Prospective Study of Immunomodulation with GM-CSF, IL-2, and Rituximab Following Autologous Stem Cell Transplant (SCT) in Patients with Relapsed Lymphomas.

SCT induces durable remissions in approximately 30–50% of patients with chemosensitive relapse of large B-cell Hodgkin’s lymphoma. Cure rates are lower in recurrent follicular and mantle cell lymphoma. Peri-transplant rituximab might improve duration of remission somewhat, due to purging effects on stem cells and/or by elimination of minimal residual disease. We hypothesized that the addition of GM-CSF to chemotherapy priming results in improved mobilization of immunologic effector cells. We further hypothesized that GM-CSF and IL-2 enhance the efficacy of post-SCT rituximab by upregulating immunologic effector cells. We studied these concepts in chemosensitive relapsed lymphoma. The treatment regimen was as follows: 1) following mobilization chemotherapy, pts received GM-CSF 200 mcg/m2/d starting day +4 and G-CSF 10 mcg/kg/day starting day +9 until completion of stem cell apheresis; 2) following BEAM conditioning and SCT, GM-CSF 250 mcg/m2/d was started d +1 until ANC >1500 cells/mL; 3) starting d 30 (but no later than d120), pts received rituximab 375 mg/m2. This was followed by 3 cycles of GM-CSF (250 mcg/d SQ days 1–5), IL-2 (1.5 MIU/m2/d SQ days 6–12), and rituximab (375 mg/m2 IV day 9) q 21 days.

Results: Between December 2001 and July 2004, 24 pts with relapsed lymphomas were enrolled. Histologic subtypes include diffuse large B cell lymphoma (11 pts), mantle cell lymphoma (5 pts), follicular lymphoma (3 pts), Hodgkin lymphoma (3 pts), marginal zone lymphoma (1 pt) and small lymphocytic lymphoma (1 pt). The median age was 46 yrs (range, 21–66). Median number of treatment regimens prior to relapse was 1(range 1–5). Disease status prior to transplant was CR/CRu in 10 pts, PR in 8 pts, and SD in 3 pts. One pt with follicular lymphoma failed to mobilize. For all other pts, a median of 7.83 x 10⁶ (range, 2.1 to 46.4 x 10⁶) CD34+ cells were successfully collected. Two pts that had stem cell collection did not undergo the planned HDT/SCT due to disease progression. 21 pts underwent SCT and are included in the analysis. 9 pts completed the entire post-SCT immunotherapy, 7 pts received incomplete post-SCT immunotherapy ( 4 due to toxicity, 2 noncompliance, 1 other)and 3 pts did not receive any of the post-SCT immunotherapy (refusal and/or insurance denial); 2 pts have not yet started immunotherapy. Toxicities of immunotherapy include grade IV neutropenia (2 pts), grade III thrombocytopenia (1 pt), IL-2 associated hypotension and chest pain (1 pt), and a grade II cutaneous eruption (1 pt). With a median follow-up of 365 days (range, 113–677), 19 of 21 pts undergoing HDT/SCT are alive, and 18 are still in remission. One pt with SLL who had received 5 prior treatment regimens died of sepsis after the SCT but before starting immunotherapy. Another patient died of progressive disease 581 days following SCT. The median progression free survival is 664 days (range, 113–669), and the median overall survival has not yet been reached.

Summary: The delivery of post-SCT immunomodulation as described above is feasible and relatively well tolerated. Early PFS and OS in this ongoing study are encouraging and suggest therapeutic efficacy of this regimen of immunotherapy. Samples for correlative studies have been collected and are undergoing analysis.