Toxicity Is Not Associated with Age or Comorbidity Score in a Randomised Study of Oral Fludarabine and Cyclophosphamide and IV Rituximab (FCR) As First-Line Therapy of Fit, Elderly Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Mulligan Stephen P. , Gill Devinder , Turner Paul , Renwick William E. P. , Latimer Maya , Mackinlay Naomi , Berkahn Leanne , Simpson David R , Campbell Philip , Forsyth Cecily J , Cull Gavin , Harrup Rosemary , Sulda Melanie , Best Giles , Bressel Mathias , Di Iulio Juliana , Kuss Bryone J 
Published: October 2019

Abstract
BACKGROUND Fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free (PFS) and overall survival (OS) versus (vs) FC in the CLL8 Study. The median age in CLL8 was 61 years compared to 72 years for CLL overall. There has been considerable debate regarding the tolerability and toxicity of FCR based therapy in older patients (pts) and those with comorbidities.
METHODS Previously untreated fit pts with progressive CLL aged ≥65 were randomised to one of 3 therapy arms: (i) FR5: F 24mg/m2 po D1-5 + R iv D1 (375mg/m2 cycle 1, 500mg/m2 cycles 2-6), (ii) FCR3: F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 or (iii) FCR5: F 24mg/m2 po+ C 150mg/m2 po D1-5 + R iv D1 all at 4 weekly intervals for an intended 6 cycles. Cycles could be delayed up to 2 weeks for grade 3+ toxicity, and if unresolved by 2 weeks, pts were taken off study. Fitness was assessed using the Cumulative Illness Rating Scale (CIRS) score with eligibility restricted to CIRS ≤6.
RESULTS Recruitment of 120 pts was completed in July 2012. 117 fulfilled eligibility and 1 had no treatment or follow-up reducing the cohort to 116. Median age was 71 (range 65-82) years (yrs) with 78 males (67%) and 39 females (33%). Patient registration by age was 65-69 yrs – 44, 70-74 yrs – 44, 75-79 yrs – 20 and 80-84 yrs – 8 pts, and by CIRS score was 0-2 – 61, 3-4 – 38, 5-6 – 17 pts. Toxicity data by age and CIRS score are shown in tables 1 and 2 respectively. All 6 protocol cycles were completed in 69% but less on FCR5 44% vs FR5 89% and FCR3 76% (p<0.001). Selected toxicity and early stopping rates in table 3. Overall response and toxicity are presented separately. Table 1:Grade 3+ Adverse Events by AgeAgeTotal65-6970-7475-7980-84(n=116)(N=44)(N=44)(N=20)(N=8)Hematological28 (64%)29 (66%)10 (50%)3 (38%)70 (60%)Neutropenia24 (55%)21 (48%)10 (50%)3 (38%)58 (50%)Thrombocytopenia9 (20%)9 (20%)1 (5%)0 (0%)19 (16%)Anaemia7 (16%)6 (14%)2 (10%)0 (0%)15 (13%)Haemolytic Anaemia1 (2%)2 (5%)1 (5%)1 (12%)5 (4%)Febrile Neutropenia / Infection9 (20%)5 (11%)8 (40%)2 (25%)24 (21%)Skin/Allergy/Fatigue/hypersensitivity3 (7%)2 (5%)4 (20%)2 (25%)11 (9%)Other (Card / resp / neuro / metabolic)13 (30%)10 (23%)3 (15%)1 (12%)27 (23%)At least 1 grade 3+ AE37 (84%)34 (77%)13 (65%)6 (75%)90 (78%)
There was no statistically significant difference by age (p=0.429). Table 2:Grade 3+ Adverse Events by CIRS scoreCIRS scoreTotal0-23-45-6(n=116)(N=61)(N=38)(N=17)Hematological38 (62%)21 (55%)11 (65%)70 (60%)Neutropenia31 (51%)16 (42%)11 (65%)58 (50%)Thrombocytopenia11 (18%)6 (16%)2 (12%)19 (16%)Anaemia7 (11%)5 (13%)3 (18%)15 (13%)Haemolytic Anaemia1 (2%)4 (11%)0 (0%)5 (4%)Febrile Neutropenia / Infection11 (18%)9 (24%)4 (24%)24 (21%)Skin/Allergy/Fatigue/hypersensitivity6 (10%)4 (11%)1 (6%)11 (9%)Other (Card / resp / neuro / metabolic)12 (20%)9 (24%)6 (35%)27 (23%)At least 1 grade 3+ AE78 (79%)27 (71%)15 (88%)90 (78%)
There was no statistically significant difference by CIRS score (p=0.355). Table 3:Abbreviated Grade 3+ Adverse Events by Treatment ArmTreatment armTotal (n=116)FR5 (N=37)FCR3 (N=41)FCR5 (N=38)Hematological15 (41% )26 (63% )29 (76% )70 (60%)At least 1 grade 3+ AE21 (57%)34 (83%)35 (92%)90 (78%)Early cessation due to toxicity2 (5.6%)1 (2.4%)13 (34%)16 (14%)
Early cessation due to toxicity was significantly more common with FCR5 (p<0.001). However, of the 13 patients on FCR5 arm that stopped early due to toxicity, there was no difference by age or CIRS score: by age, 5 were 65-69 yrs, 3 were 70-74 yrs, 4 were 75-79 yrs and 1 was 80-84 yrs and by CIRS score, 3 were 0-2, 6 were 3-4 and 4 were 5-6.
CONCLUSIONS Final analysis in this randomised dose de-escalation study shows oral FCR therapy is generally safe and well tolerated in CLL pts aged ≥65 years requiring first-line treatment, when early stopping is utilised if prolonged toxicity occurs. Early cessation due to toxicity was more common with full dose FCR5, but not associated with age or CIRS score within this arm. Overall in this relatively fit elderly CLL cohort, neither age nor CIRS score were associated with toxicity, or early cessation of therapy due to toxicity. The results highlight the difficulty of predicting toxicity based on age and comorbidity in elderly CLL pts.

Disclosures
Mulligan: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria. Gill:Roche: Research Funding; Sanofi Aventis: Research Funding. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Roche: Research Funding; Sanofi: Research Funding. Latimer:Roche: Research Funding; Sanofi: Research Funding. Mackinlay:Roche: Research Funding; Sanofi: Research Funding. Berkahn:Roche: Research Funding; Sanofi: Research Funding. Simpson:Roche: Research Funding; Sanofi: Research Funding. Forsyth:Roche: Research Funding; Sanofi: Research Funding. Harrup:Roche: Research Funding; Sanofi: Research Funding. Kuss:Roche: Research Funding; Sanofi: Research Funding.