waldenstrom Macroglobulinemia: Final Analysis from the Randomized Phase III ASPEN Study. Dimopoulos MA, Opat S, D’Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous J, Motta M, Siddiqi T, Tani M, Trněný M, Minnema MC, Buske C, Leblond V, Treon SP, Trotman J, Chan WY, Schneider J, Allewelt H, Patel S, Cohen A, Tam CS. J Clin Oncol. 2023 Jul 21:JCO2202830. doi: 10.1200/JCO.22.02830. Epub ahead of print. The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenstrom macroglobulinemia (WM). They report long-term follow-up outcomes from ASPEN. The primary endpoint was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory endpoints were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation (CXCR4), VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.

IgM-Associated Cryoglobulinemia. Khwaja J, Salter SJ, D’Sa S. Hemato 2023; 4(3):240-249. https://doi.org/10.3390/hemato4030019 Type I and II cryoglobulins may be present in patients with IgM-associated disorders and are part of a distinctive entity of IgM monoclonal gammopathy of clinical significance. Presentations range from asymptomatic disease to multisystem involvement, meaning that a careful evaluation of the features and thorough interrogation of organ systems and the underlying clone is critical. Patients may present with WM, IgM MGUS or NHL. Treatment approaches and the formal assessment of severity and response criteria in cryoglobulinemia are not standardized. Immediate management is required for clinical red-flag features.

Waldenstrom macroglobulinemia: a review of pathogenesis, current treatment, and future prospects. Ghafoor B, Shaik Masthan S, Hameed M, Akhtar H, Khalid A, Ghafoor S, Allah H, Arshad M, Iqbal I, Ahmad I, Muhammad H,  Anwer F. (2023). Annals of Hematology. https://doi.org/10.1007/s00277-023-05345-9. This excellent review summarizes WM pathogenesis, current treatment, and future prospects.

Extramedullary hematopoietic pleural effusion in Waldenström’s macroglobulinemia. Ito, K, Harada, K, Uchino, Y, Hirano, K, Sekiguchi, N.  eJHaem. 2023; 1– 4. https://doi.org/10.1002/jha2.754 Extramedullary hematopoietic effusion (EHE) is one of the extremely rare phenomena associated with extramedullary hematopoiesis, which is caused by serous effusions, including pleural effusion, and may be related to hematologic disorders and neoplasms. The authors present the case of an 81-year-old man with EHE accompanying Waldenstrom’s macroglobulinemia (WM). The patient complained of anemia and shortness of breath (dyspnea). The chest X-ray and computed tomography (CT) showed a massive left pleural effusion, and the aspirates revealed infiltration of the immature myeloid cells and megakaryocytes, in addition to the lymphoma cells. To the authors’ knowledge, this is the first report of EHE in WM.

SARS-CoV-2 Infection in Patients with Waldenstrom’s Macroglobulinemia: A Multicenter International Cohort Study. Defrancesco I, Ferretti VV, Morel P, Kyriakou C, Kastritis E, Tohidi-Esfahani I, Tedeschi A, Buske C, García-Sanz R, Vos JMI, Peri V, Margiotta Casaluci G, Ferrari A, Piazza F, Oostvogels R, Lovato E, Montes L, Fornecker LM, Grunenberg A, Dimopoulos MA, Tam CS, D’Sa S, Leblond V, Trotman J, Passamonti F, Arcaini L, Varettoni M. on behalf of the European Consortium for Waldenstrom’s Macroglobulinemia. HemaSphere 7(6):p e887, June 2023. | DOI: 10.1097/HS9.0000000000000887 In their series, WM vaccinated individuals had a significant survival advantage compared with unvaccinated patients, suggesting that WM patients may exhibit an effective response to vaccination, translating into reduced mortality. Besides COVID-19 severity, patient-related features (age >70 y and male gender) were associated with higher risk of death to patients with WM at multivariable analysis, in line with data from the general population. Their findings suggest that patient-related features, COVID-19 severity, and anti-SARS-CoV-2 vaccination, rather than WM treatment characteristics, influence the outcome of WM patients with SARS-CoV-2 infection.

*Report of consensus panel 7 from the 11th international workshop on Waldenström macroglobulinemia on priorities for novel clinical trials. Tam CS, Kapoor P, Castillo JJ, Buske C, Ansell SM, Branagan AR, Kimby E, Li Y, Palomba ML, Qiu L, Shadman M, Abeykoon JP, Sarosiek S, Vos J, Yi S, Stephens D, Roos-Weil D, Roccaro AM, Morel P, Munshi NC, Anderson KC, San-Miguel J, Garcia-Sanz R, Dimopoulos MA, Treon SP, Kersten MJ. Semin Hematol. 2023 Mar 24:S0037-1963(23)00023-9. doi: https://doi.org/10.1053/j.seminhematol.2023.03.006  Consensus panel 7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (>VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs.

*Report of Consensus Panel 6 from the 11th International Workshop on Waldenstrom’s Macroglobulinemia on Management of Waldenström’s Macroglobulinemia Related Amyloidosis. Merlini G, Sarosiek S, Benevolo G, Cao X, Dimopoulos M, Garcia-Sanz R, Gatt ME, Fernandez de Larrea C, San-Miguel J, Treon SP, Minnema MC. Semin Hematol. 2023 Mar 29:S0037-1963(23)00022-7. DOI: 10.1053/j.seminhematol.2023.03.002 The key recommendations included: (1) The need to improve the diagnostic process by recognizing red flags and using biomarkers and imaging; (2) The essential tests for appropriate workup; (3) The diagnostic flowchart, including mandatory amyloid typing, that improves the differential diagnosis with transthyretin amyloidosis; (4) Criteria for therapy response assessment; (5) State of the art of the treatment including therapy of wild type transthyretin amyloidosis associated with WM.

*Report of consensus panel 5 from the 11th international workshop on Waldenstrom’s macroglobulinemia on COVID-19 prophylaxis and management. Terpos E, Branagan AR, García-Sanz R, Trotman J, Greenberger LM, Stephens DM, Morel P, Kimby E, Frustaci AM, Hatjiharissi E, San-Miguel J, Dimopoulos MA, Treon SP, Leblond V. Semin Hematol. 2023 Mar 29:S0037-1963(23)00024-0  https://doi.org/10.1053/j.seminhematol.2023.03.004  The key recommendations included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton’s Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae.

*Report of Consensus Panel 3 from the 11th International Workshop on Waldenstrom’s Macroglobulinemia: Recommendations for Molecular Diagnosis in Waldenstrom’s Macroglobulinemia. Garcia-Sanz R, Varettoni M, Jimenez C, Ferrero S, Poulain S, San-Miguel JF, Guerrera ML, Drandi D, Bagratuni T, McMaster M, Roccaro AM, Roos-Weil D, Leiba M, Li Y, Qiu L, Hou J, Fernandez De Larrea C , Castillo JJ, Dimopoulos M , Owen RG, Treon SP, Hunter ZR, Seminars in Hematology (2023), doi: https://doi.org/10.1053/j.seminhematol.2023.03.007 Apart from the MYD88L265P mutation, extensive information exists on the molecular mechanisms in Waldenstrom’s Macroglobulinemia and its potential utility in the diagnosis and treatment tailoring. However, no consensus recommendations are yet available. Key recommendations from IWWM-11 CP3 included: 1) molecular studies are warranted for patients in whom therapy is going to be started; such studies should also be done in those whose bone marrow (BM) material is sampled based on clinical issues; 2) molecular studies considered essential for these situations are those that clarify the status of 6q and 17p chromosomes, and MYD88, CXCR4, and TP53 genes. These tests in other situations, and/or other tests, are considered optional; 3) independently of the use of more sensitive and/or specific techniques, the minimum requirements are Allele Specific Polymerase Chain Reaction for MYD88L265P and CXCR4S338X using whole BM, and Fluorescence in situ hybridization for 6q and 17p and sequencing for CXCR4 and TP53 using CD19+ enriched BM; 4) these requirements refer to all patients; therefore, samples should be sent to specialized centers.

*Report of Consensus Panel 2 from the 11th International Workshop on Waldenstrom’s Macroglobulinemia on the Management of Relapsed or Refractory WM Patients. D’Sa S, Matous JV, Advani R, Buske C, Castillo JJ, Gatt M, Kapoor P, Kersten MJ, Leblond V, Leiba M, Palomba ML, Paludo J, Qiu L, Sarosiek S, Shadman M, Tam CS , Tedeschi A, Thomas SK, Tohidi-Esfahani I, Trotman J , Varettoni M, Vos JMI, Garcia-Sanz R, San-Miguel J, Dimopoulos MA, Treon SP, Kastritis E , Seminars in Hematology (2023), doi: https://doi.org/10.1053/j.seminhematol.2023.03.003 The key recommendations from    IWWM-11 consensus panel 2 include: i) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. ii) In selecting treatment, biological age, co-morbidities, and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. iii) The trigger for initiating treatment in RRWM should utilize knowledge of patients’ prior disease characteristics to avoid unnecessary delays. iv) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and

new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.

Report of Consensus Panel 1 from the 11th International Workshop on Waldenstrom’s Macroglobulinemia on Management of Symptomatic, Treatment-Naive Patients.  Buske C, Castillo J, Abeykoon JP, Advani R, Arulogun SO, Branagan AR, Cao X, D’Sa S, Hou J, Kapoor P, Kastritis E, Kersten MJ, LeBlond V, Leiba M, Matous JV, Paludo J, Qiu L, Tam CS, Tedeschi A, Thomas SK, Tohidi-Esfahani I, Varettoni M, Vos JMI, Garcia-Sanz R, San-Miguel J, Dimopoulos MA, Treon SP, Trotman J, Seminars in Hematology (2023), doi: https://doi.org/10.1053/j.seminhematol.2023.03.005 The panel reiterated that watchful waiting remains the gold standard for asymptomatic patients without critically elevated IgM or compromised hematopoietic function. For first-line treatment, chemoimmunotherapy (CIT) regimens such as dexamethasone, cyclophosphamide, rituximab (DRC), or bendamustine, rituximab (Benda-R) continue to play a central role in managing WM, as they are effective, of fixed duration, generally well-tolerated, and affordable. Covalent BTK inhibitors (cBTKi) offer a continuous, generally well-tolerated alternative for the primary treatment of WM patients, particularly those unsuitable for CIT. In a Phase 3 randomized trial updated at IWWM-11, the second-generation cBTKi, zanubrutinib, was less toxic than ibrutinib and induced deeper remissions, thus categorizing zanubrutinib as a suitable treatment option in WM. While the overall findings of a prospective, randomized trial updated at IWWM-11 did not show superiority of fixed duration rituximab maintenance over observation following attainment of a major response to Benda-R induction, a subset analysis showed benefit in patients >65 years and those with a high IPPSWM score. Whenever possible, the mutational status of MYD88 and CXCR4 should be determined before treatment initiation, as alterations in these two genes predict sensitivity towards cBTKi activity. Treatment approaches for WM-associated cryoglobulins, cold agglutinins, AL amyloidosis, Bing-Neel syndrome (BNS), peripheral neuropathy, and hyperviscosity syndrome follow the common principle of reducing tumor and abnormal protein burden rapidly and deeply to improve symptoms. In BNS, ibrutinib can be highly active and produce durable responses. In contrast, cBTKi are not recommended for treating AL amyloidosis. The panel emphasized that continuous improvement of treatment options for symptomatic, treatment-naïve WM patients critically depends on the participation of patients in clinical trials, whenever possible.

The epidemiology of Waldenstrom macroglobulinemia. McMaster ML. Semin Hematol. 2023 Mar 31:S0037-1963(23)00036-7. doi: 10.1053/j.seminhematol.2023.03.008. Epub ahead of print. This introductory overview provides summary of the current understanding of the epidemiology of WM/LPL as a backdrop for a series of consensus panel recommendations arising from research presented at the 11th IWWM. The incidence, distribution and survival patterns of WM/LPL show distinctive variation by age, sex, and race/ethnicity. These patterns, though still poorly understood, strongly suggest that genetic, infectious, environmental, and possibly lifestyle factors in addition to other host factors are important in the etiology of WM/LPL. 

Incidence of solid malignancies (SM) among patients with Waldenström macroglobulinemia (WM): Analysis of the SEER database (2000-2019). Taneja A,  Mishra R,  Kumar SA, Iyer A, Hillengass J.  Journal of Clinical Oncology 2023 41:16_suppl, e18902-e18902 DOI: 10.1200/JCO.2023.41.16_suppl.e18902 There was a 10% incidence of secondary malignancies in WM survivors during 2000-2019. Lung and bronchus cancer carried worst overall survival among WM survivors and was the most prevalent, second to gender specific cancer, among patients with relatively younger onset WM. Most common site of secondary malignancy in young WM females was breast, while it was lung and bronchus in the older group. In males, prostate, and lung and bronchus were two most common sites in each age-groups. One percent of older male patients developed breast cancer. Of note, thyroid was a common site, 9.3% of secondary malignancy, in young WM female cohort. Cecum and most brain cancers were noted among patients with older age at WM diagnosis.

Treatment of relapsed and refractory Waldenstrom Macroglobulinemia, Amaador K, Kersten MJ, Minnema MC & Vos JMI (2023) Leukemia & Lymphoma, 64:1, 30-41, https://doi.org/10.1080/10428194.2022.2131423 Several effective agents such as monoclonal antibodies, in combination with chemotherapy, Bruton’s tyrosine kinase inhibitors, proteasome inhibitors, and BCL2 inhibitors are becoming available for the treatment of relapsed and refractory WM. There is however no consensus on a preferred treatment in the relapsed setting. Choice of therapy in relapsed WM should be individualized by taking several treatment and patients characteristics into account, such as treatment duration, toxicity, age, comorbidities and MYD88L265P and CXCR4 mutational status. Due to better understanding of WM biology and the arrival of novel anti-lymphoma agents, the therapeutic options are increasing. Non-cytotoxic and fixed duration regimens, such as those explored in other indolent NHLs should be the focus of future clinical trials in WM.

Risk of a second cancer and infection in patients with indolent B-cell lymphoma exposed to first-line bendamustine plus rituximab: A retrospective analysis of an administrative claims database. Dote S, Inose R, Goto R, Kobayashi Y, Muraki Y. Hematol Oncol. 2023 Feb 15. https://doi.org/10.1002/hon.3128 Bendamustine has a potent immunosuppressive effect because it causes T-cell lymphopenia, which might lead to a second primary malignancy (SPM) and would increase the risk of infection. Using the Medical Data Vision administrative claims database, the authors compared the cumulative incidence of SPM, infections within 6 months, and overall survival (OS) among untreated patients with indolent B-cell lymphomas (iBCL) who received rituximab-based chemotherapy. 5234 patients were assigned to three cohorts: rituximab monotherapy (N = 780), RCHOP/RCVP/RTHPCOP (doxorubicin replaced with pirarubicin) (N = 2298), or bendamustine/rituximab (BR) (N = 2156). There were 589 recorded SPMs, of which myelodysplastic syndromes were the most common (1.7%). The cumulative incidence of SPM was significantly higher in patients treated with BR than in those treated with rituximab monotherapy (p < 0.01) or RCHOP/RCVP/RTHPCOP (p < 0.0001): the 5-year cumulative incidence function was 18.1%, 12.5%, and 12.9%, respectively. In the Fine-Gray subdistribution hazards model, BR showed a significantly higher cumulative incidence of SPM than RCHOP/RCVP/RTHPCOP (subhazard ratio, 1.33; 95% confidence interval [CI], 1.10–1.61). Furthermore, in sensitivity analysis, a nested case-control study using an entire cohort showed consistent results: the SPM odds ratios (95% CI) of first-line bendamustine, bendamustine after first-line, and any-line bendamustine were 1.43 (1.14–1.78), 1.26 (0.96–1.64), and 1.33 (1.09–1.62), respectively. Regarding infections, adjusted odds ratios (95% CI) of BR compared to RCHOP/RCVP/RTHPCOP were as follows: cytomegalovirus infection, 13.7 (4.88–38.4); bacterial pneumonia, 0.63 (0.50–0.78); and pneumocystis pneumonia, 0.24 (0.11–0.53). There was no significant difference in OS between RCHOP/RCVP/RTHPCOP and BR in patients with follicular, mantle cell, marginal zone, or lymphoplasmacytic lymphomas. In conclusion, treatment strategies that consider the risk of SPM and infections after chemotherapy are warranted in patients with iBCL.

Multimodal Imaging Characteristics and Risk Factors Analysis of Waldenstrom Macroglobulinemia Retinopathy: Risk Factors of Waldenstrom Macroglobulinemia Retinopathy. Chen H, Wang Y, Xu Z, Li D, Du H, Chen Y, Feng J. Am J Ophthalmol. 2023 Mar  DOI: 10.1016/j.ajo.2023.03.011  Epub ahead of print. WM retinopathy (WMR) was characterized by tortuous retinal vessels, extensive retinal hemorrhage, and distinctive shape of macular edema in multimodal images. The presence of WMR in WM patients was significantly correlated with M protein and serum IgM, with cut-off value of 26.2g/L and 51.0g/L. It is important to monitor WMR by ophthalmic exam and hematological parameters.

Artificial intelligence-enabled screening strategy for drug repurposing in monoclonal gammopathy of undetermined significance. Ryu, A.J., Kumar, S., Dispenzieri, A. et al.  Blood Cancer J. 13, 28 (2023). https://doi.org/10.1038/s41408-023-00798-7 Monoclonal gammopathy of undetermined significance (MGUS) is a benign hematological condition with the potential to progress to malignant conditions including multiple myeloma and Waldenstrom macroglobulinemia. The presence of multivitamins, immunosuppression, non-coronary NSAIDS, proton pump inhibitors, vitamin D supplementation, opioids, statins and beta-blockers were associated with significantly lower hazard ratio for MGUS progression in our primary model; multivitamins and non-coronary NSAIDs remained significant across both sensitivity analyses.

Waldenstrom macroglobulinemia whole genome reveals prolonged germinal center activity and late copy number.  Maclachlan KH, Bagratuni T, Kastritis E, Ziccheddu B, Lu S, Yellapantula V, Famulare C, Argyropoulos K, Derkach A, Papaemmanuil E, Dogan A, Lesokhin A, Usmani SZ, Landgren CO, Palomba LM, Maura F, Dimopoulos MA.. Blood Adv 2023; 7 (6): 971–981. doi: https://doi.org/10.1182/bloodadvances.2022008876 The genomic landscape of Waldenstrom macroglobulinemia (WM) is characterized by somatic mutations in MYD88, present from the precursor stages. Using the comprehensive resolution of whole genome sequencing (WGS) in fourteen CD19-selected primary WM samples; comparing clonal and subclonal mutations revealed that germinal center (GC) mutational signatures SBS9 (poly-eta) and SBS84 (AID) have sustained activity, suggesting that the interaction between WM and the GC continues over time. The authors found that WGS reveal that precursors with low genomic complexity have a lower risk for progression to WM. Molecular time analysis shows chr12 gain occurred early in development, whereas other gains occur later and may be associated with progression.

BeEAM Conditioning including High-Dose Bendamustine before Autologous Stem Cell Transplantation Is Safe and Effective in Patients with Waldenstrom’s Macroglobulinemia. Heini AD, Beck P, Bacher U, Seipel K, Zander T, Daskalakis M, Pabst T. Journal of Clinical Medicine. 2023; 12(6):2378. https://doi.org/10.3390/jcm12062378 High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is an option to consolidate remission in Waldenstrom’s macroglobulinemia (WM), particularly in selected younger patients with chemosensitive disease. BEAM, consisting of BCNU, etoposide, cytarabine, and melphalan, is often used as a conditioning regimen. However, problems with BCNU, including pneumotoxicity, tolerance, and availability, necessitate the search for alternatives. In this pilot study, we investigated high-dose chemotherapy with BeEAM, in which BCNU (carmustine), is replaced with high-dose bendamustine as an alternative conditioning regimen in six subsequent patients with WM. Bendamustine treatment was well tolerated without unexpected toxicities. The overall response rate was 6/6 patients (2 very good partial responses (VGPR) and 4 PR). After a median follow-up of 72 months, two (33%) patients relapsed. Median progression-free and overall survivals were not reached, and no severe late-onset toxicities were observed so far. In this pilot study, BeEAM conditioning before ASCT seems feasible, safe, and effective in patients with WM.

Sequential central retinal artery occlusions associated with cryoglobulinemia Wang P, Kanda P, Wang Y. et al. . Int J Retin Vitr 9, 16 (2023).  DOI: 10.1186/s40942-022-00423-y  Cryoglobulinemia, the presence of serum cryoglobulins which are immunoglobulins or complement components that precipitate at temperatures below 37 °C, commonly present with cutaneous manifestations initially, but are more rarely associated with ocular manifestations. The authors report the first case of a patient presenting with sequential central retinal artery occlusion (CRAO) associated with cryoglobulinemia.

Systematic literature review of quality-of-life questionnaires in Waldenström macroglobulinaemia—need for a disease-specific tool. Bristogiannis S, Khwaja J, Lwin Y, Uppal E, D’Sa S and Kyriakou C. (2023), eJHaem. https://doi.org/10.1002/jha2.668 .WM is an incurable but treatment-responsive disease with multiple treatment options that have advanced survival.  Treatments include chemoimmunotherapy and targeted agents, of fixed or continuous duration. As more effective therapies develop, disease and therapy-related quality of life (QoL)is increasingly recognized as an important endpoint. Although patients can engage in and evaluate the effects of the disease on their QoL, no WM-specific validated QoL assessment tool exists. Therefore, the authors conducted a literature review  of the currently used QoL tools in WM.

Waldenstrom macroglobulinemia and non-IgM-type lymphoplasmacytic lymphoma are genetically similar. Awata-Shiraiwa M, Yokohama A, Kanai Y, Gotoh N, Kasamatsu T, Handa H, Saitoh T, Murakami H, Hirato J, Ikota H, Tsukamoto N. Acta Haematol March 2023  DOI: 10.1159/000530100 These researchers from Japan evaluated genetic differences between WM and LPL with non-IgM paraprotein (non-IgM-type LPL) using targeted next-generation sequencing in 20 Japanese patients (10 with WM, 10 with non-IgM-type LPL). Their next-generation sequencing analyses revealed genetic characteristics in LPL patients and suggest genetic similarities between these two subsets of LPL, WM and non-IgM-type.

Bortezomib-dexamethasone, rituximab, and cyclophosphamide as first-line treatment for Waldenstrom’s Macroglobulinemia: A prospectively randomized trial of the European Consortium for Waldenström’s Macroglobulinemia. Buske C, Dimopoulos MA, Grunenberg A, Kastritis E, Tomowiak C, Mahé B, Troussard X, Hajek R, Viardot A, Tournilhac O, Aurran T, Lepretre S, Zerazhi H, Hivert B, Leblond V, de Guibert S, Brandefors L, Garcia-Sanz R, Gomes da Silva M, Kimby E, Schmelzle B, Kaszynski D, Dreyhaupt J, Muche R, and Morel P. Journal of Clinical Oncology DOI: 10.1200/JCO.22.01805 In this European study, treatment-naïve patients were randomly assigned to DRC or bortezomib-DRC B-DRC for six cycles. This large, randomized study illustrates that B-DRC is highly effective and well tolerated in WM. The data demonstrate that fixed duration immunochemotherapy remains an important pillar in the clinical management of WM.

Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience. Chohan, KL, Paludo, J, Vallumsetla, N, et al.  Am J Hematol. 2023; 98(3): 432- 439. doi:10.1002/ajh.26807  In this retrospective study, the authors investigated the characteristics and outcomes of younger (<50 years of age) and older patients with WM treated between 1960 and 2013. The duration of the disease-specific survival was similar among younger patients throughout the study period, whereas an improvement was observed among older patients. Deaths were more commonly attributable to WM in younger patients. Despite treatment advances over the 5-decade period, outcomes remain similar among younger patients with WM. Although this study does not capture the impact of Bruton tyrosine kinase inhibitors, it highlights the need for additional studies in this younger population.

Managing Ibrutinib-Intolerant Patients With B-Cell Malignancies. Javier Muñoz, Shayna Sarosiek, Jorge J Castillo, , The Oncologist, 2023;, oyac260, https://doi.org/10.1093/oncolo/oyac260 . The authors review the literature and provide guidance on treating ibrutinib-intolerant patients with B-cell malignancies. Side effects, such as atrial fibrillation, hypertension, and bleeding, have been observed and may limit a patient’s tolerance for treatment. Currently, there is no well-established treatment regimen for patients who cannot tolerate ibrutinib. Approaches to address such patients include managing ibrutinib side effects with supportive care or dose reductions, switching to an alternative covalent BTK inhibitor, or abandoning covalent BTK inhibitors for alternative forms of treatment.

Diagnosing, imaging, and successfully treating a debilitating case of Bing-Neel syndrome: a multidisciplinary feat. Kerley, O’Donnell N, Lynott F, Mulcahy R, Hennessey. Authorea, January 20, 2023. DOI: 10.22541/au.167419288.80264053/v1  The authors, from Ireland, present a case of Bing-Neel syndrome successfully treated with systemic chemoimmunotherapy and ibrutinib, with remarkable clinical response.

Bruton tyrosine inhibitors in the management of Waldenstrom macroglobulinemia. Castillo JJ, Buske C, Trotman J, Sarosiek S, Treon SP. Am J Hematol. 2023; 98(2): 338- 347. doi:10.1002/ajh.26788 Bruton tyrosine kinase (BTK) inhibitors have taken a central role in the management of patients with Waldenstrom macroglobulinemia and are the only agents approved by the Food and Drug Administration (FDA) to treat these patients. Although associated with high rates of durable responses, unmet needs with BTK inhibitor therapy include indefinite duration therapy, high cost, scarcity of complete responses, and lower rates and shorter duration of response in patients with CXCR4 mutations. The authors from DFCI review the data supporting the use of covalent BTK inhibitors, selected management issues, clinical trials with covalent BTK inhibitor combination regimens, and up-and-coming non-covalent BTK inhibitors.

Zanubrutinib in patients with treatment-naïve or relapsed/refractory Waldenström macroglobulinemia: An expanded-access study of 50 patients in the United States. Castillo JJ, Kingsley EC, Narang M, Yimer HA, Dasanu CA, Melear JM, Coleman M, Farber CM, Shulman J, Mantovani EH, Zhang X, Cohen A, Huang J. (2023), eJHaem. https://doi.org/10.1002/jha2.619 This phase 2 expanded-access study evaluated zanubrutinib 320 mg daily (160 mg twice a day or 320 mg per day per investigator selection) in patients with WM who had relapsed/refractory(R/R) disease or were treatment naïve (TN) and considered unsuitable for standard chemotherapy. Treatment continued in 28-day cycles until progressive disease (PD), unacceptable toxicity, death, study termination by the sponsor, or commercial availability of zanubrutinib, among other reasons. Study limitations included a small sample size, unblinded design, short follow-up duration, infrequent response assessments, unreported gene sequence status, and US-only enrollment. Although this is a non-comparative study, the results of zanubrutinib in patients with R/R or TN WM at 160 mg twice a day or 320 mg per day are consistent with the previous observations from earlier studies.

Does early disease progression predict survival after first line-treatment of Waldenstrom macroglobulinemia? Labreuche J, Assouan D, Durot E, et al.  Hematol Oncol. 2022; 40(3): 400- 408. https://doi.org/10.1002/hon.2996 In symptomatic Waldenstrom macroglobulinemia (sWM) patients, prognosis is assessed with the international prognostic scoring system (IPSSWM). In follicular lymphoma and other B-cell and T-cell lymphomas, disease progression within 24 months (POD24) or (in patients without POD24) after 24 months has been proposed as the start date for stratifying subsequent survival. In the present report, these French researchers assessed in a large series of 472 sWM patients, the prognostic value of this new dynamic endpoint already reported in many other lymphomas subtypes. The 3-year subsequent survival for patients with POD24 was 75% and 93% for patients without POD24. In sWM patients, departure from the proportional hazards assumption complicated this analysis. In patients without POD24, the median subsequent progression-free survival time of 43 months accounted for favorable outcome, whereas survival after progression was not influenced by the time to progression. In addition, sensitivity analysis showed that the baseline IPSSWM score also influenced survival after POD24. In sWM patients, we conclude that the apparent difference in survival after POD24 or the 24 months time-point (in patients without POD24) is mainly explained by the prolonged subsequent progression free survival of latter patients. Indeed, the mortality after progression is not influenced by the time to this event.

Dose reduction in patients with Waldenstrom macroglobulinemia treated with ibrutinib. Sarosiek S, Gustine JN, Flynn CA, Leventoff C, Little M, White T, Meid K, Treon SP, Castillo JJ.  Br J Haematol. 2023; 00: 1– 8. https://doi.org/10.1111/bjh.18643 Ibrutinib was the first BTK inhibitor approved for WM. Intolerance to ibrutinib frequently leads to dose reductions, though the impact of reducing ibrutinib dosing has not been systematically studied. The authors from DFCI performed a retrospective study to determine the frequency and impact of reducing ibrutinib dosing in WM patients. With a median treatment time of 64 months, 96 (27%) of 353 WM patients required a dose reduction due to adverse events such as musculoskeletal symptoms, cardiac events, dermatologic symptoms, cytopenias, and gastrointestinal symptoms. The median time to initial dose reduction was 9.3 months. Dose reductions were more common in those 65 years of age or older versus under 65, and in females versus males. Most patients (65%) had improvement or resolution of adverse effects after initial dose reduction. With a median follow-up of three years from dose reduction, hematologic response sustained or deepened in 79% of patients. These data suggest that dose reduction of ibrutinib is a reasonable treatment approach for patients with intolerable side effects.

Bone involvement as a primary rare manifestation of Waldenstrom macroglobulinemia: a case report and prevalence in a nationwide population-based cohort study. Bhatti K, Nazir A, Ostergaar S, Schejbel L, Norgaar P, Gjerdrum L, Moghaddas M, Nielsen T, Munksgaard L, Pedersen L. (2023). Journal of Hematology, North America, 11, Jan. 2023 https://www.thejh.org/index.php/jh/article/view/1073/697   These Danish authors describe an unusual case of a patient with WM who presented with lower back pain and focal bone lesions at initial diagnosis. As a follow-up to this unusual case, the authors carried out an analysis based on the Danish Lymphoma Registry (LYFO) covering the entire national population in the period 2000-2020. The registry study included a cohort of 2,459 patients with WM and lymphoplasmacytic lymphoma. Their data revealed that primary bone involvement at diagnosis occurs in 1.75% of adults with WM. 

Waldenstrom macroglobulinemia: 2023 update on diagnosis, risk stratification, and management. Gertz, MA.  Am J Hematol. 2022; 1- 11. doi:10.1002/ajh.26796  Age, hemoglobin level, platelet count, β2 microglobulin, LDH, and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteasome inhibitor, or a BTK inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib. Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM’s natural history, the reduction of therapy toxicity is an important part of treatment selection.

IgM-related immunoglobulin light chain (AL) amyloidosis. Sarosiek S, Branagan AR, Treon SP, Castillo JJ. Hemato 2022, 3, 731–741.  https://doi.org/10.3390/hemato3040049  Amyloidosis is a protein-folding disorder in which vital organ damage occurs due to the accumulation of misfolded protein aggregates. The most common type of amyloidosis in patients with an IgM paraprotein is light chain (AL) amyloidosis, although other types of amyloidosis may occur. IgM-related amyloidosis has distinct clinical features when compared with other subtypes of AL amyloidosis. This review highlights the diagnostic criteria of IgM-related AL amyloidosis, as well as the clinical characteristics and treatment options for this disorder.

Single-cell profiles reveal tumor cell heterogeneity and immunosuppressive microenvironment in Waldenstrom macroglobulinemia. Sun H, Fang T, Wang T, et al.  J Transl Med 20, 576 (2022). https://doi.org/10.1186/s12967-022-03798-6  Data from China uncovered the heterogeneity of malignant cells in WM, and the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19+ CD3+ and CD138+ CD3+, co-expressing T-cell marker genes were identified at single cell resolution. Pseudotime-ordered analysis elucidated that CD19+ CD3+ malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19+CD3+ malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, the authors speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, their study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor of exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells.

Differential diagnosis of Waldenstrom’s Macroglobulinemia and early management: Perspectives from clinical practice. Shashank C, Surbhi S. (2022) Blood and Lymphatic Cancer: Targets and Therapy, 12:, 107-117, DOI: 10.2147/BLCTT.S259860 Several  mature  B-cell  and  plasma cell disorders can potentially produce monoclonal IgM immunoglobulin and hence, careful consideration of the differential diagnosis is vital. Clinical pathological features, immunophenotype, and MYD88 mutation status help distinguish WM from other plasma cell and lymphoproliferative disorders. Treatment is only indicated in patients symptomatic from adenopathy or organomegaly, neuropathy, hyperviscosity, cryoglobulinemia, cold agglutinin disease, cytopenias or amyloidosis. Alkylators (cyclophosphamide, bendamustine) in combination with anti-CD20 antibodies and novel targeted agents including Bruton tyrosine kinase (BTK) inhibitors like ibrutinib are the mainstay of frontline treatment in symptomatic WM.

Patient reported outcome measures in Waldenstrom macroglobulinemia: A real-world data analysis from the WMUK Rory Morrison Registry. Khwaja, J, Uppal, E, Bristogiannis, S, McCarthy, H, Kothari, J, Rismani, A, et al.  eJHaem. 2022; 1– 5. https://doi.org/10.1002/jha2.640 These researchers from the United Kingdom used questions from four quality of life questionnaires in the UK national WM registry, the Rory Morrison Registry to obtain reliable information of the patients experience of disease beyond traditional outcome measures. Their data suggest that these widely used questionnaires may not be suitable for patients with WM and may not capture the experience of patients with this disorder. They advocate the development of WM-specific outcome measures. WM-tailored tools developed by patients could reflect the diverse immunological paraproteinemia complications.

*Light chain amyloidosis associated with Waldenström macroglobulinemia: treatment and survival outcomes. Gustine J, Szalat R, Staron A, Joshi T, Mendelson L, Sloan J, Sanchorawala V. (2022). Haematologica. DOI:10.3324/haematol.2022.282264  Light chain (AL) amyloidosis is an uncommon clinical manifestation of WM. The authors, from the Boston University Amyloidosis Center sought to describe the treatment and survival outcomes in a group of patients with WM-AL amyloidosis. Their findings demonstrate that standard Wm regimens such as BDR or Benda-R can also be effective in WM-AL amyloidosis. They report deep and durable responses with stem cell transplants.  They also report that maintenance Rituxan may have a role in WM-AL amyloidosis. Ibrutinib is associated with mixed efficacy and tolerability in WM-AL amyloidosis and must be used with caution, particularly in patients with cardiac involvement.  This work was supported by the International Waldenstrom’s Macroglobulinemia Foundation through a Young Investigator Award for Dr. Gustine.

Refractory chylothorax in a patient with Waldenstrom macroglobulinemia: a case report.  Mullen ND, Bukhari A, Koroscil M., Science Direct 2022 https://doi.org/10.1016/j.rmcr.2022.101780 This is case report of a patient with WM and chylothorax. Chylothorax is a rare, but serious condition in which lymph formed in the digestive system (chyle) accumulates in the chest cavity, pleural effusions. It usually responds to chemotherapy, but this patient required surgical intervention, pleurectomy.

Insurance-based disparities impact survival outcomes in Waldenström macroglobulinemia within the United States. Chohan KL, Abeykoon JP, Ansell SM, Gertz MA, Kapoor P, Paulus A, Ailawadhi S, Reeder CB, Witzig TE, Habermann TM, Lacy MQ, Kyle RA, Go RS, Paludo J. Leuk Lymphoma. 2022 Jul 23:1-10.  DOI: 10.1080/10428194.2022.2102623  Epub ahead of print. The authors conducted a National Cancer Database analysis of newly diagnosed cases of active WM to evaluate the impact of insurance status on outcomes. For patients <65 years old (n = 1249, male sex: 62.4%, median age: 58 years), significant insurance-based survival differences were observed on multivariable analysis; patients who were uninsured, on Medicaid, or on Medicare had inferior survival compared to patients with private insurance. In patients ≥65 years, no insurance-based survival differences were found. Overall, significant insurance-based outcome disparities exist in WM.

Inflammation in Waldenström Macroglobulinemia Is Associated With 6q Deletion and Need for Treatment Initiation. Forgeard N, Baron M, Caron J, Boccon-Gibod C, Krzisch D, Guedes N, Morel V, Jacque N, Ouzegdouh M, Choquet S, Bravetti C, Nguyen-Khac F, Chapiro E, Leblond V, and Roos-Weil D, on behalf of FILO group (French Innovative Leukemia Organization) group. 2022 Haematologica 107 (11). Pavia, Italy, 2720-24. https://doi.org/10.3324/haematol.2022.281053.The most frequent cytogenetic abnormality found in patients with WM is 6q deletion (del6q), found in 30% to 55% of cases. The authors highlight clinical and biological specificities of WM patients with chronic inflammation, notably a higher prevalence of del6q, more frequent need for therapy initiation and a trend for poorer overall survival, which will have to be confirmed by further studies.

Coming of Age for BTK Inhibitor Therapy: A Review of Zanubrutinib in Waldenström Macroglobulinemia. Muñoz J, Paludo J, Sarosiek S, Castillo JJ. Cells 2022, 11, 3287. https://doi.org/10.3390/cells11203287Zanubrutinib is a next-generation covalent BTK inhibitor designed to have fewer off-target effects than previous BTK inhibitors. This review summarizes the pharmacokinetic and pharmacodynamic properties of zanubrutinib as well as safety and efficacy findings. Then, it explores the health economic and outcomes research associated with the costs of treating patients with WM and the reasons why zanubrutinib may be a more cost-effective treatment option compared with ibrutinib, a first-generation BTK inhibitor. Future directions for the treatment of WM focus on the use of zanubrutinib in combination therapy. Combinations based on effective ibrutinib or acalabrutinib treatments may be effectively applied with zanubrutinib given the similar mechanism of action for these BTK inhibitors. Combination therapies could also help prevent the development of disease resistance, minimize toxicity, and support treatment regimens of finite duration.

Should Patients with Waldenström Macroglobulinemia Receive a BTK Inhibitor as Frontline Therapy? Deodato M, Frustaci AM, Zamprogna G, Cotilli G, Cairoli R, Tedeschi A. Hemato. 2022; 3(4):689-703. https://doi.org/10.3390/hemato3040046

As there are no randomized trials suggesting the best treatment option in treatment-naive patients, guidelines suggest either rituximab-combining regimens or BTK-inhibitors (BTKi) as feasible alternatives. Several factors play in the decision-making process: patients’ age and fitness, disease characteristics and genotype. Chemoimmunotherapy (CIT) represents a fixed duration, less expensive and effective option, able to achieve prolonged time-to-next treatment even in patients with unfavorable genotypes. Immunosuppression and treatment-related second cancers may represent serious concerns. Proteasome-inhibitor-based regimens are effective with rapid disease control, although bortezomib-related neuropathy discourages the choice of these agents and treatment schedules may not be easily manageable in the elderly. BTKi have demonstrated high rates of response and prolonged survival together with the convenience of an oral administration and limited cytopenias. However, outcomes are impacted by genotype and some concerns remain, in particular the continuous drug exposure that may result in extra-hematological complications and drug resistance. Although next-generation BTKi have improved treatment tolerance, the question whether BTKi should be offered as frontline therapy to every patient is still debated. Given a fixed duration schedule, prolonged time-to-next treatment and outcomes independent of genotype, CIT is still the preferred choice in WM by these authors from Milan, Italy. However, BTKi remains a valuable option in frail patients unsuitable for CIT.

Bortezomib-based therapy is effective and well tolerated in frontline and multiply pre-treated Waldenström macroglobulinaemia including BTKi failures: A real-world analysis. Khwaja J, Uppal E, Baker R, Trivedi K, Rismani A, Gupta R, et al. EjHaem. 2022; 1-5. https://doi.org/10.1002/jha2.597 These British authors assessed the real-world efficacy and tolerability of bortezomib-containing regimens in patients with WM at frontline and relapse including those with prior BTKi resistance. Forty-one patients were identified with 44 bortezomib-containing regimens administered (n = 12 frontline, n = 32 relapse). Of patients treated at relapse, the median prior lines of therapy was 3 (range 1–7). 24% of the cohort were refractory or intolerant to BTKi prior to bortezomib delivery. The median follow-up after bortezomib administration was 34 months. Overall response rate was 88%; 2-year overall survival and progression-free survival were 90% and 76% respectively. Median time-to-next-treatment was 66 months. Neuropathy (grade 1–2) occurred in 24% (8/34) and did not result in treatment cessation in any case. Gastrointestinal disturbance occurred in 7% (3/41). Treatment discontinuations were rare (1/44; 2%), suggesting a manageable safety profile. Major response rate was comparable in those with prior BTKi compared with those without (75% [6/8] vs 84% [27/32], p = 0.61). Bortezomib should be considered as a treatment modality particularly in those who are refractory to BTKi.

IgM Monoclonal Gammopathies of Clinical Significance: Diagnosis and Management. Khwaja J, D’Sa S, Minnema MC, Kersten MJ, Wechalekar A, and Vos JM. 2022. Haematologica 107 (9). Pavia, Italy, 2037-50. https://doi.org/10.3324/haematol.2022.280953. IgM monoclonal gammopathy of undetermined significance is a premalignant condition for Waldenstrom macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. The aim of this review is to alert clinicians to IgM related disorders that are a distinct clinical entity termed monoclonal gammopathy of clinical significance (IgM MGCS) and to provide practical guidance on when to screen for these phenotypes. They discuss the clinical characteristics, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease (CAD), cryoglobulinemia, IgM-associated AL amyloidosis, IgM-related neuropathies and Schnitzler syndrome.

The National Comprehensive Cancer Network® (NCCN) is a non-profit alliance of 31 cancer centers in the U.S. whose goal is to improve the quality and effectiveness of care provided to cancer patients. They provide updated guidelines (last update July, 2022) based on the most current diagnosis and treatment guidelines available. You must establish an account on the NCCN website to login and view these guidelines.

Treatment and survival of Waldenstrom macroglobulinemia in Latin American patients: A multinational retrospective cohort study. Riva E, Duarte PJ, Valcárcel B, Remaggi G, Murrieta I, Corzo A, Del Carpio D, Peña C, Vásquez J, Bove V, Teixeira L, Fleury-Perini G, Yantorno S, Samánez C, Lopresti S, Altamirano M, Villela L, Ruiz-Arguelles GJ, Ruiz-Delgado GJ, Montaño E, Verri V, Zamora Pérez E, Pérez Jacobo F, Idrobo H, Martínez-Cordero H, Beltran BE, Ramírez J, Castillo JJ, Malpica Castillo LE. JCO Glob Oncol. 2022 Aug;8:e2100380. doi: 10.1200/GO.21.00380 This group of researchers retrospectively analyzed patients with WM diagnosed between 1991 and 2019 from 24 centers in seven Latin American countries. The study outcomes were overall survival (OS) and progression-free survival (PFS). They identified 159 cases (median age 67 years, male 62%). Most patients (95%) were symptomatic at diagnosis. The International Prognostic Scoring System for WM (IPSSWM) at diagnosis was available in 141 (89%) patients (high-risk 40%, intermediate-risk 37%, and low-risk 23%). Twenty-seven (17%) patients were tested for MYD88^L265P, with 89% (n = 24 of 27) carrying the mutation. First-line and second-line therapies were administered to 142 (89%) and 53 (33%) patients, respectively. Chemoimmunotherapy was the most commonly used first-line (66%) and second-line (45%) approach; only 18 (11%) patients received ibrutinib. With a median follow-up of 69 months, the 5-year OS rate was 81%. In treated patients, the 5-year OS and PFS rates were 78% and 59%, respectively. High-risk IPSSWM at treatment initiation was an independent risk factor for OS and PFS. In Latin America, the management of WM is heterogeneous, with limited access to molecular testing and novel agents. However, outcomes were similar to those reported internationally. We validated the IPSSWM score as a prognostic factor for OS and PFS. There is an unmet need to improve access to recommended diagnostic approaches and therapies in Latin America.

Therapeutic activation of G protein-coupled estrogen receptor 1 in Waldenström Macroglobulinemia. Morelli E, Hunter ZR, Fulciniti M. et al.  Exp Hematol Oncol 11, 54 (2022). https://doi.org/10.1186/s40164-022-00305-x Activating G protein-coupled estrogen receptor 1 (GPER1) is an attractive therapeutic strategy for treating a variety of human diseases including cancer. Here, the authors show that GPER1 is significantly upregulated in tumor cells from different cohorts of Waldenström Macroglobulinemia (WM) patients compared to normal B cells. Using the clinically applicable GPER1-selective small-molecule agonist G-1 (also named Tespria), they found that pharmacological activation of GPER1 leads to G2/M cell cycle arrest and apoptosis both in vitro and in vivo in animal models, even in the context of the protective bone marrow milieu. Activation of GPER1 triggered the TP53 pathway, which remains actionable during WM progression. This study identifies a novel therapeutic target in WM and paves the way for the clinical development of the GPER1 agonist G-1.

Differential Diagnosis of Waldenstrom’s Macroglobulinemia and Early Management: Perspectives from Clinical Practice. Cingam S, Sidana S. Blood Lymphat Cancer. 2022 Aug 18;12:107-117. doi: 10.2147/BLCTT.S259860  The differential diagnosis of WM is broad, and workup including a bone marrow biopsy, cytogenetic and molecular studies are helpful to rule out other mature B cell NHLs. Early recognition and effective treatment of complications, including using plasmapheresis when indicated, is prudent to avoid premature mortality and morbidity in this otherwise indolent lymphoma. Multiple effective therapies with comparable outcomes are now available for the treatment of WM. Patient preference, clinical presentation, comorbidities, molecular features, and treatment goals should be considered before choosing appropriate initial therapy for newly diagnosed WM. It is also essential to consider the financial toxicities of indefinite treatments such as oral BTK inhibitors and patients’ ability to obtain these medications. Population-based studies have shown considerable improvement in the outcomes of WM over the last two decades, mainly owing to an improved understanding of the pathophysiology of the disease and the introduction of targeted agents.

A Focus on Waldenstrom Macroglobulinemia and AL Amyloidosis. Lu R, Richards T. J Adv Pract Oncol. 2022 Jul;13(Suppl 4):45-56. doi: 10.6004/jadpro.2022.13.5.14. Epub 2022 Jul 28. While light chain amyloidosis in patients with WM only occurs in about 10% of patients, it is important that advanced practitioners are able to recognize concurrent AL amyloidosis, which will affect the patient’s treatment trajectory. Diagnosis of WM with AL amyloidosis is based on bone marrow biopsy and a fat pad biopsy. If AL amyloidosis is suspected, the bone marrow and fat pad biopsy should undergo Congo red staining. If it is negative, and there is a strong suspicion of AL amyloidosis, then an organ biopsy can be considered. Treatment of WM uses rituximab-based therapy in combination with a variety of other agents, including proteasome inhibitors, alkylating agents, and BTK inhibitors. Treatment of light chain amyloidosis uses bortezomib as the backbone of therapy and can be administered with cyclophosphamide, dexamethasone, and now daratumumab, which was recently approved. Waldenstrom macroglobulinemia and light chain amyloidosis are both rare diseases and can lead to a variety of disease-related complications. Fortunately, many options exist for both diseases. The authors highlight a case of WM with amyloidosis and a case of a patient with relapsing WM with considerations for managing this patient population.

The efficacy and safety of zanubrutinib and dexamethasone in symptomatic Waldenstrom macroglobulinemia. Liu A, Yin J, Lu J, Ma Y, Gao D, Hua L, Tian Y, Jian Y, Chen W. HemaSphere: June 2022:6, 1010-1011 doi: 10.1097/01.HS9.0000847348.63031.af  Symptomatic patients with WM were enrolled to the regimen of zanubrutinib and dexamethasone (ZD). The primary endpoint was objective response rate (ORR), progression-free survival (PFS). Key secondary endpoints included the proportion of patients achieving a complete or very good partial response (CR or VGPR), duration of response (DOR), time to response (TOR), disease burden, and safety. The control group was matched patients treated by chemotherapy or immunochemotherapy previously in Beijing Chaoyang Hospital. A total of 22 Patients with WM were enrolled in this study, median age 67(36-89); 68.2% males, 12 patients were untreated, others were treated patients. IPSS assessment grade 1 23.8%; grade 2 19.0%; grade 3 57.2%. 90.9% (20/22) patients with MYD88L265P mutation, 27.3% (3/11) patients with CXCR4 mutation. 21 patients received ≥1 dose of study treatment. Median follow-up of 8.2 months, median DOR and PFS were not reached; 95% of patients were progression-free at 6 months. ORR was 95% in those (17/18) who received ZD regimen more than 2 months. No patient achieved a CR. 33.3% of patients in the ZD group achieved a VGPR, time to VGPR within 3 months in 57.1% of patients a statistically significant difference with the control group. Time to PR in the ZD group was 2 months, much faster than the control group (11 months). The study-safety profile was consistent with previous BTK inhibitor clinical trial data. 45% of patients had any grade AEs. In which, the most frequent grade <=2 AEs were hemorrhage (18.2% all grade 1), rash (9.1%), hyperglycemia (13.6%), infection (9.1%), nausea and vomiting (9.1%), hypogammaglobulinemia (4.5%), neutropenia(9.1%). Grade 3/4 AEs were atrial fibrillation (4.5%), leading to treatment discontinuation. Other causes of treatment discontinuation is hyperglycemia, bowel obstruction by disease. The authors conclude that these results demonstrate that zanubrutinib and dexamethasone are quickly effective in the treatment of WM with a deep response and less toxicity.

Patient preferences regarding treatment options for Waldenstrom’s macroglobulinemia: A discrete choice experiment. Amaador K, Nieuwkerk PT, Minnema MC, Kersten MJ, Vos JMI.  Cancer Med. 2022; 00: 1- 11. doi: 10.1002/cam4.5080  Treatment options for Waldenstrom’s Macroglobulinemia (WM) have expanded rapidly in the last decades. However, there is no consensus on a preferred treatment. Therefore, patient preferences become increasingly important in making individualized treatment plans. Still, WM patients’ priorities and perspectives regarding their treatment options are unknown. These researchers from The Netherlands evaluated treatment preferences of WM patients using a discrete choice experiment (DCE). The DCE questionnaire included five attributes: type of agent (targeted versus chemotherapy); frequency and route of administration; 5- year progression- free survival (PFS); adverse events; and risk of secondary malignancies. In total, 214 complete questionnaires were included for data analysis.  The 5- year PFS, followed by risk of secondary malignancies were the most important attributes for making treatment choices. Regarding side effects, patients chose to avoid neuropathy the most compared to nausea/vomiting and extreme fatigue. Patients preferred a fixed-duration treatment with IV/SC administration at the hospital over a continuous daily oral regimen at home. These are the first systematic data obtained on WM patient preferences for treatment.

Bing-Neel Syndrome, a Rare Presentation of Waldenström Macroglobulinemia—A Multicenter Report by the Polish Lymphoma Research Group. Drozd-Sokołowska J, Waszczuk-Gajda A, Witkowska M, Sienkiewicz E, Kopińska A, Kołkowska-Leśniak A, Barankiewicz J, Długosz-Danecka M, Smolewski P, Helbig G, Lech-Marańda E, Jurczak W, Biecek P, Giebel S, Wiktor-Jędrzejczak W, Basak G.  Journal of Clinical Medicine. 2022; 11(15):4447. https://doi.org/10.3390/jcm11154447 These Polish authors performed a multicenter retrospective analysis of BNS patients diagnosed and treated in centers aligned with the Polish Lymphoma Research Group. Eleven patients were included, 55% females and the median age at BNS diagnosis was 61 years. The median time from WM to BNS was 3.5 years; 27% of patients did have a diagnosis of WM and BNS made simultaneously or within 30 days from each other. Isolated parenchymal involvement was the least frequent (20%). Patients were treated with different regimens, mostly able to cross the blood-brain barrier, including 18% treated with ibrutinib first line therapy. The cumulative objective response to treatment was 73%. With the median follow-up of 20 months, the 36-month estimates were: overall survival (OS) 47%, progression-free survival (PFS) 33%, and cumulative incidence of BNS-associated death 41%. The performance status according to ECOG was significant for PFS (HR = 7.79) and the hemoglobin concentration below 11 g/dL was correlated with PFS. They concluded that BNS is a very rare manifestation of WM and it is associated with a poor outcome with most patients succumbing to BNS.

Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IGM monoclonal gammopathy of undetermined significance and smoldering Waldenstrom macroglobulinemia. Moreno, DF, López-Guerra, M, Paz, S, Oliver-Caldés, A, Mena, M-P, Correa, JG, et al. Br J Haematol. 2022; 00: 1– 10. https://doi.org/10.1111/bjh.18502 These researchers from Barcelona, Spain show that MYD88 and CXCR4 mutations can be analyzed by droplet digital PCR with high sensitivity, making them excellent disease biomarkers for asymptomatic IgM-MGUS in the clinic. The main advantages of droplet digital PCR are that it can be applied in almost any academic center, due to its easy setup, and that it avoids the need of sample sorting, making it an excellent candidate to replace standard AS-PCR for MYD88 mutation analysis. They also show that MYD88 testing in cell free DNA is a promising tool that might overcome diagnostic challenges. They also propose the first genomic risk classification of asymptomatic IgM monoclonal gammopathies using novel techniques.

Using biology to determine type and duration of treatment in Waldenstrom macroglobulinemia. Castillo JJ. Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S87-S88. doi: 10.1016/S2152-2650(22)00675-9Castillo reviews the  biology of WM (MYD88 and CXCR4 mutations) and three genomic profiles of  patients with WM to help tailor treatment options for these patients.  He cites the seminal phase II study evaluating ibrutinib in 63 patients with previously treated WM and the randomized INNOVATE study of 150 patients with previously treated and treatment naïve WM who were randomized to ibrutinib plus rituximab and placebo plus rituximab.

Plamotamab (XmAb 13676) for ibrutinib-refractory CXCR4-mutated extramedullary Waldenstrom macroglobulinemia.  Parrondo RD, Paulus A, Alegria V, Liebowitz D, Johnson C, Clynes R, Roy V, Menke DM, Jiang L, Chanan-Khan AA, Ailawadhi S. Leuk Lymphoma. 2022 Mar;63(3):738-742. https://doi.org/10.1080/10428194.2021.2005045 . Epub 2021 Nov 16. In this letter to the editor, the authors based at Mayo describe a case study of a 54 year old female with relapsed, ibrutinib refractory, CXCR4 mutated, extramedullary WM treated with bispecific antibodies, XmAB 13676, who achieved a minor hematologic response (MR) and near-complete resolution of extramedullary tumors after 4 cycles of therapy but ultimately relapsed after 7.5 cycles due to the emergence of CD20-negative WM.

New treatment strategies for Waldenstrom macroglobulinemia. Moreno DF, Fernandez de Larrea C, Castillo JJ.  Clinical Advances in Hematology & Oncology, August 2022, Vol 20, No. 8. MYD88 L265P and CXCR4 nonsense and frameshift mutations are the most common recurrent variants observed in patients who have WM, with detection rates of 90% and 40%, respectively. Knowing about these mutations has made it possible to develop agents that target the underlying signaling pathways. In this review, the authors describe the various treatment strategies for WM and detail the genotype of the malignant WM cell.

Bleeding propensity in Waldenstrom macroglobulinemia: Potential causes and evaluation.
Brysland SA, Maqbool MG, Talaulikar D, Gardiner EE. Thromb Haemost 2022. https://doi.org/10.1055/a-1896-7092  In this review, the authors detail the evidence for various contributing factors to the bleeding phenotype in WM and focus on current and emerging diagnostic tools that will aid evaluation and management of bleeding in patients with WM.

Concurrent Waldenstrom’s Macroglobulinemia and Myelodysplastic Syndrome with a Sequent t(10;13) (p13;q22) Translocation. DeRosa PA, Roche KC, Nava VE, Singh S, Liu M-L, Agarwal A. Current Oncology. 2022; 29(7):4587-4592. https://doi.org/10.3390/curroncol29070363 The authors present a case of concurrent myelodysplastic syndrome (MDS) and Waldenstrom macroglobulinemia (WM) with several somatic mutations and a novel balanced reciprocal translocation between 10 and 13. Despite a myeloid origin, MDS can sometimes lead to decreased production, abnormal apoptosis or dysmaturation of B cells, and the development of lymphoma.

Cutaneous manifestations of monoclonal gammopathy. Claveau, JS., Wetter, D.A. & Kumar, S. Blood Cancer J. 12, 58 (2022). https://doi.org/10.1038/s41408-022-00661-1 Monoclonal gammopathy associated with dermatological manifestations are a well-recognized complication. These skin disorders can be associated with infiltration and proliferation of a malignant plasma cells or by a deposition of the monoclonal immunoglobulin in a nonmalignant monoclonal gammopathy. These disorders include POEMS syndrome, light chain amyloidosis, Schnitzler syndrome, scleromyxedema and TEMPI syndrome. This article provides a review of clinical manifestations, diagnostics criteria, natural evolution, pathogenesis, and treatment of these cutaneous manifestations.

An extended prognostic index of the ISSWM score based on thyroid complications in Waldenstrom macroglobulinemia/lymphoplasmacytoid lymphoma.  Xinting H, Hua W, Dai Y, Huiting Q, Ying L, Na W, Xianghua W, Xin L, Hongzhi X, Ya Z, Xin W.  Front Oncol. May 2022 https://www.frontiersin.org/article/10.3389/fonc.2022.870258  This research group from China explored the prognostic significance of thyroid complications in WM/LPL. They found that 13.3% of WM/LPL patients were diagnosed with thyroid complications, which were significantly associated with unfavorable progression-free survival (PFS), overall survival (OS), and adverse treatment response. Furthermore, the presence of thyroid complications was identified as an independent prognostic indicator for PFS in WM/LPL. Incorporating the ISSWM score with thyroid complications was superior to ISSWM alone in risk stratification and prognostic prediction. Subgroup analyses of WM/LPL patients revealed that subclinical hypothyroidism predicted undesirable outcomes at the early stage.

A pilot study on dasatinib in patients with Waldenstrom macroglobulinemia progressing on ibrutinib. Castillo JJ, Sarsiek S, Flynn CA, Leventoff C, Little M, White T, Meid K, Treon SP. eJHaem. 2022;1-3.  https://doi.org/10.1002/jha2.493 The hematopoietic cell kinase (HCK) regulates BTK activation and represents a potential therapeutic target in Waldenstrom macroglobulinemia (WM). This group from Dana-Farber Cancer Institute investigated dasatinib, a potent HCK inhibitor, in patients with WM progressing on ibrutinib. Study treatment consisted of dasatinib administered at 100 mg by mouth once daily in four-week cycles for up to 24 cycles. Three participants were enrolled and received at least one cycle of dasatinib. The best response was stable disease. Two patients received 5 months and one patient received 1 month of therapy. The dose of dasatinib was decreased in one participant due to volume overload. Based on the lack of responses observed, the study was terminated. Dasatinib might not be effective in patients with WM progressing on ibrutinib.

A case of Bing-Neel syndrome successfully treated with tirabrutinib. Oyama T, Taoka K, Chiba A, Matsuda K, Maki H, Masamoto Y, Kurokawa M. Internal Medicine, The Japanese Society of Internal Medicine. https://www.jstage.jst.go.jp/article/internalmedicine/advpub/0/advpub_9545-22/_pdf These Japanese authors report a 62-year-old man with WM in relapse who was then diagnosed with Bing-Neel syndrome who developed Bing Neel syndrome and was treated with tirabrutinib 480 mg daily. Within three months, he showed clinical and radiographic improvement.

Body mass index associated with monoclonal gammopathy of undetermined significance (MGUS) progression in Olmstead County, Minnesota. Kleinstern, G., Larson, D.R., Allmer, C. et al. Blood Cancer J. 12, 67 (2022). https://doi.org/10.1038/s41408-022-00659-9  Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder that progresses to plasma-cell/lymphoid disorders, such as WM. This research group from Mayo Clinic evaluated the contribution of body mass index (BMI) to MGUS progression beyond clinical prognostic factors in a population-based study and examined differential associations by sex. They found that a BMI < 25, non-IgG MGUS, high monoclonal (M) protein, and abnormal free light chain ratio (FLC) were associated with an increased risk of MGUS progression. The BMI association was stronger among females vs. males, although the interaction between BMI and sex was not significant.

Zanubrutinib in treating Waldenstrom macroglobulinemia, the last shall be the first. Deshpande A, Munoz J. Therapeutics and Clinical Risk Management 2022:18;657-668 https://doi.org/10.2147/TCRM.S338655  The authors, from Mayo Clinic, discuss the available data regarding the use of zanubrutinib, as well as other therapies, in WM. Within the therapeutic landscape of WM, BTK inhibitors have emerged as greatly effective therapies. The first BTK inhibitor used in WM was ibrutinib; however, this treatment as a single agent displayed reduced efficacy in patients with the CXCR4 mutation. Additionally, ibrutinib was associated with many adverse events that led to drug dose reduction or discontinuation. Subsequently, the newer, highly specific BTKi zanubrutinib emerged. This drug showed efficacy in treating WM, regardless of CXCR4 mutation status, with a favorable toxicity profile. Randomized trials comparing zanubrutinib directly to ibrutinib in B-cell lymphoproliferative disorders such as CLL or WM showed that zanubrutinib conferred fewer toxicities and greater tolerability. Thus, the last of this drug class to become FDA approved in B-cell lymphoproliferative disorders, zanubrutinib, rises as a major player for the treatment of WM. 

Waldenstrom’s macroglobulinemia: Tailoring therapy for the individual.  Gertz MA, J Clin Oncol 2022  https://doi.org/10. 1200/JCO.22.00495  Because of the lack of large prospective trials comparing different classes of therapy, a uniform recommendation applicable to all patients cannot be made, and the approach must be individualized incorporating patient preferences, comorbidities, and the range of therapeutic toxicities. Therapeutic options for patients with newly diagnosed and previously treated macroglobulinemia are presented on the basis of the best available evidence in the literature. This Mayo Clinic hematologist/oncologist also reviews phase II and III treatment trials over the past 20 years and high-quality trials are summarized.

Treatment paradigm in Waldenstrom macroglobulinemia: frontline therapy and beyond. Zanwar S, Abeykoon JP. Ther Adv Hematol 2022, 13:1-16. https://doi.org/10.1177/20406207221093962  In this review, the authors from Mayo Clinic, discuss the role of MYD88L265P mutation and CXCR4 mutation in treatment selection and current data for frontline and salvage treatment options in patients with WM.

Monoclonal antibody-based therapies for Waldenstrom macroglobulinemia. Fotiou D, Theodorakakou, F Kastritis E. Leukemia Research Reports 17 (2022) https://doi.org/10.1016/j.lrr.2022.100324  In this review from the University of Athens, the authors provide an overview of the mechanisms of action of monoclonal antibodies and discuss clinical evidence that support their use in WM and their therapeutic potential.

Response to vaccination against SARS-CoV-2 in 168 patients with Waldenstrom macroglobulinemia: A French Innovative Leukaemia Organization study. Tomowiak C, Leblond V, Laribi K, Baron M, Puppinck C, Gérard P, Courret E, Gorochov G, Sterlin D, Tournilhac O, Morel P, Cymbalista F, Roos-Weil D. The authors evaluated anti-S antibody response to anti-SARS-CoV-2 vaccination in 168 patients in France, provided information on the efficacy of a third booster dose in patients with suboptimal response after two doses of vaccines and on specific anti-SARS-CoV-2 T-cell responses. 67.5% of the patients with WM exhibited anti-SARS-CoV-2 anti-S humoral response after two vaccine doses, which increased to 75% after a third booster for seronegative patients. Ongoing BTK inhibitor treatment and anti-CD20 therapy in the last year were associated with the lowest response rates. Their results confirm the value of a third booster dose for post dose two seronegative patients, but also indicate that a fraction of patients with WM still have partial or combined impaired anti-SARS-CoV-2 humoral/T-cell responses despite a complete vaccination schedule.

Natural history of Waldenstrom macroglobulinemia following acquired resistance to ibrutinib monotherapy. Gustine JN, Sarosiek S, Flynn CA, Meid K, Leventoff C, White T, Guerrera ML, Xu L, Kofides A, Tsakmaklis N, Munshi M, Demos M, Patterson CJ, Liu X, Yang G, Hunter ZR, Branagan AR, Treon SP, Castillo JJ. Haematologica 2021;107(5):1163-1171; https://doi.org/10.3324/haematol.2021.279112. This group of researchers from Dana-Farber Cancer Institute evaluated the natural history and treatment outcomes in 51 patients with WM with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years. Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days. The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months. Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease and salvage therapy ≤7 days after discontinuing ibrutinib were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44%. Response to salvage therapy was associated with better OS after ibrutinib. TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.

Zanubrutinib for the treatment of adults with Waldenstrom macroglobulinemia. Sarosiek S, Sermer D, Branagan AR, Treon SP, Castillo JJ. 2022 Expert Review of Anticancer Therapy, DOI:10.1080/14737140.2022.2064849 In this review, the authors review the pivotal studies that have formed the foundation for the use of zanubrutinib in WM, including safety and efficacy data from prospective clinical trials of the currently available BTK inhibitors. They conclude that BTK inhibitors are very effective in WM and have an overall response rate higher than 90%. The side effect profile of these medications is manageable, but does include a risk of atrial fibrillation, infection, and bleeding. The newer BTK inhibitors, such as acalabrutinib and zanubrutinib, are known to have less off-target effects and are potential treatment options. BTK inhibitors should be considered as a treatment option in treatment-naïve and previously treated disease depending on the individual patient preferences, comorbidities, and molecular profile.

Two-year outcomes of tirabrutinib monotherapy in Waldenstrom’s macroglobulinemia. Sekiguchi N, Rai S, Munakata W, Suzuki K, Handa H, Shibayama H, Endo T, Terui Y, Iwaki N, Fukuhara N, Tatetsu H, Iida S, Ishikawa T, Iguchi D, Izutsu K. Cancer Sci. 2022 Mar 25. doi:10.1111/cas.15344 Epub ahead of print. This Japanese phase II study of tirabrutinib monotherapy for treatment naïve and relapsed Waldenstrom’s macroglobulinemia demonstrated a promising efficacy and tolerable safety profile after 24.8 months for 22 patients who are still enrolled in the study. The progression-free and overall survival rates at 24 months were 92.6% and 100%, respectively.

Targeted therapies and emerging novel treatment approaches for Waldenstrom Macroglobulinemia. Sermer D, Sarosiek S,. Branagan AR, Treon SP, Castillo JJ. Clinical Lymphoma, Myeloma and Leukemia (2022), doi: https://doi.org/10.1016/j.clml.2022.02.005 Standard treatment regimens combine the anti-CD20 antibody rituximab with alkylating agents (e.g. bendamustine, cyclophosphamide), nucleoside analogs (e.g. fludarabine, cladribine), or proteasome inhibitors (e.g. bortezomib, carfilzomib, and ixazomib). Covalent BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib) have shown to be safe and highly effective in patients with WM. Novel and promising agents in this disease include next-generation covalent BTK inhibitors (e.g. tirabrutinib, orelabrutinib), non-covalent BTK inhibitors (e.g. pirtobrutinib, ARQ531), BCL-2 antagonists (e,g. venetoclax), and CXCR4-targeted agents (e.g. mavorixafor, ulocuplumab), among others. Future studies will focus on developing fixed-duration combinations regimens with these novel agents aimed at increasing durable responses while minimizing toxicity and cost.

Mast cell density and its clinical relevance in Waldenstrom’s macroglobulinemia. Lemal R, Poulain S, Ledoux-Pilon A, Veronese L, Tchirkov A, Lebecque B, et al. eJHaem. 2022;1–8. https://doi.org/10.1002/jha2.378 High mast cell density is associated with aggressive features and a poor clinical outcome, emphasizing the need for further investigation of the involvement of mast cells in the pathophysiology of WM.

Utility of Bruton’s tyrosine kinase inhibitors in light chain amyloidosis caused by lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinemia). Bou Zerdan M, Valent J, Diacovo MJ, Theil K, Chaulagain CP. Adv Hematol. 2022 Jan 19;2022:1182384. http://doi.org/10.1155/2022/1182384

The authors retrospectively evaluated the tolerability and effectiveness of BTK inhibitors ibrutinib and acalabrutinib therapy in 4 patients with IgM-related AL amyloidosis with underlying WM. Treatment was well tolerated with both hematologic and organ response in patients with AL amyloidosis in the setting of WM. Atrial fibrillation led to the discontinuation of ibrutinib in one patient, and acalabrutinib caused significant thumb hematoma needing dose reduction in another patient. All patients evaluated had the MYD88 mutation. This may explain the good response to BTK inhibitors therapy in our series. The authors conclude that BTK inhibitors should be further investigated in larger prospective studies for treatment of AL amyloidosis in patients with lymphoplasmacytic lymphoma/WM.

Determinants of drug resistance in B cell non-Hodgkin lymphomas: the case of lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia. Piazza F, Di Paolo V, Scapinello G, Manni S, Trentin L and Quintieri L (2022) Front. Oncol. 11:801124. http s://doi.org/10.3389/fonc.2021.801124 In this review, the authors describe the essential clinical and pathobiological features of WM. They analyzed key aspects about the current knowledge on the mechanisms of drug resistance in WM by concisely focusing on conventional drugs, monoclonal antibodies, and novel agents, chiefly BTK-inhibitors.

Preneoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma. Rodriguez S, Celay J, Golcoechea I, et al. Sci Adv. 2022 Jan 21;8(3):eabl4644. https://doi.org/10.1126/sciadv.abl4644 The authors uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model LPL in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88L265P is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.

Guidelines on the diagnosis and management of Waldenstrom macroglobulinemia – A British Society for Haematology guideline. Pratt G, El-Sharkawi R, Kothari J, D’Sa S, Auer R, McCarthy H, Krishna R, Miles O, Kyriakou C, Owen R. e. Br J Haematol. 2022;00:1– 17. https://doi.org/10.1111/bjh.18036 The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with WM.

Response and survival predictors in a cohort of 319 patients with Waldenstrom macroglobulinemia treated with ibrutinib monotherapy. Castillo JJ, Sarosiek SR, Gustine JN, Flynn CA, Leventoff CR, White TP, Meid K, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Hunter ZR, Patterson CJ, Branagan AR, Treon SP; Blood Adv 2022; 6 (3): 1015–1024. doi: https://doi.org/10.1182/bloodadvances.2021006106 In this study, the authors evaluate factors predictive of response and prognostic of survival in WM patients treated with ibrutinib monotherapy. CXCR4 mutations are associated with lower rates of major (67% vs 86%) and deep responses (16% vs 35%) in ibrutinib-treated WM patients. CXCR4 mutations and platelet count 100 K/uL or less were associated with worse progression free survival (PFS) and a scoring system using these 2 factors is proposed.

CD19- directed chimeric antigen receptor T cell therapy in Waldenstrom macroglobulinemia:  a preclinical model and initial clinical experience.  Palomba ML, Qualls D, Monette S, Sethi S, Dogan A, Roshal M, Senechal B, Wang X, Riviere I, Sadelain M, Brentjens RJ, Park JH, Smith EL. Journal for ImmunTherapy of Cancer 2022;10:e004128.  https://doi.org/10.1136/jitc-2021-004128 This study summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.

Current approach to Waldenstrom Macroglobulinemia. Ravi G, Kapoor P. Cancer Treatment and Research Communications, 31, 2022, 100527.  https://doi.org/10.1016/j.ctarc.2022.100527. This review summarizes the current literature pertaining to the diagnosis, prognosis, and the treatment of WM.

The Rory Morrison Registry. Second United Kingdom Waldenstrom’s Macroglobulinemia Registry Report 2021. This registry was named after the beloved BBC presenter and WM patient, Rory Morrison. The first registry report was published in 2018. This second report provides updated data and further insights on diagnosis, treatment, and outlook for people living with WM.

MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis. Yu X, Li W, Deng Q, Liu H, Wang X, Hu H, Cao Y, Xu-Monette ZY, Li L, Zhang M, Lu Z, Young KH, Li Y. Blood March 2021 https://doi.org/10.1182/blood.2020004918 Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from Toll-like and interleukin receptors to downstream nuclear factor-κB (NF-κB). MYD88L265P (leucine changed to proline at position 265) is a gain-of-function mutation that occurs frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. In this study, E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked nonproteolytic polyubiquitination of MYD88L265P, resulting in enhanced recruitment of interleukin-1 receptor–associated kinases and elevated NF-κB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P did not constitutively activate NF-κB. A20, a negative regulator of NF-κB signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88L265P-mediated NF-κB activation and lymphoma growth. Furthermore, A20 expression correlated negatively with RNF138 expression and NF-κB activation in lymphomas with MYD88L265P and in those without. Strikingly, RNF138 expression correlated positively with NF-κB activation in lymphomas with MYD88L265P, but not in those without it. Our study revealed a novel mutation-specific biochemical reaction that drives B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88L265P, while sparing MYD88WT, which is critical to innate immunity. This work was supported by the International Waldenstrom’s Macroglobulinemia Foundation through a grant to Dr. Li.

Venetoclax in Previously Treated Waldenstrom Macroglobulinemia. Castillo JJ, Allan JN, Siddiqi T, Advani RH, Meid K, Leventoff C, White TP, Flynn CA, Sarosiek S, Branagan AR, Demos MG, Guerrera ML, Kofies A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Patterson CJ, Hunter ZR, Davids MS, Furman RR, Treon SP. J of Clinical Oncology 2021, DOI: https://doi. org/10.1200/JCO.21. 01194 The findings in this study establish venetoclax as an active and tolerable therapy in patients with previously treated WM, regardless of previous exposure to BTKis. CXCR4 mutation status did not affect treatment response. Given the manageable safety profile, future studies evaluating venetoclax in combination with anti-CD20 monoclonal antibodies or BTKis are warranted.

Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database. Allouchery M, Tomowiak C, Lombard T, Pérault-Pochat MC, Salvo F., Frontiers in Pharmacology 2021 https://doi.org/10.3389/fphar.2021.769315 The aim of the study was to characterize the safety profile of ibrutinib through the identification of potential safety signals in a large-scale pharmacovigilance database (WHO). The potential safety signals that emerged in ibrutinib-treated patients were mainly ischemic heart diseases, pericarditis, uveitis, retinal disorders, and fractures.

Assessment of fixed-duration therapies for treatment-naive Waldenstrom macroglobulinemia. Abeykoon JP, Zanwar S, Ansell SM, Muchtar E, He R, Greipp PT, King RL, Ailawadhi S, Paludo J, Larsen JT, Habermann TM, Inwards D, GO RS, Thanarajasingam G, Buadi F Dispenzieri A, Thampson CA, Witzig TE, Lacy M, Gonsalves W, Nowakowski GS, Dingli D, Rajkumar SV, Kyle RA, Sher T, Roy V, Rosenthal A, Chanan-Khan Aa, Reeder C, Gertz MA, Kumar S, Kapoor P. Am J Hematol. 2021:96:945-953 https://doi.org/10.1002/ajh.26210
The authors evaluated three commonly used rituximab-based frontline regimens: rituximab-bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment-naive patients with WM, seen at Mayo Clinic. Although the three regimens that were studied are effective, irrespective of the MYD88L265P mutation status, their data supported the use of R-Benda as primary therapy, considering the superior outcomes (major response rate, superior progression free survival, time to next treatment and event free survival) observed with this regimen in comparison to frontline DRC or BDR in patients with WM. Although the quality-of-life data were unavailable, they speculated that the longer duration of response with R-Benda is likely to be associated with improved quality of life following completion of therapy. Notably, the clinically relevant endpoints were not significantly different in patients who received DRC compared to BDR in the frontline setting and the toxicity profiles across the three groups were comparable, barring a higher incidence of neutropenia and neuropathy in patients who received R-Benda and BDR regimens, respectively. Given the indolent course and incurability of WM with the current regimens, it is not surprising to observe similar overall survival rates among the three cohorts with the current follow-up.

Conditional relative survival in Waldenstrom’s macroglobulinemia: a population-based study in The Netherlands. Amaador, K., Kersten, M.J., Visser, O., Posthuma, E.F.M., Minnema, M.C., Vos, J.M.I. and Dinmohamed, A.G. (2021), Br J Haematol. https://doi.org/10.1111/bjh.17926 Contemporary diagnosed WM patients, compared to the general population, continue to experience excess mortality regardless of having survived up to 15 years post-diagnosis. This gradual increase in excess mortality might result from the incurable nature of this disease characterized by multiple relapses throughout the disease course with limited efficacious treatment options in the released/refractory setting.

Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies. Tam CS, Dimopoulos MA, Garcia-Sanz R, Trotman J, Opat S, Roberts AW, Owen RG, Song Y, Xu W, Zhu J, Li J, Qiu L, D’Sa S, Jurczak W, Cull G, Marlton P, Gottlieb DJ, Munoz J, Phillips T, Du C, Ji M, Zhou L, Guo H, Zhu H, Chan WY, Cohen A, Novotny W, Huang J, Tedeschi A. Blood Adv. 2021 Nov 1:bloodadvances.2021005621. DOI: 10.1182/bloodadvances.2021005621 Epub ahead of print. PMID: 34724705. The authors from multiple institutions conducted a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N=779). Most patients had Waldenstrom macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough, pneumonia (21% each), urinary tract infection (UTI), fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events (AEs) included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%). Treatment discontinuations and dose reductions for AEs occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n=9), sepsis (n=4), unspecified cause (n=4), and multiple organ dysfunction syndrome (n=5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.

Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia. Castillo, J.J., Meid, K., Gustine, J.N. et al. Leukemia (2021). https://doi.org/10.1038/s41375-021-01417-9 Findings from Dana Farber Cancer Institute show that ibrutinib monotherapy is highly active with long-term disease control in treatment-naive patients with WM. While ibrutinib responses were affected by CXCR4 mutations, long-term disease control was attained regardless of CXCR4 mutational status. Furthermore, treatment was well tolerated, with no unexpected toxicities. The findings further establish ibrutinib as one of the most active agents in WM. Prospective, randomized studies against other commonly used treatment options, such as bendamustine and rituximab, other BTK inhibitors, and combinations with CXCR4 or BCL2 inhibitors, are needed to further define the optimal use of ibrutinib in patients with WM. The authors gratefully acknowledge the generous support of the David and Janet Bingham Research Fund of the International Waldenstrom’s Macroglobulinemia Foundation, the Yang Family Research Fund of the International Waldenstrom’s Macroglobulinemia Foundation.

The HCK/BTK inhibitor KIN-8194 is active in MYD88 driven lymphomas and overcomes mutated BTK^Cys481 ibrutinib resistance. Yang G, Wang J, Tan L, Munshi M, Liu X, Kofides A, Chen JG, Tsakmaklis N, Demos M, Guerrera ML, Xu L, Hunter ZR, Che J, Patterson CJ, Meid KE, Castillo J, Munshi NC, Anderson KC, Cameron M, Buhrlage S, Gray NSS, Treon SP, Blood  June2021; blood.2021011405. doi: https://doi.org/10.1182/blood.2021011405 This group from Dana Farber Cancer Institute performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88 mutated lymphoma cells, including ibrutinib resistant BTK^Cys481Ser expressing cells. KIN-8194 overcomes ibrutinib resistance with a survival benefit in TMD-8 ABC DLBCL xenografted mice and synergizes with venetoclax. These findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK. This research was supported in part by the IWMF through a Legacy grant to Dr. Treon.

Clinical Application of genomics in Waldenstrom macroglobulinemia. Branagan AR, Lei M, Treon SP, Castillo JJ. (2021) Leukemia & Lymphoma https://doi.org/10.1080/10428194.2021.1881514 The discovery of the highly recurrent somatic mutations in the MYD88 gene detected in 90–95% and the CXCR4 gene detected in 30–40% of WM patients has provided an opportunity to develop novel targeted approaches. Mutational status has important implications in predicting response to therapies such as BTK inhibitors. Treatment of WM should be guided by many factors including performance status, comorbidities, goals of therapy, and toxicities. In this review, the authors describe how current genomics may be utilized to optimize WM treatment selection. As the therapeutic landscape of WM continues to expand with more targeted approaches, the genomics in WM will likely play a greater role in individualizing treatment.

Screening and identification of a novel FHL2 mutation by whole exome sequencing in twins with familial Waldenstrom macroglobulinemia. Wan, Y, Cheng, Y, Liu, Y, Shen, L, Hou, J. Cancer. 2021. https://doi.org/10.1002/cncr.33454 The authors performed whole exome sequencing (WES) of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Among the 10 shared candidate mutations in the twins, the authors identified a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) as a familial WM–associated mutation. FHL2 appeared to be connected with reported signaling pathways and disease-driving genes such as IL6 and HCK in WM. In addition, the authors found reduced FHL2 messenger RNA and protein expression in peripheral blood samples from the patient with WM in comparison with the healthy siblings. Taken together, these findings indicate that an FHL2g226a mutation may play an important role in familial WM, and they provide new screening possibilities for familial cases.

Plasmablastic lymphoma transformation in a patient with Waldenstrom Macroglobulinemia treated with ibrutinib. Castillo, J.J., LaMacchia, J., Flynn, C.A., Sarosiek, S., Pozdnyakova, O. and Treon, S.P. (2021). Br J Haematol. https://doi.org/10.1111/bjh.17759 The authors present a case report of a 67-year-old female with WM who was on watch and wait until age 83 years. A diagnosis of plasmablastic lymphoma was made and the patient received treatment with bortezomib plus CHOP, then CHOP alone.

Current and emerging treatments for Waldenstrom macroglobulinemia. Grimont CN, Castillo Almeida NE, Gertz MA March 2021 Acta Haematol 2021;144:146–157 https://doi.org/10.1159/000509286 Some patients with WM have a smoldering form that may be surveilled without intervention. For patients requiring treatment, Benda-R therapy can be considered the first-line treatment. Other chemoimmunotherapy combinations with DRC and BR provide effective and durable responses, but are limited by drug-specific toxicities. The success of ibrutinib in WM may change the current management of WM. Moreover, the recent and promising advances in the understanding of WM biology may expand future initial treatment options.

Tailoring therapy in Waldenstrom macroglobulinemia. Castillo JJ. Clinical Lymphoma, Myeloma, and Leukemia 2021 https://doi.org/10.1016/S2152-2650(21)01210-6 The rarity of WM limits the ability to perform large randomized clinical trials comparing treatment regimens. Prospective single-arm studies, however, have led to the development of effective therapies. The choice of treatment should consider patient-specific characteristics and anticipated toxicities, as well as patient and provider preference. Additionally, MYD88 and CXCR4 mutations are known to affect treatment response and progression-free survival.

Combining ixazomib with subcutaneous rituximab and dexamethasone in relapsed or refractory Waldenstrom macroglobulinemia: final analysis of the phase I/II HOVON124/ECWM-R2 study. Kersten MJ, Amaador K, Minnema MC, Vos JMI, Nasserinejad K, Kap M, Kastritis E, Gavriatopoulou M, Kraan W, Chamuleau MED, Deeren D, Tick LW, Doorduijn JK, Offner F, Böhmer LH, Liu RD, Pals ST, Dimopoulos MA. 2021 J Clin Oncol. Epub ahead of print. DOI:10.1200/JCO.21.00105 The authors conducted a European multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD) in patients with relapsed or refractory WM. Treatment with IRD achieved a major response rate of 51% including 14% very good partial response (PR) and 37% PR, which improved until month 12 to a major response rate of 61% with 15% very good PR and 46% PR with manageable toxicity. Use of subcutaneous rituximab did not result in infusion-related reactions or immunoglobulin M flare. Median progression-free survival and overall survival were not reached, and after median follow-up of 24 months, progression-free survival and overall survival were 56% and 88%, respectively. This phase I/II clinical trial demonstrates that the IRD regimen, with oral ixazomib and subcutaneous rituximab, provides an effective and well-tolerated treatment in patients with heavily pretreated WM.

Cytogenetic and molecular abnormalities in Waldenstrom’s macroglobulinemia patients: correlations and prognostic impact. Krzisch D, Guedes N, Boccon-Gibod C, Baron M, Bravetti C, Davi F, Armand M, Smagghe L, Caron J, Bernard OA, Susin S, Chapiro E, Leblond V, Nguyen-Khac F, Roos-Weil D, FILO (French Innovative Leukemia Organization) group. Am J Hematol. 2021 Aug 31. doi: 10.1002/ajh.26339. To investigate the clinical impact of genetic alterations in WM, this group from France evaluated cytogenetic and molecular abnormalities by chromosome banding analyses (CBA), FISH and targeted NGS in a retrospective cohort of WM patients, including patients treated by first-line chemotherapy or immunochemotherapy. Most frequent mutations were identified in MYD88 (93%), CXCR4 (29%), MLL2 (11%), ARID1A (8%), TP53 (8%), CD79A/B (6%), TBL1XR1 (4%) and SPI1 (4%). The median number of cytogenetic abnormalities was two. Main cytogenetic abnormalities were 6q deletion (del6q) (27%), trisomy 4 (tri4) (12%), tri18 (11%), del13q (11%), tri12 (7.5%) and del17p (7%). Fifty-three percent of patients with hyperviscosity harbored CXCR4 mutations.

Extramedullary Waldenstrom macroglobulinemia presenting as a subcutaneous penile mass. Palmer CJ, Sahagun J, David AG, Taylor CW, Al-Shraideh Y. September 2021 Cureus 13(9): e17809. doi:10.7759/cureus.17809. The authors present a case report of a 65-year-old male with a history of WM previously in remission who complained of a painless subcutaneous bump on the base of the penis that was confirmed as a recurrence of WM.

Aberrant extrafollicular B cells, immune dysfunction, myeloid inflammation and MyD88-mutant progenitors precede malignancy in Waldenstrom macroglobulinemia. Kaushal, A., Nooka AK, Carr AR, Pendleton KE, Barwick BG, Manalo J, McCachren SS, Gupta VA, Joseph NS, Hofmeister CC, Kaufman JL, Heffner LT, Ansell SM, Boise LH, Lonial S, Dhodapkar KM, Dhodapkar MV. (2021) Blood Cancer Discovery. doi.org/10.1158/2643-3230.BCD-21-0043. These researchers from Emory University examined individual cells with a combination of high-dimensional approaches and genome sequencing of subpopulations. They showed that WM and its precursor, IgM gammopathy originate in the backdrop of several alterations in non-cancer cells as well as MYD88 mutations in blood progenitors. These alterations include inflammation in the bone marrow, as well as depletion of naïve B and T cells, and instead, an increase in a distinct type of B cells called extrafollicular B cells. This work was supported in part by funds from the International Waldenstrom’s Macroglobulinemia Foundation.

Waldenstrom’s macroglobulinemia: an exploration into the pathology and diagnosis of a complex B-cell malignancy. Askari E, Rodriguez S, Garcia-Sanz R, 2021 Journal of Blood Medicine 2021;12:795-807 https://doi.org/10.2147/JBM.S267938 This group from Spain review their considerations in making the diagnosis of WM with an emphasis on the presence of somatic mutations and how these mutations can modulate the response to new treatments with Bruton’s tyrosine kinase inhibitors.

Watch and wait in Waldenstrom macroglobulinemia: looking for who to watch carefully and who can wait without worrying. Is it that simple? Durot E., Delmer A. (2021) Br J Haematol. https://doi.org/10.1111/bjh.17699 In this commentary to the previous Zanwar paper, the authors commend Zanwar et al. for their long patient follow-up and for distinguishing between IgM MUS and smoldering WM (SWM). They suggest that further studies on SWM should report quality of life outcomes, not just treatment initiation.

Disease outcomes and Biomarkers of progression in smoldering Waldenstrom macroglobulinemia. Zanwar, S., Abeykoon, J.P., Ansell, S.M., Gertz, M.A., Colby, C., Larson, D., Paludo, J., He, R., Warsame, R., Greipp, P.T., King, R.L., Thompson, C.A., Witzig, T.E., Lacy, M.Q., Gonsalves, W., Nowakowski, G.S., Dingli, D., Go, R.S., Habermann, T.M., Vincent Rajkumar, S., Kyle, R.A., Kumar, S. and Kapoor, P. (2021), Br J Haematol. https://doi.org/10.1111/bjh.17691 This study from Mayo Clinic evaluated 143 patients with smoldering WM (SWM) and a follow-up of 9.5 years. The cumulative rate of progression to active WM was 11% at 1 year, 38% at 3 years, and 55% at 5 years. Hemoglobin counts of <123 g/l and β2-microglobulin >2.7µg/ml were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with MYD88 wild type genotype demonstrated a trend towards shorter TTP 1.7 vs. 4.7 years for the MYD88L265P cohort. The presence of CXCR4 mutation did not impact the TTP 3 vs.5.6 years in wild type vs. mutation. The overall survival for patients with SWM (median 18.1 years) was comparable to an age-, sex-, and calendar year-matched USA population (median 20.3 years). This argues against pre-emptive intervention in this patient population.

Novel agents for Waldenstrom macroglobulinemia. Castillo JJ. Clinical Lymphoma, Myeloma, and Leukemia. Vol 21, supplement 1, 2021, pp S34-S35, https://doi.org/10.1016/S2152-2650(21)01200-3. The BTK inhibitor, ibrutinb is one of the most effective agents in WM. Three novel BTK inhibitors are under active investigation for WM: zanubrutinib, acalabrutinib, and tirabrutinib. Many patients with WM will develop BTK mutations with subsequent resistance to covalent BTK inhibitors. The non-covalent BTK inhibitor pirtobrutinib has been evaluated, as has the BCL2 antagonist venetoclax in previously treated WM. A study evaluating the combination of ibrutinib and venetoclax in treatment naïve patients with WM is ongoing. CXCR4, PI3K, CD38 and HCK are additional targets of interest in WM. The CXCR4 inhibitor mavorixafor is being evaluated in combination with ibrutinib in WM patients who carry CXCR4 mutations. The PI3K inhibitor idelalisib show early efficacy in patients with WM but it seems to be associated with a high rate of liver toxicity. A multicenter study evaluating umbralisib in patients with WM has stopped accrual. The anti-CD38 monoclonal antibody daratumumab had a lower-than-expected efficacy rate in WM. Dasatanib is an HCK inhibitor being studied in patients with WM progressing on covalent BTK inhibitors. The phospholipid-drug conjugate CLR-131 was recently granted a Fast-Track Designation for WM patients having received two or more prior treatment regimens.

How to sequence therapies in Waldenstrom macroglobulinemia. Sarosiek S, Treon SJ, Castillo JJ. August 2021 Curr. Treat. Options in Oncol. DOI 10.1007/s11864-021-00890-9 The choice of therapy should consider the patient’s clinical presentation, comorbidities, and preferences. A thorough discussion should take place to outline the administration, safety, and efficacy of the regimens under consideration. The patient’s genomic profile can provide insightful information for the treatment selection. In the frontline and relapsed settings, the authors from DFCI favor ibrutinib monotherapy over chemoimmunotherapy or proteasome inhibitor-based regimens in patients with MYD88 and without CXCR4 mutations. For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome inhibitor-based regimens are favored, but efficacy data with ibrutinib in combination with rituximab and with novel covalent BTK inhibitors are emerging. Autologous stem cell transplant should be considered in special cases in the relapsed setting. Participation in clinical trials is positively encouraged in WM patients in frontline and relapsed settings. Agents of interest include the BCL2 antagonist venetoclax, the CXCR4 inhibitor mavorixafor, and the noncovalent BTK inhibitors pirtobrutinib and ARQ-531.

Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4 mutated Waldenstrom macroglobulinemia. Treon SP, Meid KE, Hunter ZR, Flynn C, Sarosiek S, Leventoff C, White TP, Cao Y, Roccaro A, Sacco A, Demos M, Guerrera ML, Kofides A, Liu X, Xu L, Patterson CJ, Munshi M, Tsakmaklis N, Yang G, Ghobrial IM, Branagan AR, Castillo J. Blood 2021; blood.2021012953. doi: https://doi.org/10.1182/blood.2021012953 The CXCR4 antagonist uloculumab with ibrutinib is tolerated in CXCR4Mut WM patients with thrombocytopenia as the most frequent adverse event. The combination was associated with short time to a major response, major response attainment in all patients, and 90% two-year progression free survival. This was a first-ever study to target CXCR4Mut in WM. This research was supported in part by grants from the David and Janet Bingham Research Fund and the Yang Family Research Fund of the International Waldenstrom Macroglobulinemia Foundation.

Reducing treatment toxicity in Waldenstrom macroglobulinemia. Sarosiek, S, Treon SP, Castillo JJ. March 2021 expert Opinion on Drug Safety, https://doi.org/10.1080/14740338.2021.1897565
There are multiple highly effective treatment options for patients with WM. All these treatment options, however, can be associated with a variety of adverse events. For example, chemotherapy has been associated with the development of myeloid neoplasms, anti-CD20 monoclonal antibodies with paradoxical IgM flares and infusion reactions, proteasome inhibitors with neuropathy, and BTK inhibitors with bleeding and cardiac arrhythmias. Dose reductions, lower number of cycles and changes in route of administration are some of the tools a clinician has available for managing and minimizing toxicity. Future research will focus on improving patient safety without sacrificing the efficacy of treatment.

Plasmablastic lymphoma transformation in a patient with Waldenstrom macroglobulinemia treated with ibrutinib. Castillo, J.J., LaMacchia, J., Flynn, C.A., Sarosiek, S., Pozdnyakova, O. and Treon, S.P. (2021), Br J Haematol. https://doi.org/10.1111/bjh.17759 The authors present a unique case of transformation from Waldenstrom’s macroglobulinemia to plasmablastic lymphoma, a rare and aggressive CD20-negative lymphoma characterized by a high recurrence rate and short survival with standard regimens. The patient in this care report responded to ibrutinib therapy.

Blistering lesions associated with Waldenstrom macroglobulinemia: new insights into pathogenesis. Dermatologic Therapy. Garcovich, S., Didona, D., Simone, C.D., Stefano, V.D., Mariotti, F., Di Zenzo, G. (2021), Dermatologic Therapy e15072. https://doi.org/10.1111/dth.15072 This case report from Italy provides new insights into recurrent blistering skin lesions (vesicles) that may be found in patients with WM. The lesions are associated with lymphocytic infiltration or skin deposition of IgM antibodies.

Bruton’s tyrosine kinase Inhibitors and Cardiotoxicity: More Than Just Atrial Fibrillation. Sestier, M., Hillis, C., Fraser, G. et al. Curr Oncol Rep 23, 113 (2021). https://doi.org/10.1007/s11912-021-01102-1 This review is to summarizes the epidemiology, mechanisms, and management of cardiovascular complications of Bruton’s Tyrosine Kinase inhibitors (BTKIs). Ibrutinib increases the risk of atrial fibrillation, bleeding, and hypertension compared with non-BTKI therapies. The evidence to support an association between ibrutinib and other cardiovascular complications including ventricular tachyarrhythmias or cardiomyopathy is limited. Ibrutinib metabolism can be inhibited by some medications used to treat cardiovascular complications. The cardiovascular effects of more selective BTKIs, such as acalabrutinib, remain to be determined.

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M.Lancet. 2021 Mar 6;397(10277):892-901. DOI: 10.1016/S0140-6736(21)00224-5. Patients with previously treated B-cell malignancies (323 patients), including 26 with WM, were enrolled in a multicenter, open-label, 1/2 clinical trial of a highly selective and reversible BTK inhibitor pirtobrutinib (LOXO-305). The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of patients were, fatigue, diarrhea, and contusion. Contusions are a class effect of all BTK inhibitors reflecting on-target BTK inhibition on platelets. The most common adverse event of grade 3 or higher was neutropenia. Grade 3 atrial fibrillation or flutter was not observed. The data shows favorable safety and efficacy in multiple B-cell neoplasms, including heavily pre-treated CLL, MCL, WM, and follicular lymphoma, including patients with resistance and intolerance to previous BTK inhibitor treatment.

Cell‐free DNA analysis for detection of MYD88L265P and CXCR4S338X mutations in Waldenstrom macroglobulinemia. Demos, M.G., Hunter, Z.R., Xu, L., Tsakmaklis, N., Kofides, A., Munshi, M., Liu, X., Guerrera, M.L., Leventoff, C.R., White, T.P., Flynn, C.A., Meid, K., Patterson, C.J., Yang, G., Branagan, A.R., Sarosiek, S., Castillo, J.J., Treon, S.P. and Gustine, J.N. (2021), Am J Hematol. https://doi.org/10.1002/ajh.26184 Recent studies have demonstrated the feasibility of identifying MYD88 and CXCR4 mutations using cell-free DNA (cfDNA) from the plasma of WM patients. The authors prospectively collected matched bone marrow (BM) and peripheral blood (PB) samples from 28 consecutive WM patients. Both MYD88L265P and CXCR4S338X were identified with high sensitivity and specificity in cfDNA derived from the plasma of WM patients, including previously treated patients. The use of cfDNA represents a non-invasive, convenient, and potentially cost-effective method for genotyping patients with WM.

Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenstrom macroglobulinemia. Tomowiak C, Poulain S, Herbaux C, Perrot A, Mahé B, Morel P, Aurran T, Tournilhac O, Leprêtre S, Assaad S, Villemagne B, Casasnovas O, Nollet D, Roos-Weil D, Chevret S, Leblond V; on behalf of the FILO Group, Blood Adv 2021; 5 (9): 2438–2446. doi: https://doi.org/10.1182/bloodadvances.2020003895 the authors present the results of a phase 2 study evaluating the combination of obinutuzumab and idelalisib in relapsed/refractory (R/R) in Waldenstrom macroglobulinemia (WM). The goal was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment (2-years). The median progression-free survival was 25.4 months without significant impact of CXCR4 genotypes on responses and survivals, but a deleterious impact of TP53 mutations on survival. Twenty-six patients of the 48 patients with R/R WM who were treated with combination of obinutuzumab and idelalisib were removed from the study because of side effects; the most frequent were neutropenia (9.4%), diarrhea (8.6%), and liver toxicity (9.3%). The combination of obinutuzumab and idelalisib is effective in R/R WM with an apparent lack of impact of genotype on outcome.

WhiMSICAL: A global Waldenstrom’s macroglobulinemia patient-derived data registry capturing treatment and quality of life outcomes. Tohidi‐Esfahani, I., Warden, A., Malunis, E., DeNardis, P.L., Haurat, J., Black, M., Opat, S., Kee, D., D’Sa, S., Kersten, M.J., Spearing, R.L., Palomba, M.L., Olszewski, A.J., Harrington, C., Scott, C.L. and Trotman, J. (2021), AM J Hematol. https://doi.org/10.1002/ajh.26173 In this letter to the editor, the authors present WhiMSICAL (Waldenstrom’s macroglobulinemia Study Involving CART-WHEEL), the first global database capturing WM patient-derived demographic, clinical and patient-reported outcomes (PRO) data, and insights gained from 453 patients with WM. Developed by WM clinicians and IWMF patient-investigators, WhiMSICAL addresses patient priorities in WM research and maps quality of life (QoL) and PRO data with treatment to help guide patients and their clinicians. The results show marked global variation in WM treatment, despite comprehensive treatment guidelines being released in 2016. Direct patient-reporting shows a higher proportion of patients with leg cramps at diagnosis, and 10% of participants have stress levels consistent with post-traumatic stress disorder. Despite a higher treatment burden, patients currently on BTK inhibitors have better QoL scores compared to those who have never been exposed to BTK inhibitors and have been treated within 12 months.

Identification of a Candidate Gene Set Signature for the Risk of Progression in IgM MGUS to Smoldering/Symptomatic Waldenström Macroglobulinemia (WM) by a Comparative Transcriptome Analysis of B Cells and Plasma Cells.
Trojani A, Di Camillo B, Bossi LE, Leuzzi L, Greco A, Tedeschi A, Frustaci AM, Deodato M, Zamprogna G, Beghini A, Cairoli R. Cancers. 2021; 13(8):1837. https://doi.org/10.3390/cancers13081837 Although comparative gene expression studies on WM, IgM MGUS, and normal B-cells (CTRLs) identified several differentially expressed genes, reliable predictors of progression from IgM MGUS to WM have not yet been identified. The authors performed a microarray study on CD19+ and CD138+ cells of WM vs. IgM MGUS vs. CTRLs to determine gene signatures for both cell populations. They demonstrated that hematopoietic antigens, cell-adhesion molecules, Wnt-signaling, BCR-signaling, calcium signaling, coagulation cascade, and pathways responsible for cell cycle and proliferation were significantly enriched for genes expressed in B-cells of WM vs. IgM MGUS vs. CTRLs. They also showed nine genes which displayed the same expression levels in WM and IgM MGUS compared to CTRLs, suggesting their possible role in the risk of transformation of IgM MGUS to WM.

Progression from monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom’s macroglobulinemia is associated with an alteration in lipid metabolism. Jalali S, Shi J, Ahsan N, Wellik LE, Serres M, Buko A, Paludo J, Kim H, Tang XY, Yang Z-Z, Novak AJ, Kyle RA, Ansell SM. Redox Direct Volume 41, May 2021, 101927 https://doi.org/10.1016/j.redox.2021.101927 The molecular events that modulate the progression of monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom macroglobulinemia (WM) are mostly unknown. The authors implemented comparative proteomics and metabolomics analyses on patient serum samples to identify differentially expressed molecules crucial to the progression from IgM-MGUS to WM. Their data identified altered lipid metabolism as a discriminating factor between MGUS, WM, and matched normal controls. Levels of many fatty acids, including polyunsaturated fatty acids and dicarboxylic acids, were significantly downregulated in WM sera when compared to MGUS. These data highlight the novel metabolic role played by lipids in contributing to the progression of IgM-MGUS to WM. The authors acknowledge the International Waldenstrom’s Macroglobulinemia Foundation (IWMF), David and Janet Bingham Research Fund of the IWMF, Elting Family Research Fund of the IWMF for supporting this study.

Current and novel BTK inhibitors in Waldenstrom’s macroglobulinemia. 2021 Ntanasis-Stathopoulos I, Gavriatopoulou M, Fotiou D, and Dimopoulos MA. Ther Adv Hematol 2021, 12: 1–14 https://doi.org/10.1177/2040620721989586 The current therapeutic approach in Waldenstrom’s macroglobulinemia (WM) is being driven by insights in disease biology and genomic landscape. Bruton’s tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of the Waldenstrom’s macroglobulinemia (WM) clone. BTK inhibition has changed the treatment landscape of the disease. Ibrutinib has resulted in deep and durable responses both as an upfront and salvage treatment with a manageable toxicity profile. However, the need for fewer off-target effects and deeper responses has resulted in the clinical development of second-generation BTK inhibitors. Zanubrutinib, acalabrutinb, and tirabrinib has resulted in clinically meaningful antitumor activity, including deep and durable responses, with a low discontinuation rate due to treatment-related toxicities. LOXO-305 and ARQ531 are two non-covalent, reversible BTK inhibitors that are being currently evaluated in WM. Long-term data will determine whether next-generation BTK inhibitors are more potent and safer compared with ibrutinib, and whether they are able to overcome resistance to ibrutinib, either alone or in combination with inhibitors of other interrelated molecular pathways.

Severe and irreversible pancytopenia associated with SARS-CoV-2 bone marrow infection in a Waldenstrom’s Macroglobulinemia patient. Velier M, Priet S, Appay R, Atieh T, Lepidi H, Kaplanski G, Jarrot PA, Koubi M, Costello R, Dignat-George F, Lamballerie XD, Tichadou A, Arcani R, Couderc AL, Touati J, Varoquaux A, Berda-Haddad Y, Venton G, Clinical Lymphoma, Myeloma and Leukemia (2021), doi: https://doi.org/10.1016/j.clml.2021.01.005. The authors describe a case report from France of a patient with WM who developed pancytopenia (low RBC, WBC, and platelets) after contracting SARS-COV-2. They present this case as the first evidence of SARS-CoV-2 infected cells and neutralizing antibodies in bone marrow samples of a patient suffering from WM despite negative real-time polymerase chain reactions to test for mRNA (RT-PCR). This case confirms that patients with compromised immunity or underlying hematological malignancies have an elevated risk of severe and/or atypical forms of SARS-CoV-2 infection and highlights the importance of bone marrow investigations in case of severe and persistent pancytopenia, even if repeated SARS-CoV-2 RT-PCR are negative.

CXCR4 in Waldenstrom’s Macroglobulinemia: chances and challenges. Kaiser LM, Hunter ZR, Treon SP, Buske C. Leukemia (2021) 35:333-345 https://doi.org/10.1038/s41375-020-01102-3 MYD88 with an almost constant and recurrent point mutation present in over 90% of patients with WM and CXCR4 with over 40 different mutations in the coding region affecting up to 40% of patients. Intriguingly, both mutations are activating mutations leading in the case of CXCR4 to an indelible activation and perpetual signaling of the chemokine receptor. These data have shed light on the essential role of CXCR4 in WM and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.

Clinical Application of genomics in Waldenstrom macroglobulinemia. Branagan AR, Lei M, Treon SP, Castillo JJ. (2021) Leukemia &Lymphoma https://doi.org/10.1080/10428194.2021.1881514 Thediscovery of the highly recurrent somatic mutations in the MYD88 genedetected in 90–95% and the CXCR4 gene detected in 30–40% of WMpatients has provided an opportunity to develop novel
targeted approaches. Mutational status has important implications inpredicting response to therapies such as BTK inhibitors. Treatment ofWM should be guided by many factors including performance status,comorbidities, goals of therapy, and toxicities. In this review, the authorsdescribe how current genomics may be utilized to optimize WMtreatment selection. As the therapeutic landscape of WM continues toexpand with more targeted approaches, the genomics in WM will likelyplay a greater role in individualizing treatment.

Epigenetic targeting of Waldenstrom macroglobulinemia cells with BET inhibitors synergizes with BCL2 or histone deacetylase inhibition. Matissek SJ, Han W, Karbalivand M, Sayed M, Reilly BM, Mallat S, Ghazal SM, Munshi M, Yang G, Treon SP, Walker SR, Elsawa SF. Future Medicine/Epigenomics 2020 doi: 10.2217/epi-2020-0189.  Little is known about the efficiency of epigenetic targeting in Waldenstrom macroglobulinemia (WM). WM cells were treated with BET inhibitors (JQ-1 and I-BET-762) and venetoclax, panobinostat or ibrutinib. BET inhibition reduced growth of WM cells, with little effect on survival. This finding was enhanced by combination therapy, with panobinostat (LBH589) showing the highest synergy. This study identified BET inhibitors as effective therapy for WM, and these inhibitors can be enhanced in combination with BCL2 or histone deacetylase inhibition. These studies lay the foundation for the investigation of these drugs in WM patients. This work was supported in part by a grant from the International Waldenstrom Macroglobulinemia Foundation.

Discovery of a selective, covalent IRAK1 inhibitor with antiproliferative activity in MYD88 B-cell lymphoma. Hatcher JM, Yang G, Wang L, Ficarro SB, Buhrlage S, Wu H, Marto JA, Treon SP, Gray NS. ACS Med. Chem. Lett. 2020, 11, 2238-2243 https://dx.doi.org/10.1021/acsmedchemlett.0c00378  Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) play critical roles in initiating the innate immune response against foreign pathogens. Dysregulation of IRAK1 signaling plays a role in neoplastic disorders. IRAK1 was shown to be important for survival and proliferation in many B-cell lymphomas, including Waldenstrom macroglobulinemia (WM) and ABC subtype diffused large B-cell lymphoma (DLBCL) cells.  The authors report the discovery of a highly potent and selective covalent inhibitor of IRAK1, JH-X-119-01. This compound exhibited cytotoxic activity in a panel of WM, DLBCL, and lymphoma cell lines expressing MYD88. Co-treatment of JH-X-119-01 with the BTK inhibitor ibrutinib resulted in synergistic killing effects in these systems requiring further development. This research was funded in part by the Yang Family Fund of the IWMF.

A prognostic index predicting survival in transformed Waldenstrom macroglobulinemia. Durot E, Kanagaratnam L, Zanwar S, Kastritis E, D’Sa S, Garcia-Sanz R, Tomowiak C, Hivert B, Toussaint E, Protin C, Abeykoon JP, Guerrero-Garcia T, Itchaki G, Vos JM, Michallet A-S, Godet S, Dupuis J, Leprêtre S, Bomsztyk J, Morel P, Leblond V, Treon SP, Dimopoulos MA, Kapoor P, Delmer A, Castillo JJ. Haematologica; https://doi.org/10.3324/haematol.2020.262899 Histological transformation into diffuse large B-cell lymphoma is a rare complication in patients with Waldenstrom macroglobulinemia (WM) usually associated with a poor prognosis. The objective of this study was to develop and validate a prognostic index for survival in transformed WM patients. Through this multicenter, international collaborative effort, the authors developed a scoring system based on data from 133 patients with transformed WM. They identified three adverse covariates as independent predictors of 2-year survival after transformation: elevated serum LDH (2 points), platelet count < 100 x 109 /L (1 point) and any previous treatment for WM (1 point). They defined three risk groups based on this scoring system that could be used for the development of risk-adapted treatment strategies.

 A multicenter, open‐label, phase II study of tirabrutinib in patients with Waldenstrom’s macroglobulinemia. Sekiguchi, N, Rai, S, Munakata, W, et al. Cancer Sci.   2020; 111: 3327– 3337. https://doi.org/10.1111/cas.14561  The authors demonstrated that tirabrutinib monotherapy is highly effective with rapid responses and is well tolerated in both treatment‐naïve patients and those with relapsed/refractory symptomatic WM. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug‐related atrial fibrillation or hypertension. The major response rate (88.9%) as the primary endpoint and the overall response rate (96.3%) were met. However, some efficacy endpoints, such as progression free survival and overall survival, could not be evaluated because of the limited observation period. Therefore, future studies with a longer follow‐up period are warranted.

Treatment facility volume and patient outcomes in Waldenstrom macroglobulinemia. Gunaratne MDSK, Sahakian AJ, Abeykoon JP, Ansell SM, Gertz MA, Kapoor P, Paulus A, Ailawadhi S, Reeder CB, Witzig TE, Habermann TM, Novak AJ, Lacy MQ, Kyle RA, Go RS, Paludo J. Leukemia & Lymphoma (2020) https://doi.org/10.1080/10428194.2020.1832669 The National Cancer Data Base was used to identify 3064 patients with newly diagnosed Waldenstrom macroglobulinemia (WM) requiring initiation of therapy and the annual facility volume in 795 facilities were analyzed in this study. Results demonstrated that a volume–outcome relationship exists in WM and is an independent predictor of overall survival in addition to the established risk factors as age and disease severity. (Dr. Paludo was a recipient of the 2014 Young Investigator Award for WM)

 Partial response or better at six months is prognostic of superior progression‐free survival in Waldenstrom macroglobulinemia patients treated with ibrutinib. Castillo, J.J., Abeykoon, J.P., Gustine, J.N., Zanwar, S., Mein, K., Flynn, C.A., Demos, M.G., Guerrera, M.L., Kofides, A., Liu, X., Munshi, M., Tsakmaklis, N., King, R., Yang, G., Hunter, Z.R., Advani, R.H., Palomba, M.L., Ansell, S.M., Gertz, M.A., Kapoor, P. and Treon, S.P. (2020), Br J Haematol. https://doi.org/10.1111/bjh.17225  Waldenstrom macroglobulinemia (WM) is an indolent non-Hodgkin lymphoma that usually responds well to treatment with long survival. Due to its natural history, it is particularly difficult to find early predictors for survival outcomes in WM. In the era of chemo-immunotherapy, several studies have identified a correlation between depth of response and long-term survival. The authors investigated whether different depth of response to treatment at defined time-points could be a predictor of progression free survival (PFS) in patients with WM treated with ibrutinib. Major response at 6 months, considered as partial response (PR) or better (≥PR) was shown to correlate with higher rates of 3-year PFS. According to the results of this study, attaining a ≥PR after 6 months of exposure to ibrutinib was a good predictor of treatment efficacy and may be considered as a surrogate of prolonged PFS.

 Short term results of vaccination with adjuvanted recombinant varicella zoster glycoprotein E during initial BTK inhibitor therapy for CLL or lymphoplasmacytic lymphoma. Zent, C.S., Brady, M.T., Delage, C. et al. Leukemia (2020). https://doi.org/10.1038/s41375-020-01074-4  Patients with hematological malignancies have a significantly increased risk of shingles from reactivation of latent herpes zoster (VZR). Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) often have severe immunocompromise that increases the risk of infections including VZR. This prospective study showed that rVZgE vaccination (Shingrex) of CLL or LPL/WM patients on initial Bruton tyrosine kinase (BTKi) therapy for progressive disease can respond to rVZgE vaccine (Shingrex) while on BTKi therapy.

The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19–infected patients. Treon, SP, Castillo JJ, Skarbnik AP, Soumerai JD, Ghobrial IM, Guerrera ML, Meid K, Yang G; Blood 2020; 135 (21): 1912–1915. doi: https://doi.org/10.1182/blood.2020006288 In this letter to the editor, the authors sought to clarify the impact of ibrutinib in COVID-19 patients with preliminary observations. They identified 6 patients receiving ibrutinib for Waldenstrom macroglobulinemia (WM) who were diagnosed with COVID-19. The median time on ibrutinib was 52 months and 5 of the 6 patients were on the recommended treatment dose of 420 mg/d, except one patient who was on a reduced dose because of arthralgias. All patients on the full dose did not experience dyspnea (difficult or labored breathing) and did not require hospitalization. Their course was marked by steady improvement, and resolution or near resolution of COVID-19 related symptoms during the follow-up period. Ibrutinib, and possibly other BTK inhibitors, may provide protection against lung injury and even improve pulmonary function in hypoxic patients with COVID-19, as the authors observed in this series of patients with WM on ibrutinib. These findings should be considered hypothesis generating and preliminary in nature. Patients on ibrutinib, and possibly other BTK inhibitors, may well benefit with continuation of their therapy, despite the diagnosis of COVID-19.

Ibrutinib’s Cardiotoxicity—An Opportunity for Postmarketing Regulation (Viewpoint). Ratin MJ, Moslehi JJ, Lichter AS. JAMA Oncology November 2020 E1-2 doi:10.1001/jamaoncol.2020.5742 Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) that is indicated for multiple hematological  malignancies, including previously untreated chronic lymphocytic leukemia (CLL) and Waldenstrom macroglobulinemia. This drug is known to have cardiotoxic properties, probably due to off-target inhibition of another kinase. While in randomized trials ibrutinib has been demonstrated to increase survival, some studies have demonstrated fatal toxic effects associated with the drug. This was most obvious in a 3-arm study of CLL in which the 2 ibrutinib arms were associated with a 7% rate of death during treatment or within 30 days after treatment cessation, compared with a 1% rate of death in the control arm.

Targeting of CXCR4 by the naturally occurring CXCR4 antagonist EPI-X 4 in Waldenstrom ‘s macroglobulinemia. Kaiser LM, Harms M, Sauter D, Rawat VPS, Glitscher M, Hildt E, Tews D, Hunter Z, Munch J, Buske C. bioRxiv 2020. 10.19.344812; doi: https://doi.org/10.1101/2020.10.19.344812 Up to 40% of all patients with Waldenstrom’s macroglobulinemia (WM) carry an activating mutation of CXCR4 that leads to a more aggressive clinical course and inferior outcome with Bruton’s tyrosine kinase inhibitor, ibrutinib treatment. Little is known about physiological mechanisms counteracting CXCR4 signaling in hematopoietic neoplasms. The authors demonstrate that the naturally occurring, endogenous anti-CXCR4 peptide human peptide, EPI-X4, interferes with WM growth, and that optimized derivatives of EPI-X4 may represent a promising approach in suppressing growth promoting CXCR4 signaling in WM.  This research was funded in part by the IWMF.

Consensus treatment recommendations from the tenth International Workshop for Waldenstrom macroglobulinemia. Castillo JJ, Advani RH, Branagan AR, Buske C, Dimopoulos MA, D’Sa S, Kersten MJ, Leblond V, Minnema MC, Owen RG, Palomba ML, Talauikar D, Tedeschi A, Trotman J, Varettoni M, Vos JM, Treon SP, Kastritis E. Lancet Haematol, November, 2020; 7:e827-37.  According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenstrom macroglobulinemia. In previously treated patients with Waldenstrom macroglobulinemia who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active and represent emerging options for the treatment of Waldenstrom macroglobulinemia. The choice of therapy should be guided by the patient’s clinical profile, genomic features, and drug availability.

Waldenstrom Macroglobulinemia – 2020 Update on Management and Future Directions. Thomas SK. Clinical Lymphoma, Myeloma & Leukemia EXABS – MM-195 20:Supplement 1, S39-S41. September, 2020 doi.org/10.1016/S2152-2650(20)30456-0. The author presents a short review of what is known about Waldenstrom macroglobulinemia. This update includes the incidence, genetics, clinical presentation, frontline therapy, therapy at relapse, and future directions for treatment.

Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients with Waldenstrom Macroglobulinemia. Treon SP, Meid K, Gustine J, Yang G, Xu L, Liu X, Patterson CJ, Hunter ZR, Branagan AR, Laubach JP, Ghobrial IM, Palomba L, Advani R, and Castillo JJ. Journal of Clinical Oncology DOI: 10.1200/JCO.20.00555 Sixty-three symptomatic patients with prior therapies, of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity. The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL. Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88^Mut, wild-type (WT) CXCR4 showed higher major (97.2% v 68.2) and very good partial (47.2% v 9.1%) response rates and a shorter time to major response (1.8 v 4.7 months;) versus patients with MYD88^MutCXCR4^Mut. Conversely, four patients who had MYD88^WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached and was 70% and 38% for those with MYD88^MutCXCR4^WT and MYD88^MutCXCR4^Mut WM, respectively. In patients with MYD88^WT, the median PFS was 0.4 years. The 5-year overall survival rate for all patients was 87%. Grade >3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management.

Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenstrom macroglobulinemia: long-term follow-up. Castillo JJ, Meid K, Flynn CA, Chen J, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Patterson CJ, Yang G, Hunter Z, Treon SP. Blood Adv 2020; 4 (16): 3952–3959. doi.org/10.1182/bloodadvances.2020001963 The authors present the long-term follow-up of a prospective, phase II clinical trial that evaluated the combination of ixazomib, dexamethasone, and rituximab (IDR) in 26 treatment-naive patients with WM. The overall, major, and very good partial response (VGPR) rates were 96%, 77%, and 19%, respectively. The rate of VGPR in patients with and without CXCR4 mutations were 7% and 36%, respectively (P = .06). The median progression-free survival (PFS) was 40 months, the median duration of response (DOR) was 38 months, and the median time to next treatment (TTNT) was 40 months. PFS, DOR, and TTNT were not affected by CXCR4 mutational status. The safety profile was excellent with no grade 4 adverse events or deaths to date. IDR provides a safe and effective frontline treatment option for symptomatic patients with WM.

Younger patients with Waldenstrom Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies. Varettoni M, Ferrari A, Frustaci AM, Ferretti VV, Rizzi R, Motta M, Piazza F,  Merli M, Benevolo G, Visco C, Laurenti L, Ferrero S, Gentile M, Del Fabro V, Abbadessa A, Klersy C, Musto P, Fabbri N, Deodato M, Dogliotti I, Greco C, Corbingi A, Luminari  S, Arcaini L. Amer J of Hematol, August 2020 doi.org/10.1002/AJH.25961. The authors analyzed 160 young patients diagnosed with WM,median age of 49 years (range 23-55 ) from 18 treatment centers in Italy. Early diagnosis, absence of high‐risk features in symptomatic patients, and high efficacy of modern treatments are the main determinants of the excellent outcome of young patients with WM.

6q deletion in Waldenstrom macroglobulinemia negatively affects time to transformation and survival. Garcıa-Sanz R, Dogliotti I, Zaccaria GM, Ocio EM, Rubio A, Murillo I, Escalante F, Aguilera C, Garcıa-Mateo A, Garcıa de Coca A, Hernandez R, Davila J, Puig N, Garcıa-Alvarez M, del Carmen Chillon M, Alcoceba M, Medina A, Gonzalez de la Calle V, de la Calle, Sarasquete ME, Gonzalez M, Gutierrez NC and Jimenez C. Br J of Haematol, August 2020 doi.org/10.1111/bjh.17028. Deletion of the long arm of chromosome 6 (del6q) is the most frequent cytogenetic abnormality in Waldenstrom macroglobulinemia (WM), occurring in approximately 50% of patients. The presence of del6q translated into shorter overall survival (OS), irrespective of the initial diagnosis, with a median OS of 90 compared with 131 months in non‐del6q patients). This study shows that del6q in IgM gammopathy is associated with symptomatic disease, need for treatment and poorer clinical outcomes.

A Randomized Phase 3 Trial of Zanubrutinib Versus Ibrutinib in Symptomatic Waldenstrom Macroglobulinemia:The Aspen Study. Tam CS, Opat S, D’Sa S, Jurczak W, Lee H-P, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo J, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous JV, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Trotman J, Chan WY, Schneider JY, Ro S, Cohen A, Huang J, Dimopoulos MA; Blood.2020006844. doi.org/10.1182/blood.2020006844  This study established that zanubrutinib is highly effective in the treatment of WM; zanubrutinib is associated with important safety advantages, especially with respect to cardiovascular toxicity. While the study did not meet its primary endpoint, there was a trend toward better disease control for zanubrutinib versus ibrutinib, including higher rates of very good partial response (VGPR), greater and more sustained IgM reduction, and greater improvement in most quality of life (QoL) measures. Longer follow-up will allow for a more comprehensive assessment of the relative efficacy and safety profiles of zanubrutinib and ibrutinib.

Zanubrutinib for the treatment of patients with Waldenstrom macroglobulinemia: three years of follow-up. Trotman J, Opat S, Gottlieb D, Simpson D, Marlton P, Cull G, Munoz J, Tedeschi A, Roberts AW, Seymour JF, Atwal SK, Yu Y, Novotny W, Holmgren E, Tan Z, Hilger JD, Huang J, and Tam CS.  Blood July 2020. doi:10.1182/blood.2020006449 Long term zanubrutinib treatment of patients with WN resulted in an overall response rate of 96% and VGPR/CR (very good partial response/complete response) of 45%. Additionally, long term treatment with single agent zanubrutinib was well tolerated in both treatment naïve and lapsed/refractory patients.

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia. Milanesi S, Locati M,  Borroni EM. Int. J. Mol. Sci. August 2020,21(16),5696. doi.org/10.3390/ijms21165696 These Italian researchers review the current knowledge of the biochemical properties of C-X-C chemokine receptor type 4 (CXCR4). Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome. Similar mutations in CXCR4 have also been identified in 30% of patients affected by WM.

Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Milanesi S, Locati M,  Borroni EM. Int. J. Mol. Sci. August 2020,21(16),5696. doi.org/10.3390/ijms21165696 These Italian researchers review the current knowledge of the biochemical properties of C-X-C chemokine receptor type 4 (CXCR4). Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome. Similar mutations in CXCR4 have also been identified in 30% of patients affected by WM.

Identification of 2 DNA methylation subtypes of Waldenstrom macroglobulinemia with plasma and memory B-cell features. Roos-Weil D, Giacopelli B, Armand M, Della-Valle V, Ghamlouch H, Decaudin C, Metzner M, Lu J, Le Garff-Tavernier M, Leblond V, Vyas P, Zenz T, Nguyen-Khac F, Bernard OA, Oakes CC. Blood 2020; 136 (5): 585–595. doi.org/10.1182/blood.2020005081 Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenstrom macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. The authors integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. These two WM methylation subtypes demonstrate distinct tumor-specific molecular, morphological, genetic, and phenotypic features and pathways.

Epigenomics in Waldenstrom macroglobulinemia. Hunter ZR, Treon SP; Blood 2020; 136 (5): 527–529. doi.org/10.1182/blood.2020006244  In a response to the previous Roos-Weil et al article, the authors note that although individual epigenetic events have been previously characterized, this is the first genome-wide characterization and represents an important milestone for understanding WM pathogenesis. Central to the findings of Roos-Weil et al was the finding that within mutated MYD88 WM patients, the methylome stratified patients into 2 camps: one with similar profiling to healthy donor (HD) memory B cells (MBC-like) and the other similar to HD plasma cells (PC-like). Those WM patients with MBC-like profiling showed DNA methylation changes that targeted functional domains related to transcriptional activation, whereas among those with PC-like profiling, broader losses in methylation that impacted repressed, heterochromatic, as well as intergenic regions were observed. The notion that certain WM patients have greater plasmacytic differentiation has been long recognized at the morphological and transcriptional level. However, the ability to so clearly define and characterize these groups by differences in methylation offers new and valuable insights, particularly the association of chr6q deletions with a PC-like clone.

TLR-mediated activation of Waldenstrom macroglobulinemia B cells reveals an uncoupling from plasma cell differentiation. Shrimpton J, Care MA, Carmichael J, Walker K, Evans P, Evans C, de Tute R, Owen R, Tooze RM, Doody GM. Blood Adv (2020) 4 (12): 2821–2836. doi.org/10.1182/bloodadvances.2019001279. The authors report the first detailed investigation of the differentiation of primary WM B cells in vitro. They examine the response of WM cells expressing MYD88L265P to multiple stimuli that generate plasma cells, including TLR engagement and uncover an unanticipated effect on differentiation. This technique is particularly useful for investigating WM because it enables analysis of the spectrum of B-cell differentiation, which is impossible in cell lines. An understanding of the bone marrow microenvironment is increasingly being recognized as an essential component for treating WM. Currently, a mouse model that sufficiently recapitulates this neoplasm does not exist; thus, the flexibility of the in vitro system will enable superior modeling of the BM niche with patient-derived primary cells and allow further evaluation of the WM plasma cell compartment, including the impact of molecular subtypes, such as CXCR4^WHIM. This work was funded in part by Waldenstrom’s Macroglobulinemia UK, an affiliate of the IWMF.

Hyperviscosity syndrome in paraprotein secreting conditions including Waldenstrom macroglobulinemia. Weaver A, Rubenstein S, and Cornell RF. Front Oncol 19 May 2020 doi.org/10.3389/fonc.2020.00815 Hyperviscosity syndrome most commonly occurs in Waldenstrom macroglobulinemia and affects 10-30% of patients. The predominant symptoms are hemorrhage in the nose and oral cavity, blurred or double vision, retinal hemorrhage, and neurologic manifestations ranging from mild headache and lightheadedness to seizures and coma. The authors discuss plasmapheresis or therapeutic plasma exchange to initially alleviate symptoms but recommend chemotherapy for long-term disease control for reduction of the serum proteins and prevention of recurrence.

Clinical, Laboratory, and Bone Marrow Findings of 31 Patients with Waldenstrom Macroglobulinemia. Ahn A, , Park C-J, Cho Y-U, Jang S, Seo E-J, Lee J-H, Yoon DH, and Suh C. Ann Lab Med 2020; 40(3): 193-200  doi.org/10.3343/alm.2020.40.3.193 The authors reviewed the medical records and bone marrow studies and/or flow cytometric immunotyping of 31 patients with untreated Waldenstrom macroglobulinemia (WM) in South Korea. Semiquantitative immunohistochemistry (CD20, CD138, tryptase, and CD154) of the bone marrow was performed. Approximately one third of patients with WM showed other malignancies and all patients had increased mast cells, some in close contact with tumor cells.The authors concluded that immunohistochemistry and flow cytometric immunophenotyping are useful for diagnosing WM, and increased CD154-positive mast cells can indicate poor prognosis.

Genomic landscape of Waldenstrom macroglobulinemia and its impact on treatment strategies. Treon SP, Xu L, Guerrera ML, Jimenez C, Hunter ZR, Liu X, Demos M, Gustine J, Chan G, Munshi M, Tsakmaklis N, Chen JG, Kofides A, Sklavenitis-Pistofidis R, Bustoros M, Keezer A, Meid K, Patterson CJ, Sacco A, Roccaro A, Branagan AR, Yang G, Ghobrial IM, and Castillo JJ. J Clin Oncol 2020 DOI doi.org/10.1200/JCO.19.02314 Next-generation sequencing has revealed recurring somatic mutations in WM that include MYD88 and CXCR4. The genomic findings have contributed to ongoing targeted drug development and the recognition of a precision-guided treatment approach to WM. MYD88 and CXCR4 mutation status can be used to guide treatment decisions in WM. This research was funded in part by the IWMF.

Good profile of efficacy/tolerance of bortezomib or idelalisib in Waldenstrom macroglobulinemia associated with acquired Von Willebrand syndrome. Ojeda-Uribe M, Rimelen V, Marzullo C. J Blood Med 2020;11:67-72. doi.org/10.2147/JBM.S233059. The authors report their experience treating three elderly patients with WM and Von Willebrand syndrome. The use of a bortezomib-based chemotherapy regimen showed a good profile of tolerance and efficacy even in a long-term follow-up period.

SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas. Munshi M, Liu X, Chen JG, Xu L, Tsakmaklis N, Demos MG, Kofides A, Guerrera ML, Jimenez C, Chan GG, Hunter ZR, Palomba ML, Argyropoulos KV, Meid K, Keezer A, Gustine J, Dubeau T, Castillo JJ, Patterson CJ, Wang J, Buhrlage SJ, Gray NS, Treon SP, and Yang G. Blood Cancer Journal (2020) 10:12 doi.org/10.1038/s41408-020-0277-6. The authors have identified activated SYK as an integral component of the mutated MYD88 signaling apparatus and an intermediary for AKT and STAT3 prosurvival signaling. Combined use of ibrutinib and SYK inhibitors produces synergistic lethality in MYD88-mutated B cells, including those with accompanying CD79 activating mutations. The findings provide a framework for the clinical investigation of ibrutinib with SYK inhibitors in MYD88-mutated lymphomas. This research was funded in part by the IWMF.

Cause‐specific mortality in individuals with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia, 2000–2016. Dalal NH, Dores GM, Curtis RE, Linet MS, MPH, Morton LM. BR J Haematol February 2020 doi.org/10.1111/bjh.16492 The authors found 16‐year cumulative mortality was 23.2% for lymphomas, 8.4% for non‐lymphoma cancers and 14.7% for non‐cancer causes for patients aged <65 years at diagnosis of LPL/WM, versus 33.4%, 11.2% and 48.7%, respectively, for those aged ≥75 years. Compared with the general population, patients with lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) had a 20% higher risk of death due to non‐cancer causes, most commonly from infectious, respiratory, and digestive diseases, but no excess mortality from cardiovascular diseases. Risks were highest for non‐cancer causes within 1 year of diagnosis, declining thereafter.

Autologous Stem Cell Transplant for Waldenstrom Macroglobulinemia in the Era of Novel Therapies: Still an Underutilized Tool? Parrondo RD, Moustafa MA, Kapoor P , Roy V, Reeder C, Ailawadhi S. Biology of Blood and Marrow Transplantation V 26, No 3, Supplement, March 2020, Page S238 doi.org/10.1016/j.bbmt.2019.12.483  The authors present outcomes of patients with Waldenstrom’s macroglobulinemia (WM) who underwent autologous stem cell transplant (ASCT) at three Mayo Clinic sites. They conclude that ASCT for patients with WM is a safe and efficacious treatment modality with an overall response rate of 100% and affords eligible patients a median treatment-free interval of 4 years. To obtain the maximum progression free survival benefit, ASCT should be performed earlier in the disease course, prior to receiving more than 2 lines of therapy.

Genomic evolution of ibrutinib-resistant clones in Waldenstrom macroglobulinemia. Jiménez C, Chan GG, Xu L, Tsakmaklis N, Kofides A, Demos MG, Chen J, Liu X, Munshi M,  Yang G, Castillo JJ, Wiestner A, García‐Sanz R, Treon SP, Hunter ZR. BR J Haematol 2020 doi: 10.1111/bjh.16463 Ibrutinib is highly active in Waldenstrom macroglobulinemia (WM) patients, but disease progression can occur due to acquired mutations in BTK, the target of ibrutinib, or PLCG2, the protein downstream of BTK. However, not all resistant patients harbor these alterations. The authors performed a whole‐exome sequencing study to identify alternative molecular mechanisms that can drive ibrutinib resistance. Their findings include deletions on chromosomes 6q, including homozygous deletions, and 8p, which encompass key regulators of BTK, MYD88/NF‐κB, and apoptotic signaling. They have identified recurring mutations in ubiquitin ligases, innate immune signaling, and TLR/MYD88 pathway regulators in ibrutinib‐resistant WM patients. This research was funded in part by the IWMF.

CXCR4 mutational status does not impact outcomes in patients with Waldenstrom macroglobulinemia treated with proteasome inhibitors. Castillo JJ, Gustine JN, Meid K, Flynn CA, Demos MG, Guerrera ML, Jimenez C, Kofides A, Liu X, Munshi M, Tsakmaklis N, Patterson CJ, Xu L, Yang G, Hunter ZR, Treon SP. First published: 13 January 2020 doi.org/10.1002/ajh.25730, American Journal of Hematology. In this study, there were no detectable differences in the rates of major response at 6 and 12 months to proteasome inhibitor-based therapy between patients with and without CXCR4 mutations. Similarly, there were no detectable differences in median progression free survival (PFS) between groups. The results of this study support a CXCR4-agnostic response and PFS in patients with WM treated with proteasome inhibitor-containing regimens. Therefore, bortezomib, carfilzomib and ixazomib-based regimens are appropriate frontline treatment options for patients with WM who have CXCR4 mutations.

Clinical, Laboratory, and Bone Marrow Findings of 31 Patients with Waldenstrom Macroglobulinemia. Ahn A, , Park C-J, Cho Y-U, Jang S, Seo E-J, Lee J-H, Yoon DH, and Suh C. Ann Lab Med 2020; 40(3): 193-200  doi.org/10.3343/alm.2020.40.3.193 The authors reviewed the medical records and bone marrow studies and/or flow cytometric immunotyping of 31 patients with untreated Waldenstrom macroglobulinemia (WM) in South Korea. Semiquantitative immunohistochemistry (CD20, CD138, tryptase, and CD154) of the bone marrow was performed. Approximately one third of patients with WM showed other malignancies and all patients had increased mast cells, some in close contact with tumor cells.The authors concluded that immunohistochemistry and flow cytometric immunophenotyping are useful for diagnosing WM, and increased CD154-positive mast cells can indicate poor prognosis.

Deepening of response after completing rituximab-containing therapy in patients with Waldenstrom macroglobulinemia. Castillo JJ, Gustine JN, Keezer A, Meid K, Flynn CA, Dubeau TE, Chan G, Chen J, Demos MG, Guerrera ML, Jimenez C, Kofides A, Liu X, Munshi M, Tsakmaklis N, Patterson CJ, XU L, Yang G, Hunter ZR, Treon SP. Am J Hematol. 2020;1–7. doi.org/10.1002/ajh.25712  This retrospective study found that deepening of response (>25% decrease in serum IgM levels) occurs in approximately 30% of patients with Waldenstrom macroglobulinemia (WM) months to years after completion of rituximab-containing therapy regimens. Characteristics that were tied to lower odds of deepening of response after therapy completion included baseline hemoglobin <11.5 g/dL, bone marrow involvement ≥50%, CXCR4 mutations, and serum IgM ≥4000 mg/dL. Furthermore, deepening of response was found to be linked with better progression-free survival and survival after initiation of front-line therapy.

Clinical, Laboratory, and Bone Marrow Findings of 31 Patients with Waldenstrom Macroglobulinemia. Ahn A, , Park C-J, Cho Y-U, Jang S, Seo E-J, Lee J-H, Yoon DH, and Suh C. Ann Lab Med 2020; 40(3): 193-200  doi.org/10.3343/alm.2020.40.3.193 The authors reviewed the medical records and bone marrow studies and/or flow cytometric immunotyping of 31 patients with untreated Waldenstrom macroglobulinemia (WM) in South Korea. Semiquantitative immunohistochemistry (CD20, CD138, tryptase, and CD154) of the bone marrow was performed. Approximately one third of patients with WM showed other malignancies and all patients had increased mast cells, some in close contact with tumor cells.The authors concluded that immunohistochemistry and flow cytometric immunophenotyping are useful for diagnosing WM, and increased CD154-positive mast cells can indicate poor prognosis.

Response and survival outcomes to ibrutinib monotherapy for patients with Waldenstrom macroglobulinemia on and off clinical trials. Castillo JJ, Gustin JN, Meid K, Flynn CA, Demos MG, Guerrera ML, Jimenez C, Kofides A, Liu X, Munshi M, Tsakmaklis N, Patterson CJ, Xu L, Yang G, Hunter ZR, Treon SP. HemaSphere (2020) 4:3(e363). http://dx.doi.org/10.1097/ HS9.0000000000000363 The authors evaluated whether there were differences in clinical characteristics, response, and survival outcomes to ibrutinib monotherapy between WM patients treated on and off clinical trials. Treatment naïve and previously treated patients who received ibrutinib monotherapy at Dana-Farber Cancer Institute and participated in two prospective studies (ON trial; n=72) or a prospective database (OFF trial; n=157) were included. Similar rates of categorical response at 6, 12, and 24 months and at best response were also observed between ON trial and OFF trial patients. The 4-year progression-free survival and overall survival rates for ON trial and OFF trial patients were 72% and 63%, respectively and 83% and 81%, respectively. CXCR4 mutations impacted response and survival outcomes to ibrutinib monotherapy. The 4-year rates of ibrutinib discontinuation in ON and OFF trial patients were 36% and 44%, respectively, Ibrutinib is effective in the routine clinical care of both treatment-naïve and previously treated WM patients. The findings of this study validate the efficacy of ibrutinib monotherapy reported in multiple phase II clinical trials.

The bone marrow microenvironment in Waldenstrom macroglobulinemia. Jalali S and Ansell SM. Hematol Oncol Clin N Am 32 (2018) 777–786 doi.org/10.1016/j.hoc.2018.05.005. Although our understanding of the role of BM microenvironment in WM has significantly increased in recent years, there are still many unknown factors that promote WM cell growth that need to be studied. This review provides an insightful examination of the BM constituents that support WM cells and explains in part which ligands or cell subpopulations promote malignant cell growth and proliferation or stimulate immunoglobulin production. The research for this publication was funded in part by the IWMF.

Gene expression profile signature of aggressive Waldenstrom macroglobulinemia with chromosome 6q deletion. Sekiguchi N, Nomoto J, Nagata A, Kiyota M, Fukuda I, Yamada K, Takezako N, Kobayashi Y. BioMed Research International, 2018, Article ID 6728128, doi.org/10.1155/2018/6728128 This study suggests that the BCR signaling pathway and IL21R expression are activated in WM with 6q del. FOXP1 and CBLB appear to act as positive regulators of the BCR signaling pathway. These findings might be attributed to the aggressiveness of the WM with 6q del expression signature.

Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer. Varughese T, Taur Y, Cohen N, Palomba ML, Seo SK, Hohl TM, and Redelman-Sidi G. Clinical Infectious Diseases, 67: 5, September 2018, 687–692, doi.org/10.1093/cid/ciy175 Patients with lymphoid cancer, including chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, and mantle cell lymphoma, are at risk for serious infections, primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 53.5% of patients, and invasive fungal infections (IFIs) in 37.2%. The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%).

Dose-limiting stomatitis associated with ibrutinib therapy: a case series. Vigarios E, Beylot-Barry M, Jegou MH, Oberic L, Ysebaert L, Sibaud V. Brit J of Haematology 2018, doi 10.1111/bjh.15620 Ibrutinib can trigger severe impairing stomatitis (an oral toxicity of the tongue and oral mucosa with ontense pain, difficulty swallowing, and subsequent weight loss) that may require temporary discontinuation of the drug. Lesions can develop after several months of treatment. The authors recommend topical or short courses of systemic corticosteroids for managing oral ulcers and relieving pain, once an active infection has been ruled out. The clinical outcomes observed in their patients (with CLL) suggest that ibrutinib may be resumed at a lower dose, without any recurrence.

Risk of Herpes Zoster Prior to and Following Cancer Diagnosis and Treatment: A Population-Based Prospective Cohort Study. Qian J, Heywood AE, Karki S, Banks E, Macartney K, Chantrill L, Liu B. The Journal of Infectious Diseases, 2018  jiy625, doi.org/10.1093/infdis/jiy625 In this analysis of data from 240,000 older adults with over 8 years of follow-up, the authors found that a diagnosis of cancer was associated with about a 40% higher risk of developing zoster compared to those without cancer. The risk was substantially greater among those with hematological cancers compared to those with solid organ cancers. For both types of cancer, risks were highest in the first year following diagnosis, decreasing thereafter.

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenstrom macroglobulinemia. McMaster ML, Berndt SI, Zhang J, Slager SL, et al. Nat Comm (2018)9:4182. DOI: 10.1038/s41467-018-06541-2. Characterizing the genetic factors influencing susceptibility to WM/LPL is an important step toward understanding its etiology. To discover genetic loci for WM/LPL susceptibility, the researchers performed a two-stage genome-wide association study of WM/LPL, leveraging a family-based oversampling approach in the discovery followed by replication in an independent, predominantly non-familial, cohort. They report new susceptibility loci at 6p25.3 and 14q32.13 for WM/LPL and provide insights into the genetic etiology of this distinctive B-cell lymphoma.

Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology: A Systematic Review and Quantitative Analysis. Kovic B, Jin X, Kennedy SA, Hylands M, Pedziwiatr M, Kuriyama A, Gomaa H, Lee Y, Katsura M, Tada M, Hong BY, Cho SM, Hong PJ, Yu AM, Sivji Y, Toma A, Xie L, Tsoi L, Waligora M, Prasad M, Bhatnagar N, Thabane L, Brundage M, Guyatt G, Xie F. JAMA Intern Med. 2018 Dec 1;178(12):1586-1596. doi: 10.1001/jamainternmed.2018.4710. Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs.  The researchers aimed to answer how strongly is progression-free survival (PFS) associated with health-related quality of life (HRQoL) in studies of cancer treatments. This systematic review and quantitative analysis of 52 articles reporting on 38 randomized clinical cancer trials did not find a significant association between PFS and HRQoL. These findings raise questions about the assumption that interventions prolonging PFS also improve HRQoL in patients with cancer and suggest that HRQoL should be measured directly and accurately, with adequate follow-up time, in future studies.

Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenstrom macroglobulinemia. Paludo J, Abeykoon JP, Shreders A, Ansell SM, et al. Ann Hematol (2018) 97: 1417. doi.org/10.1007/s00277-018-3311-z The treatment approaches for Waldenstrom macroglobulinemia (WM) are largely based upon information from single-arm phase II trials, without comparative data. The researchers compared the efficacy of two commonly used regimens in routine practice (bendamustine-rituximab (BR) and dexamethasone, rituximab plus cyclophosphamide (DRC)) and evaluated their activity with respect to the patients’ MYD88L265P mutation status. A trend for longer progression free survival was observed with BR, although the regimens have comparable toxicities. The activity of BR and DRC appears to be unaffected by patients’ MYD88 mutation. status.

Carfilzomib-based combination regimens are highly effective frontline therapies for multiple myeloma and Waldenstrom’s macroglobulinemia. Chaudhry M, Steiner R, Claussen C, Patel K, Lee H, Weber D, Thomas S, Feng C, Amini B, Orlowski R, Feng L, Manasanch EE, (2018) Leukemia & Lymphoma, DOI: 10.1080/10428194.2018.1508668. The authors conducted a retrospective study to report the efficacy and safety of frontline carfilzomib-based combinations in a standard of care setting. They identified newly diagnosed multiple myeloma (MM) and Waldenstrom’s macroglobulinemia (WM) patients treated with carfilzomib as initial therapy who met study inclusion criteria. The clinical benefit for WM was 100% with all patients having a resolution of B symptoms and anemia after treatment. The authors conclude that carfilzomib-based regimens are well tolerated and offer a neuropathy sparing approach with excellent responses, both in newly diagnosed MM and WM, making them a good choice for the frontline treatment of these diseases.

Prognostic factors and primary treatment for Waldenstrom’s macroglobulinemia – a Swedish Lymphoma Registry Study.  Brandefors L, Melin L, Lindh J, Lundqvist K, Kimby E. British Journal of Haematology, 2018, DOI: 10.1111/bjh.15558. The authors present a nationwide prospective physician led Swedish registry-based study of Waldenstrom macroglobulinemia (WM) that focuses on incidence and survival in relation to clinical prognostic factors and primary therapies. A retrospective review showed that 981 patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analyzed further. The overall survival (OS) improved between two periods, 2000–2006 and 2007–2014, with a five year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and hemoglobin ≤115 g/l for patients receiving therapy 0–3 months after diagnosis, and age, poor performance status, hemoglobin ≤115 g/l,  and female sex in “watch and wait” patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival.

MYD88 mutated and wild-type Waldenström’s Macroglobulinemia: characterization of chromosome 6q gene losses and their mutual exclusivity with mutations in CXCR4. Guerrera ML, Tsakmaklis N, Xu L, Yang G, Demos M, Kofides A, Chan GG, Manning RJ, Liu X, Chen JG, Munshi M, Patterson CJ, Castillo JJ, Dubeau T, Gustine J, Carrasco RD, Arcaini L, Varettoni M,  Cazzola M, Treon SP, Hunter ZR. Haematologica Sep 2018, 103 (9) e408-e411; DOI: 10.3324/haematol.2018.190181. The authors identified 19 genes co-regulated by 6qdel and CXCR4 mutation status, which may be involved in WM clonal evolution. Their findings provide new insights into WM pathogenesis, including loss of key regulators of BTK, apoptosis, BCL2 and NF-κB signaling in asymptomatic and symptomatic WM patients, and shared regulatory signaling for MYD88 mutated WM patients with either 6qdel or CXCR4 mutated disease.

Treatment and outcome patterns in European patients with Waldenström’s macroglobulinaemia: a large, observational, retrospective chart review. Buske C, Sadullah S, Kastritis E, Tedeschi A, García-Sanz R, Bolkun L, Leleu X, Willenbacher W, Hájek R, Minnema MC, Cheng M, Bilotti E, Graef T, Dimoupoulos A. Lancet Haematol July 2018, 5(7);e299-e309. In this large, observational, retrospective chart review, academic and community physicians in ten European countries retrospectively completed electronic records for patients with symptomatic Waldenström’s macroglobulinemia who had begun treatment 2000-2014, and had available clinical and biological data. They assessed the variables that affected choice of front-line therapy, progression-free survival, and overall survival in multivariate analyses. This large observational dataset should inform and help set guidelines, and improve understanding of treatment practices and outcomes, for European patients with Waldenström’s macroglobulinemia.

Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Kastritis E, Leblond V, Dimopoulos M A, Kimby E, Staber P, Kersten M J, Tedeschi A, Buske C, ESMO Guidelines Committee 2018, Annals of Oncology  dy146, doi.org/10.1093/annonc/mdy146. The European Society for Medical Oncology (ESMO) published new guidelines for diagnosis, treatment, and follow up for patients with WM in European practices.

Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients with Waldenström Macroglobulinemia. Treon SP, Gustine J, Meid K, Yang G, Xu L, Liu X, Demos M, Kofides A, Tsalmaklis N, Chen JG, Munshi M, Chan G, Dubeau T, Raje N, Yee A, O’Donnell E, Hunter ZR, Castillo JJ. 2018 J Clin Oncology DOI: doi.org/10.1200/JCO.2018.78.6426. The authors report on a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect of CXCR4 mutation status on outcome. Thirty patients with WM received ibrutinib. All carried MYD88 mutation and 14 (47%) carried a CXCR4 mutation. Overall and major responses for all patients were 100% and 83%, respectively. Rates of major (94% v 71%) and very good partial (31 v 7%) responses were higher and time to major responses more rapid (1.8 v 7.3 months; P = 0.01) in patients with wild-type CXCR4 versus those with CXCR4 mutation, respectively. The 18-month, estimated progression-free survival is 92%. All patients are alive. Grade 2/3 treatment-related toxicities in > 5% of patients included arthralgia (7%), bruising (7%), neutropenia (7%), upper respiratory tract infection (7%), urinary tract infection (7%), atrial fibrillation (10%), and hypertension (13%). There were no grade 4 or unexpected toxicities. It was concluded that ibrutinib is highly active, produces durable responses, and is safe as primary therapy in patients with symptomatic WM. CXCR4 mutation status affects responses to ibrutinib.

Selecting Initial Therapy for Newly Diagnosed Waldenström Macroglobulinemia, Editorial. Gertz MA, 2018 J Clin Oncology 2018 ascopubs.org/doi/abs/10.1200/JCO.2018.79.3273 This editorial accompanies the Treon publication on newly diagnosed patients with WM treated with ibrutinib (see above) and references the Dimopoulos and colleagues iNNOVATE Study of ibrutinib or placebo in combination with rituximab in subjects with WM (see elsewhere on this page). He suggests that all initial combination therapies seem to be highly effective, with clear superiority over single-agent rituximab, which should no longer be considered appropriate initial therapy for this disorder.  He goes on to question how one decides among available therapies given the side effects, age of the patient at diagnosis, fixed duration therapy vs. the need for continuous therapy until progression, and cost as a barrier to access. He adds that it is important to have multiple options, and ibrutinib with its high activity is a welcome addition to the current armamentarium. He ends with a discussion of new drugs on the horizon and concludes that, “the future is bright for patients with WM who now have many choices for treatment type, and the likely outcome is that few patients will succumb to this disease in the future.”

Prospective Clinical Trial of Ixazomib, Dexamethasone, and Rituximab as Primary Therapy in Waldenström Macroglobulinemia. Castillo JJ, Meid K, Gustine JN, Dubeau T, Severns P, Hunter ZR, Yang G, Xu L, and Treon SP. Clin Cancer Res July 2018; 24(14); 3247-52. DOI: 10.1158/1078-0432.CCR-18-0152. This Dana Farber Cancer Institute group reports results of a prospective phase II study evaluating ixazomib, dexamethasone, and rituximab (IDR) as primary therapy in symptomatic patients with WM. All patients had MYD88 L265P mutation, and 58% of patients had a CXCR4 mutation. The median time to response was 8 weeks, which was longer (12 weeks) in WM patients with CXCR4 mutations. The overall response rate was 96%, and the major response rate was 77%. The median follow-up was 22 months. Adverse events included infusion-related reactions (19%), rash (8%), and insomnia (8%).  IDR offers a highly effective and well tolerated, neuropathy sparing regimen for primary therapy in patients with WM.

A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia. Tam CS, LeBlond V, Novotny W, Owen RG, Tedeschi A, Atwal S, Cohen A, Huang J, Buske C. Future Oncol. 2018 Jun 5. doi: 10.2217/fon-2018-0163. [Epub ahead of print]. This is a head-to-head Phase III study comparing efficacy and safety of zanubrutinib and ibrutinib in WM patients. WM is sensitive to Bruton tyrosine kinase (BTK) inhibition with ibrutinib, a first-generation BTK inhibitor. Side effects of ibrutinib against TEC- and EGFR-family kinases are implicated in some adverse events. Patients with CXCR4WHIM and MYD88L265P mutations or who are MYD88WT have less sensitivity to ibrutinib than those with MYD88L265Pand CXCR4WT disease. Zanubrutinib, a next-generation BTK inhibitor with potent preclinical activity in WM and minimal side effects, showed sustained BTK occupancy in peripheral blood mononuclear cells from patients with B-cell malignancies and promising responses in advanced WM.

Fifty-Year Incidence of Waldenstrom Macroglobulinemia in Olmsted County, Minnesota, From 1961 Through 2010: A Population-Based Study With Complete Case Capture and Hematopathologic Review. Kyle RA, Larson DR, McPhail ED, Therneau TM, Dispenzieri  A, Kumar S, Kapoor P, Cerhan  JR and Rajkumar SV.  Mayo Clin Proc.  June 2018;93(6):739-746  doi.org/10.1016/j.mayocp.2018.02.011. This study is the first epidemiological study to evaluate the clinical, laboratory, and pathologic features of WM in a specifically prescribed area and time of diagnosis. Patients with smoldering WM, lymphoplasmacytic lymphoma with an IgG or IgA monoclonal protein, and those with an IgM monoclonal gammopathy of undetermined significance were excluded from the study.  Results show Waldenstrom macroglobulinemia is a rare malignancy with an incidence of approximately 0.6 per 100,000 person-years, which is severalfold lower than that of multiple myeloma. The incidence of WM increased with age and the incidence of this disease has not changed during the past half century. Patients diagnosed with WM after 2000 had an approximately 2-fold excess mortality compared with the expected population mortality. Infection was the major cause of death. Most patients who died had advanced, symptomatic WM in addition to the immediate causes of death.

Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia. Dimopoulos MA, Tedeschi A, Trotman J, García‑Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C,  Tam C,  Orsucci L, Palomba ML, Matous JV,  Shustik C, Kastritis E, Treon SP,  Li J, Salman Z,  Graef T, and C. Buske, for the iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. N Engl J Med 2018; 378:2399-2410 DOI: 10.1056/NEJMoa1802917. Among patients with Waldenström’s macroglobulinemia, the use of ibrutinib– rituximab resulted in significantly higher rates of progression-free survival than the use of placebo–rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib–rituximab, whereas infusion reactions and IgM flare were more common with placebo–rituximab.

Immunizing Cancer Patients: Which Patients? Which Vaccines? When to Give? Shah MK, Kamboj M. Oncology May 2018;32(5):254-8. Patients receiving treatment for cancer should be considered for age- and indication-appropriate vaccinations, and the responsibility for administration of these vaccines is shared between the oncologist and the primary care provider. Certain vaccine-preventable diseases have higher incidence rates among cancer patients and are associated with worse clinical outcomes. The Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices recommend certain vaccines for routine use in adults, including those with cancer. This article provides guidance to oncology clinicians on vaccine recommendations and safety of use in their patients. Key Points are: (1) Indicated vaccines are ideally administered before cancer treatment is initiated. (2) Live vaccines are contraindicated due to risk of severe vaccine-induced infection. (3) Injectable influenza vaccine is given annually, and both pneumococcal vaccines should be administered according to the recommended schedule from the Centers for Disease Control and Prevention. (4) The newer recombinant vaccine (RZV) is the safer and preferred vaccine. (5) Family members and close contacts of cancer patients can be safely immunized with most, but not all, live vaccines.

Impact of Ibrutinib dose intensity on patient outcomes in previously treated Waldenström macroglobulinemia. Castillo JJ, Gustine JN, Meid K, Dubeau TE, Xu L, Yang G, Hunter ZR, Advani R,  Palomba L, and Treon SP. Haematologica May 2018: haematol.2018.191999; Doi:10.3324/haematol.2018.191999. This multicenter study suggests that, similar to CLL patients, low dose intensity adversely impacts progression free survival in WM patients. Ibrutinib therapy is indefinite and compliance should be strongly emphasized to optimize outcomes.

Ibrutinib Withdrawal Symptoms In Patients With Waldenström Macroglobulinemia. Castillo JJ, Gustine JN, Meid K, Dubeau T, Severns, P, Treon SP.  Haematologica February 2018 : haematol.2017.186908; Doi:10.3324/haematol.2017.186908. Ibrutinib is the first approved therapy for the treatment of patients with Waldenström macroglobulinemia (WM). The approval was based on results of a study in WM patients that showed overall response rate (ORR) of 91% and median time to response of 4 weeks. Temporary interruption of ibrutinib is sometimes needed to manage toxicities or perioperatively to minimize bleeding. Some WM patients developed withdrawal symptoms (fever, body aches, night sweats, arthralgias, chills, headache, fatigue) while holding ibrutinib, which then resolved promptly after ibrutinib reinitiation. A retrospective study shows that withdrawal symptoms develop in 20% of WM patients who hold ibrutinib therapy. The rate of withdrawal symptoms was lower in patients who started ibrutinib at serum IgM levels ≥4,000 mg/dl and CXCR4 mutated patients, and higher in patients who had achieved a very good partial response (VGPR) on ibrutinib. Symptoms ensue within 2 days of ibrutinib hold and resolve rapidly following reinitiation of therapy. In two thirds of the patients who experience withdrawal, there is no evidence of disease progression during ibrutinib hold. In the patients who progress during the hold, response is regained within 3 months of ibrutinib reinitiation.

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound. Gustine JN, Meid K, Dubeau T, Severns P, Hunter ZR, Guang Y, Xu L, Treon SP, Castillo JJ.  American J. Hematol. 2018;93:511–517. doi.org/10.1002/ajh.25023. This is a retrospective review of patients with WM who discontinued ibrutinib and their subsequent outcomes. Reasons for discontinuation include: disease progression, toxicity, non-response, and other unrelated reasons. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4‐fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival. Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.

Phase I study of an active immunotherapy for asymptomatic phase lymphoplasmacytic lymphoma with DNA vaccines encoding antigen-chemokine fusion: study protocol. Thomas SK, Cha S, Smith DL, Kim KH, Parshottam SR, Rao S, Popescu M, Lee VY, Neelapu SS, Kwak LW. BMC Cancer 2018 18:187 doi.org/10.1186/s12885-018-4094-2. There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Asymptomatic patients with lymphoplasmacytic lymphoma (LPL) are currently managed by a “watchful waiting” approach, as available therapies provide no survival advantage if started before symptoms develop. Tumor-specific markers and effective vaccination was demonstrated in a positive controlled phase III trial for LPL patients. This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and aid the development of other personalized approaches.

Long-term follow-up of monoclonal gammopathy of undetermined significance. Kyle RA, Larson DR, Therneau TM, et al., N Engl J Med 2018: 378:241-249.
MGUS affects more than 5% of persons older than seventy years and shortens survival, as compared to age-matched controls. In a long term study involving more than 1000 patients, those with IgM GUS had a higher rate of progression to B-cell cancer than those with IgG MUS.

Acute hyperviscosity: syndromes and management. Gertz M, Blood. 2018;132(13):1379-1385 Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Plasma exchange is the therapy of choice and is relatively safe. Patients should always have confirmation of the diagnosis by measurement of the viscosity level. This publication was funded in part by the IWMF.

Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia. Jalali S, Price-Troska T, Paludo J, Villasboas J, Kim H-J, Yang Z-, Novak AJ, Ansell SM. Blood Adv. 2018  Aug 14; 2(15): 1985-1997 doi: 10.1182/bloodadvances.2018021113 The authors identify that soluble PD-1 ligands are elevated in WM patients and, in addition to surface-bound ligands in WM bone marrow, could regulate T-cell function. Given the capability of secreted forms to be bioactive at distant sites, soluble PD-1 ligands have the potential to promote disease progression in WM. This research was funded in part by the Elting Family Research Fund of the IWMF.