👤 Shayna Sarosiek

Approximately 95% of lymphoplasmacytic lymphomas (LPL) are IgM secreting and are characterized as Waldenstrom Macroglobulinemia (WM). Conversely, non-IgM secreting LPL are rare. As part of the 12th International Workshop on WM (IWWM-12), a consensus panel of experts was tasked to develop recommendations for the management and response assessment of non-IgM LPL. The panel considered that in view of available molecular, pathological and clinical data, non-IgM LPL should be considered as a separate sub-entity of LPL. The panel further recommended that the IWWM-2 consensus criteria used for IgM LPL (WM) treatment initiation, should also be used for non-IgM LPL and be independent of IgG or IgA paraprotein level unless symptomatic hyperviscosity is present. The panel agreed that based on current evidence, there is insufficient data to support a different clinical management for non-IgM vs IgM (WM) LPL. Moreover, the panel advised that patients with non-IgM LPL should be treated in a similar manner to patients with IgM LPL independent of MYD88 mutation status until more is known about its impact on treatment outcomes for non-IgM LPL patients. The panel therefore recommends the use of the IWWM-11 IgM LPL (WM) response criteria for cases of non-IgM LPL with a monoclonal IgA or IgG paraprotein component, but creating a specific panel to develop formal response criteria for this LPL subset was also recommended. Show less

Venetoclax showed promising activity in a small phase II trial in relapsed/refractory Waldenström macroglobulinemia (WM). To report the clinical activity of venetoclax and prognostic factors associated with outcomes in a larger cohort, we retrospectively identified 76 patients with relapsed/refractory lymphoplasmacytic lymphoma (LPL)/WM treated with venetoclax monotherapy at nine US medical centers. The median age at venetoclax treatment initiation was 66 years. MYD88, CXCR4, and TP53 mutations were detected in 65 (94%), 23 (40%), and 10 (22%) patients, respectively. The median number of prior lines of treatment was 3, including covalent BTK inhibitor in 82% and alkylating agent in 71% of patients. The overall and major response rates to venetoclax were 70% and 63%, respectively. The median and 2-year progression-free survival (PFS) were 28.5 months and 57%, respectively. The median and 2-year overall survival were not reached and 82%, respectively. Prior treatment with BTK inhibitor was the only factor associated with PFS in multivariate analysis (hazard ratio 2.97, p = 0.012). Venetoclax dose interruptions and/or reductions occurred in 27 patients (41%). Five patients (7%) developed laboratory tumor lysis syndrome (TLS), including 3 (4%) with clinical TLS. Venetoclax resulted in a high response rate and a prolonged PFS in patients with heavily pretreated LPL/WM. Show less

The diagnosis and treatment of Waldenstrom macroglobulinemia (WM) are the subjects of this two-part review, which aims to provide current and thorough knowledge of these topics. The first portion of the study, previously published, investigated the epidemiology, etiology, clinicopathological aspects, differential diagnosis, prognostic factors, and impact on WM-specific groups. Specifically, this second section examines both the standard consolidated method and the new therapeutic strategy to handle the complex topic of the treatment of WM. WM has no cure, but therapies can improve survival. Treatment for WM/LPL patients should be initiated when they exhibit symptoms, and the IgM level should not determine WM treatment.Current guidelines suggest various initial personalized therapy treatments, typically chemoimmunotherapy (CIT) or BTK inhibitors (BTKi).Patients with WM can be put into three groups based on their MYD88 and CXCR4 mutational status: those with MYD88 mutations but no CXCR4 mutations (MYD88MUT/CXCR4WT), those with both MYD88 and CXCR4 mutations (MYD88MUT/CXCR4MUT) and those who do not have both MYD88 and CXCR4 mutations (MYD88WT/CXCR4WT).The objective of treatment is to alleviate symptoms and mitigate the risk of organ impairment.The timing of response evaluations, including BM, should be established on a case-by-case basis, informed by clinical and laboratory assessments.Patients with relapsed/refractory WM following chemotherapy and covalent Bruton tyrosine kinase inhibitors may choose non-covalent Bruton tyrosine kinase inhibitors, novel anti-CD20 monoclonal antibodies, BCL-2 inhibitors, or more intensive chemotherapy regimens.Patients who are younger and healthier and have not responded to both CIT and BTKi may be good candidates for an autologous stem cell transplant (ASCT).Second-generation anti-CD19 CAR T cells exhibit anti-WM activity in both in vitro and in vivo settings.From 2.4% to 11% of patients with WM undergo histological transformation, predominantly to diffuse large B-cell lymphoma (DLBCL). The median duration between diagnosis and transformation is 4.6 years.WM patients have a higher risk of secondary cancers.HSV and HZV prophylaxis may be beneficial for patients needing extensive treatment. Screening for Hepatitis B is necessary. Pneumocystis jiroveci prophylaxis is highly recommended. SARS-CoV- 2 and seasonal flu vaccines should be available to all WM patients. Show less