Rituximab plus sargramostim for the treatment of newly diagnosed follicular lymphoma: Final results of a phase II study

Background: Rituximab (R) works in part through antibody dependant cellular cytotoxicity (ADCC). Several cytokines can enhance ADCC. Sargramostim (granulocyte macrophage-colony stimulating factor - GM-CSF) is an FDA-approved cytokine that stimulates the proliferation and differentiation of hematopoietic progenitor cells. In addition to stimulating multi-lineage hematopoietic recovery GMCSF may augment dendritic cell numbers and promote antigen presentation. We and others (Cartron G, JCO 2008) have explored the combination of R + GM-CSF for patients (pts) with follicular lymphoma (FL). Following encouraging pilot experience (Liu N. ASH 2003) in 2006 we organized a multi-center trial of R + GM-CSF for pts with untreated FL. Methods: Pts with untreated FL were eligible for study. R was administered at 375mg/ m2 once weekly x 4 weeks plus GM-CSF, 250 μg sc three times weekly x 8 weeks. The planned sample size was 52 with a primary endpoint of complete response (CR) rate at 3 mo. Secondary endpoints included progression free survival (PFS) and safety of the combination. Response was assessed using the 1999 International Working Group Criteria. Results: From 12/2006-5/2009, 52 pts enrolled and all were eligible for assessment. The median age was 56 (31-78) and 62% were male.56% of patients had intermediate or high risk FLIPI. Fifteen (29%) pts had bulky disease (>5cm) and 29 (56%) pts had elevated B2M.Tolerance was good and effects attributable to GM-CSF were minor. Absolute granulocyte count above 15K occurred in only 2 pts; conversely, ≥ grade 3 neutropenia occurred in 8 pts. No significant infections occurred. At 3 months, the overall response rate was 69%, including 23% of pts with a CR. With continued follow up response rates improved (ORR 74%, CR 42%). Twenty four (46%) pts remain in remission without further treatment. At a median follow up of 14 mo, the median PFS of all pts was 28 mo including pts with bulky disease (median PFS, 16 mo). No difference in PFS was observed when comparing FLIPI score (0-1) vs (2-3) or B2M. Conclusion: Rituximab plus GM-CSF is well tolerated and active in untreated pts with FL. There did not appear to be a significant difference in outcomes when comparing FLIPI scores, although PFS was inferior in patients with bulky disease. Randomized studies are required to determine whether this combination is superior to rituximab as a single agent.