By Sue Herms,

IWMF Research Committee Member

Long-Term Results Published from French Clinical Trial of Bendamustine and Rituximab Therapy in Treatment Naïve WM The British Journal of Haematology has published an update with long-term results from the 2013- 2017 clinical trial of bendamustine and rituximab therapy in 69 treatment naïve WM patients that was conducted by the French Innovative Leukemia Organization (FILO). With a median follow-up of 76.1 months, the five-year progression-free survival rate was 66.63%, and the overall survival rate was 80.01%. Nineteen patients died—six from disease progression (including aggressive B cell transformation and amyloidosis), two from acute myeloid leukemia, five from solid cancers, and six from other causes (including brain hemorrhage, cardiac failure, organ failure, lung fibrosis, and flu). Sixteen patients relapsed, with a median time of 35.3 months from the end of first treatment to initiation of second treatment. Ibrutinib-based second-line therapy was more efficient than other second-line approaches, with a median progression-free survival of 45 months as compared with the whole group of relapsed patients who had a median progression-free survival of 21 months after second-line therapy with other drugs. Persistent toxicity from bendamustine and rituximab therapy was primarily from low blood counts, which were observed in 51% of patients, and included neutropenia (low neutrophil count), anemia, and thrombocytopenia (low platelet count); the median duration of low blood counts was less than one year. The rate of secondary cancers was 17.66% at 66 months. Although a lower overall survival was observed for the six patients in the study who did not have an MYD88 mutation, it was not statistically significant. Similarly, while CXCR4-mutated patients fared somewhat less well, this too did not reach statistical significance.

Chinese Researchers Look at Survival Effect of Early Progression in WM Patients – Researchers from the Chinese Working Group of Waldenström Macroglobulinemia performed a retrospective analysis of WM patients from the database of the Chinese Registration Network for WM to determine the outcomes on prognosis and survival of early disease progression, defined as progression that occurs within 24 months of diagnosis and first-line treatment. All 373 WM patients in the study received 3-10 courses of first-line therapy, including 143 with rituximab-based chemotherapy, 51 with bortezomib (Velcade)-based therapy, eight with BTK inhibitors, and 171 with traditional chemotherapy such as fludarabine with or without cyclophosphamide, chlorambucil alone, or cyclophosphamide with vincristine and prednisone. Progression within 24 months after diagnosis and treatment occurred in 98 patients (26.3%). The median overall survival was 40 months in these patients, which was significantly shorter than the 156 months achieved by patients who had not progressed with 24 months of diagnosis and first-line treatment. The researchers noted some limitations to their study, including the fact that BTK inhibitors and bendamustine-based treatments have only recently been available in China. Also, genetic characteristics of these patients (including MYD88 and CXCR4 mutation status) were not available, and their impact on prognosis and survival could not be analyzed. This research was published in the journal Holistic Integrative Oncology.

Median progression-free survival was less in patients with chromosome abnormalities compared to those with normal chromosomes…

Researchers from Italy Study Impact of Chromosome Abnormalities on Clinical Outcomes in WM – Italian researchers looked at how the presence and number of chromosomal abnormalities in WM cells affected clinical outcomes in WM patients. This retrospective study was based on a group of WM patients diagnosed between 2000 and 2023 at the University of Padua, 64 of whom had chromosome analyses (called karyotypes) of their cancer cells and were followed up for a median of 51 months. It was determined that 30 of the 64 (46.9%) had some abnormality of their chromosomes, either in their number or structure. A majority had one abnormality, but there were several with multiple abnormalities. The most frequent abnormalities included the 6q deletion (a missing part of the genetic material in the long arm of chromosome 6); trisomy of chromosome 3 (three instead of the normal number of two chromosomes); and the 11q deletion (a missing part of the genetic material in the long arm of chromosome 11). Loss of the Y chromosome was also detected. These patients tended to be older at diagnosis, suggesting a correlation between older age and higher prevalence of chromosome abnormalities. The researchers also observed a higher prevalence of secondary cancers in patients with chromosome abnormalities. Major response rates to first-line therapy tended to be less in those with abnormal chromosomes than in those with normal chromosomes, although statistical significance was not reached. Median progression-free survival was less in patients with chromosome abnormalities compared to those with normal chromosomes (65.8 months vs. 117.8 months, respectively); similarly, median overall survival was less in patients with chromosome abnormalities (76.1 months vs 167.7 months, respectively). This study was published in the journal Annals of Hematology.

NCI Researchers Analyze Genes from WM Family Pedigrees – It is known that the risk for WM is elevated among first-degree relatives (parents, siblings, and children) of WM patients; however, the list of genes and their variants that cause genetic susceptibility to WM is incomplete. Researchers from the US National Cancer Institute (NCI) performed genetic sequencing of 64 WM family pedigrees, most of which had at least three members with WM, to look for evidence of the genes and gene variants that cause susceptibility to the disease. This study, published in the journal Blood Neoplasia, identified several genes and gene variants that were pathogenic or likely to be pathogenic in each family pedigree. Variants seen in a few family pedigrees that may warrant further investigation were identified in two genes, TREX1 and SAMHD1. In addition, the researchers identified other cancer pre-disposing genes of interest, such as POT1, RECQL4, PTPN11, and PMS2, that play a role in the regulation of the immune response, DNA repair, and the maintenance of telomeres (sections of DNA at the ends of the chromosomes that protect chromosomes from damage). However, the overlap of these genes between different WM families was modest, indicating that each WM family pedigree is largely unique and that multiple genes are likely to be involved in the pathogenesis of WM.

Texas Study Compares Survival Outcomes in Hispanic and Non-Hispanic Patients with LPL/WM – A study presented by the University of Texas Health Science Center at the 2024 American Association of Cancer Research (AACR) Annual Meeting examined patient characteristics, treatment, and survival patterns in Hispanic vs. non-Hispanic patients with lymphoplasmacytic lymphoma (LPL)/WM. Data reported to the National Cancer Database were analyzed from 2004-2019 and identified 17,915 such patients, 3% of whom were Hispanic and 92% non-Hispanic. Hispanic patients were mostly male, as were non-Hispanics, and the median age at diagnosis for Hispanics was 68 years, compared to non-Hispanics at 71 years. Education levels and income tended to be less for Hispanics than non-Hispanics. More Hispanics were uninsured and were less likely to have government-sponsored insurance. During this period, 68% of Hispanics and 62% of non-Hispanics received treatment, and most Hispanics were treated at academic/research centers, while most non-Hispanics received treatment from community cancer centers. There was no difference in overall survival between the two groups, and there were no independent factors in either group associated with better or worse overall survival.

Phase 2 Trial of Loncastuximab Tesirine for Relapsed or Refractory WM is First Trial in WM-NET Clinical Trials Network – A Phase 2 clinical trial of the drug loncastuximab tesirine (Zynlonta) for relapsed or refractory WM is the first trial to be included in the newly formed WM-NET clinical trial network established by the Dana-Farber Cancer Institute and funded by the IWMF. The drug, already approved by the US Food and Drug Administration for diffuse large B cell lymphoma, will be available to WM participants who have received at least two prior treatments, including an anti-CD20 antibody such as rituximab and a BTK inhibitor such as ibrutinib (Imbruvica). Loncastuximab tesirine is an antibody drug conjugate that combines a monoclonal antibody (in this case an anti-CD19 antibody) with a toxin in order to deliver the killing toxin directly to the cancer cells. The trial will be conducted at Dana-Farber Cancer Institute, Mayo Clinic, and Fred Hutchinson Cancer Center. The trial identifier on www. is NCT05190705. For more information on WM-NET, see the article “WM-NET: A New Solution to the Clinical Trial Challenges in WM” on page 5 of the January 2024 Torch.

Phase 2 Trial Available for Newer BCL-2 Inhibitor Therapy in Relapsed or Refractory WM – BeiGene is sponsoring a Phase 2 clinical trial to evaluate the safety and effectiveness of its oral BCL-2 inhibitor called BGB- 11417 (Sonrotoclax) in patients with relapsed or refractory WM. The trial, which expects to enroll approximately 85 participants, is open at 31 locations in the US, Australia, China, France, Spain, and the United Kingdom. BGB- 11417 is a second-generation drug in the same drug class as venetoclax (Venclexta). On, the trial identifier is NCT05952037.

Article Compares Immunoglobulin Replacement Therapy to Prophylactic Antibiotics in Blood Cancer Patients with Hypogammaglobulinemia – An article in the journal Blood Advances compared immunoglobin replacement therapy to prophylactic antibiotics to treat hypogammaglobulinemia (low levels of normal antibodies) in people with blood cancers. Hypogammaglobulinemia may put one at a greater risk of getting infections. This trial, conducted in seven hospitals in Australia and New Zealand from August 2017-April 2019, enrolled 63 patients with either a history of repeated serious infections or IgG levels less than 400 mg/dL (4 g/L). Participants were randomized to receive intravenous IgG every four weeks or daily antibiotics (either trimethoprim-sulfamethoxazole or doxycycline) for a total of 12 months. The primary outcome was the proportion of patients alive on the assigned treatment at 12 months; 76% in the immunoglobulin replacement arm and 71% in the antibiotic arm achieved this result. The lowest time point to first major infection was 11.1 months for the immunoglobulin replacement group and 9.7 months for the antibiotic arm. The rates of major infections were similar in both arms. Three participants in the immunoglobulin replacement arm and two in the antibiotic arm experienced Grade 3 or greater (severe to life threatening to causing death) treatment-related adverse events.

BI-1206 targets a mechanism of resistance to rituximab therapy and aims to restore rituximab’s benefit to patients who are demonstrating resistance to therapy.

Early Phase 1 Data Available for Novel Monoclonal Antibody Combined with Rituximab for Relapsed/ Refractory NHL – Early data are available from a Phase 1 clinical trial of the monoclonal antibody BI-1206 in combination with rituximab for the treatment of relapsed or refractory non-Hodgkin’s lymphoma (NHL). BI-1206 targets a mechanism of resistance to rituximab therapy and aims to restore rituximab’s benefit to patients who are demonstrating resistance to therapy. Among eight patients evaluated, there were four partial responses and one complete response (by a patient with marginal zone lymphoma).

Phase 1 Trial Reports First Results for BTK Degrader Used in Blood Cancer Patients with CNS Involvement – Nurix Therapeutics announced its first response results in patients with B cell blood cancers who had central nervous system (brain and spinal cord) involvement and were treated in a Phase 1 clinical trial with its oral BTK degrader called NX-5948. NX-5948 was detected in all spinal fluid samples available from treated patients, demonstrating that the drug was able to cross the blood-brain barrier. The company’s presentation included case studies of two patients who had progressed after multiple lines of previous treatment, one with chronic lymphocytic leukemia (CLL) and one with aggressive primary central nervous system lymphoma (PCNSL). Both patients had complete responses to NX-5948 therapy in their brain scans and spinal fluid. While the CLL patient remained in response at the time of this report, the PCNSL patient developed a new brain lesion. The findings were presented during the 2024 American Association of Cancer Research (AACR) Annual Meeting.

The author gratefully acknowledges the efforts of Grete Cooper, Peter DeNardis, Julianne Flora-Tostado, Tom Hoffmann, Richard Savoy, and others in disseminating research news of interest to the WM community. The author can be contacted at for questions or additional information.