Rituximab, bendamustine and cytarabine (R-BAC) in patients with relapsed-refractory aggressive B-cell lymphoma
Authors: Maria Chiara Tisi, Rossella Paolini, Francesco Piazza, Erika Ravelli, Cristina Tecchio, Roberto Sartori, Barbara Famengo, Emanuele Stefano Giovanni D'Amore, Giuseppe Carli, Omar Perbellini, Eros Di Bona, Marco Ruggeri, Carlo Visco
Journal: American Journal of Hematology (2018)

Management of diffuse large B-cell lymphoma (DLBCL) after failure of front-line immunochemotherapy is a treatment challenge, without a clear optimal salvage strategy, especially for patients not candidate to autologous stem cell transplantation (ASCT).1 Few patients achieve long-term disease control and no standard therapy exists. The British Columbia Cancer Agency reported a median progression-free survival (PFS) and overall survival (OS) of 2.1 and 3.9 months, respectively, in 326 patients who were not candidate for ASCT.2 Among most widely used salvage regimens, the combination of rituximab and bendamustine (BR) was associated with overall response (OR) ranging from 32 to 63%, and PFS of 3-8 months.3, 4 When combined with cytarabine, bendamustine has demonstrated significant synergistic activity in preclinical studies on DLBCL.5 Thus, we conducted a pilot trial to explore the efficacy and tolerability of R-BAC (rituximab, bendamustine, and cytarabine) in a cohort of patients with B cell relapsed/refractory (R/R) aggressive lymphoma. This study enrolled previously treated, histologically confirmed DLBCL, either de-novo or transformed B-cell lymphoma (t-DLBCL), treated with R-BAC between November 2012 and September 2017 in six Centers from Northern Italy. To be included patients had to be: (1) treated with at least one previous line if not eligible for ASCT; (2) treated with two or more previous lines of therapy including ASCT or not; (3) aged 18 years or more, with no upper age limit; (4) not treated with prior bendamustine. The study was approved by the ethics review board of the participating institutions and patients signed informed consent before being enrolled. All histological diagnosis were centrally reviewed by two expert hematopathologists (B.F. and E.SG.D.). The primary end-point was the complete remission (CR) rate. Secondary end-points included OR, PFS, OS, duration of response (DOR), and safety. The response rate was based on local radiologists evaluation, and was evaluated according to Cheson criteria, 2007. A boundary of 30% CR rate was considered indicative of a positive trial, based on results obtained with BR in similar patient series.3, 4 The R-BAC regimen6 consisted of rituximab (375 mg/m2, Day 1 of the cycle), bendamustine (70 mg/m2, Days 1-2, given as a 1-h infusion) and cytarabine (500 mg/m2, Days 1-3, given as a 2-h infusion starting 2 h after bendamustine), administered every 21 days. Patients were meant to receive at least four cycles, but in case of good tolerance and/or partial response after four cycles patients continued treatment to a maximum of six cycles. Patients older than 70 years or with poor performance status (ECOG >2) not due to lymphoma progression had cytarabine dose limited to Days 1 and 2. The same dose reduction was applied to patients experiencing an excess of toxicity, defined as hematological or non-hematological toxicity of Grade 4 lasting for more than 5 days during any of the treatment cycle. Primary prophylaxis with granulocyte colony-stimulating factor was routinely used starting from Day 5 after chemotherapy completion, and lasting for 3-6 days or until neutrophil count recovery. Overall, 39 patients were included. Median age was 68 years (range 21-84), and 23 (59%) were males. The majority of patients (29, 74%) were recruited and treated in Vicenza, since other participating centers joined the study later in 2015. All patients had received rituximab-CHOP (R-CHOP) or R-CHOP-like induction treatment, median number of prior treatments was 2 (range 1-4), and six patients (15%) had prior ASCT. The majority of patients (n = 21, 54%) had refractory disease, with 23% of patients (n = 9) being double refractory (both to R-CHOP and R-DHAP). Median time from initial lymphoma diagnosis to enrollment was 21 months (range 4-120). Median follow-up of the entire population from lymphoma diagnosis was 30 months (12-172). Patients characteristics are listed in Table 1. Patients received a median of 4 cycles (range 1-6). Early discontinuations (before cycle 4) were due to infections in 2 (1 had febrile neutropenia in two consecutive cycles despite dose reductions, 1 had colitis complicated by salmonellosis), and tumor progression in 10; 2 patients were consolidated with allogeneic stem-cell transplantation after achieving CR; 4 patients were consolidated with ASCT; 20 patients (51%) had to delay or reduce treatment dose at least once along cycles, however, delays lasted <14 days. Overall, OR was 69% (CI 58-76), and CR was 41% (CI 32-48). Among different histologies, OR was 78% in de novo DLBCL (CR 48%) and 55% in t-DLBCL (CR 27%). Refractory patients had an OR of 48% (CR 24%). The nine double refractory patients had an OR of 56% (2 CR, 3 PR, 2 stable disease, 2 progressive disease). Interestingly, tumor shrinkage was observed in the majority of patients (79%), irrespective of tumor histology (P = .23 by Mann-Whitney test), as shown in Figure 1A. Median follow-up for survivors from study entry was 14 months (range 2-55). Median PFS was 13.9 months, and median OS was 17.3 months (Figure 1B,C). Median duration of response was 16 months, significantly different between CR and PR (nr vs. 9.9 months, P = .05, Figure 1D). The two patients receiving allogeneic transplant are still in remission after 52 and 25 months, respectively. Of the four patients that were consolidated with ASCT, two experienced early relapse (2 and 5 months later) and two are still in complete remission after 4 and 7 months, respectively. At univariate analysis, the variables associated with a significantly impaired PFS were refractory as opposed to relapsed disease (P = .03), shorter time since prior anti-lymphoma treatment (<6 vs. ≥6 months, P = .007), and nongerminal center (GCB) cell-of-origin (non-GCB vs. GCB, P = .01). Interestingly, international prognostic index (P = .15), t-DLBCL as opposed to de novo DLBCL (P = .87), and number of prior lines of therapy (1 vs. ≥2) were not associated with PFS (P = .57). Cox proportional hazard model identified refractoriness to prior treatment as the strongest independent prognostic variable in terms of PFS (P = .01, hazard ratio, 3.88; 95% CI 1.37-11.71). The primary toxicity was reversible myelosuppression. Grades 3-4 neutropenia (median duration 3 days, range 0-7) and thrombocytopenia (median duration 4 days, range 0-8) occurred in 45% and 32% of patients, respectively. Febrile neutropenia occurred in two patients (5%). There was no clear trend towards an increase in cytopenia severity or transfusion requirements with subsequent cycles. Most nonhematological adverse events attributed to R-BAC were Grades 1-2, leaded by isolated gamma-glutamyl transferase elevation (16%). Skin rash, sometimes accompanied by localized itchy areas of cutaneous desquamation, was reported in 15%. No secondary malignancy was observed during follow-up. Of the 15 deaths reported during the study, all patients except one were attributed to disease progression. This patient died of unknown cause while he was in remission. No toxic death has been reported. No alopecia was observed. In conclusion, R-BAC demonstrated promising anti-tumor activity in this series of patients with de-novo or transformed aggressive lymphomas (2 median prior lines, and 54% refractory disease) unsuitable for ASCT, with tumor shrinkage observed in 79% of patients. The response rate compared favorably with previously reported prospective phase two studies in R/R patients with DLBCL treated with the combination of BR.3, 4 Indeed, our patients presented with higher risk features compared to patients enrolled in these trials, due to a worse performance status, higher IPI and greater number of previous treatment lines. Patients treated with R-BAC experienced mainly hematological toxicity, as expected, which was managed with dose reductions. Importantly, R-BAC was administered in outpatient setting in the majority of patients. Based on our observations, R-BAC may warrant further investigation in this setting, both as a bridge to allogeneic stem-cell transplantation, or in combination with targeted therapies. Maria Chiara Tisi and Carlo Visco performed the research, acquired and analyzed the data, and wrote the manuscript. Giuseppe Carli and Omar Perbellini contributed to data acquisition. Marco Ruggeri, Rossella Paolini, Francesco Piazza, Erika Ravelli, Cristina Tecchio, Roberto Sartori and Eros Di Bona contributed to recruitment of patients, and critically revised the manuscript. Barbara Famengo and Emanuele SF D'Amore centrally reviewed all histological diagnosis. All authors approved the final version of the paper for publication. The authors have no conflicts of interest to disclose. The results shown here are original and are not under review in any other journal.