A Phase 2 Study Of Lenalidomide, Rituximab, Cyclophosphamide and Dexamethasone (LR-CD) For Untreated Low Grade Non-Hodgkin Lymphoma Requiring Therapy: Waldenström’s Macroglobulinemia Cohort Results

Single agent therapy with the novel agent lenalidomide has shown efficacy in relapsed lymphomas, through anti-proliferative and immunomodulatory mechanisms, and may have a synergistic effect with rituximab. There is limited data on the efficacy and safety of lenalidomide in multidrug combinations in treatment naïve patients. We designed a phase II single arm trial of untreated low grade NHL patients with lenalidomide, rituximab, cyclophosphamide, and dexamethasone (LR-CD) to evaluate tumor response, toxicity (adverse events) and survival¹. Initial analysis showed promising results in patients with lymphoplasmacytic lymphoma (WM), and the cohort was expanded for analysis. Lenalidomide has previously been studied with rituximab in this population but significant toxicity, mainly anemia (8/16 (50%) grade 2 and 1/16 (6%) grade 3), caused cessation of study enrollment². We report here results of the Waldenström’s macroglobulinemia cohort.

Eligibility: 18 years of age, untreated indolent NHL, ECOG PS ≤2, nodes ≥ 2cm by MRI or CT or IgM ≥ 400mg/dL, ANC >1400 mm³, platelet count ≥ 100,000/mm³, creatinine ≤ 2mg/dL. Treatment consisted of IV rituximab 375mg/m2 on day 1, oral lenalidomide 20mg days 1-21, cyclophosphamide 250mg/m2 days 1, 8, 15, and dexamethasone 40mg days 1, 8,15, 22, on a 28 day cycle. All patients received aspirin 325 mg daily. Treatment continued 2 cycles beyond best response up to a maximum of 12 cycles. Toxicity was assessed using NCI CTCAE v3.0.

Sixteen patients with lymphoplasmacytic lymphoma, with monoclonal IgM present at baseline, have enrolled at Mayo Clinic with 15 evaluated for toxicity and response (1 withdrew before treatment). Four patients are still receiving treatment. Patient characteristics: median age 69 (47-83), 87% male, 100% Caucasian, median IgM 4480 (1740-7890). At baseline 4/15 (27%) patients had grade 2 anemia and 2/15 (13%) had grade 3. Median number of cycles administered was 8, and 73% completed the study per protocol. Overall best response rate was 80%, 1 patient with CR and 11 with PR. The most common grade 3 or 4 adverse events were neutropenia (13% grade 3 and 33% grade 4), anemia (27% grade 3, 13% grade 4), and leukopenia (grade 3, 13%, grade 4, 20%). Six patients had grade 3 or higher nonhematologic toxicity. At a median follow up of 17 months (0.9-38.3), 11 patients had not progressed and 4 progressed. The median PFS is 24.9 months, and the OS at 2 years is 86%. One death secondary to relapsed disease occurred 7.7 months after completing 12 cycles of treatment.

LR-CD can be safely administered in newly diagnosed symptomatic Waldenström’s macroglobulinemia. The main toxicities are anemia and neutropenia, with more anemia (≥gr3 40% vs. 14%) than seen in other low grade histologies treated with LR-CD¹. A prior study of lenalidomide and rituximab in WM was stopped due to the development of anemia suggesting that lenalidomide was not a safe or efficacious drug in this disease. However, while we did see anemia develop during therapy with LR-CD, 6/15 patients had grade≥2 anemia at baseline. Compared to historical results this highly active regimen deserves study in a randomized trial.

¹ Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 2741

² Clin Cancer Res 2009; 355 15(1) January 1, 2009

This trial is sponsored by Celgene

Off Label Use: lenalidomide is not approved for treatment of waldenstrom macroglobulinemia. Nowakowski:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Stewart:Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Fonseca:millennium: Consultancy; amgen: Consultancy; Binding site: Consultancy; onyx: Consultancy; medtronic: Consultancy; Genzyme: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; lilly: Consultancy; Onyx: Research Funding; cylene: Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.