Bendamustine in Combination with Rituximab for Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients: An Italian Retrospective Multicentre Study
Authors: Gentile Massimo , Ciolli Stefania , Molica Stefano , Di Renzo Nicola , Selleri Carmine , Villa Maria Rosaria , De Paolis Maria Rosaria , Scortechini Ilaria , Giannotta Angela , Minoia Carla , Rago Angela , Boncompagni Riccardo , Bonanno Vincenza , Levato Luciano , Musso Maurizio , Mastrullo Lucia , Melpignano Angela , Murru Roberta , Angelucci Emanuele , Tarantini Giuseppe , Caparrotti Giuseppe , Guarini Attilio , Ferrara Felicetto , Cimino Giuseppe , Zinzani Pier Luigi , Morabito Fortunato 
Published: October 2019

Abstract
BACKGROUND: The combination schedule of rituximab, fludarabine and cyclophosphamide is considered the standard therapy for fit and young untreated chronic lymphocytic leukemia (CLL) patients. However, although this therapy improves progression free survival (PFS) and overall survival (OS), it has been associated with increased toxicity: 76% of the patients experienced at least one grade 3 or 4 event. Recently, encouraging clinical results in terms of safety and efficacy have been obtained using bendamustine in combination with rituximab (R-B) in untreated CLL patients.
PURPOSE: We performed a multicentre retrospective study to assess safety and efficacy of R-B in a large group of untreated CLL patients.
METHODS: One hundred and thirty six untreated CLL patients were recruited from 16 Italian Institutions and included in the present analysis. The median age was 69 years (range 43–85), with 49.3% of patients older than 70 years; 53.7% of cases were male. All patients had active disease as defined by the NCI-WG, and 27.2% were at Binet stage C. FISH data, available in 86/136 cases, identified a del(17p) in 5.1% of the patients and del(11q) in 5.9%. Sixty-four patients (47.1%) had a creatinine clearance ≤70 mL/min. Fifty-six % of cases showed a WHO performance status (PS) of I-II and 61% a CIRS comorbidity index >0.
RESULTS: Among the 136 patients, 90 cases (66.2%) received B at the dosage of 90 mg/m2 on day 1 and 2 every 28 days, the remaining 46 cases received B at the dosage of 70 or 80 mg/m2. R was administered at the dosage of 375 mg/m2 on day 1 of all cycles in 59.6% of cases, while 40.4% received 375 mg/m2 on day 1 of the first cycle and 500 mg/m2 on day 1 of the other cycles. A total of 725 cycles were administered with a median number of 6 cycles per patient. Eighteen patients (13.2%) required early discontinuation of therapy before the sixth cycle for serious infections (n=7), persistent hematological toxicity (n=5), grade 4 dermatological toxicity (n=3), withdrawal of consent (n=2), hypersomnia and depression (n=1). Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 25.8%, 25.8%, and 16.2% of patients, respectively. Grade 3 or 4 severe infections occurred in 6.6% of patients. The overall response rate (ORR) was 93.4%, 48 patients (35.3%) achieved a complete response (CR), 79 (58.1%) a partial response (PR), 8 (5.9%) a stable disease (SD) and in 1 patient (0.7%) no response assessment was performed due to death prior to terminating therapy. In the high-risk group with del17p, 5/7 (71.4%) cases achieved a PR and 2 a SD. Age >70 years (P=0.026) and del17p (P=0.007) were the only two parameters significantly associated with a lower response rate, while del11q and unmutated IGHV, as well as creatinine clearance <70 ml/min, elevated β2-microglobulin, PS and CIRS CI >0 did not seem to impact on achievement of response. The only parameter predictive of the probability of achieving a CR was an age <70 years (P=0.03). When the analysis was restricted to cases with available FISH data, excluding patients with del17p, biological (CD38, ZAP-70, IGHV mutational status, FISH risk) and clinical parameters (age, β2-microglobulin, LDH, PS, CIRS CI, and creatinine clearance) did not significantly impact on the probability of achieving a response or on quality of response. After a median follow-up of 14 months, 2-year PFS was 87% and 2-year OS 84.5% (14 deaths occurred). Eight of 14 deaths were CLL-related (infections in 6 cases and disease progression in 2).
CONCLUSIONS: The clinical practice of the Italian centers taking part in the study confirms that chemoimmunotherapy with R-B was an effective and well-tolerated treatment for untreated CLL patients. In patients with del17p the therapy appears to be less efficacious.

Disclosures
Off Label Use: Bendamustine in diffuse large B-cell lymphoma. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees.