Real Life Use of Bendamustine Plus Rituximab Versus Chlorambucil Plus Rituximab As Front-Line Therapy for Elderly CLL Patients. Retrospective Multicenter Study in the Lazio Region
Authors: Autore Francesco , Innocenti Idanna , Corrente Francesco , Del Principe Maria Ilaria , Rosati Serena , Falcucci Paolo , Conte Esmeralda , Limongiello Maria Assunta , Renzi Daniela , De Padua Laura , Andriani Alessandro , Pisani Francesco , Cimino Giuseppe , Tafuri Agostino , Montanaro Marco , Mauro Francesca Romana , Del Poeta Giovanni , Laurenti Luca 
Published: October 2019

Abstract
Introduction. Elderly patients with chronic lymphocytic leukemia (CLL) are often treated with chemoimmunotherapeutic regimens. Because of ineligibility for Fludarabine-based protocol, Bendamustine plus Rituximab (B-R) or Chlorambucil plus Rituximab (Chl-R) are the common preferred schemes, chosen in fit or unfit elderly patients, which can obtain good response and less toxicity. In literature overall response rates (ORR) between 66% to 84% and complete responses (CR)ranging from 8% to 26% have been reported Chl-R; for B-R, the ORR ranged between 88% and 98% with CRbetween 25% to 38%.
Aim and methods. We compared these two regimens in a multicentre group to understand why and how physicians could choose among these schemes and to establish the advantages and disadvantages of each one in terms of safety and efficacy. To this end, we performed a subgroup analysis: high-risk group (HR) included patients with 17p or 11q and/or unmutated IGHV, standard-risk group (SR) patients without 11q or 17p but with mutated IGHV.
We conducted a retrospective analysis on the experience, in clinical practice, of B-R and Chl-R as frontline treatment for elderly (≥65 years) CLL patients treated at 8 haematological centres in the Lazio region.
Results. One hundred and ninety-two patients who underwent treatment between 2009 and 2016 were enrolled into the study: 111 patients with B-R and 81 with Chl-R. Patients' characteristics are summarized in Table 1.
The median number of B-R cycles was 6 (range 1-6); B dose was 90 mg/m2 (administered at baseline 70 mg/m2 in 19 patients, 17%). The median number of Chl cycles was 6 (range 3-10) and of R was 6 (range 1-8). The two main schedules used for Chl were 1 mg/kg for each cycle every 28 days, given at a fixed daily dose of 10 mg starting from day 1 and repeated for 8 cycles, and 8 mg/m2/day for seven days of each of eight 28-day-cycles. R was administered in both the 2 schemes on day 1 of each cycle at a dose of 375 mg/m2 during the first administration and 500 mg/m2 for the subsequent cycles.
On an intention to treat basis, the ORR was 93.6% in B-R (54.9% complete response, CR, and 38.7% partial response, PR) and 86.5% in Chl-R (30.9% CR and 55.6% PR).
In B-R group 45 patients (40.5%) progressed with a median progression-free survival (PFS) of 46 months (CI 95%, 40-59), 38 (34.2%) required re-treatment with a median time to retreatment (TTR) of 53 months (CI 95%, 43-63), 10 (9.0%) died but median overall survival (OS) was not reached; we registered 47.8% of haematological toxicity (36.0% grade III-IV) and 46% of extra-haematological toxicity (13.5% grade III-IV); the most frequent serious adverse events were neutropenia and cutaneous reactions, respectively. Thirty-eight (34.2%) patients had to reduce B dose, 13 (11.7%) were hospitalized.
In Chl-R group 45 patients (55.6%) progressed with a median PFS of 37 months (CI 95%, 30-39), 39 (48.2%) required re-treatment with a median TTR of 46 months (CI 95%, 36-58), 18 (22.2%) died with a median OS greater than 100 months; we registered 28.4% of haematological toxicity (22.2% grade III-IV) and 27.2% of extra-haematological toxicity (11.1% grade III-IV); the most frequent serious adverse events were neutropenia, R infusion reactions and respiratory events, respectively. Fifteen (18.5%) patients had to reduce Chl dose, 7 (8.6%) were hospitalized.
We found a statistical difference among the schemes in terms of ORR (better response in B-R, p=0.002, but it was not significant when analysed considering B cycles, 6 cycles vs less than 6 cycles, and dose reduction) and in terms of haematological and extra-haematological toxicity (more toxicities in B-R than Chl-R, p=0.007 and p=0.010 respectively, but it was not different if considered the type and the grade). When comparing Kaplan-Meier curves of PFS, TTR and OS we did not find any statistical difference. Subgroup analysis of the HR and SR showed that no differences were found in the outcome curves for both PFS, TTR and OS in B-R group and Chl-R group.
Conclusions. ORR are very good in both groups, confirming the role of Chl and of B in association with R in elderly patients. The high rate of ORR in comparison with other published study was also due to the main dose of B and Chl used. Our study focused on elderly (≥65 years) untreated CLL patients, in whom B-R regimen is associated with better response but also higher toxicity in comparison to Chl-R. In the real life, the physician seems to apply the Chl-R protocol to very elderly or unfit CLL patients.

Disclosures
Del Principe: Gilead: Membership on an entity's Board of Directors or advisory committees. Mauro:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.