Efficacy of Front-Line Ibrutinib Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) in Patients with CLL. a Multicenter "Real-World" Study
Authors: Herishanu Yair , Levi Shai , Goldschmidt Neta , Morabito Fortunato , Bairey Osnat , Del Poeta Giovanni , Ziv Baran Tomer , Fineman Riva , Mauro Francesca Romana , Gutwein Odit , Reda Gianluigi , Ruchlemer Rosa , Sportoletti Paolo , Laurenti Luca , Shvidel Lev , Coscia Marta , Tadmor Tamar , Varettoni Marzia , Aviv Ariel , Murru Roberta , Breaster Andrei , Bronstein Yotam , Chiarenza Annalisa , Visentin Andrea , Pietrasanta Daniela , Loseto Giacomo , Zucchetto Antonella , Bomben Riccardo , Olivieri Jacopo , Neri Antonino , Rossi Davide , Gaidano Gianluca , Trentin Livio , Foa Robin , Cuneo Antonio , Gattei Valter , Gentile Massimo 
Published: November 2021

Abstract
Introduction: In previously untreated patients with chronic lymphocytic leukemia (CLL), treatment with ibrutinib plus rituximab improved progression-free survival (PFS) and overall survival (OS) compared to the standard fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapeutic regimen, based on the results of the phase III ECOG-E1912 trial. The improvement in PFS with ibrutinib plus rituximab was observed in patients with unmutated immunoglobulin heavy chain variable region gene (IGHV) but not in those with an IGHV mutated profile. However, the efficacy of ibrutinib compared to FCR has not yet been investigated in the real-world setting.
Methods: A multi-center retrospective "real-world" study to compare the efficacy of front-line ibrutinib monotherapy versus standard FCR in patients with CLL. Demographic and clinical data of the FCR cohort were retrieved from the Israeli CLL Study Group database and of the ibrutinib from the Italian multicenter "Campus CLL" network and the CLL database of the department of hematology at the Sourasky Medical Center. Patients with a documented del(17p) or those who are participating in clinical trials were excluded. In order to fit both treatment samples, the maximum follow-up was censored at 48 months. IBM SPSS Statistics was used to analyze PFS and OS by Kaplan Meier Estimator, Log-Rank test and Cox Regression. In order to control for differences in patients' characteristics, the inverse probability of treatment weighting (IPTW) method with stabilized weights and truncation of 5% extreme score was applied by R.
Results: A total of 235 patients who had been front-line treated with either FCR (n=136, 57.9%) or ibrutinib (n=99, 42.1%) were included (Table 1). Most patients were males (n=160, 68.1%), had an unmutated IGHV status (n=115, 70.6%) and were Binet stage B/C (n=191, 83.8%). By FISH, the most frequent abnormality was del(11q) (n=45, 23.1%) followed by trisomy12 (n=34, 17.4%) and del(13q) (n=43, 22.1%). Median time to first treatment was 29.4 months (IQR, 11.9-56.2), and it was not significantly different between ibrutinib (median=24.9 months, IQR 10.3-46.6) and FCR (median=34.0 months, IQR 13.8-60.1; p=0.101). Patients treated with FCR were younger than those treated with ibrutinib (median=58.4 years vs. 71.9 years; p&lt;0.001). The median follow-up for the entire cohort was 48.0 months (37.2 months and 48 months for ibrutinib and FCR, respectively). PFS was longer with ibrutinib than with FCR, with a 3-year rate of PFS of 89.7% vs. 65.8%, respectively (HR=3.5, 95% CI [1.8-6.9], p&lt;0.001) (Figure 1). By subgroup analysis, the PFS benefit with ibrutinib over FCR was maintained in the subgroups of patients age &gt;65 years (n=100, 3-year PFS 89.4% vs. 53.1%; HR=3.9, 95% CI [1.6-9.9], p=0.002), Binet stage B/C (3-year PFS: 90.5% vs. 67.8%; HR=3.5, 95% CI [1.7-7.5], p&lt;0.001) and unmutated IGHV (3-year PFS: 83.0% vs. 78.0%; HR=5.8, 95% CI [2.4-14.5], p&lt;0.001). Among mutated IGHV patients the PFS was not significantly different between ibrutinib and FCR (3-year PFS: 83.0% vs. 78.0%; HR=1.2, 95% CI [0.3, 4.5]; P=0.795). In multivariate analysis (Table 2), only FCR was an independent predictor of decreased PFS (HR=5.1, 95% CI [1.8, 14.3], p=0.002). OS was also better with ibrutinib than with FCR, with a 3-year OS of 96.8% vs. 87.5%, respectively (HR=3.52, 95% CI [1.04-11.92], p=0.031) (Figure 2). Using IPTW, both PFS and OS were still superior with ibrutinib compared to FCR (HR=0.2, 95% CI 0.1-0.5, p&lt;0.001 and HR=0.2, 95% CI [0.1-0.7], p=0.008, respectively).
Conclusions: In a real-world setting, front-line treatment with ibrutinib improves PFS and OS in patients with CLL. Similar to the results of the phase III ECOG-E1912 trial, the improvement in PFS was preferentially observed in patients with unmutated IGHV.
Figure 1 Figure 1.

Disclosures
Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Fineman: AbbVie: Research Funding. Mauro: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Tskeda: Consultancy, Honoraria. Reda: Abbvie: Consultancy; Astra Zeneca: Consultancy; Beigene: Consultancy; Janssen: Consultancy. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Shvidel: AbbVie: Honoraria, Research Funding. Coscia: Janssen: Honoraria, Other, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Other; AstraZeneca: Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Varettoni: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees. Aviv: AbbVie: Honoraria, Research Funding. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Rossi: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Cellestia: Honoraria, Research Funding. Gaidano: Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo: AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Gattei: abbVie: Research Funding; Janssen: Research Funding; Menarini: Research Funding.