A Phase II Randomized Study of Lenalidomide or Lenalidomide and Rituximab As Maintenance Therapy Following R-CHOP Chemotherapy for Patients with High Risk Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) patients with an intermediate/high to high risk international prognostic index (IPI) score are at an increased risk of disease relapse in the first year after completion of standard therapy with R-CHOP. Lenalidomide (LEN), an immunomodulatory drug, enhances the natural-killer cell mediated antibody-dependant cellular cytotoxicity of rituximab in lymphoma cell lines, inhibits angiogenesis, alters cytokine production, and has been shown to have clinical activity against B-cell lymphoma including relapsed DLBCL.

DLBCL patients with high risk features (IPI scores of 3 or greater) who achieved CR after R-CHOP were randomized to LEN (arm A) alone or LEN and rituximab maintenance therapy (arm B) within 12 weeks of last dose of R-CHOP. The primary endpoint of the study was to assess the one year relapse-free survival. We expected that a 25% difference of relapse compared with current standard therapy will have clinical significance. Patients in arm A received LEN at a dose of 25 mg daily for 21 days of 28 days. Patients in arm B received LEN at a dose of 20mg daily for 21 days of 28 days along with rituximab (375mg/m²) on day 8 of even cycles. Treatment on both arms was continued for one year. Treatment was discontinued for disease progression. LEN dose adjustments were incorporated in the protocol.

Thirty five patients, 19 arm A/16 arm B, 20 female/15 male, with a median age of 59 yrs were enrolled. The median IPI was 3 for all patients. For patients over the age of 60 the median IPI score was 4 and the median aa-IPI was 3. Two patients received XRT to areas of bulky disease at the completion of R-CHOP prior to start of maintenance. At a median follow up of 22 months, the 2 yr PFS and DFS was 86% and 96% respectively. For patients in arm A and arm B the 2 yr PFS was 92% vs.77% and the 2 yr DFS was 100% vs. 92% respectively (p=0.52). Two patients discontinued treatment due to adverse events. Grade 3–4 toxicities include neutropenia (25%), fatigue (17%), diarrhea (8%), DVT (3%), rash (3%), febrile neutropenia (3%). Related grade 1–2 toxicities include hypothyroidism (11%) and rash (47%). There were no treatment related deaths.

Lenalidomide as maintenance therapy demonstrates encouraging clinical activity following standard chemotherapy and results in superior survival outcomes in DLBCL patients with high risk prognostic features. The 2-yr OS was 90% in our study as compared with historical controls of 70%. Our study suggests that maintenance strategy with lenalidomide based therapy may increase cure rate and needs to be prospectively evaluated in a phase III study.

Reddy:Celgene: Research Funding. Off Label Use: Lenalidomide in Lymphoma. Park:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Research Funding.