Recent updates in the indolent lymphomas: Update on marginal zone lymphoma and Waldenström's macroglobulinemia.

Marginal Zone Lymphoma (MZL) and Waldenström's Macroglobulinemia (WM) are indolent lymphomas that both arise from post germinal center lymphocytes. Both can secrete a monoclonal protein but high levels are mostly only seen in WM. The MYD88 L256P somatic mutation that is present in an estimated 95% of patients with WM has helped greatly in differentiating the two lymphomas. Several large clinical studies with new drugs have been performed that have provided new treatment options for both MZL and WM patients. In this short review we will discuss the recent literature published and provide some recommendations.

Treatment of relapsed and refractory Waldenstrom Macroglobulinemia.

Waldenström's Macroglobulinemia (WM) is a rare type of indolent non-Hodgkin lymphoma (NHL) that remains incurable. Several effective agents such as monoclonal antibodies (in combination with chemotherapy), Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and BCL2 inhibitors are (becoming) available for the treatment of relapsed and refractory WM. There is however no consensus on a preferred treatment in the relapsed setting. Choice of therapy in relapsed WM should be individualized by taking several treatment and patients characteristics into account, such as treatment duration, toxicity, age, comorbidities and MYD88L265P and CXCR4 mutational status. Due to better understanding of WM biology and the arrival of novel anti-lymphoma agents, the therapeutic options are increasing. Non-cytotoxic and fixed duration regimens, such as those explored in other indolent NHLs should be the focus of future clinical trials in WM.

Patient preferences regarding treatment options for Waldenström's macroglobulinemia: A discrete choice experiment.

INTRODUCTION: Treatment options for Waldenström's Macroglobulinemia (WM) have expanded rapidly in the last decades. However, there is no consensus on a preferred treatment. Therefore, patient preferences become increasingly important in making individualized treatment plans. Still, WM patients' priorities and perspectives regarding their treatment options are unknown. We evaluated treatment preferences of WM patients using a discrete choice experiment (DCE). METHODS: A mixed-method approach was utilized for identification and selection of attributes/levels. The DCE questionnaire included five attributes: type of agent (targeted versus chemotherapy); frequency and route of administration; 5-year progression-free survival (PFS); adverse events; and risk of secondary malignancies. An orthogonal design and a mixed logit panel data model were used to construct choice tasks and assess patient preferences, respectively. RESULTS: Three hundred thirty WM patients participated in the project. In total, 214 (65%) complete questionnaires were included for data analysis. The 5-year PFS, followed by risk of secondary malignancies were the most important attributes for making treatment choices. Regarding side effects, patients chose to avoid neuropathy the most compared to nausea/vomiting and extreme fatigue. Patients preferred a fixed-duration treatment with IV/SC administration at the hospital over a continuous daily oral regimen at home. CONCLUSION: These are the first systematic data obtained on WM patient preferences for treatment. The results may help discussions with individual patients about their treatment choices. Also, these data can help design clinical trials in WM and inform health-care decision-making regarding outcomes that are most relevant to patients.

Dutch Physician's Perspectives on Diagnosis and Treatment of Waldenström's Macroglobulinemia Before and After the Implementation of a National Guideline.

Waldenström's macroglobulinemia (WM), a rare low-grade B-cell non-Hodgkin lymphoma (NHL), has a distinct clinical presentation and different treatment-related side effects compared with other NHL. Currently, a wide variety of therapeutic agents are available for the treatment of WM but there is no consensus on optimal treatment in first line and/or at relapse. The aim of this survey was to evaluate the current knowledge and perspectives of hematologists on diagnosis and treatment of WM. Also, we compare these results to a similar survey done before the publication of the first Dutch national guideline, in order to evaluate the impact of the implementation of a national guideline. A link to an online survey was sent out to all registered hematologists and hemato-oncologists in the Netherlands with the request to participate. The survey contained questions regarding the preferred diagnostic and treatment methods in patients with WM as well as treatment goals. We also compared physicians preferred treatment goals to those of patients (as studied in a recent nationwide patient questionnaire). Ninety-five responses (30% response rate) were obtained, out of which 82 (86%) surveys were complete. The respondents most commonly used dexamethasone-rituximab-cyclophosphamide as first-line treatment. For second-line treatment, bendamustine with rituximab and ibrutinib monotherapy were the most frequently applied. Compared with the initial survey, serum IgM M-protein was determined in all cases, MYD88 mutation analysis was currently widely implemented, prevention of an IgM "flare" was uniformly managed by the respondents and use of rituximab-cyclophosphamide-vincristine-prednisone was entirely abandoned. Physicians differed somewhat from patients with regard to most important treatment goals. The approach to diagnostic methods and treatment options in WM was more consistent with international guidelines and was more homogeneous after implementation of the national guideline. These data indicate an increase in knowledge on WM diagnosis and treatment. This may have resulted from implementation of a local guideline or the global rise in awareness and attention for WM.

Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy.

INTRODUCTION: In anti-myelin-associated glycoprotein IgM paraprotein-related peripheral neuropathy (anti-MAG PN), there is a lack of reliable biomarkers to select patients eligible for therapy and for evaluating treatment effects, both in routine practice and in clinical trials. Neurofilament light chain (NfL) and contactin-1 (CNTN1) can serve as markers of axonal and paranodal damage. Complement activation is involved in the pathogenesis in anti-MAG PN. We, therefore, hypothesized that serum NfL, CNTN1, C3b/c and C4b/c may function as biomarkers of disease activity in anti-MAG PN. METHODS: In this prospective cohort study, we included 24 treatment-naïve patients with anti-MAG PN (mean age 69 years, 57% male) that had IgM paraproteinemia, a high IgM MAG-antibody, and clinical diagnosis of anti-MAG PN by a neurologist specialized in peripheral nerve disorders. We measured serum NfL, CNTN1, C3b/c and C4b/c, reference values were based on healthy controls. As controls, 10 treatment-naïve patients with IgM Monoclonal gammopathy of undetermined significance (MGUS) or Waldenström's Macroglobulinemia (mean age 69 years, 60% male) without signs of neuropathy were included (non-PN). RESULTS: NfL, CNTN1 levels in serum were mostly normal in anti-MAG PN patients and comparable to non-PN patients. C3b/c and C4b/c levels were normal in anti-MAG PN patients. CONCLUSION: Our results do not support serum NfL, CNTN1, and C3b/c and C4b/c as potential biomarkers in anti-MAG PN, although we cannot exclude that subgroups or subtle abnormalities could be found in a much larger cohort with longitudinal follow-up.

Discriminating between Waldenström macroglobulinemia and marginal zone lymphoma using logistic LASSO regression.

Discrimination between Waldenström macroglobulinemia (WM) and marginal zone lymphoma (MZL) of the bone marrow (BM) can be difficult due to overlap in clinical, histopathologic, and immunophenotypic characteristics. We determined which characteristics can aid in the differential diagnosis of 'gray zone' cases. We compared clinical, histopathologic, immunophenotypic, and molecular features of 222 WM and 65 MZL patients. LASSO regression was employed for variable selection. The most distinguishing clinical features of WM compared to MZL were the presence of the B-symptom weight loss and IgM paraprotein. Histopathological findings were plasmacytoid differentiation, monoclonal plasma cells, and increased mast cells in the BM. Regarding flow cytometry, only CD10 and CD38 were distinguishing markers. Finally, as the expected presence of the MYD88L265P mutation showed to be of great value in the distinction between WM and MZL. Despite the great overlap, WM can often be distinguished from MZL by using a combination of characteristics. These characteristics should be weighed in complex, 'gray zone' cases.

Conditional relative survival in Waldenström's macroglobulinaemia: a population-based study in The Netherlands.

Contemporary diagnosed WM patients, compared to the general population, continue to experience excess mortality regardless of having survived up to 15 years post-diagnosis. This gradual increase in excess mortality might result from the incurable nature of this disease characterized by multiple relapses throughout the disease course with limited efficacious treatment options in the released/refractory setting.

Primary therapy and relative survival in patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia: a population-based study in the Netherlands, 1989-2018.

It is unclear how treatment advances impacted the population-level survival of patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (LPL/WM). Therefore, we assessed trends in first-line therapy and relative survival (RS) among patients with LPL/WM diagnosed in the Netherlands between 1989 and 2018 (N = 6232; median age, 70 years; 61% males) using data from the nationwide Netherlands Cancer Registry. Patients were grouped into three age groups (<65, 66-75 and >75 years) and four calendar periods. Overall, treatment with anti-neoplastic agents within 1 year post-diagnosis gradually decreased over time, following a broader application of an initial watch-and-wait approach. Approximately 40% of patients received anti-neoplastic therapy during 2011-2018. Furthermore, use of chemotherapy alone decreased over time, following an increased application of chemoimmunotherapy. Detailed data among 1596 patients diagnosed during 2014-2018 revealed that dexamethasone-rituximab-cyclophosphamide was the most frequently applied regimen; its use increased from 14% to 39% between 2014 and 2018. The 5-year RS increased significantly over time, particularly since the introduction of rituximab in the early-mid 2000s. The 5-year RS during 1989-1995 was 75%, 65%, and 46% across the age groups compared to 93%, 85%, and 79% during 2011-2018. However, the survival improvement was less pronounced after 2011. Collectively, the impressive survival improvement may be accounted for by broader application of rituximab-containing therapy. The lack of survival improvement in the post-rituximab era warrants studies across multiple lines of therapy to further improve survival in LPL/WM.

Combining Ixazomib With Subcutaneous Rituximab and Dexamethasone in Relapsed or Refractory Waldenström's Macroglobulinemia: Final Analysis of the Phase I/II HOVON124/ECWM-R2 Study.

PURPOSE: Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS: We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS: A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction (P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION: Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.