Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

Abstract

Waldenstrom's macroglobulinemia is generally treated with alkylating agents, purine analogs and monoclonal antibodies, alone or in combination. We report the outcomes of 82 patients (median age 61 years) treated with the RFC combination. Twenty-five patients were treatment-naive. RFC was administered every 4 weeks, for a median of five cycles. At treatment discontinuation, the overall response rate was 85.4%. The responses improved after treatment discontinuation in 25 patients, with a median time to best response achievement of 10.8 months, raising the major response rate (PR, VGPR and CR) from 64.6% to 76.8%. With a median follow-up of 47 months, the median progression-free survival time had not been reached (67% PFS at 48 months) and was influenced by age and treatment status before RFC. Likewise, the median time to next therapy had not been reached. Two cases of myelodysplastic syndrome/AML and 3 cases of transformation to aggressive lymphoma occurred. Thirteen patients died. The 3-year overall survival rate was 90%. Long-lasting cytopenias occurred in 19 patients. The RFC combination thus gave a high response rate and durable responses, even in heavily treatment-experienced patients. The high incidence of long-lasting cytopenia might be reduced by giving fewer courses and thereby minimizing myelotoxicity. Waldenstrom's macroglobulinemia (WM) is a rare B-cell malignancy characterized by the production of a monoclonal immunoglobulin (IgM) by welldifferentiated plasmacytic lymphocytes. Therapy is currently reserved for patients with constitutional symptoms, bone marrow or peripheral lymphoid organ involvement, and complications due to the monoclonal IgM component [1]. There is no consensus treatment strategy, and most clinical trials in WM have so far consisted of small phase II studies with widely differing inclusion and response criteria. Classically used chemotherapeutic agents consist of alkylating agents (chlorambucil, cyclophosphamide), purine analogues (fludarabine, 2-chlorodeoxyadenosine or 2CDA), a proteasome inhibitor (bortezomib) and bendamustine, used either alone or, more often, combined with immunotherapy (principally rituximab). A combination of cyclophosphamide and purine analogues offers synergistic activity, as DNA breaks caused by cyclophosphamide cannot be repaired in the presence of a purine analogue [2]. Studies of the cyclophosphamide and fludarabine combination in WM patients showed an overall response rate (ORR) of 55-77%, and a median time to treatment failure of around 24 months [3]. The fludarabine and rituximab combination has also been studied in a phase II trial, with an ORR of 95.3%, a 4-year progression-free survival rate (PFS) of 67%, and a median time to progression (TTP) of 77 months [4]. Rituximab, fludarabine, and cyclophosphamide combination therapy (RFC) yields a high response rate in patients with chronic lymphocytic leukemia (CLL), both as first-line treatment and after relapse [5,6], and is more effective than the FC combination in untreated CLL patients [7]. Until no...

Treatment recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia

“…[5][6][7] Both rituximab and fludarabine, as well as rituximab, fludarabine, and cyclophosphamide are effective as primary therapy, and salvage therapy has a median PFS exceeding 50 months. [27][28][29][30] However, because of the risk of long-lasting cytopenias and secondary malignancies with these combinations, first-line treatment is not recommended but could be an option in patients with a high-risk of relapsing.…”

How I treat Waldenström macroglobulinemia

“…Combinations of nucleoside analogs with rituximab 57-59 are very active, but have significant short-and long-term toxicity and are not primary options. [58][59][60] Combinations with intensive chemotherapy, such as rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone, are only considered if transformation to DLBCL occurs. Single-agent chemotherapy is rarely considered, but single-agent oral fludarabine is more effective than chlorambucil.…”

Diagnostic framing of IgM monoclonal gammopathy: Focus on Waldenström macroglobulinemia

“…Nucleoside analogues (NA) have been largely used in WM both either alone or in different combinations. Both fludarabine and cladribine have been associated with rituximab with or without cyclophosphamide . Response rates with NA combinations are high (ORRs ranging from 89% to 95%) even in patients with relapsed or refractory WM, but NA have been associated with a high rate of myelosuppression, treatment discontinuation, prolonged tardive neutropenia, and infections.…”