Five-Year Survival and Durability Results of the Phase 2 Trial Using the Begev Regimen (Bendamustine, Gemcitabine And Vinorelbine)As Salvage Therapy Prior to Autologous Stem Cell Transplant for Relapsed/Refractory Classic Hodgkin Lymphoma
Authors: Santoro Armando , Mazza Rita , Pulsoni Alessandro , Re Alessandro , Bonfichi Maurizio , Zilioli Vittorio Ruggero , Salvi Flavia , Anastasia Antonella , Luminari Stefano , Gotti Manuel , Peli Annalisa , Liberati Anna Marina , Di Renzo Nicola , Castagna Luca , Giordano Laura , Carlo-Stella Carmelo 
Published: October 2019

Abstract
INTRODUCTION: High-dose salvage chemotherapy followed by autologous stem cell transplantation (Auto-SCT) in chemosensitive patients still remains the standard-of-care treatment for relapsed/refractory classic Hodgkin lymphoma (R/R CHL). As previously reported in a multicenter phase 2 study (Santoro et al., J Clin Oncol, 2016), the BEGEVregimen induces an objective response rate (ORR) >80% in the second-line salvage setting of R/R cHL, thereby resulting a highly effective treatment. Here, we assess efficacy and safety of the BEGEV regimen after extended follow-up (registered at www.clinicaltrials.gov as #NCT01884441).
PATIENTS AND METHODS: cHL patients who were refractory to, or have relapsed after first-line chemotherapy were eligible. The primary endpoint was CR rate after 4 cycles of therapy. Secondary endpoints were: ORR, stem cell mobilization activity, and toxicity. Progression free survival (PFS) and overall survival (OS) were also evaluated. The 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 September 2011 and March 2014, 59 consecutive patients with relapsed (46%) or refractory (54%) cHL were enrolled. The median age was 33 years (range 18-68). By intention to treat (ITT), after 4 cycles of therapy, 44 (75%) achieved a CR and 5 (8%) 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. In univariate analysis, the only factor which resulted associated with a different probability to reach CR was disease status at study entry, with CR being achieved by 84% of relapsed patients and 59% of refractory patients (P=0.031). With a median follow-up of 56 months (range, 3.4-79), the overall patient population (n=59) has an OS of 78% and a PFS of 61%, respectively, without significant difference between relapsed and refractory patients. Fifty-seven out of 59 patients were evaluable for CD34+ cell mobilization. Two of 57 patients (3.5%) experienced CD34+ cell mobilization failure, whereas the planned target dose of CD34+ cells (3×10^6 CD34+ cells/Kg body weight) was successfully harvested in the remaining 55 patients (96.5%). After AutoSCT, engraftment of neutrophils and platelets was recorded on day 11 (range 9-21) and day 12 (range 9 - 26), respectively. Of the 49 responding patients, 43 (73% by intention to treat) proceeded to Auto-SCT (39/43 in CR, 4/5 in PR); the remaining 6 patients did not proceed to Auto-SCT due to mobilization failure (n=2), physician decision (n=2), early relapse (n=1), patient refusal (n=1).After transplant, 4 patients died [pneumonia (n=1), infection (n=1), multi-organ failure (n=1), PD (n=1)] and 7 patients relapsed. No patient has developed secondary leukemia or myelodysplasia. For transplanted patients, the 5-yr OS and PFS are 91% and 77%, respectively.
CONCLUSIONS: These 5-year follow-up data demonstrate that BEGEV is a highly effective and safe salvage regimen. Nearly 80% of BEGEV-treated R/R cHL patients who experience an objective response and are addressed to Auto-SCT achieve long-term disease control and may potentially be cured. These data provide a strong rationale for further development of the BEGEV regimen.

Disclosures
Luminari: Roche: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Servier: Consultancy; Sandoz: Consultancy. Carlo-Stella:ADC Therapeutics: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; AstraZeneca: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Genenta Science: Speakers Bureau; MSD Italia: Speakers Bureau.