Bendamustine with Rituximab Is Safe and Effective As FRONT LINE Therapy in Elderly B-CLL Patients. an ITALIAN RETROSPECTIVE MULTICENTER Experience
Authors: Laurenti Luca , Autore Francesco , Innocenti Idanna , Vannata Barbara , Cantonetti Maria , Del Principe Maria Ilaria , Mauro Francesca Romana , Paola Anticoli Borza , Bongarzoni Velia , Ciolli Stefania , Boncompagni Riccardo , Sciumé Mariarita , Vincenti Daniele , Ghio Francesco , Cecconi Nadia , Pitini Vincenzo , Mondello Patrizia , Lanza Cariccio Maria Rosa , Gozzetti Alessandro , D'Arena Giovanni , Murru Roberta , Piccirillo Nicola , Petrini Mario , Cortelezzi Agostino , Del Poeta Giovanni , Foà Robin , Sica Simona 
Published: October 2019

Abstract
The front-line therapy for CLL young and fit patients is chemo-immunotherapy with Fludarabine-Cyclophosphamide and Rituximab (FCR). However, around three quarter of the patients with a newly diagnosed CLL are 65 years or older, with approximately 42% being older than 75 years and with age-related comorbidities. FCR regimen results in a significant myelosuppression and high rates of early and late infections. Hence, other less toxic regimens are under evaluation. Recently the German CLL study group reported an interim analysis of the CLL10 trial, who compared FCR vs Bendamustine-Rituximab (BR). The response rates to the 1st-line treatment with BR or FCR were comparable, and BR could be an alternative 1st-line treatment for medically fit pts. Notably, this study showed that pts treated with BR were often older (median 71 vs. 65 yrs; p<0.0001) and frequently with comorbidities (67% vs. 62%), suggesting that it may be a suitable option for this wide subpopulation. Here we report retrospective data from 12 Italian centres focused on the evaluation of efficacy and safety of BR in elderly SLL/CLL patients.
Data on 70 untreated SLL/CLL patients with age ≥ 65 years assigned to receive front-line therapy with 6 monthly courses of Bendamustine (90 mg/sm at days 1-2) and RTX (375 mg/sm at day 1 for the first course, then 500 mg/sm for subsequent cycles) were collected. The primary end points were the Overall Response (CR/PR) and toxicity rates. Responses, evaluated at 2 months after the end of therapy, were defined according to the updated National Cancer Institute-Working Group guidelines.
Seventy patients (47 males and 23 females) with a median age of 72 years (range, 65-87 years) were included in the study. Eight patients (11.4%) were unfit (CIRS score =/> 7). All patients had an ECOG performance status ranging from 0 to 2. Twenty-nine of 70 patients had Binet stage C, 12 patients were Binet A, 29 Binet B.
Thirty-nine patients showed karyotype abnormalities at FISH analysis (data available in 54/70 patients). High risk FISH karyotype according to Döhner´s hierarchical model was detected in 17 patients (14 with del 11q, 3 with del 17p). Ten of them had del(13q14), 12 had trisomy 12 and 15 had normal karyotype. The analysis of the IGHV status, available in 50 patients, showed 25 patients with somatic mutation and 25 patients with germ-line sequences. Zap-70 data were available for 37/70 pts, 19 of them (51.3%) were Zap-70 positive. CD38 was available for 52 patients: it was positive in 27/52 pts (51.9%). (Table 1)
A mean number of 5.46 courses of BR were given and the Bendamustine dose was reduced by more than 10% in 39 patients (55,7%). The main reason for dose reduction was haematological toxicities. The ORR rate was 88,6%,with 22 patients (31.4%) obtaining a CR and 40 patients (57,2%) obtaining a PR. Progression Free Survival, Time To Retreatment and Overall Survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only the presence of del17 resulted to affect the response rate (p= 0.023) and PFS (p<0.001). Grade 3-4 hematological toxicity was recorded in 25 patients (35,7%). Extra-hematological toxicity grade I-III (skin reactions, gastrointestinal and cardiovascular symptoms, infusion related reactions, etc). was noticed in 35 patients (50,0%). Eleven patients (15.7%) were admitted to the hospital.
Retrospective data from this group of elderly CLL patients indicate that Benda-R front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a Bendamustine dose reduction until 70 mg/sm. Even in this cohort of patients we confirmed del17 as a bad prognostic parameter.
Table 1: Patients’ clinical-biological characteristics. Median age at diagnosis 72 years (range 65-87) M:F 47/23 CIRS score =/>7 8/70 pts (11.4%) PB lymphocytes 33.203/mmc Binet stage A 12/70 pts (17.2%) Binet stage B 29/70 pts (41.4%) Binet stage C 29/70 pts (41.4%) ZAP70>20% 19/37 pts (51.3 %) CD38> 30% 27/52 pts (51.9%) Beta2microglobulin increased 51/59 pts (86.4%) IgVH homology < 98% 25/50 pts (50%) Normal FISH 15/54 pts (27.8%) del 13q 10/54 pts (18.5%) +12 12/54 pts (22.2%) del 11q 14/54 pts (25.9%) del 17p 3/54 pts (5.6%) Bulky syndrome 16/70 pts (22.9%)
PB, peripheral blood; IgVH, immunoglobulin heavy chain variable genes;
FISH, Fluorescent In Situ Hybridization.

Disclosures
No relevant conflicts of interest to declare.