WM Medical Practice Guidelines & Research Articles

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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.

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.
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.

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 MYD88Mut, 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 MYD88MutCXCR4Mut. Conversely, four patients who had MYD88WT 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 MYD88MutCXCR4WT and MYD88MutCXCR4Mut WM, respectively. In patients with MYD88WT, 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.

NCCN Clinical Practice Guidelines in Oncology for Waldenstrom’s Macroglobulinemia/Lymphoplasmacytic Lymphoma(link is external). The NCCN is a non-profit alliance of 30 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 based on the most current diagnosis and treatment guidelines available. The discussion section of these guidelines is still being updated to correspond with the most recent algorithms (last update 4/15/2020). You must establish an account on the NCCN website to login and view these guidelines.

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.

Current and Emerging Treatments for Waldenstrom Macroglobulinemia. Grimont CN, Castillo Almeida NE, Gertz MA. August 2020 Acta Haematol DOI: 10.1159/000509286 The primary goal of therapy for Waldenstrom macroglobulinemia (WM) is to reduce symptoms related to direct infiltration of the bone marrow and decrease monoclonal IgM-associated complications. Active agents in the management of WM can be broadly classified as rituximab-alkylator combination therapy, proteasome inhibitor-based therapy, and Bruton’s tyrosine kinase inhibitor-based therapy. MYD88L265P and CXCR4 genetic status are pivotal for tailoring treatment options. Ibrutinib is a suitable treatment option for both treatment naïve and relapsing patients with WM. Recent advances in the intracellular B cell and cytokine signaling pathways have contributed to the development of novel therapeutic strategies.

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.

Consensus Statement on the Management of Waldenstrom Macroglobulinemia Patients During the COVID-19 Pandemic. Talaulikar, D, Advani R H, Branagan AR, Buske C, Dimopoulos MA, D’Sa S,  Kersten MJ,  Leblond V,  Minnema MC, Owen RG, Palomba ML,  Tedeschi A, Trotman J, Varettoni M,  Vos JM, Treon SP,  Kastritis E,  Castillo JJ. HemaSphere: August 2020 – Volume 4 – Issue 4 – p e433 doi: 10.1097/HS9.0000000000000433. In this consensus statement, the International Workshop on Waldenstrom Macroglobulinemia (IWWM) Recommendations Panel addresses questions related to treatment initiation, preferred therapies, minimizing visit to clinics and infusions centers, supportive care and guidance for WM patients in clinical trials. Finally, we also provide information on timing and appropriateness of testing and management of COVID-19 infected patients, as well as ways to get physicians and patients involved in registry studies that could help others.

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. Berentsen S, Barcellini W, D’Sa S, Randen U, Tvedt THA, Fattizzo B, Haukås E, Kell M, Brudevold R, Dahm AEA, Dalgaard J, Frøen H, Hallstensen RF, Jæger PH, Hjorth-Hansen H, Małecka A, Oksman M, Rolke J, Sekhar M, Sørbø JH, Tjønnfjord E, Tsykunova G, Tjønnfjord GE. July 2020 Blood (2020) 136 (4): 480–488. doi.org/10.1182/blood.2020005674  This large study of patients with verified cold agglutinin disease (CAD) found a fourfold difference in prevalence and incidence between cold and warmer climate. Rituximab-bendamustine therapy yielded 78% response rate, 53% complete response, response duration >88 months, and few late malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.

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 CXCR4WHIMThis work was funded in part by Waldenstrom’s Macroglobulinemia UK, an affiliate of the IWMF.

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.org/10.1182/blood.2020006288  Although preliminary, observations from a small group of patients with WM on ibrutinib suggest that ibrutinib, and possibly other BTK inhibitors, may provide protection against lung injury and even improve pulmonary function in hypoxic patients with COVID-19.

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.

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.

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.

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.

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.

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.

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.

Long term survival in patients with Waldenstrom macroglobulinemia diagnosed at a young age. Babwah A, Gustine J, Meid K, Dubeau T, XU L, Yang G, Hunter ZR, Treon SP, Castillo JJ. Br J Haematol. 2019 May;185(4):799-802. doi: 10.1111/bjh.15634. Because patients younger than age 50 make up only about 10 percent of all cases of WM, there is little data about how the disease affects this age group.  The authors conducted a study of patients diagnosed with WM at age 45 or younger and treated at Dana-Farber to gain insight into the clinical characteristics and survival outcomes of these patients. While patients under age 50 have a much higher 10-year overall survival rate than the broader WM population, they also appear to have a higher rate of hyperviscosity. CXCR4 mutations, which occurred in 44 percent of the patients studied, have been associated with hyperviscosity, which may explain the findings. The researchers also found that younger patients had longer responses and progression-free survival when treated with combination regimens rather than rituximab alone. These findings have important implications for the care of young patients with WM. (Dr. Babwah received a 2017 ASH Abstract Achievement Award and a 2018 IWWM Young Investigator Award for this research)

Primary Systemic Amyloidosis in Waldenstrom’s Macroglobulinemia. Zanwar S, Abeykoon J, Ansell SM, Gertz MA, Dispenzieri A, Muchtar E,  Sidana S, Tandon N, Rajkumar SV, Dingli D, Go RS, Lacy MQ, Kourelis TV, Witzig TE, Inwards D,  Buadi FK, Gonsalves WI, Habermann T, Johnston P, Nowakowski G, Kyle RA, Kumar SK and Kapoor P.  Leukemia 33, 790–794 (2019). doi.org/10.1038/s41375-018-0286-7. IgM paraprotein is implicated in 5-7% of patients with light and/or heavy chain immunoglobulin amyloidosis (AL/AHL). In this study, the authors address the impact of AL/AHL on the clinical course of WM and vice versa. Although AL/AHL is an uncommon complication of WM, it confers a significantly poorer survival (median 2.5 years) compared to WM patients without AL/AHL (median 12.1 years at Mayo Clinic). In contrast, the survival of AL/AHL patients with or without associated WM appears comparable. A free light chain ratio of >10 at diagnosis may predict future development of AL/AHL, but this finding requires external validation. This study was supported, in part, by the Katharine McCleary Research Fund and K. Edward Jacobi Research Partners Fund of the IWMF.

IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features. Sidana S, Larson DP, Greipp PT, He R, McPhail ED, Dispenzieri A, Murray DL, Dasari S, Ansell SM, Muchtar E, Gonsalves WI, Kourelis TV, Ramirez-Alvarado M, Kapoor P, Rajkumar SV, Lacy MQ, Buadi FK, Leung N, Kyle RA, Kumar SK, King RL, Gertz MA. Leukemia November 2019 doi.org/10.1038/s41375-019-0667-6  Patients with IgM amyloidosis have inferior outcomes compared with non-IgM amyloidosis, which may be attributed to lower hematologic response rates. The authors have characterized two different subtypes in this disease based on morphology (LPL and PPCN type), with distinct genetic features. To help improve future outcomes in these patients treatment should be targeted toward the underlying clone to achieve a deep response. This research was funded in part by the Katharine McCleary Research Fund and K. Edward Jacobi Research Partners Fund of the IWMF.

Incidental Lymphoplasmacytic Lymphoma Diagnosed Following Robotic-Assisted Laparoscopic Prostatectomy for Prostate Cancer. El-Taji O, Omer A, Al-Mitwalli A A, Agarwal S, Sharma A, Vasdev N.Curr Urol. 2019;13(3):166–168. doi:10.1159/000499275. The authors report a case of a 64-year-old male who presented with lower urinary tract symptoms and the first documented diagnosis of lymphoma (lymphoplasmacytic lymphoma/WM) involving the prostate.

Outcomes of bendamustine‐ or cyclophosphamide‐based first‐line chemotherapy in older patients with indolent B‐cell lymphoma.Olszewski AJ,  Butera JN,  Reagan JL, Castillo JJ. 2019 American Journal of Hematology, doi.org/10.1002/ajh.25707 This assessment of first-line regimens of bendamustine/rituximab (BR) among older patients (Medicare beneficiaries) with indolent B-cell lymphomas suggests that first-line bendamustine, despite longer event -free survival (EFS) and lower toxicity, did not improve overall survival (OS), and it still results in frequent hospitalizations, infections, and cardiovascular events during therapy. These results highlight the need for novel treatments with higher efficacy and lower toxicity in this population. Interventions that could mitigate the infectious toxicity (including growth factors, dose attenuations, and prophylactic antibiotics), as well as data on health-related quality of life are needed to establish the full value of BR in this setting. This study also alleviates concerns about high risk of opportunistic infections or secondary cancers associated with bendamustine, with no excess observed in this large, population-based cohort.

Severe nephritis as initial sign of Waldenstrom’s macroglobulinemia. Knoop T, Larsen KK, Leh F, Hemsing AL, Teigen IA, Reikvam H. Clin Pract. 2019 Dec 19;9(4):1184. doi.org/10.4081/cp.2019.1184 eCollection 2019. This team of Norwegian clinicians present a patient with severe renal involvement as an initial manifestation of Waldenstrom’s macroglobulinemia (WM). The usual presentation of WM is as an indolent lymphoma and renal involvement is, in contrast to multiple myeloma, very rarely seen.

Distal ileal ulcers as gastrointestinal manifestation of Waldenstrom macroglobulinemia. Kantamaneni V, Gurram K, Khehra R, Koneru G, and Kulkarni A. ACG Case Rep J. 2019;6(4):e00058. doi.org/10.14309/crj.0000000000000058  A 69-year-old man with Waldenstrom’s macroglobulinemia presented with chronic watery diarrhea for 6 months. He was treated with rituximab and bendamustine as well as budesonide, which relieved the diarrhea that was accompanied by weight loss. This case report adds to the many different clinical ways that WM can present and demonstrates that gastrointestinal symptoms of WM respond well to therapy.

Acalabrutinib monotherapy in patients with Waldenstrom macroglobulinemia: a single-arm, multicentre, phase 2 study. Owen RG, Rule S, D’Sa S, Thomas SK, et al. The Lancet Haematology, December 2019, doi.org/10.1016/S2352-3026(19)30210-8  This single-arm, multicenter (19 European academic centers and 8 academic centers in the US), phase 2 trial evaluated the activity and safety of acalabrutinib in 106 patients with Waldenstrom’s macroglobulinemia (14 were treatment naïve and 92 had relapsed or refractory disease). The responses observed for acalabrutinib were consistent with those reported for ibrutinib monotherapy in relapsed or refractory patients (overall response 91%) and treatment naive patients (overall response 100%) with similar follow-up times. Median duration of response, progression-free survival, and overall survival for acalabrutinib were not reached, but seemed similar to those reported for ibrutinib with or without rituximab. The quality of life improvement suggested with acalabrutinib further contributes to its treatment value in patients with Waldenstrom’s macroglobulinemia. The most common adverse events of any grade were headache, diarrhea, contusion, dizziness, fatigue, nausea, upper respiratory tract infection, constipation, and arthralgia. Headaches and diarrhea were low grade. Serious adverse events occurred in 53% of patients with the most common high-grade effects reported as lower respiratory tract infection and pneumonia. The adverse events reported are consistent with the known safety profile of acalabrutinib, with low atrial fibrillation, hypertension, and higher-grade bleeding. The authors conclude that single-agent acalabrutinib represents a valid treatment option for patients with relapsed or refractory disease; however, further studies are needed to establish whether outcomes can be improved with combination strategies.

Health-related quality of life in Waldenstrom Macroglobulinemia and IgM-related disorders: A single institution experience. Frustaci AM, Nichelatti M, Deodato M, Zamprogna G, Minga P, Pioltelli ML, Cairoli R, Tedeschi A. December 2019,  Hematological Oncology doi.org/10.1002/hon.2699. Assessment of health-related quality of life (HRQuoL) is becoming a critical component of disease outcome evaluation, predicting in some cases patient survival. The concept of HRQuoL encompasses several aspects of a patients’ well-being, ranging from physical health to functional, psychological, and social features and is a key component in judging the value of the health care provided or value -incorporated therapeutic efficacy. WM and IgM-MGUS/IgM-RD (related diseases) are chronic diseases with advanced median age at presentation that have clinical courses that are extremely heterogeneous, therefore HRQuoL assumes even greater importance in this setting. The authors analyzed the impact of diagnosis and patients’ characteristics on QuoL for 143 patients from Italy every six months for three years.  Patients with WM were more anxious than those with IgM-MGUS/IgM-RD. Age and clinical condition rather than diagnosis strongly influenced well-being. IgM related neuropathy also impacted the scores.

CXCR4S338X clonality is an important determinant of ibrutinib outcomes in patients with Waldenstrom macroglobulinemia. Gustine JN, Xu L, Tsakmaklis N, et al. Blood Adv. 2019;3:2800-2803. doi.org/10.1182/bloodadvances.2019000635  CRCX4 mutations confer both in vitro and clinical resistance to ibrutinib, particularly nonsense variants, such as CRCX4S338X. Therefore, high CRCX4S338X clonality adversely impacts clinical outcomes to ibrutinib therapy in patients with WM.

Chimeric antigen receptor T cells for treatment of transformed Waldenstrom macroglobulinemia. Bansal R, Jurcic JG, Sawas A, Mapara MY, Reshef R. Leuk Lymphoma. 2019 Sep:1-4. doi: 10.1080/10428194.2019.1665668. The authors, from Columbia University Irving Medical Center, NY, describe a patient with relapsed/refractory WM and histological transformation to high-grade B cell lymphoma which was also refractory to treatment which included autologous hemopoietic stem cell transplantation. The patient achieved complete remission (CR) following CD19-targeting chimeric antigen receptor T cell therapy without evidence of transformed disease or underlying WM after one year. The authors conclude that longer term follow up is necessary, but CAR-T cell therapy may be an effective treatment for relapsed/refractory WM that has not undergone histological transformation, as CD 19 is almost universally expressed on LPL cells. They are in ongoing, early phase clinical trials with CAR-T cell therapy that specifically include patients with WM.

Disseminated cytomegalovirus disease after bendamustine: a case report and analysis of circulating B- and T-cell subsets. Andrea Cona, Daniele Tesoro, Margherita Chiamenti, Esther Merlini, Daris Ferrari, Antonio Marti4, Carla Codecà, Giuseppe Ancona, Camilla Tincati, Antonella d’Arminio Monforte and Giulia Marchetti. BMC Infect Dis 19, 881 (2019). doi.org/10.1186/s12879-019-4545-7. The authors describe a severe form of disseminated CMV disease after R-bendamustine treatment in a patient with LPL/WM with massive bone marrow infiltration.

Spectral-domain optical coherence tomography of retinal vessels in Waldenstrom macroglobulinemia. Willerslev A, Larsen M,  Rothenbuehler SP,  Sørensen TL, Hammer T,  Paques M, Munch IC,  ACTA Ophthalmologica 2019 doi.org/10.1111/aos.14211 These authors found that Waldenstrom’s macroglobulinemia and total IgM > 60 g/l were associated with abnormal retinal blood vessels on optical coherence tomography. Awareness of these signs of hyperviscosity could potentially enable earlier detection of critical conditions in patients with Waldenstrom’s macroglobulinemia and improve the assessment of severity and treatment effect.

What is new in the treatment of Waldenstrom macroglobulinemia? Castillo JJ, Treon SP. Leukemia 2019. DOI: 10.1038/s41375-019-0592-8. Two experts in the treatment of WM focus on current treatments and exciting strategies under development for patients with WM.

Symptomatic hypoalbuminemia as an indication for treatment of Waldenstrom macroglobulinemia: a case report and review of the literature. Larsen JT, Leonard FD. Case Reports in Hematology, 2019, Article ID 1929124, doi.org/10.1155/2019/1929124. IWMF member, Dr. Fred Leonard, co-authored this case report of a patient with WM who presented with symptomatic hypoalbuminemia as the primary indication for initiating treatment. Clinicians seeing patients with WM with hypoalbuminemia and edema might not attribute these findings to the disease but instead to other comorbid conditions commonly seen in the elderly population that is typical of WM. This case report and literature review illustrate that hypoalbuminemia is frequently associated with WM, it can improve when WM responds to treatment, and it should be included in lists of both the common and protean manifestations of the disease.

How I treat Waldenstrom macroglobulinemia. Dimopoulos M and Kastritis E. Blood, 2019, DOI:10.1182/blood.2019000725 Two experts in WM from National and Kapodistrian University of Athens School of Medicine, Greece present different clinical scenarios and discuss treatment options, based on available data. The choice of therapy is based on the need for rapid disease control, presence of specific disease complications, and the patient’s age.

Ibrutinib monotherapy outside of clinical trial setting in Waldenstrom macroglobulinemia: practice patterns, toxicities, and outcomes. Abeykoon JP, Saurabh Z, Ansell SM, Gertz MA, Kumar S, Manske M, Novak AJ, King R, Greipp P, Go R, Inwards D, Muchtar E, Habermann T, Witzig TE, Thompson CA, Dingli D, Lacy MQ, Leung N, Dispenzieri A, Gonsalves W, Warsame R, Kyle RA, Rajkumar V, Parikh SA, and Kapoor P. 2019 BR J Haematol. doi-org.pitt.idm.oclc.org/10.1111/bjh.16168.  In this Mayo Clinic retrospective study of 80 patients who received ibrutinib for WM, the researchers found that ibrutinib is an effective drug for previously treated and treatment naïve MYD88L265P mutant WM. Other noteworthy findings include the unique rebound phenomenon associated with abrupt discontinuation of ibrutinib in patients with WM, toxicities, such as atrial fibrillation, as well as the poor outcomes of patients following ibrutinib discontinuation. It should be noted that ibrutinib was generally well tolerated in their study, but 18% of patients required dose reduction and 21% discontinued the therapy for reasons other than disease progression.

Gait speed, grip strength, and clinical outcomes in older patients with hematological malignancies. Liu MA, DuMontier, C, Murillo A, Hshieh TT, Bean JF, Soiffer RJ, Stone RM, Abel GA, Driver JA. Blood 2019;134(4):374-382. doi:10.1182/blood.2019000758. Gait speed is a marker of frailty and can independently predict survival and hospital utilization among older patients with blood cancers, including WM. Decreased grip strength was associated with worse survival, but not hospital utilization.

CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenstrom macroglobulinemia treated with ibrutinib. Castillo JJ, Xu L, Gustine JN, Keezer A, et al. 2019, Br J Haematol. doi:10.1111/bjh.16088 The results of this study suggest different response and progression free survival rates to ibrutinib for patients with WM with CXCR4NS (nonsense mutation) and CXCR4FS  (frameshift mutation), and advocate in favor of CXCR4 mutational testing as well as CXCR4-directed therapy.

Targeting IL-6 receptor reduces IgM levels and tumor growth in Waldenstrom macroglobulinemia. Han W, Matissek SJ, Jackson DA, Skiavanitis B, Elsawa SF. Oncotarget, 2019, 10(36), 3400-3407. Their data found that administration of Tocilizzumab to tumor bearing mice results in significant reduction in tumor volume and IgM secretion. The evaluation of the role of Tocilizzumab in patients with WM may provide therapeutic efficacy by reducing IgM production and slowing the rate of tumor growth. This research was funded in part by the IWMF.

Updates in prognostication and treatment of Waldenstrom’s macroglobulinemia. Advani P, Paulus A, Ailawadhi S. Hematology/Oncology and Stem Cell Therapy, May 2019, doi.org/10.1016/j.hemonc.2019.05.002 Recently, there has been an increase in research dedicated to WM that better explains the pathobiology of the disease. Researchers have identified several clinical and genetic markers that serve to prognosticate disease course and patient outcomes. This has led to dedicated clinical trials and the development of novel drugs/regimens. This review article from Mayo, Jacksonville aims to document some of the recent advancements with respect to prognostic markers and therapeutic options for patients with WM, as well as certain selected novel treatments with unique mechanisms of action, that are currently under development.

Current therapeutic options in Waldenstrom macroglobulinemia. Zanwar S, Abeykoon JP, Kapoor P. Oncology & Hematology Review. May 2019, 15(1):39-47. In this review, the authors summarize the implications of the different mutational profiles in WM, elaborate on the expanding therapies for WM, and discuss the factors that guide frontline and relapse/refractory therapy.

Targeting IL-6 receptor reduces IgM levels and tumor growth in Waldenstrom macroglobulinemia. Han, W, Matissek SJ, Jackson DA, Sklavanitis B, Elsawa SF. Oncotarget, 2019, 10(36):3400-3407. In Waldenstrom macroglobulinemia (WM), the tumor microenvironment (TME) modulates WM biology by secreting cytokines that promote the malignant phenotype. In previous work, the researchers have shown that TME-IL-6 promotes WM cell growth and IgM secretion in WM. Tocilizumab/Actemra is an anti-IL-6R antibody, which can competitively block IL-6 binding to the IL-6R. The authors investigated the efficacy of Tocilizumab in a preclinical mouse model of WM that considers the role of the TME in disease biology.  They found that administration of Tocilizumab to tumor bearing mice, results in a significant reduction in tumor volume and IgM secretion. Therefore, the evaluation of the role of Tocilizumab in WM patients may provide therapeutic efficacy by reducing IgM production and slowing the rate of tumor growth. This research was funded in part by the IWMF.

Progression risk stratification of asymptomatic Waldenstrom macroglobulinemia. Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, et al. J Clin Oncol 2019 DOI doi.org/10.1200/JCO.19.00394. The researchers studied 439 patients with asymptomatic Waldenstrom macroglobulinemia (AWM), who were diagnosed and observed at Dana-Farber Cancer Institute. Two different AWM cohorts were used for external validation; Mayo Clinic, Rochester MN and Clinical Therapeutics, National and Kapodistrian University of Athens, Greece. During the 23-year study period, with a mean follow-up of 7.8 years, 317 patients progressed to symptomatic Waldenstrom macroglobulinemia (72%). To assess progression risk in patients with AWM, they used a proportional hazards model using bone marrow infiltration, immunoglobulin M, albumin, and beta-2 microglobulin values as measures. The model divided the cohort into three distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.8 years, an intermediate-risk group with a median TTP of 4.8 years, and a low-risk group with a median TTP of 9.3 years. This classification system is useful for patient monitoring and care and, for the first time, to identify patients with high-risk AWM who may need closer follow-up or benefit from early intervention. The research leading to this risk stratification was funded in part by the IWMF. Note – try out their predictive model yourself – go to the website(link is external) they created for it.  The Markers they are focusing on in their predictive model are levels of:
* Bone Marrow Infiltration, * IgM Protein Level, * Beta2-Microglobulin Level, * Albumin Level.
Their model provides a quick way to analyze whether an asymptomatic patient is in a low risk, medium risk, or high risk of progression to needing treatment. The analysis they performed provide “statistical medians” in terms of time to progression in each category, so there would be an equal probability of someone progressing in less than the stated mean time period and in someone progressing in longer than the stated time period.

Importance of sequential analysis of TP53 variation in patients with Waldenstrom Macroglobulinaemia. Christian A, Davis Z, Walewska R, McCarthy H. Brit J of Haematology 2019, doi: 10.1111/bjh.15909. This pilot study targeted next generation sequencing (NGS) to test for TP53 variation in WM patients. Despite the small cohort size, a variant was detected in 4/14 (29%) patients. Two patients with a TP53 variant progressed while on BTK therapy and both patients were MYD88L265P negative and ibrutinib was insufficient to control progression. While TP53 may not be the contributing factor to therapy resistance, it may be an indicator of genomic instability. The development of TP53 variation over time indicates that TP53 gene testing should be performed to guide therapy choice and identify genetically high-risk patients. This could be performed as part of a panel to include the pertinent genes involved in WM, such as MYD88, CXCR4 and BTK. This study has also shown that targeted NGS has a greater potential for use in a clinical laboratory, showing that liquid biopsies can be used to monitor patients for TP53 variation. This would enable regular monitoring of patient disease while eliminating the need for repetitive invasive bone marrow testing. Further longitudinal studies of these patients in a larger multicenter setting are required to further elucidate the incidence and significance of acquired TP53 variation.

Serum cytokine patterns in immunoglobulin m monoclonal gammopathy‐associated polyneuropathy. Stork A, Rijkers G, Vlam L, Cats E, de Jong B, Fritsch‐Stork R, Veldink J, van den Berg L, Notermans N, van der Pol W-L. Muscle Nerve, 2019 doi:10.1002/mus.26462 Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM‐PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. The pathogenesis of IgM‐PNP is probably dominated by B cells or plasma cells because evidence for T‐cell involvement is lacking. The mechanisms underlying B‐cell activation and pathogenic antibody production that ultimately cause nerve damage are largely unknown. Immunoglobulin M monoclonal gammopathy‐associated polyneuropathy does not respond to treatments that have been successfully used for other demyelinating neuropathies, including intravenous immunoglobulin (IVIg) and cyclophosphamide given with prednisone. Cytokine expression patterns may suggest specific pathophysiological pathways that could help to design novel treatment strategies. To test whether B‐cell‐stimulating cytokines are increased in IgM‐PNP, the researchers measured serum concentrations of 11 cytokines in 81 patients with IgM‐PNP and 113 controls. They found median IL‐6 and IL‐10 serum concentrations differ between patients with anti‐MAG neuropathy and other patients with IgM‐PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune‐mediated disease mechanisms.

Prevalence and survival of smouldering Waldenstrom macroglobulinaemia in the United States. Pophali PA, Bartley A, Kapoor P, et al. Br J Haematol 2019; 184:1014. Using the data on WM from the 2004-2012 US National Cancer Database (NCDB) the researchers determined that approximately one in three or 28% of WM cases are smoldering at diagnosis. The 5-year conditional survival for smoldering WM of 70% is similar to ~80% in institutional reports with males have a 3-fold higher relative risk of progression to symptomatic disease compared to females, which is in agreement with this study’s results of longer survival in females. In a Surveillance, Epidemiology and End Results (SEER) study of WM (active + smoldering), older age, male sex and black race were associated with worse outcomes. Using the NCDB, these authors show that outcomes in smoldering WM are also associated with age and sex, but not with race. These proportion and survival rates vary by demographics.

Management of Immunotherapy-Related Toxicities, Version 1.2019. Thompson JA, Schneider BJ, Brahmer J, et al. J Natl Compr Canc Netw 2019;17(3):255-289 doi.org/10.6004/jnccn.2019.0013  These NCCN Guidelines provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. Medical and hematologic oncologists with experts from the fields of dermatology, gastroenterology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy present a consensus of the currently accepted approaches to treatment. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockage and a review of existing evidence.

How Recent Advances in Biology of Waldenstrom’s Macroglobulinemia May Affect Therapy Strategy. Baron M, Simon L, Poulain S, Leblond V. Curr Oncol Rep (2019) 21: 27. doi.org/10.1007/s11912-019-0768-4  Recently, WM has been described as a new oncogenic model. MyD88 mutation has been described as a key driver mutation and has functional consequences which could be targeted. Other mutations, such as CXCR4 or TP53, have been reported. These mutations are associated with different clinical presentation, prognosis, and treatment response. Mutational status may influence therapeutic choice in some patients, but additional data are required. New targeted therapies are on development.

CD13 expression in B cell malignancies is a hallmark of plasmacytic differentiation. Raimbault A, Machherndl-Spandl S, Itzykson R, Clauser S, Chapuis N, Mathis S, Lauf J, Alary A-S, Burroni B, Kosmider O, Fontenay M, Bene MC, Durrieu F, Bettelheim P, Bardet V. Brit J Haematology, 2019, 184, 625-633. doi.org/10.1111/bjh.15584  The diagnosis of Waldenstrom Macroglobulinaemia (WM)/lymphoplasmacytic lymphoma (LPL) remains one of exclusion because other B‐cell lymphoproliferative disorders (B‐LPD), such as marginal zone lymphoma (MZL), can fulfil similar criteria, including MYD88L265P mutation. It has been suggested that expression of the myeloid marker CD13 is more frequent in LPL than in other B‐LPD and has also been described on normal and malignant plasma cells. Here, the authors tested CD13 expression in a cohort of 1037 B‐LPD patients from 3 centers by flow cytometry. Their results suggest that testing for CD13 expression in routine flow cytometry panels could help to discriminate WM/LPL from other B‐LPD.

Ibrutinib for the treatment of Bing-Neel syndrome: A multicenter study. Castillo JJ, Itchaki G, Paludo J, Varettoni M, Buske C, Eyre TA, Chavez JC, Shain KH, Issa S, Palomba ML, Pasvolsky O, Simpson D, Talaulikar D, Tam CS, Tedeschi A, Ansell SM, Nayak L, Treon SP. Blood. 2019;133(4):299-305. In this multicenter study ibrutinib was administered to 28 patients with Bing-Neel syndrome. The oral Bruton tyrosine kinase (BTK) inhibitor showed rapid and durable symptomatic and radiologic responses in patients with the syndrome. The authors conclude that ibrutinib therapy is effective in patients with Bing-Neel syndrome and should be considered as a treatment option in these patients.

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.

Ibrutinib-associated bleeding: pathogenesis, management, and risk reduction strategies. Shatzel KK, Olson SR, Tao DL, McCarty OJT, Danilov AV, DeLoughery TG. J Thromb Haemost 2017, 15: 835-47. Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that has proven to be an effective therapeutic agent for multiple B-cell-mediated lymphoproliferative disorders, including WM. Ibrutinib carries an increased bleeding risk compared with standard chemotherapy. This can range from minor bleeding to life-threatening hemorrhage.  In this review, the authors caution against using non-steroidal anti-inflammatory drugs, fish oils, vitamin E, and aspirin containing products, vitamin K antagonists, among other risk reduction strategies.

The importance of the genomic landscape in Waldenstrom’s macroglobulinemia for targeted therapeutical interventions. Sacco A, Fenotti A, Affo L, Bazzana S, Russo D, Presta M, Malagola M, Anastasia A, Motta M, Patterson CJ, Rossi G, Imberti L, Treon SP, Ghobrial IM, Roccaro AM. Oncotarget, 2017, Vol 8, (No.21), pp:35435-35444. The authors review the genomics and miRNAs aberrations in WM providing an overview of the clinical relevance of the latest acquired knowledge. The research for this publication was funded in part by the IWMF.

How I manage monoclonal gammopathy of undetermined significance. Go, RS, Rajkumar SV.  Blood 2018 131:163-173; doi.org/10.1182/blood-2017-09-807560 Monoclonal gammopathy of underdetermined significance (MGUS) is, in many ways a unique hematologic entity. MGUS is considered an obligate precursor to several lymphoplastic malignancies, including immunoglobulin light-chain amyloidoisis, multiple myeloma, and Waldenstrom macroglobulinemia. The authors present 7 vignettes to illustrate common clinical management questions that arise during the course of MGUS. They describe how they practice provide a rationale for their approach. They also discuss the potential harms associated with MGUS diagnosis, a topic rarely broached between patients and providers.

Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenstrom macroglobulinaemia. Gustine JN, Meid K, Dubeau T, Hunter ZR, Xu L, Yang G, Ghobrial IM, Treon SP and Castillo JJ. British Journal of Haematology, 2017, 177, 717–725; DOI: 10.1111/bjh.14743. Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenstrom macroglobulinaemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. A large retrospective study showed the odds of developing symptomatic hyperviscosity were 370-fold higher with serum IgM levels >60 g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival. The findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.

Diagnosis and Management of Waldenström Macroglobulinemia Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. Kapoor P, Ansell SM, Fonseca R, et al. JAMA Oncol.2017;3(9):1257–1265. i:10.1001/jamaoncol.2016.5763. The Mayo Clinic Cancer Center Myeloma, Amyloidosis and Dysproteinemia and Lymphoma Disease-Oriented Groups have updated their evidence-based recommendations for the management of WM. Important advances have led to a broader understanding of the biology of WM since their initial risk stratification–based approach was published in 2010. Clinical and observational studies published or presented through December 2015 are reviewed to provide consensus recommendations for clinicians. The guidelines are formulated using a grading system of evidence and grades of recommendations

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and WM. Chen C, Siegel D, Gutierrez M, et al, Blood, 2017, doi:10.1182/blood-2017-08-797886. The XPO1 inhibitor selinexor is an oral agent with a completely novel mechanism of action and anti-MM/WM activity in combination with dexamethasone that could provide a new option for patients with relapsed or refractory disease.

Acquired mutations associated with ibrutinib resistance in Waldenstrom macroglobulinemia. Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, Kofides A, Patterson CJ, Meid K, Gustine J, Dubeau T, Palomba ML, Advani R, Castillo JJ, Furman RR, Hunter ZR, Treon SP,Blood 2017 129:2519-2525; doi.org/10.1182/blood-2017-01-761726  Ibrutinib produces high response rates and durable remissions in Waldenstrom macroglobulinemia (WM) that are impacted by MYD88 and CXCR4WHIM mutations. Disease progression can develop on ibrutinib, although the molecular basis remains to be clarified. This study showed that Bruton tyrosine kinase (BTK) mutations are common in WM patients with clinical disease progression while on ibrutinib, and are associated with mutated CXCR4. The research for this publication was funded in part by the IWMF.

New developments in the management of Waldenstrom macroglobulinemia. Abeykoon, J. P., Yanamandra, U., & Kapoor, P. (2017), Cancer Management and Research, 9, 73–83. doi.org/10.2147/CMAR.S94059 The management of WM is evolving, with a deeper understanding of the disease pathophysiology and introduction of new drugs. In this excellent review article, the authors discuss new developments in the management of WM based on data published over the past 15 years, with an emphasis on the role of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib.

Once-weekly ofatumumab in untreated or relapsed Waldenström’s macroglobulinaemia: an open-label, single-arm, phase 2 study. Furman RR, Eradat HA, DiRienzo CG, Hofmeister CC, Hayman SR, Leonard JP, Coleman M, Advani R, Chanan-Khan A, Switzky J, Liao QM, Shah D, Jewell RC, Lisby S,and Lin TS, Lancet Haematol 2017; 4: e24–3, dx.doi.org/10.1016/S2352-3026(16)30166-1. The aim of the study was to assess the safety and clinical activity of intravenous ofatumumab monotherapy for untreated and relapsed Waldenström’s macroglobulinaemia. They found a high proportion of patients achieved an overall response with ofatumumab as a single therapy and this treatment was well tolerated, with a low incidence of IgM flare. This therapy might be a non-chemotherapeutic treatment option for patients with Waldenström’s macroglobulinaemia, especially those with high IgM concentrations.

How I treat cryoglobulinemia. Muchtar E, Magen H and Gertz MA, Blood. 2017;129(3):289-298. Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Found in some patients with Waldenstrom’s macroglobulinemia, the authors explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients, including one with WM.

Dexamethasone, rituximab and cyclophosphamide for relapsed and/or refractory and treatment-naïve patients with Waldenström macroglobulinaemia. Paludo J, Abeykoon JP, Kumar S, et al.  Br J Haematol. 2017 Aug 8. doi: 10.1111/bjh.14826. The management of Waldenstrom macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab, and cyclophosphamide (DRC) as upfront treatment . The authors report on the efficacy of DRC, focusing on relapsed/refractory patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88WT genotype. They additionally report on the activity of DRC based on the MYD88L265P mutation status. They conclude that in contrast to ibrutinib, DRC offers a less expensive, fixed-duration option, with preliminary data suggesting efficacy independent of the patients’ MYD88 status.

Waldenstrom’s Macroglobulinemia(link is external). 1st ed, Leblond V, Treon S, Dimoploulos M (eds.), Springer International Publishing, Switzerland. 2017. With the  participation of many widely-recognized experts, this comprehensive book sheds new light on clinical, biological, and therapeutic data on Waldenstrom’s macroglobulinemia. The book is divided into seven parts; tumor cells and microenvironment, epidemiology and genetic predisposition, clinical features, laboratory investigations, response, prognostic factors, and treatment options and recommendations.

Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenstrom macroglobulinemia. Gustine, J. N., Meid, K., Dubeau, T., Hunter, Z. R., Xu, L., Yang, G., Ghobrial, I. M., Treon, S. P. and Castillo, J. J. (2017), Br J Haematol, 177: 717–725. doi:10.1111/bjh.14743. Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenstrom macroglobulinemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. They carried out a large retrospective study in newly diagnosed WM patients, Their findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.

Investigation and management of IgM and Waldenström-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel(link is external). D’Sa, S., Kersten, M. J., Castillo, J. J., Dimopoulos, M., Kastritis, E., Laane, E., Leblond, V., Merlini, G., Treon, S. P., Vos, J. M. and Lunn, M. P. (2017), Br J Haematol. doi:10.1111/bjh.14492
The International Workshops on Waldenström Macroglobulinaemia (IWWM) have proposed criteria for diagnosis and therapy (Owen et al, 2003), response (Owen et al, 2013), and treatment (Dimopoulos et al, 2014) in WM patients. As part of its latest consensus deliberations (IWWM8, London 2014), the panel reviewed the management of peripheral neuropathies associated with IgM monoclonal gammopathies, including WM.  Importantly, a consensus regarding the use of clinical outcome measures and recommended models of care for this group of patients is discussed, as well as appropriate treatment interventions.

Genomics, Signaling, and Treatment of Waldenström Macroglobulinemia. Zachary R. Hunter, Guang Yang, Lian Xu, Xia Liu, Jorge J. Castillo, and Steven P. Treon Journal of Clinical Oncology  2017, 35(9):994-1001. Next-generation sequencing studies have identified highly recurrent somatic mutations in MYD88, CXCR4, ARID1A, and CD79, and other genes, as well as copy number alterations effecting important regulatory genes in chromosome 6q and elsewhere. Transcriptional changes, disease presentation, therapeutic outcome, and overall survival are affected by mutations in MYD88 and/or CXCR4. (Article provided with permission of the Bing Center for Waldenstrom’s Macroglobulinemia.)

Ibrutinib for patients with rituximab-refractory Waldenström’s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Dimopoulos, Meletios A et al. The Lancet Oncology, 2017,18(2):241 – 250. In the era of widespread rituximab use for Waldenström’s macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström’s macroglobulinaemia. This study assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. (Article provided with permission of the Bing Center for Waldenstrom’s Macroglobulinemia.)

Waldenstrom Macroglobulinemia: 2017 Update on Diagnosis, Risk Stratification, and management. Gertz, MA, Am. J. Hematol. 92:209–217, 2017. This Mayo Clinic clinician provides a technical clinical update of WM, as part of the Annual Clinical Updates in Hematological Malignancies Series from the American Journal of Hematology.

Guidelines for the diagnosis, treatment and response criteria for Bing-Neel syndrome. Minnema  MC. et al. Haematologica, 2017 Volume 102(1):43-51 obtained from the Haematologica Journal website(link is external). Bing Neel syndrome is a rare disease manifestation of Waldenstrom’s macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. These technical guidelines describe the clinical symptoms, as well as, the appropriate laboratory and radiological studies that can aid in the diagnosis. A discussion of prospective clinical trials and protocols that employ uniform treatment for delineating treatment outcomes is included.

Prospective, multicenter clinical trial of everolimus as primary therapy in Waldenstrom macroglobulinemia (WMCTG 09-214). Treon SP, Meid K, Christina Tripsas C, Heffner L, Eradat H, Badros AZ, Xu L, Hunter ZR, Yang G, Patterson CJ, Gustine J, Castillo JJ,  Matous J, Ghobrial IM. Blood Dec. 2016 128(22):4487. Everolimus inhibits mTOR, a component of PI3K/AKT pro-survival signaling triggered by MYD88 and CXCR4 activating mutations in Waldenstrom’s Macroglobulinemia (WM). They evaluated everolimus in a prospective, multicenter study of symptomatic, previously untreated WM patients. They found that everolimus is active in previously untreated WM. Serum IgM discordance with bone marrow disease burden was common and treatment cessation often lead to rapid serum IgM rebound. Pneumonitis also appeared more pronounced in untreated versus previously treated WM patients. They concluded that risks and benefits of everolimus should be carefully weighed against other primary WM therapy options.

Treatment Recommendations for Waldenström Macroglobulinemia from the Eighth International Workshop on WM. Leblond, V., et al. Blood, September 8, 2016, Volume 128, Number 10. These are updated treatment recommendations from the August 2014 International Workshop in London, England. (Article provided with permission of Dr. Steven Treon of the Bing Center for Waldenstrom’s Macroglobulinemia.)

Paraproteinemic neuropathy: a practical review.  Rison RA, Beydoun SR, BMC Neurology 2016 16:13 doi.org/10.1186/s12883-016-0532-4 The term paraproteinemic neuropathy describes a heterogeneous set of neuropathies characterized by the presence of homogeneous immunoglobulin in the serum. An abnormal clonal proliferation of B-lymphocytes or plasma cells produces the immunoglobulins in excess. In this review, the authors provide a clinically practical approach to diagnosis and management of patients with this condition.

Future therapeutic options for Waldenstrom macroglobulinemia. Castillo JJ, Hunter ZR, Yang G, Argyropoulos K, Palomba ML, Treon SP. Best Practice & Research Clinical Haematology 29 (2016) 206-215. This review focuses on potential therapies that could change the landscape of treatment of patients with WM, specifically focusing on inhibitors

Waldenström’s Macroglobulinemia: Subtype Review. Lymphoma Coalition, August 2016. This is an overview of the disease prepared by the Lymphoma Coalition with review and editing assistance provided by the IWMF. It covers the basic biology of WM, along with current treatment recommendations from NCCN and from Dr. Steven Treon of the Bing Center for WM. Special sections of this report look at treatment availability and clinical trial activity in multiple countries and discuss the patient experience in terms of physical symptoms and psychological and social factors that impact the patient’s sense of well being.

Waldenstrom macroglobulinemia: biology, genetics, and therapy(link is external). Paludo J, Ansell SM, Blood and Lymphatic Cancer: Targets and Therapy, 2016, 6:49-58. An excellent review that covers the pathophysiologic understanding of WM in light of the discovery of MYD88 and CXCR4, as well as treatment regimens with a focus on ibrutinib.

Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia. Jorge J. Castillo et al, British Journal of Haematology, 2016. A multi-institutional task force was formed during the 8th International Workshop for WM in London to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, recommendations are provided for history-taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis, and imaging studies. Guidance is also provided on the initial evaluation of special situations, such as anemia, hyperviscosity, neuropathy, Bing-Neel syndrome, and amyloidosis. (Article provided with permission of Jorge J. Castillo of the Bing Center for Waldenstrom’s Macroglobulinemia.)

Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenstrom macroglobulinemia. Tompkins VS, Sompallae R, Rosean TR, Walsh S, Acevedo M, Kovalchuk AL, Han S-S, Jing X, Holman C, Rehg JE, Herms S, Sunderland JS, Morse HC, and Janz S. Blood Cancer Journal (2016) 6, e488; doi:10.1038/bcj.2016.95. The authors presented a genetically engineered mouse mode (GEMM) of human Ig M+ LPL in which WM-like neoplasms develop predictably with short latency and high tumor incidence. However, the BCL2+IL6+AID− model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM. This research was funded by the IWMF.

How I Treat Waldenstrom Macroglobulinemia. Treon, S. P., Blood. First Edition Paper, prepublished online May 22, 2015, DOI 10.1182. Treatment recommendations published by Dr. Steven Treon of the Dana-Farber Cancer Institute in 2015. (Article provided with permission of the Bing Center for Waldenstrom’s Macroglobulinemia.)

Biology, Prognosis, and Therapy of Waldenstrom Macroglobulinemia(link is external). Castillo JJ, Ghobrial IM, Treon SP,  in Non-Hodgkin Lymphoma, Cancer Treatment and Research 165, Springer International Publishing, Switzerland, 2015, A.M. Evens and K.A. Blum (eds.), DOI 10.1007/978-3-319-13150-4_7. In this chapter, the authors review the recent advances in the biology of WM and the current therapeutic options for untreated and relapsed WM patients. They also discuss the role of prognostic factors and current evidence supporting an improvement in the survival of WM patients in the last decade.

Systemic Light Chain Amyloidosis: an update for treating physicians(link is external). Merlini G, Wechalekar AD, Palladini G, Blood. 2013;121(26):5124-5130. In immunoglobulin light chain amyloidosis a small, indolent plasma cell clone synthesizes light chains that cause devastating organ damage. Early diagnosis, based on prompt recognition of “red-flags” before advanced cardiomyopathy ensues, is essential for improving outcomes, such as recovery of organ function and prolonged survival.

MYD88 L265P Somatic Mutation in Waldenström’s Macroglobulinemia(link is external). Steven P. Treon et al, Dana-Farber Cancer Institute, Boston MA. This article, published in the New England Journal of Medicine in 2012, outlines the seminal discovery of the prevalence of the MYD88 L265 P mutation in WM patients. The research leading to this discovery was funded in part with the support of the IWMF.

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