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Bendamustine in Combination with Gemcitabine and Vinorelbine Is An View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia VOLUME 34 • NUMBER 27 • SEPTEMBER 20, 2016 JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT Bendamustine in Combination With Gemcitabine and Vinorelbine Is an Effective Regimen As Induction Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma: Final Results of a Multicenter Phase II Study Armando Santoro, Rita Mazza, Alessandro Pulsoni, Alessandro Re, Maurizio Bonfichi, Vittorio Ruggero Zilioli, Flavia Salvi, Francesco Merli, Antonella Anastasia, Stefano Luminari, Giorgia Annechini, Manuel Gotti, Annalisa Peli, Anna Marina Liberati, Nicola Di Renzo, Luca Castagna, Laura Giordano, and Carmelo Carlo-Stella Armando Santoro, Rita Mazza, Luca Castagna, Laura Giordano, and Carmelo ABSTRACT Carlo-Stella, Humanitas Cancer Center; Armando Santoro, Humanitas University, Purpose Rozzano; Alessandro Pulsoni and Giorgia This multicenter, open-label, phase II study evaluated the combination of bendamustine, gemci- Annechini, Sapienza University, Rome; tabine, and vinorelbine (BeGEV) as induction therapy before autologous stem-cell transplantation Alessandro Re, Antonella Anastasia, and (ASCT) in patients with relapsed or refractory Hodgkin lymphoma (HL). Annalisa Peli, Spedali Civili, Brescia; Maurizio Bonfichi and Manuel Gotti, Patients and Methods Istituto di Ricovero e Cura a Carattere Patients with HL who were refractory to or had relapsed after one previous chemotherapy line were Scientifico (IRCCS) Policlinico San Matteo, eligible. The primary end point was complete response (CR) rate after four cycles of therapy. Pavia; Vittorio Ruggero Zilioli, Niguarda Ca’ Granda Hospital; Carmelo Carlo-Stella, Secondary end points were: overall response rate, stem-cell mobilization activity, and toxicity. University of Milano, Milan; Flavia Salvi, Progression-free and overall survival were also evaluated. SS Antonio e Biagio Hospital, Alessandria; Results Francesco Merli, Arcispedale S. Maria Nuova/IRCCS, Reggio Emilia; Stefano In total, 59 patients were enrolled. After four cycles of therapy, 43 patients (73%) achieved CR, and Luminari, University of Modena and six (10%) achieved partial response, for an overall response rate of 83%. The most common grade Reggio Emilia, Modena; Anna Marina 3 to 4 nonhematologic toxicities included febrile neutropenia (n = 7) and infection (n = 4). Regarding Liberati, A.O. Santa Maria, Terni; and hematologic toxicities, grade 3 to 4 thrombocytopenia and neutropenia were each experienced by Nicola Di Renzo, Vito Fazzi Hospital, eight patients (13.5%). CD34+ cells were successfully harvested in 55 of 57 evaluable patients, Lecce, Italy. and 43 of 49 responding patients underwent ASCT. With a median follow-up of 29 months, the Published online ahead of print at 2-year progression-free and overall survival rates for the total population were 62.2% and 77.6%, www.jco.org on July 5, 2016. respectively. The same figures for patients undergoing autograft were 80.8% and 89.3%, Support information appears at the end respectively. of this article. A.S. and R.M. contributed equally to this Conclusion work. This phase II study demonstrates that BeGEV is an effective salvage regimen able to induce CR in Authors’ disclosures of potential conflicts a high proportion of patients with relapsed or refractory HL before ASCT. These data provide a strong of interest are found in the article online at rationale for further development of the BeGEV regimen. www.jco.org. Author contributions are found at the end of this article. J Clin Oncol 34:3293-3299. © 2016 by American Society of Clinical Oncology Clinical trial information: NCT01884441, 2010-022169-91 (EudraCT). than 10 years ago showed an improved failure-free INTRODUCTION Corresponding author: Armando Santoro, survival rate with high-dose chemotherapy and MD, Humanitas Cancer Center, Via autologous stem-cell transplantation (ASCT) com- Manzoni 56, Rozzano (MI), Italy; e-mail: 4,5 armando.santoro@cancercenter. First-line chemoradiotherapy yields cure rates ap- pared with conventional-dose chemotherapy. humanitas.it. proaching 80% in patients with advanced-stage However, the efficacy of this approach has been 1,2 3 © 2016 by American Society of Clinical Hodgkin lymphoma (HL). Patients who are challenged by a recent meta-analysis. Therefore, Oncology refractory to or relapse after initial therapy usually further investigation of the optimal therapeutic 0732-183X/16/3427w-3293w/$20.00 have a worse prognosis, and second-line salvage strategy in patients with relapsed or refractory 6,7 DOI: 10.1200/JCO.2016.66.4466 treatment programs are required as early as pos- HL seems warranted. sible to reduce the risk of treatment failure, avoid Achieving complete response (CR) after unnecessary toxicity, and prolong survival.3 Two induction chemotherapy administered before randomized, phase III studies conducted more ASCTrepresents the strongest prognostic factor in © 2016 by American Society of Clinical Oncology 3293 Downloaded from ascopubs.org by 137.108.70.7 on February 3, 2017 from 137.108.070.007 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Santoro et al patients receiving second-line salvage chemotherapy.8 Thus, in- Patients received four cycles of the BeGEV regimen administered every creasing the rate of CR achieved with induction chemotherapy 21 days. Growth factor support with granulocyte colony-stimulating factor represents a primary goal in patients with refractory or relapsed HL. (G-CSF) was administered at each cycle. Patients received Pneumocystis pneumonia prophylaxis and antiemetics in accordance with institutional Our group developed the IGEV regimen, consisting of ifos- guidelines. Treatment was interrupted in case of disease progression, famide, gemcitabine, and vinorelbine, as pretransplantation sal- unacceptable toxicity, or withdrawal of consent. Patients who achieved CR 8 vage chemotherapy. In a study of 91 patients, the overall response or partial response (PR) after completion of the planned four cycles re- rate (ORR) was 81%, with a 54% CR rate and no toxicity con- ceived myeloablative therapy with BEAM (carmustine, etoposide, cytar- cerns.8 Furthermore, the IGEV regimen demonstrated excellent abine, and melphalan; n = 20) or FEAM (fotemustine, etoposide, 9 cytarabine, and melphalan; n = 23) followed by reinfusion of mobilized mobilizing potential of peripheral-blood stem cells. 2 Bendamustine hydrochloride comprises a 2-chloroethylamine CD34+ circulating stem cells. BEAM consisted of carmustine 300 mg/m on day 26, etoposide 200 mg/m2 on days 25to22, cytarabine 400 mg/m2 alkylating group and a benzimidazole ring similar to cladribine. intravenously (IV) on days 25to22, and melphalan 140 mg/m2 IV on Despite its structural similarities to both alkylating agents and day 21. FEAM consisted of fotemustine 150 mg/m2 IVon days 27 and 26, purine analogs, the exact mechanism of action of bendamustine etoposide 200 mg/m2 on days 25to22, cytarabine 400 mg/m2 IV on is unknown.10 Retrospective and prospective studies have shown days 25to22, and melphalan 140 mg/m2 IV, on day 21. Both mye- promising activity of bendamustine monotherapy in the treat- loablative regimens were followed by the reinfusion of at least 2 3 106 per m ment of patients with multirelapsed HL who were ineligible kilogram of body weight of CD34+ cells on day 0 and G-CSF 5 g/kg subcutaneously per day from day +5 until achievement of WBC of 3,000/mL ASCTor for whom ASCT had failed, with a remarkable incidence . 11-15 or greater for 3 days. Patients with residual lymphoma ( 1.5 cm on of CR (range, 25% to 35%). The use of bendamustine in computed tomography [CT] scan) at 100 days after ASCT received 30-Gy combination regimens as second-line salvage chemotherapy in involved-field radiotherapy. patients with relapsed or refractory HL has been proposed to increase the CR rate.11 Therefore, in this multicenter phase II study, we replaced ifosfamide in the IGEV regimen with Response Criteria bendamustine to evaluate this combination (BeGEV) as in- Responses were assessed according to the International Working Group response criteria.17 CT and [18F]fluorodeoxyglucose–positron duction therapy before ASCT in patients with relapsed or re- emission tomography scans were performed before and after the fourth fractory HL. BeGEV cycle. According to the 2007 criteria of Cheson et al,17 a metabolic response was scored as CR when positron emission tomography scan results were negative on the basis of visual analysis, independent from the PATIENTS AND METHODS presence of residual masses on CT scan. Patient Eligibility CD34+ Cell Mobilization and Collection Consecutive patients with HL age 18 years or older who were re- To elicit CD34+ cell mobilization, G-CSF (10 mg/kg body weight) was fractory to or had relapsed after receiving one previous chemotherapy line administered once per day beginning on day 7 and continued until fi were eligible. Refractory disease was de ned as disease progression during completion of the target cell harvesting (3 3 106 CD34+ cells/kg). Col- or within 3 months of doxorubicin-based chemotherapy, and relapsed lection of CD34+ cells was usually performed after the first or second cycle, disease was defined as reappearance of disease after CR lasting 3 months or m 16 when circulating CD34+ cells were 10/ L or greater using a COBE Spectra longer. Other inclusion criteria were
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