Remarkable Clinical Efficacy, Stem Cell Mobilization Activity and Good Toxicity Profile of the Novel Begev Regimen (Bendamustine, Gemcitabine And Vinorelbine) Used As Salvage Therapy Prior to Autologous Stem Cell Transplant for Relapsed/Refractory Hodgkin Lymphoma

INTRODUCTION: High-dose salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care for refractory/relapsed (R/R) Hodgkin lymphoma (HL). Achieving complete remission (CR) prior to ASCT represents the strongest prognostic factor for R/R HL patients receiving salvage chemotherapy. Therefore, increasing the CR rate prior to ASCT represents a primary goal in these patients. Since Bendamustine monotherapy induces CR in a substantial proportion (25% to 35%) of R/R HL patients, the present phase II study aimed at investigating efficacy and toxicity of a novel salvage regimen combining Bendamustine, Gemcitabine and Vinorelbine (BeGEV) as second-line salvage chemotherapy in patients with relapsed/refractory HL.

PATIENTS AND METHODS: HL patients who were refractory to, or have relapsed after one previous chemotherapy line were eligible. The primary endpoint was CR rate after four cycles of therapy. Secondary endpoints were: overall response rate (ORR), stem cell mobilization activity, and toxicity. Progression free survival (PFS) and overall survival (OS) were also evaluated. BeGEV regimen consisted of: Bendamustine (90 mg/sqm, days 2-3), Gemcitabine (800 mg/sqm, day 1 and 4) and Vinorelbine (25 mg/sqm, day 1) every 3 weeks for a total of 4 courses.

RESULTS: Between August 2011 and March 2014, 59 consecutive patients with relapsed (46%) or refractory (54%) HL were enrolled. The median age was 33 years (range 18-68). Out of 59 enrolled patients, 43 (73%) achieved a CR and 6 (10%) a partial response (PR) for an ORR of 83%. One case (2%) showed stable disease (SD), while 8 patients (14%) progressed, and 1 (2%) was not evaluable for response. With a median follow-up of 16 months, the 2-year PFS and OS were 51% and 69%, respectively, without significant difference between relapsed and refractory patients. OS was higher for BeGEV-responding (CR+PR) patients compared with those who failed the induction regimen (2-year OS: 86% vs 0%, p<0.001). Fifty-seven out of 59 patients were evaluable for CD34+ cell mobilization. Mobilization failure was detected in 2 of 57 patients (3.5 %) while CD34+ cells were successfully harvested in 55 out of 57 evaluable patients (96.5 %). Forty-two patients (76%) required 1 leukapheresis to harvest the planned target CD34+ cell yield (3×10⁶ CD34+ cells/Kg body weight) while 13 patients (24%) required 2 leukaphereses. The median total yield of CD34+ cells/Kg body weight was 8.8×10⁶ CD34+ cells (range, 3-56). After ASCT, engraftment of neutrophils and platelets was recorded on day 11 (range 9-21) and day 12 (range 9 - 26), respectively. Among the 49 responding patients, 43 (88%) proceeded to ASCT (38/43 in CR, 5/6 in PR); the remaining 6 patients did not proceed to ASCT due to mobilization failure (n=2), physician's decision (n=2), early relapse (n=1), and patient's refusal (n=1). Hematological and non-hematological side effects were acceptable. Out of 204 administered cycles, 23 (11%) had to be delayed and 4 (2%) reduced, respectively; only 1 patient stopped therapy for toxicity. The most common grade 3-4 nonhematologic toxicities included febrile neutropenia (n=7), and infections (n=4). Among hematologic toxicities, grade 3-4 thrombocytopenia and neutropenia were experienced by 8 (13.5%) patients.

CONCLUSIONS: This phase II study demonstrates that BeGEV is a highly effective salvage regimen able to induce a remarkable proportion of complete remission prior to ASCT in relapsed/refractory HL patients. These data provide a strong rationale for further development of the BeGEV regimen.