Rituximab And Sargramostim Immunotherapy Following Autologous Stem Cell Transplant For Aggressive Non-Hodgkin's Lymphoma

Abstract

High dose chemotherapy with autologous stem cell transplant (ASCT) improves survival in patients with aggressive non-Hodgkin's lymphoma (NHL), but relapse occurs in 40-50% of patients. Rituximab exerts its anti-tumor effect through complement and antibody-dependent cell cytotoxicity (ADCC). Sargramostim is involved in the activation and differentiation of macrophages and dendritic cells and increases monocyte-mediated ADCC. The addition of sargramostim to rituximab may potentiate the anti-tumor effect of rituximab by enhancing recruitment and activation of effector cells that mediate ADCC. We evaluated the safety and efficacy of rituximab and sargramostim given as “adjuvant immunotherapy” to patients following ASCT for aggressive NHL. 8 patients (5 male, 3 female; median age 53, range 34-69) with CD20+ diffuse large B cell (6) or mantle cell (2) NHL relapsed, primary refractory or in first complete remission (intermediate-high or high risk IPI) underwent stem cell mobilization using rituximab and cyclophosphamide followed by high dose chemotherapy with rituximab, carmustine, etoposide, cytarabine and melphalan. Adjuvant immunotherapy consisted of rituximab 375 mg/M2 IV weekly and sargramostim 250 ug s.c. TIW during weeks 5 to 8 and 24 to 27 post transplant. Seven patients had successful mobilization (mean CD34/kg collected 12.5E6 and infused 9E6) and underwent transplant. Median time to neutrophil and platelet engraftment was 9 and 10 days respectively. Six patients are alive with no evidence of disease from 3 to 18 months post transplant. One patient relapsed at 11 months. 4/4 patients receiving at least once cycle of adjuvant immunotherapy developed grade 1 to 4 neutropenia from 3 to 34 weeks post adjuvant rituximab. Neutrophil counts recovered following treatment with G-CSF, but recurred in all 4 patients without additional exposure to rituximab. One patient who had engrafted platelets developed grade 2 thrombocytopenia on day 33 post transplant. Platelets spontaneously recovered. Delayed-onset neutropenia is a known complication of rituximab. The incidence may be higher when rituximab is used following ASCT. It is not clear if the timing of rituximab administration post transplant or the concomitant use of sargramostim contributed to the high incidence of delayed neutropenia in this study. Larger studies and longer followup will be needed to determine if adjuvant immunotherapy decreases relapse.