CD20-Directed Antibody-Mediated Immunotherapy Induces Responses and Facilitates Hematologic Recovery in Patients With Waldenstrom’s Macroglobulinemia

Abstract

Waldenstrom's macroglobulinemia (WM, lymphoplasmacytic lymphoma) is a B-cell lymphoproliferative disorder in which CD20 is expressed on tumor cells from most patients. Several small studies have suggested a benefit from the anti-CD20 monoclonal antibody rituximab (Rituxan, MabThera) in patients with WM. In this retrospective study, we examined the outcome of 30 previously unreported patients with WM who received treatment with single-agent rituximab (median age 60; range 32-83 years old). The median number of prior treatments for these patients was 1 (range 0-6), and 14 patients (47%) received a nucleoside analogue before rituximab therapy. Patients received a median of 4.0 (1-11.3) infusions of rituximab (375 mg/m2). Three patients received steroids with their infusions for prophylaxis of rituximab-related infusion syndrome. Overall, treatment was well tolerated. Median immunoglobulin M (IgM) levels for all patients declined from 2,403 mg/dL (range 720-7639 mg/dL) to 1,525 mg/dL (range 177-5,063 mg/dL) after rituximab therapy (p = 0.001), with 8 of 30 (27%) and 18 of 30 (60%) patients demonstrating >50% and >25% decline in IgM, respectively. Median bone marrow lymphoplasmacytic (BM LPC) cell involvement declined from 60% (range 5-90%) to 15% (range 0-80%) for 17 patients for whom pre- and post-BM biopsies were performed (p < 0.001). Moreover, 19 of 30 (63%) and 15 of 30 (50%) patients had an increase in their hematocrit (HCT) and platelet (PLT) counts, respectively. Before rituximab therapy, 7 of 30 (23.3%) patients were either transfusion or erythropoietin dependent, whereas only 1/30 (3.3%) patients required transfusions (no erythropoietin) after rituximab. Overall responses after treatment with rituximab were as follows: 8 (27%) and 10 (33%) of the patients achieved a partial (PR) and a minor (MR) response, respectively, and an additional 9 (30%) of patients demonstrated stable disease (SD). No patients attained a complete response. The median time to treatment failure for responding (PR and MR) patients was 8.0 months (mean 8.4: range 3-20+ months), and 5.0 months (mean 6.1; range 3-12+ months) for patients with SD. These studies therefore demonstrate that rituximab is an active agent in WM. Marked increases in HCT and PLT counts were noted for most patients, including patients with WM who had MR or SD. A prospective clinical trial to more completely define the benefit of single-agent rituximab in patients with WM has been initiated by many of our centers.

Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines

“…[38][39][40] In patients with both treatment-naïve and previously treated Waldenström macroglobulinemia, rituximab has been associated with response rates ranging from 29% to 65%. [40][41][42][43][44] Over time, it has become clear that the best response to rituximab may not be seen for many months after treatment. 43 This may result in an underestimation of the activity of rituximab considering that the response end points in most clinical trials are at earlier time points.…”

How I treat Waldenström macroglobulinemia

“…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 …”

“…The use of rituximab as a single agent can also be considered in select patients with WM, such as those presenting with a low tumor burden, mild to moderate cytopenias resulting from bone marrow involvement or autoimmune-related destruction (ie, cold agglutinemia, immune mediated thrombocytopenia), or IgM-related neuropathy (see "Treatment of peripheral neuropathy"). Overall response rates with 4 weekly infusions of rituximab are 20% to 30%, [64][65][66] whereas the use of extended-dose rituximab (ie, 4 weekly infusions followed by 4 more weekly infusions at week 12) has been associated with higher overall response rates (40%-50%). 67,68 Polymorphisms in position 158 of the CD16 (Fc␥RIIIA-158) receptor have been shown in WM and related indolent lymphomas to predict response.…”

Multiple Myeloma

“…Similarly, patients treated initially with rituximab who experience relapse after 6 months or more should be treated with rituximab, alkylating agents, or nucleoside analogs; these patients who experience progressive disease or early relapse should be treated with alkylating agents or nucleoside analogs. Patients whose disease progresses after second-line therapy are candidates for salvage therapies (e.g., hematopoietic SCT; monoclonal antibodies such as rituximab; 131 thalidomide with or without dexamethasone) in the context of clinical trials. Ongoing trials are evaluating lenalidomide and bortezomib, alone and in combination, for treating Waldenström's macroglobulinemia.…”