Updated consensus recommendations for the treatment of Waldenstrӧm’s macroglobulinemia

In October 2018, as part of the tenth International Workshop for Waldenstrӧm’s Macroglobulinemia, a consensus panel was established to evaluate and update treatment recommendations based on data from recent clinical trials. The panel discussed the use of rituximab, alone and in combination with alkylating drugs, proteasome inhibitors, and Bruton's tyrosine kinase (BTK) inhibitors as preferred first-line therapy options for patients with Waldenstrӧm’s macroglobulinemia (WM).

The treatment recommendations have since been refined, and were published recently in The Lancet Haematology by Castillo et al.¹ According to these recommendations, preferred lines of treatment include bendamustine plus rituximab, cyclophosphamide and dexamethasone plus rituximab (CdR), bortezomib and dexamethasone plus rituximab (VdR), ibrutinib monotherapy, and ibrutinib plus rituximab.¹

Here, the updated recommendations and clinical trial results are outlined. 

Rituximab monotherapy

Rituximab, an anti-CD20 monoclonal antibody, is the most common monotherapy for WM treatment in the US. In several studies, rituximab monotherapy resulted in immunoglobin M (IgM) flares shortly after exposure, in around half of patients. Whilst these flares should not be considered disease progression, they may worsen symptoms and take 2–4 months to resolve. Therefore, the panel recommends against the use of rituximab monotherapy for patients with increased serum IgM concentrations above 4,000 mg/dL. Slow infusion rates or alternative drugs should be considered in patients with WM who have a rituximab intolerance, characterized by worsening infusion reactions.

Maintenance rituximab

Results of the randomized MAINTAIN study (NCT00877214) found that there were no statistically significant differences between the median progression-free survival (PFS) for patients with WM who received rituximab maintenance therapy and those who did not. Therefore, the panel concluded that for those patients with WM who attain at least a partial response after chemotherapy, maintenance with rituximab should not be recommended.

Chemoimmunotherapy

Rituximab-based chemoimmunotherapy combinations are the most commonly used WM treatment regimens across Europe. The panel analyzed selected combinations and their response rates, the results of which are summarized in Table 1. Adverse events were reported for all chemotherapeutic drug combinations, with an increased risk of prolonged immunosuppression and secondary myeloid neoplasms for the nucleoside analog combinations. This risk was demonstrated to be greater with chlorambucil than with fludarabine. An additional study reviewed by the panel outlined higher rates of alopecia, paresthesia, and stomatitis with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) treatment combination.

Table 1. Summary of selected chemotherapy and rituximab combination regimens in patients with Waldenstrӧm’s macroglobulinemia¹

Proteasome inhibitors in combination with rituximab

The panel raised some concerns when reviewing the prospective studies using either bortezomib, carfilzomib, or ixazomib in combination with rituximab. The first of these concerns was the high rate of Grade 3 peripheral neuropathy reported in 30% of patients with WM undergoing treatment with VdR. The panel indicates that given the high rate of neuropathy in regimens containing bortezomib, the proteasome inhibitor should be used with caution in patients with WM and history of neuropathy. In cases where bortezomib is prescribed, subcutaneous administration is preferred due to a lower reported risk of neuropathy.

While carfilzomib has not been associated with neuropathy, a systematic review highlighted an increased risk of cardiovascular events in patients with multiple myeloma. This led the panel to recommend cautious use of carfilzomib in patients with WM and cardiovascular disease, and in particular for those older than 65 years. Prospective study data have indicated that ixazomib, an orally administered proteasome inhibitor, has a low incidence of infusion reactions.

BTK inhibitors

Ibrutinib, an orally administered BTK inhibitor, is approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with WM, both as a single-agent therapy and in combination with rituximab.^2,3 Approval of the combination was based on the randomized phase III iNNOVATE study, which showed a faster time to response, higher rates of response, and improved PFS in patients with WM treated with an ibrutinib and rituximab combination, compared with rituximab alone.

In addition, ibrutinib has been shown to penetrate the central nervous system, and isolated case reports indicate it is effective in the treatment of patients with WM and Bing-Neel syndrome. In a multicenter, retrospective study of 28 patients, 3 months of ibrutinib treatment resulted in symptomatic improvements in 81% of patients and a radiological improvement in 60% of patients. However, ibrutinib has been associated with an increased risk of bleeding, hypertension, and atrial arrhythmia, leading the panel to recommend the BTK inhibitor to be prescribed with caution to patients with ongoing bleeding diathesis or uncontrolled arrhythmia. In addition, the co-prescription of calcium channel blockers should be avoided, given their interactions with ibrutinib. In 20% of patients who stop taking ibrutinib, withdrawal symptoms may be experienced, and consideration should be given to bridging therapies with ibrutinib in combination with the next line of treatment, before the cessation of ibrutinib.

Novel BTK inhibitors, such as acalabrutinib, zanubrutinib, and tirabrutinib, are emerging as potential new treatment options for WM. Acalabrutinib was evaluated in a phase II study in 106 patients with WM and was found to have an overall response rate of 93%, with a 24-month PFS rate ranging 82–90%. The study found that common adverse events with acalabrutinib included headaches, diarrhea, bruising, fatigue, neutropenia, and lower respiratory tract infections. Zanubrutinib was shown to have an acceptable safety profile and comparable efficacy to ibrutinib in the phase III ASPEN trial.

Hematopoietic stem cell transplantation (HSCT)

Research regarding the use of HSCT in patients with WM is limited to small case studies, without comparable groups. A study by the European Society for Blood and Marrow Transplantation reported a 5-year overall survival rate of 69% for 158 patients with WM who underwent autologous HSCT, with a cumulative incidence of secondary malignancies of 8%. Given this evidence, the panel reached a consensus that autologous HSCT is not appropriate for first-line therapy or in patients who are BTK-inhibitor naïve but can be considered following subsequent relapses in high-risk patients.

Conclusion

The panel concluded from these findings that chemoimmunotherapy (CdR or bendamustine plus rituximab), VdR, ibrutinib alone, and ibrutinib plus rituximab are preferred options for first-line therapy and the treatment of relapsed/refractory disease. However, given the lack of prospective randomized studies comparing these regimens, no consensus was drawn on the treatment providing the highest efficacy or safety for the patient. Given the lack of an ibrutinib monotherapy group in the iNNOVATE study, it was consensus that there is currently no convincing data to indicate the administration of ibrutinib monotherapy over ibrutinib plus rituximab.

The patient's preference, toxicity profile, administration schedule and route, and drug accessibility should all be considered when recommending primary and subsequent therapies, ensuring that all treatments are personalized and patient centered.