Frontline Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Shows Superior Efficacy in Comparison to Bendamustine (B) and Rituximab (BR) in Previously Untreated and Physically Fit Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Final Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study)
Authors: Eichhorst Barbara , Fink Anna Maria , Busch Raymonde , Kovacs Gabor , Maurer Christian , Lange Elisabeth , Köppler Hubert , Kiehl Michael G , Soekler Martin , Schlag Rudolf , Vehling-Kaiser Ursula , Köchling Georg R.A. , Plöger Christoph , Gregor Michael , Plesner Torben , Trneny Marek , Fischer Kirsten , Döhner Hartmut , Kneba Michael , Wendtner Clemens-Martin , Klapper Wolfram , Kreuzer Karl Anton , Stilgenbauer Stephan , Böttcher Sebastian , Hallek Michael 
Published: October 2019

Abstract

Introduction: For physically fit CLL pts with low comorbidity burden FCR is the standard frontline regimen in advanced CLL. The CLL10 study, an international phase III study evaluated the efficacy and tolerance of BR in comparison to FCR in frontline therapy of fit pts without del(17p).
Methods and Patients: 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) registered 688 CLL pts for central screening including immunophenotyping, FISH, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance > 70 ml/min and without del(17p) were enrolled between 10/2008 and 6/2011. Pts were randomly assigned 1:1 to receive 6 courses of FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days) or BR (N=280; B 90mg/m² i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days). A general prophylactic use of antibiotics or growth factors was not recommended. Three patients (2 FCR, 1 BR) were excluded because of deferred treatment.
The median CIRS score was 2. There was no difference in median age (61.6 years (yrs) for all pts), but a significantly higher proportion of pts ≥ 70 yrs was included in the BR arm (22% vs 14%, p=0.020). Binet A was present in 22%, Binet B in 38 % and Binet C in 40 %. Unmutated IGHV status was not balanced between both groups (68% in BR versus 55% in FCR arm; p=0.003). All other characteristics showed no differences. The mean number of administered FCR courses was 5.27 courses vs 5.41 BR course (p=0.017).
Results: The median observation time for all patients was 35.9 months (mo). 547 pts (FCR 274 ; BR 273) were evaluable for response and all pts (282 FCR ; 279 BR) included for progression-free survival (PFS) and overall survival (OS) analysis. The overall response rate in both arms was 97.8% (p=1.0). The complete response (CR) rate according to IWCLL and confirmed by central bone marrow immunohistology was 40.7% with FCR compared to 31.5% with BR (p=0.026). Four-colour-flow MRD data from peripheral blood (sensitivity 10-4) were available from 355 pts (185 FCR; 170 BR) at final staging. In the FCR arm 74.1% and 62.9% in the BR arm respectively of all evaluated pts were MRD negative (p=0.024). Bone marrow samples, available in 129 FCR and 98 BR pts, were MRD negative in 58.1% and 31.6% of pts, respectively (p<0.001). At 12 mo follow-up 58.2% of the pts in the FCR arm (46/79) were still MRD negative in comparison to 26.3% (20/76) after BR (p<0.001). At 18 mo there were 53.8% (35/65) MRD negative cases versus 24.6% (16/65; p=0.006). Median PFS was 53.7 mo in the FCR arm and 43.2 mo in the BR arm (HR=1.589, 95% CI 1.25-2.079; p=0.001). While PFS was statistically not significant different between both arm in pts with mutated IGHV, pts with unmutated IGHV status had a median time to progression of 43.9 mo after FCR compared to 34.0 mo after BR (p=0.015). Physically fit subgroups (CIRS max 3, only one CIRS item, age < 65 yrs) benefited most from FCR therapy. The difference in PFS was statistically not significant between both arms in pts ≥ 65 years, CIRS 4-6 or > 1 CIRS item. Multivariate analysis identified treatment arm, age ≥ 65 yrs, male sex, high serum TK, del(11q), absence of del(13q) and IGHV status as independent prognostic factors for PFS. No difference in OS was observed (at 36 mo 90.6% for FCR vs 92.2% for BR; HR=1.030, 95% CI 0.618-1.717; p=0.910). For OS male gender, age ≥ 60 yrs, high serum TK and IGHV status were assessed as independent prognostic factors.
Severe neutropenia was more often observed in the FCR arm (87.7% vs 67.8%, p<0.001), but no significant difference in the incidence of anemia (14.2% vs. 12.0%; p=0.46) or thrombocytopenia (22.4% vs 16.5%; p=0.096) was documented. Severe infections occurred significantly more frequent (39.8% vs 25.4%, p=0.001) in the FCR arm during treatment phase until 6 months follow-up, especially in older pts (48.4% vs 26.8%; p=0.001). Treatment related mortality was 3.9% (FCR) and 2.1% (BR), respectively.
Conclusion: The final analysis of the CLL10 study shows that FCR remains the standard therapy in very fit CLL patients, because it yields higher CR rates, more MRD negativity and longer PFS in comparison to BR. However, in elderly fit pts high toxicity rates and infection rates result into dose reductions leading to similar efficacy between both arms. Elderly fit pts or pts with previous infections might benefit from BR as alternative regimen.

Disclosures
Eichhorst: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Off Label Use: The Combination of Bendamustine and Rituximab is not approved for frontline chemoimmunotherapy of CLL. Fink:Celgene: Other. Maurer:Mundipharma: Travel grant Other. Kiehl:Roche: Membership on an entity's Board of Directors or advisory committees. Gregor:Roche: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria. Trneny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fischer:Roche: Other. Döhner:Roche: Research Funding. Kneba:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Wendtner:Mundipharma: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Klapper:Hoffmann-La Roche: Research Funding; Takeda/Millenium: Research Funding. Kreuzer:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Böttcher:Roche: Honoraria, Research Funding, Travel grant Other. Hallek:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding.