Phase II Study of GM-CSF, IL-2 and Rituximab Immunomodulation Following Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Lymphomas

A fraction of patients with relapsed/refractory lymphomas can achieve durable remission after autologous stem cell transplantation (ASCT). Nevertheless, relapse following ASCT remains as high as 60%, mostly related to persistent minimal residual disease (MRD) or malignant graft contamination. Post-transplantation rituximab has been proposed as a way to eradicate MRD, but its efficacy in this setting has not been proven, and may be limited due to decreased antibody-dependent cellular cytotoxicity (ADCC) during the immediate post-transplant period. GM-CSF and IL-2 might individually enhance the efficacy of rituximab by upregulating immunologic effectors. We hypothesized that given together, rituximab, GM-CSF and IL-2 would act synergistically to augment eradication of MRD, and improve event-free survival in relapsed/refractory lymphomas. The treatment regimen was as follows:

1. following mobilization chemotherapy, patients received GM-CSF 200 mg/m²/day starting day +4 and G-CSF 10 mg/kg/day starting day +9 until completion of stem cell apheresis;

2. following BEAM (BCNU, etoposide, ara-C, melphalan) conditioning and ASCT, GM-CSF 250 mg/m²/day was started day +1 until an absolute neutrophil count of >1500 cells/mL;

3. starting between days +30 and +120, patients received 1 dose of rituximab 375 mg/m² (cycle 1). This was followed by 3 cycles of GM-CSF 250 mg/day SQ days 1–5, IL-2 1.5 MIU/m²/day SQ days 6–12 and rituximab 375 mg/m² IV day 9, repeated every 21 days.

RESULTS: Between December 2001 and March 2008, 46 patients with relapsed or refractory lymphomas were enrolled. Histologic subtypes included diffuse large B-cell lymphoma (27), follicular lymphoma (3), mantle cell lymphoma (1), marginal zone lymphoma (1), small lymphocytic lymphoma (1) and Hodgkin disease (9). The median age was 50 years (range 21–68 years). Median number of regimens before salvage was 1 (range 1–4). Fifty-seven percent of patients enrolled had prior exposure to rituximab. Four patients (9%) failed mobilization. Two patients did not receive ASCT because of active disease, and another had an anaphylactic reaction to GM-CSF. Disease status prior to ASCT was complete remission (CR) (28), partial remission (PR) (7), stable disease (SD) (3) and even progressive disease (PD) (1). Overall, there were 39 patients eligible for post-ASCT immunotherapy. Ten patients (26%) did not initiate post-transplant immunotherapy due to depression, insurance rejection, cardiomyopathy, endocarditis, persistent neutropenia and autologous graft-versus-host disease. Among the 29 patients who underwent immunotherapy, 9 completed 1–2 cycles and 20 completed 3–4 cycles. Reasons for premature cessation of immunotherapy included intolerance, persistent cytopenias, chest pain, pleural effusion and infection. Main reported hematological toxicities were grade 3–4 neutropenia (12) and grade 3 thrombocytopenia (1). No increase in NK or T cells during therapy occurred. With a median follow-up of 33 months, the estimated 5 year overall survival (OS) for patients receiving 3–4 cycles is 62% and the estimated 5 year event-free survival (EFS) is 55%. When compared to patients who received no immunotherapy or 1–2 cycles, OS was similar, with a non-significant trend in improved EFS for patients receiving 3–4 cycles of immunotherapy.

CONCLUSION: post-ASCT immunomodulation with rituximab, IL-2 and GM-CSF may be an effective approach to eradicate minimal residual disease following ASCT. In selected patients, it is well tolerated. Doses and schedules of this regimen need to be further investigated to determine maximal efficacy.