Lenalidomide and Rituximab in Waldenstrom's Macroglobulinemia

Abstract

Purpose: Thalidomide and its more potent immunomodulatory derivative lenalidomide enhance rituximab-mediated antibody-dependent cell-mediated cytotoxicity. We therefore evaluated lenalidomide and rituximab in symptomatic Waldenstrom's macroglobulinemia (WM) patients naive to either agent. Experimental Design: Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1week off) along with rituximab (375 mg/m 2 /wk) dosed on weeks 2 to 5 and 13 to 16. Sixteen patients were enrolled, 12 of whom were previously untreated. Results: Unexpectedly, we observed an acute decrease in hematocrit in 13 of 16 patients (median hematocrit decrease, 4.8%), which was attributable to lenalidomide patients and which led to cessation of further enrollment on this study. Lenalidomide-related anemia was observed even at doses as low as 5 mg/d and occurred in the absence of hemolysis or other cytopenias. The overall response and major response (<50% decrease in serum IgM) rates were 50% and 25%, respectively, on an intent-to-treat basis. With a median follow-up of 31.3 months, 4 of 8 responding patients have progressed with a median time to progression of 18.9 months. Conclusion: Lenalidomide produces unexpected but clinically significant acute anemia in patients with WM. In comparison with our previous study with thalidomide and rituximab in an analogous patient population, the responses achieved in WM patients with lenalidomide and rituximab appear less favorable.Waldenstrom's macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells along with demonstration of an IgM monoclonal gammopathy (1). This condition is considered to be lymphoplasmacytic lymphoma as defined by the REAL and WHO classification systems (2, 3). Despite advances in therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM.One class of therapeutics that has been successfully used in patients with WM are monoclonal antibodies. Both rituximab and alemtuzumab have been evaluated in WM as single agents with major response rates of 30% to 40%, whereas the combination of rituximab with chemotherapy has resulted in response rates of 70% to 90% (4). With the attainment of higher response rates with chemo-antibody therapy, considerably more short-term and long-term toxicities have been reported (4, 5). In an effort to augment monoclonal antibody responses in WM patients while averting short-term and longterm chemotherapy-induced toxicities, we have sought the development of immunomodulatory agents for combination with rituximab. Thalidomide and its more potent immunomodulatory derivative lenalidomide augment antibodydependent cell-mediated cytotoxicity (5). Moreover, these agents also lead to expansion of natural killer cells, which serve as important effector cells for rituximab activity in patients with indolent non-Hodgkin's lymphoma (6 -9). As a follow-up to these findings, we recently performed a clinical trial exploring the ...

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus

“…Nevertheless, the minimal myelotoxicity of thalidomide may be important for selected patients with severe cytopenias (especially those with severe thrombocytopenia). Lenalidomide with rituximab was associated with significant hematologic toxicity 39 ; thus, it should only be considered in the context of a clinical trial. Pomalidomide is under investigation.…”

How I treat Waldenström macroglobulinemia

“…by guest www.bloodjournal.org From occurrence of the rituximab-mediated IgM flare can vary considerably and appear dependent on both the regimen used as well as the sequencing of rituximab administration. 40,43,48,[61][62][63] Because of concern over a rituximab-related IgM flare aggravating serum viscosity levels or IgM-related morbidity, the omission of rituximab can also be considered for the first 1 or 2 cycles of treatment. Serum IgM levels should be closely monitored (at least weekly) during the time patients are receiving rituximab-based therapy.…”

“…The IgM flare may last for several weeks, and even months, and does not per se herald treatment failure. 54,62 The use of rituximab is best avoided as single-agent therapy in patients with high IgM levels because in 2 studies considerably lower response rates were observed in those patients with higher serum IgM levels (Ͼ 4000 mg/dL). 64,65 …”

“…Peripheral neuropathy (Ͼ grade 2) was seen in 40% of WM patients treated with TR, in whom doses of 200 to 400 mg daily were used. 62 Lower doses of thalidomide (ie, 100 mg daily) may be more appropriate in WM patients given the increased propensity for WM patients to develop treatment-related neuropathy. The use of lenalidomide has been explored in WM and was associated in one study with an acute drop in hematocrit and hospitalizations of several patients resulting from aggravated anemia and related complications.…”

“…The use of lenalidomide has been explored in WM and was associated in one study with an acute drop in hematocrit and hospitalizations of several patients resulting from aggravated anemia and related complications. 63 Despite dose reductions, lenalidomide-related anemia persisted in many patients. As such, the use of lenalidomide should be avoided in WM patients.…”