Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)
Authors: Al-Sawaf Othman , Robrecht Sandra , Bahlo Jasmin , Fink Anna Maria , Cramer Paula , Maurer Christian , Bergmann Manuela A. , Dreyling Martin H. , Lange Elisabeth , Kneba Michael , Stilgenbauer Stephan , Döhner Hartmut , Kiehl Michael G , Jäger Ulrich , Wendtner Clemens-Martin , Fischer Kirsten , Hallek Michael , Eichhorst Barbara F. , Hopfinger Georg 
Published: October 2019

Abstract
Introduction
Chemoimmunotherapy with FCR is the current standard for physically fit CLL patients (pts) without TP53 deletion/mutation. Due to better tolerability, BR should be considered in pts aged ≥ 65. Data from studies in CLL and other lymphomas suggest that women might have a better overall survival (OS) than male pts. The aim of this study was to evaluate the impact of gender on progression-free (PFS) and OS as well as on the rate of toxicities during and after therapy with FCR or BR.
Methods
Data from three clinical trials (phase II/III) of the GCLLSG including 1078 treatment naïve pts were analyzed. 683 pts received FCR (404 in CLL8 [FCR vs FC], 279 in CLL10 [FCR vs BR]) and 395 received BR (278 in CLL10, 117 in CLL2M). Laboratory markers, genetic parameters as well as event-related data were pooled. Kaplan-Meier curves were plotted and compared by non-stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression modelling. Independent prognostic factors for PFS and OS were identified by multivariate analyses using Cox regression modelling with stepwise selection procedures.
Results
Median age was 61 years (y) (30-81). 291 (27%) pts were female, 787 (73%) were male. Distribution of Binet stages was similar between women and men, as well as age, frequency of unfavorable genetic aberrations and mutations (17p deletion, 11q deletion, unmutated IGHV) or elevated serum parameters (thymidine kinase [TK], β2-microglobulin [B2M]) except for trisomy 12 (18.7% in female vs 9.8% in male). Median observation time was 69.7 months in the CLL8 trial, 42.7 in CLL2M and 58.2 in CLL10 and 63.6 in the overall cohort.
The CR rate with FCR treatment was 50% in female pts vs 41.9% in male pts and 29.5 vs 29.1% with BR treatment. At final restaging, 66.4% of female pts were MRD negative in peripheral blood (defined as &lt;10-4) vs 66.7% of male pts. 45.2% of female pts achieved MRD negativity in bone marrow vs 44.9% of male pts.
5-y-PFS was higher for women after FCR (52.5% vs 45.5%; HR=1.197 [0.949-1.510]; p =0.13) as well as after BR (44.8% vs 23.2%; HR=1.523 [1.124-2.063]; p=0.007). While BR was significantly inferior to FCR in male pts (5-y-PFS 23.2% vs. 45.5%; HR=1.644 [1.359-1.988]; p&lt;0.001) the difference was not statistically significant in female pts (5-y-PFS 44.8% vs. 52.5%; HR=1.277 [95%CI 0.912-1.788]; p=0.154).
Median OS for all groups was not yet reached. 5-y-OS after BR was 84.6% in women vs 74.7% in men (HR=1.705 [95%CI, 0.965-3.014]; p=0.07) and 80% vs 79.6% after FCR (HR=1.179 [0.831-1.673]; p=0.36). OS according to gender did not differ significantly between men and women (5-y-OS 78.4 % vs 81.8%; HR=1.301 [0.966-1.752]; p=0.083), while PFS did differ significantly (5-y-PFS 38.6 % vs 50.1%; HR=1.283 [1.067-1.542]; p=0.008). In multivariate analyses, independent adverse prognostic factors for PFS were BR treatment, male gender, TK (&gt;10.0 U/l), unmutated IGHV, deletion 17p and deletion 11q. Factors associated with OS were age (&gt;65y), B2M (&gt;3.5 mg/l), TK (&gt;10.0 U/l), unmutated IGHV and deletion 17p, but not gender.
CTC grade 3 and 4, hematological adverse events (AE) were more frequent in female pts treated with FCR, particularly anemia (8.6% vs 5.6% in male), leukopenia (51.4% vs 41.0%) and neutropenia (57.3% vs 46.0%), but not thrombocytopenia (11.4% vs 11.8%). Frequency of dose reductions and median number of administered treatment cycles did not differ.
Though frequency of hematological AEs was lower with BR compared to FCR, female pts experienced more severe anemia (10.4 % vs 8.7%), leukopenia (50% vs 36.3%), neutropenia (50.9% vs 39.8%), but not thrombocytopenia (15.1% vs 15.2%) compared to male pts. The rate of infections and infestations did not differ between genders during FCR (18.9 % vs 20.9%) as well as BR (12.3% vs 15.6%). After 5 years less female pts developed second primary malignancies (SPM) after FCR compared to male pts (6.7% vs 12.8%), while the rate of SPM after BR was similar between both genders (13.8% vs 13.1%).
Conclusions
Based on this pooled analysis of three prospective clinical trials in CLL, women had longer PFS than men after chemoimmunotherapy with either FCR or BR although the rate of hematological toxicities during therapy was higher. Understanding the causes of this observation can enable a more tailored, gender-specific approach in CLL treatment.
Figure Overall survival (A) and progression free survival (B) according to treatment and gender. Figure. Overall survival (A) and progression free survival (B) according to treatment and gender.

Disclosures
Al-Sawaf: Gilead: Other: Travel grants. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Fink:Mundipharma: Other: Travel grants; AbbVie: Other: Travel grants; Celgene: Research Funding; Roche: Honoraria, Other: Travel grants. Cramer:Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Gilead: Other: Travel grants, Research Funding; GlaxoSmithKline/Novartis: Research Funding; Janssen-Cilag: Honoraria, Other: Travel grants, Research Funding; Astellas: Other: Travel grants; Mundipharma: Other: Travel grants. Maurer:Mundipharma: Other: Travel grants. Bergmann:Mundipharma: Honoraria; Roche: Consultancy, Honoraria; Celgene: Honoraria; Glaxo-SmithKline: Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kneba:Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants; Glaxo-SmithKline: Other: Travel grants; Amgen: Research Funding. Stilgenbauer:Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding. Kiehl:Roche: Consultancy, Other: Travel grants, Speakers Bureau. Jäger:Roche: Other: Personal fees, Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; Glaxo-SmithKline: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Fischer:Roche: Other: travel grants. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Eichhorst:Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Hopfinger:Mundipharma: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Takeda: Honoraria.