High Dose Chemotherapy Using Beam without Autologous Rescue Followed by Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Refractory or Relapsing Lymphomas - A Comparison of Delayed Versus Immediate Transplantation.
Authors: Buser Andreas S. , Stern Martin , Bucher Christoph , Arber Caroline , Heim Dominik , Halter Joerg , Meyer-Monard Sandrine , Stussi Georg , Lohri Andreas , Ghielmini Michele , Tichelli Andre , Passweg Jakob R. , Gratwohl Alois 
Published: October 2019

Abstract
Patients with refractory/relapsing lymphoma are rarely cured by chemotherapy, so that allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is often considered as an alternative despite being associated with substantial mortality. Reduced intensity conditioning (RIC) HSCT can induce a graft-vs-lymphoma (GvL) effect but relapse rate is high in advanced disease. High dose chemotherapy (HDC) for tumor debulking given before RIC HSCT has been advocated as a concept. We prospectively compared in a single center two sequential strategies in patients with refractory or relapsing lymphoma: a first cohort (group A) received BEAM chemotherapy without autologous stem cell support followed by delayed RIC HSCT at day 28. The second cohort (group B) received BEAM followed immediately by RIC HSCT. RIC HSCT was based on fludarabine 3×25 mg/m2 followed by 200 cGy TBI. Pretransplant characteristics were comparable in the two groups: group A included 10 patients, 7m/3f, median age 51 years (range 25–63) with 2 CLL, 3 follicular lymphomas (FL), 1 DLBCL, 2 Hodgkin lymphomas and 2 other B-cell lymphomas. Group B included 11 patients, 5m/6f, median age 48 years (range 31–59) with 4 CLL, 3 FL, 2 DLBCL, and 2 other lymphomas. Donors were HLA identical siblings (8 and 9 in group A and B) or unrelated donors (2 in each group).
Three patients died before day 100 in group A (all from acute GvHD), whereas none died in group B. Non-hematological toxicity of the regimen before engraftment was comparable, only gut toxicity was higher in group B. As expected, days in aplasia (36 vs 12 days; A vs B; p< 0.001), days on antibiotics (61 vs 26 days; p =0.016) and length of hospital stay (36 vs 63 days; p =0.017) were significantly different. Cumulative incidence of acute GvHD ≥ grade II (90% vs 36% p= 0.01) and incidence of cGVHD (7/7 vs 6/11, p= 0.03) was higher in group A; hence we failed to show an advantage of separating RIC HSCT from the cytokine storm induced by BEAM. At last follow up, 7/10 patients in group A (median follow up 51 months) were alive, 6 of them in CR, 1 relapsed 9 months after RIC HSCT. In group B (median follow up 20 months), 9/11 patients were alive, 7 of them in CR, 1 in PR and 1 with no change. The two deaths in group B were related to cGvHD. No significant difference in 3 year overall survival (70% ±14% vs. 76%±14%, p= 0.53) was seen. These data challenge the initial concept of debulking first and delaying allogeneic RIC HSCT. They demonstrate encouraging tumor response and acceptable toxicity in patients with relapsing or refractory lymphoma. We confirm that allogeneic HSCT is a valid alternative for patients with resistant/relapsed lymphoma. These patients should be considered candidates for allogeneic HSCT earlier in the course of their disease and direct standard full conditioning with BEAM should be considered.