A Phase 2 Study from Spanish Geltamo Group Investigating the Efficacy and Safety of Bendamustine As Part of Conditioning Regimen for Autologous Stem-Cell Transplantation in Patients with Aggressive Lymphomas: Second Interim Analysis

INTRODUCTION: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed or refractory aggressive B-cell lymphoma, and is frequently used as part of first-line therapy in patients with peripheral T-cell lymphoma (PTCL). However, long-term remission rates with this strategy are inferior to 50%, so novel approaches are required. We have designed a prospective multicenter phase II study to evaluate the safety and efficacy of bendamustine as part of conditioning regimen in patients with aggressive lymphomas undergoing ASCT.

METHODS: Inclusion criteria were: histologic diagnosis of i) relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or grade 3B follicular lymphoma (FL) in partial response (PR) or complete remission (CR) after salvage therapy, or ii) transformed DLBCL or peripheral T-cell lymphoma (PTCL) in first or subsequent PR or CR. Conditioning regimen consisted of bendamustine (200 mg/m², days -7 and -6), etoposide (200 mg/m², days -5 to -2), cytarabine (400 mg/m², days -5 to -2), and melphalan (140 mg/m², day -1) (BendaEAM regimen). Primary endpoint was progression-free survival (PFS) at 3 years. Secondary endpoints were toxicity, response to transplant at 3 months, and overall survival (OS). This trial was registered at EMEA (EUDRACT number 2010-020926-17).

RESULTS: Sixty patients (median age 54 years, range 27-70) from 22 Spanish hospitals were included since May 2011 to November 2012. Histologies were: 40 DLBCL, 3 grade 3B FL, 13 transformed DLBCL, and 7 PTCL. 82% of patients have received ³2 lines of treatment prior to ASCT. 37 patients (62%) were in CR at the time of transplant and 23 (38%) in PR. A median number of 4.05 x 10⁶/Kg (range: 1.69-19.80) CD34⁺ cells were reinfused. All patients (except one who died early) engrafted after a median of 11 (range: 9 to 72) and 14 (range: 4 to 53) days, respectively, to achieve >0.5 x10⁹/L neutrophils and >20 x10⁹/L platelets. 39 serious adverse events (SAEs) were reported before day +100, including 14 infectious episodes, 2 of them resulting in respiratory failure and death (3.3% of transplant related mortality). Another major SAE was renal toxicity developed by 5 patients (8.3%) after bendamustine administration, reversible in all cases (3 of these patients had developed mild renal failure during previous salvage therapy). Non-relapse mortality after day +100 was 3.3% (1 patient died because of Wernicke's encephalopathy, and 1 patient from infectious complications). Concerning response to transplant, 44 patients (73.3%) achieved CR, 7 (11.7%) PR, and 6 patients (10%) did not respond. Univariate analysis showed that patients who received more than 2 lines of treatment prior to transplant (1 line: 100% of CR post-transplant; 2 lines: 71%; >2 lines: 50%; p=0.013), and those who were in PR at transplant (48% vs 89%, p<0.001) had lower CR rates after ASCT (day +100), although only disease status at transplant retained the significant influence in the multivariate analysis (RR: 0.11, 95% CI: 0.03-0.42, p=0.001). Histological diagnosis had no significant influence on CR rates after ASCT (DLBCL: 73%; transformed DLBCL: 69%; PTCL: 86%; p>0.1). At the time of analysis, 13 patients (22%) had disease progression and 8 patients (13%) have died (4 from lymphoma, and 4 from other causes). With a median follow-up of 18.9 (9.5 to 32.3) months, the estimated 2-year PFS and OS were 73% and 88%, respectively.

CONCLUSIONS: The BendaEAM conditioning regimen is feasible and active in patients with aggressive lymphomas. Toxicity profile is similar to that commonly observed in the ASCT setting, but renal toxicity can occur and should be carefully monitored, especially in patients with prior history of renal failure. Longer follow-up is needed to assess the long-term toxicity and the efficacy of this regimen, although patients who are not in CR before transplant seem to have poorer outcomes.