Prognostic Impact and Risk Factors of Reducing Prescribed Doses of Fludarabine, Cyclophosphamide and Rituximab (FCR) during Frontline Treatment of Chronic Lymphocytic Leukemia (CLL)
Authors: Kovacs Gabor , Bahlo Jasmin , Kluth Sandra , Cramer Paula , Fink Anna-Maria , Fischer Kirsten , Gross-Ophoff-Mueller Carolin , Langerbeins Petra , Maurer Christian , von Tresckow Julia , Wendtner Clemens-Martin , Stilgenbauer Stephan , Hallek Michael , Eichhorst Barbara , Goede Valentin 
Published: October 2019

Abstract
Introduction: Frontline treatment with full-dose FCR is considered standard of care for physically fit patients with CLL. In routine practice, however, adverse events during treatment often lead to reduction of the planned dose of FCR which might result in loss of treatment efficacy. The aim of our study was to evaluate the prognostic impact of reducing the prescribed dose of FCR and to identify risk factors that could help to predict such dose modification.
Patients and Methods: Patients treated with FCR within two randomized phase 3 trials of the German CLL Study Group (GCLLSG) (CLL8 trial: FCR vs. FC; CLL10 trial: FCR vs. bendamustine plus rituximab) were pooled. In each patient, the planned dose of FCR (according to protocol) was compared with the actually applied dose (with deltas provided in %). Subjects with reductions of the planned dose of FCR due to early treatment discontinuation not caused by toxic adverse events, but refractory/progressive disease or other reasons were excluded from further analyses (Figure 1). Patients with ≤ 20% and with > 20% reduction of the planned dose of FCR were compared with regard to progression-free survival (PFS) and overall survival (OS). Logistic regression was used to identify risk factors of such dose modification.
Results: A total of 635 patients treated with at least one dose of FCR were included in this study. Median age was 61 years, median CIRS score 1 (range 0-7), and median ECOG performance status 0 (range 0-2). The median follow up time was 57.3 months (range 1.4-96.4). 11% of patients had Binet stage A, 55% stage B, and 34% stage C disease. Among 540 patients with IGHV results, 59% had an unmutated status. In 550 cases with FISH results, del(17p) was found in 3% (exclusion criteria in CLL10 trial), del(11q) in 25%, 12+ in 10%, del(13q) in 38%, and normal karyotype in 24% (according to the hierarchical model by Döhner et al.).
Of the 635 patients, 209 (33%) received FCR with > 20% reduction of the planned dose. These patients had significantly shorter PFS (median PFS 45.2 vs. 64.0 months, HR [hazard ratio]=1.627, 95%CI [confidence interval]=1.294-2.046, p<0.001) and OS (median OS 90.2 months vs. not reached, HR=1.849, 95%CI=1.315-2.600, p<0.001) compared with patients having received FCR at full-dose or with ≤ 20% reduction of the planned dose (Figure 2). In multivariate analysis, age > 60 years (OR=1.601, 95%CI=1.105-2.320, p=0.013), Binet stage C (OR [odds ratio]=1.790, 95%CI=1.224-2.619, p=0.003), and serum β2-microglobuline > 3.5 mg/L (OR=1.495, 95%CI=1.009-2.215, p=0.045) were identified as independent risk factors for reducing the prescribed dose of FCR.
Conclusions: This pooled analysis of patients receiving frontline therapy of CLL with FCR within two prospective GCLLSG trials for the first time indicates that reducing prescribed doses of FCR compromises not only PFS, but also reduces the benefit regarding OS. The adverse prognostic impact of a reduction of the planned dose of FCR by 20% or more is clinically meaningful and should be considered carefully, particularly if such dose reductions are made. Predictors of reducing the planned dose during FCR treatment (such as older age and advanced disease stage) may help to refine treatment decision-making in CLL.
Figure 1. Study population. Figure 1. Study population. Figure 2. a) PFS and b) OS of patients with ≤ 20% (green) vs. > 20% (blue) reduction of the planned dose of FCR. Figure 2. a) PFS and b) OS of patients with ≤ 20% (green) vs. > 20% (blue) reduction of the planned dose of FCR.

Disclosures
Kovacs: Mundipharma: Other: Travel grant. Cramer:Gilead: Other: Travel grant, Research Funding; Mundipharma: Other: Travel grant; Glaxo Smith Klein/Novartis: Research Funding; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau; Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Astellas: Other: Travel grant. Fink:Roche: Honoraria, Other: travel grant. Fischer:Roche: Other: Travel Grants. Langerbeins:Janssen: Honoraria, Other: travel grants, Research Funding; Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; Mundipharma: Honoraria, Other: travel grants, Research Funding. Maurer:Mundipharma: Other: Travel grant. von Tresckow:Hoffman-LaRoche: Other: travel grants, Research Funding; Celgene: Other: travel grants; Janssen-Cilag: Honoraria, Research Funding. Wendtner:Genentech: Consultancy, Other: travel grants, Research Funding; AbbVie: Consultancy, Other: travel grants, Research Funding; Hoffmann-LaRoche: Consultancy, Other: travel grants, Research Funding; Gilead: Consultancy, Other: travel grants, Research Funding; Glaxo-SmithKline: Consultancy, Other: travel grants, Research Funding; Janssen-Cilag: Consultancy, Other: travel grants, Research Funding; Mundipharma: Consultancy, Other: travel grants, Research Funding; Celege: Consultancy, Other: Travel grants, Research Funding; Pharmacyclics: Consultancy, Other: travel grants, Research Funding. Stilgenbauer:Gilead: Consultancy, Other: travel grants, Research Funding; AbbVie: Consultancy, Other: travel grants, Research Funding; Celgene: Consultancy, Other: travel grants, Research Funding; Boehringer-Ingelheim: Consultancy, Other: travel grants, Research Funding; Amgen: Consultancy, Other: travel grants, Research Funding; Genzyme: Consultancy, Other: travel grants, Research Funding; Hoffman-LaRoche: Consultancy, Honoraria, Other: travel grants, Research Funding; Genentech: Consultancy, Other: travel grants, Research Funding; Janssen: Consultancy, Other: travel grants, Research Funding; GlaxoSmithKline: Consultancy, Other: travel grants, Research Funding; Mundipharma: Consultancy, Other: travel grants, Research Funding. Hallek:Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Board; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding. Eichhorst:Roche: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy; MundiPharma: Consultancy, Research Funding, Speakers Bureau. Goede:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; GSK: Honoraria; Mundipharma: Honoraria; Bristol-Myers Squibb: Honoraria.