Efficacy and Safety of Bendamustine and Rituximab As First Salvage Treatment in Chronic Lymphocytic Leukemia: Results of the Gimema-Eric LLC1315 Study

Abstract

Introduction. In chronic lymphocytic leukemia (CLL), chemoimmunotherapy produced high overall response rates (ORR), prolonged progression free survival (PFS) and overall survival (OS). In the absence of a TP53 disruption, recent European guidelines recommend a chemoimmunotherapy regimen in first-line and in second line in patients who have attained a long PFS with the previous regimen. Uncertainty in the recommendations on first salvage treatment may partially derive from the consideration that the majority of studies have described efficacy data in an aggregate fashion including all relapsed/refractory setting. Since bendamustine and rituximab (BR) is one of most widely adopted second line regimen we performed a retrospective study within the GIMEMA-ERIC network to collect data on the efficacy and the safety of the BR regimen in second-line in a real-world setting. Comparison of the BR data with 114 Italian and UK non-trial patients treated with ibrutinib at first relapse will be presented at the meeting when additional follow-up is available for the ibrutinib-treated cohort.Methods . 237 CLL patients treated between January 2008 and December 2014 at 35 GIMEMA-ERIC centers were enrolled. Inclusion criteria were: i) CLL diagnosis according to the NCI-WG guidelines, ii) age ≥18 years, iii) one previous treatment with alkylating agents and/or purine analogues with or without monoclonal antibodies, iv) progression requiring second-line treatment according to the NCI criteria, v) at least 1 day of second-line treatment with BR (B 70mg/m2 days 1-2 and R 375 mg/m2 for the 1st course and 500 mg/m2 subsequently). The study was registered at ClinicalTrials.gov (NCT02491398). The primary endpoint was PFS at 12 months. The secondary endpoints were ORR, time to next antileukemic treatment (TTNT) and OS. Results. The median age was 70 years (range 39-87); 58.3% had ≥2 comorbidities, 46.9% a creatinine clearance ≤70 ml/min and 21.4% an advanced stage (i.e. Rai III-IV or Binet C). 73% had unmutated IGHV and 33.4% 11q- and/or 17p-. First-line treatment was chemoimmunotherapy in 59% of the cases; the remaining patients received chemotherapy. 18 patients (9,4%) were refractory to first line treatment. Treatment was discontinued in 72 patients (30.4%) because of toxicity (n=39), withdrawal of consent (n=7), progressive disease (n= 6) or other reasons (n=20). Treatment delay occurred in 22.5% of cases. 95 patients (40.4%) received 6 cycles without dose reduction. The PFS was 78.6%, 30.9% and 16.2% at 12, 30 and 60 months, respectively (Fig. 1a). Median PFS was 25 months with a median follow-up of 37.1 months. 17p- (p=0.0004; Fig. 1b), unmutated IGHV (p=0.0299; Fig. 1c) and advanced stage (p=0.0192) were associated with a shorter PFS at multivariate analysis, while a Disclosures Cuneo: Gilead: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria, Other: Advisory Board; Roche: Honoraria, Other: Advisory Board. Rigolin: Celgene: Honoraria, Other: Advisory Board; Mundipharma: Other: Advisory Board; Gilead: Honoraria. Moreno: Janssen: Consultancy; Gilead: Consultancy, Research Funding. Galieni: Takeda: Other: Advisory Board; Abbvie: Other: Advisory Board. Laurenti: Roche: Other: Advisory Board; Gilead: Other: Advisory Board; Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board. Molica: Roche: Other: Advisory Board; Jansen: Other: Advisory Board; AbbVie: Other: Advisory Board; Gilead: Other: Advisory Board. Montillo: Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Research Funding; Novartis: Honoraria; Genetech: Research Funding. Coscia: Abbvie: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Orlandi: Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Re: Gilead: Membership on an entity9s Board of Directors or advisory committees. Gaidano: Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Foa: Roche: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Follows: Roche: Other: advisory board and lecturing; Janssen: Other: advisory board and lecturing; Abbvie: Other: advisory board and lecturing; Gilead: Other: advisory board and lecturing. Ghia: AbbVie: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria.