Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial

Abstract

Background: Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma.

Methods: In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1-21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m(2) as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov, number NCT00695786.

Findings: 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83-95). Complete responses occurred in 65 (63%, 95% CI 53-72) and partial responses in 28 patients (27%, 19-37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]).

Interpretation: Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study (NCT01476787) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress.

Funding: Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant.

Conflict of interest statement

Declaration of interests

Fowler - Celgene: Research Funding, Honoraria (Scientific Advisory Board). Roche: Research Funding. McLaughlin - Celgene: Data Monitoring Committee for a different lenalidomide study. Gilead: Data Monitoring Committee for an idelalisib study. Fanale - Celgene: Research Funding, Honoraria (Speaker). Shah - Celgene: Research Funding, Honoraria (Scientific Advisory Board). Orlowski – Celgene: Research Grant, Advisory Board. Wang - Celgene: Research Funding. Oki – Celgene: Research Grant. Samaniego - Celgene: Research Funding. Neelapu - Celgene: Research Funding.

Davis, Rawal, Nastoupil, Hagemeister, Kwak, Romaguera, Fayad, Westin, Turturro, Claret, Feng, Baladandayuthapani, Muzzafar, and Tsai have nothing to disclose.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Kaplan-Meier estimates of overall survival and PFS in patients with indolent lymphoma receiving lenalidomide plus rituximab

Lenalidomide plus rituximab was administered to 110 patients with untreated iNHL. At a median follow-up of 38 months, the 3-year overall survival for the entire group was 96% (A). Three patients died during follow-up: 2/50 in the FL group, and 1/30 in the SLL group. In patients with FL, the 3-year PFS was 78·5% (B). The median PFS for patients with marginal zone lymphoma and SLL was 53·8 months (C) and 40·4 months (D), respectively. FL=follicular lymphoma. iNHL=indolent non-Hodgkin lymphoma. PFS=progression-free survival. SLL=small lymphocytic lymphoma.

Figure 2. Changes in immune cell subsets in peripheral blood after rituximab and lenalidomide therapy

(A–E) Immune cell subsets were determined by flow cytometry of peripheral blood mononuclear cells in 27 FL patients. Percentage change from baseline in absolute numbers or their ratios at cycle 6, day 28 (C6D28) of rituximab and lenalidomide therapy is shown. (F–H) Percentage change from baseline in immune cell subsets at C2D1, C2D15, and C6D28 of rituximab plus lenalidomide therapy was analysed in 13 FL patients. Percentage change in absolute numbers of immune cell subsets in on-therapy or post-therapy samples relative to baseline was calculated to enable normalisation of the data using the following formula: [(on therapy or post-therapy absolute value – baseline absolute value) × 100/ baseline absolute value]. Paired Student’s t-test was used to evaluate differences in immune cell subsets between the time points. *p+/CD8+CD45RO+); CD4/CD8 CM (CD4+/CD8+CD45RA−CD27+); CD4/CD8 EM (CD4+/CD8+CD45RA−CD27−); CD4/CD8 naïve (CD4+/CD8+CD45RA+ CD27+); NK cells (CD3−CD56+); NKT cells (CD3+CD1D+); γδ T cells (CD3+TCRγδ+); MDC (Lin−CD11c+CD4+); PDC (Lin− BDCA2+BDCA4+). CM=central memory. EM=effector memory. MDC=myeloid dendritic cells. Mem=memory. NK=natural killer. NKT=natural killer T. PDC=plasmacytoid dendritic cells.