Lenalidomide and Rituximab Following Autologous Stem Cell Transplantation for B-Cell Non-Hodgkin Lymphoma Is Associated with Unacceptable Myelotoxicity

Abstract 1621 Relapse remains the principal cause of treatment failure following high-dose chemotherapy with autologous stem cell transplantation (ASCT) in patients with B-cell non-Hodgkin lymphoma (NHL). There is a significant unmet need for an intervention that could effectively reduce the risk of relapse after ASCT. Pilot studies suggest that maintenance therapy with the anti-CD20 monoclonal antibody rituximab may increase progression-free survival after ASCT for NHL. The immunomodulatory drug lenalidomide increases rituximab-induced cytotoxicity in preclinical models. Both agents have clinical activity in B-cell NHL singly and in combination, and both are well-tolerated with generally manageable hematologic and other acute toxicities. In addition, lenalidomide and rituximab have each been used extensively as maintenance treatments for lymphoproliferative disorders following ASCT or chemotherapy-based induction therapies, respectively. Therefore, we initiated a prospective phase I clinical trial of post-transplant maintenance therapy using lenalidomide and rituximab. Eligibility criteria included: diagnosis of B-cell NHL; ASCT within the preceding 70 days; post-transplant staging with stable disease, partial response, or complete remission; resolution of transplant-related non-hematologic toxicities to NCI CTC grade ≤ 2; absolute neutrophil count at least 1,500/uL and platelet count 75,000/mm3 (grade ≤ 1); ECOG performance status ≤ 2. Subjects received lenalidomide PO on days 1–21 of 28-day cycles, with rituximab administered IV on day 1 of every other treatment cycle, for up to 12 cycles. Dose-limiting toxicity (DLT) was defined as potentially drug-related grade 4 hematologic or grades 3–4 non-hematologic toxicities during cycle 1 of study treatment. Five subjects were enrolled from 1/2010 through 11/2010: 2 at dose level 1 (lenalidomide 10 mg, rituximab 375 mg/m2) and 3 at dose level-1 (lenalidomide 5 mg, rituximab 375 mg/m2). Diagnoses included diffuse large B-cell (N=3) or mantle cell (N=2) lymphoma. Subjects began on-study treatment from 68 to 123 days after ASCT (median 93 days). Four subjects experienced DLT consisting of fatal pneumonitis (1 subject at dose level 1) or grade 4 neutropenia (1 subject at dose level 1, and 2 subjects at dose level-1). Three of these subjects discontinued treatment during cycle 1, per protocol. One subject completed 3 full cycles, with reduction within cycle 1 to dose level-1 because of grade 4 neutropenia, and halting treatment per protocol during cycle 4 because of grade 2 retinal vein thrombosis. One subject completed 4 cycles of treatment at dose level-1 before discontinuing per protocol because of grade 4 neutropenia. The study was closed due to dose-limiting toxicity at the lowest dose level. There was no relationship between bone marrow morphology before ASCT and hematologic toxicity on study. All subjects were in remission at study entry, without evidence of marrow involvement by lymphoma, and therefore none was evaluable for response to treatment. No surviving subject has progressed, with median follow-up of 9.5 months from study entry. We conclude that maintenance therapy with lenalidomide and rituximab is tolerated poorly in the early recovery period following ASCT, owing mainly to unacceptable hematologic toxicity. Further studies would be of interest to evaluate the feasibility of this regimen if introduced later following ASCT, or to determine the tolerability of lenalidomide alone in this setting. Disclosures: Dean:Genentech: Honoraria. Off Label Use: Lenalidomide is not approved for the treatment of NHL.