Bendamustine for Hodgkin lymphoma patients failing autologous or autologous and allogeneic stem cell transplantation: a retrospective study of the Fondazione Italiana Linfomi (2014)

First-line chemo-radiotherapy produces cure rates approaching 90% and 80% in early- and advanced-stage Hodgkin lymphoma (HL), respectively. However, 5–10% of patients with early-stage and 20–25% with advanced-stage disease experience either chemorefractoriness to, or disease relapse after, first-line chemotherapy. Whereas 50% of HL patients with chemosensitive relapse and a minority of patients with primary refractory disease will achieve long-term disease-free survival with autologous and eventually allogeneic stem cell transplantation (SCT), disease recurrence or progression after SCT is associated with very poor prognosis. The bifunctional alkylator bendamustine hydrochloride may be considered an attractive agent for use in this clinical setting because of a variety of mechanistic differences compared to other alkylating agents employed in HL. The efficacy of bendamustine in relapsed/refractory HL has previously been reported but limited information is available on bendamustine after allogeneic SCT failure (Corazzelli et al, 2013; Moskowitz et al, 2013). To extend the evaluation of bendamustine and further analyse its effect in HL patients failing allogeneic SCT, we performed a multicentre, retrospective analysis on 67 HL patients who relapsed or progressed after autologous SCT (n = 45, 67%) or autologous and allogeneic SCT (n = 22, 33%). Consecutive relapsed/refractory HL patients, who received single-agent bendamustine through patient-named off-label programmes approved by the ethical committees of 16 participating centres of the Fondazione Italiana Linfomi, were identified in the respective institutional databases. This study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the ethical committee of each participating centre. Tumour responses were assessed according to the revised response criteria of the International Working Group (Cheson et al, 2007). Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). The activity and efficacy of bendamustine were evaluated in terms of objective response rate (ORR), including complete remission (CR) and partial remission (PR), safety, progression-free survival (PFS) and overall survival (OS). Between October 2007 and May 2012, 67 HL patients (31 males, 36 females) with a median age of 34 years (range, 20–63 years) received salvage therapy with bendamustine. Patients had previously received a median of 4 (range, 2–11) lines of treatment, including autologous (n = 45, 67%) or autologous/allogeneic (n = 22, 33%) SCT. Poor prognostic features included refractory disease (n = 48, 72%), B symptoms (n = 27, 40%), bulky disease (n = 14, 21%) and extranodal involvement (n = 48, 72%). Bendamustine was administered at 90 mg/m2 (49 patients, 73%) or 120 mg/m2 (18 patients, 27%) on days 1 and 2 of each 28-d cycle for a median of three cycles (range, 1–10). Dose reduction to 90 mg/m2 was required in 15 of 18 patients receiving 120 mg/m2 bendamustine, mainly because of thrombocytopenia. Early drug discontinuation was necessary in 32 patients because of disease progression (n = 28), thrombocytopenia (n = 1) and investigator decision (n = 3). The ORR for the 67 patients was 57% [95% confidence interval (CI), 45–69%], including 17 CR (25%) and 21 PR (31%). Stable disease (SD) was observed in 3 (4·5%) and progressive disease (PD) in 26 (39%) patients. The only factor having a statistically significant impact on the likelihood of responding to bendamustine was disease status, with relapsed patients having a higher ORR than refractory patients [79% vs. 48%; Hazard Ratio (HR) = 4·1, 95% CI, 1·2–14·1, P = 0·029]. After a median follow-up of 13 months (range, 1–32 months), PFS was 49% (95% CI, 34–62%), and OS was 70% (95% CI, 56–81%) at 1 year. The median PFS was 10 months (95% CI, 37–64%), whereas the median OS was not established (Fig 1A–B). The median PFS for responding (CR + PR) and non-responding (SD + PD) patients was 11 and 3 months (P = 0·004), respectively (Fig 1D). The median OS for responding patients was not established, whereas that for non-responding patients was 7 months (P = 0·058) (Fig 1C). Forty-nine (73%) patients survived, and 18 (27%) patients died. In addition to lymphoma progression (n = 16, 89%), causes of death included acute respiratory distress syndrome (n = 1) and multi-organ failure (n = 1), which occurred at 6 and 2 months from the last dose of bendamustine, respectively. In multivariate analysis, bulky disease [HR = 3·0; 95% CI, 1·4–6·5; P = 0·006), and Eastern Cooperative Oncology Group performance status (ECOG PS) >1 [HR = 2·7, 95% CI, 1·3–5·8; P = 0·009] retained independent adverse prognostic values on PFS. Both bulky disease [HR = 3·8, 95% CI, 1·4–10·5; P = 0·011] and ECOG PS >1 [HR = 3·2, 95% CI, 1·2–8·8; P = 0·024] also retained independent adverse prognostic values for OS. Bendamustine was well tolerated without significant adverse events. Grade 3–4 therapy-related haematological adverse events included anaemia in four patients (6%), thrombocytopenia in 11 patients (16%) and neutropenia in 12 patients (18%). The most common non-haematological toxicities were grade 3–4 fever (10% of patients) and febrile neutropenia (13% of patients). Grade 3–4 sepsis, pneumonia and respiratory infections occurred in two, three and five patients, respectively. Our data add a substantial piece of information on the efficacy of bendamustine in HL failing autologous and allogeneic SCT, strongly supporting its use as an effective and well-tolerated treatment after allogeneic SCT failure. In this setting, the consistent efficacy and the limited toxicity of bendamustine qualifies this drug as one of the most promising, even when compared with brentuximab vedotin (Gopal et al, 2012). In conclusion, our results support prospective studies using bendamustine in combination with molecularly targeted agents to enhance tumour debulking in refractory patients and to reduce the risk of relapse, thereby ultimately improving survival. The authors thank the following investigators for providing patients data: A.M. D'Arco, MD (Division of Haematology, Nocera Inferiore, Italy); M. Gotti, MD (Department of Haematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, Pavia, Italy); D. Russo, MD (Chair of Haematology, Unit of Blood Diseases and Stem Cell Transplantation, University of Brescia, Brescia, Italy); C. Stelitano, MD (Division of Haematology, Reggio Calabria, Italy); L. Trentin, MD (Department of Medicine, Haematology and Clinical Immunology Branch, University of Padova, Padova, Italy). AA and LG designed the study and wrote the paper; CC-S, PC, and AS analysed the data and wrote the paper; LG and CC-S, analysed and interpreted the data; FS, CR, AP, AS, SH, PP, SV, EB, SL and SH acquired and interpreted the data. All Authors approved the submitted manuscript. The authors report no potential conflict of interests.