Impact of Age on Outcomes Following Initial Therapy with Various Chemotherapy and Chemoimmunotherapy Regimens in Patients with Chronic Lymphocytic Leukemia (CLL): Results of CALGB Studies
Authors: Woyach Jennifer A. , Ruppert Amy S. , Peterson Bercedis , Rai Kanti R. , Lin Thomas S. , Appelbaum Frederick R. , Tallman Martin S. , Belch Andrew R , Larson Richard A. , Byrd John C. 
Published: October 2019

Abstract
Abstract 289

Introduction:
Chronic lymphocytic leukemia (CLL) is a disease mainly of older adults, with a median age of 72 at diagnosis, yet landmark trials that have established chemoimmunotherapy as standard initial therapy for this disease include patients (pts) with median ages between 58–64 years. Outcomes in other types of leukemia have been shown to be influenced by age, and one randomized phase III study (German CLL5) demonstrated a lack of benefit of fludarabine (F) over chlorambucil (Ch) in CLL pts over age 64. To help determine the current optimal standard therapy for older pts with CLL we reviewed the data on all pts enrolled on successive phase II and III CALGB CLL trials for previously untreated pts to determine if the efficacy varied by age. Particular interest was paid to ideal chemotherapy choice and the benefit of rituximab or alemtuzumab in older pts.

Methods:
663 pts with untreated CLL enrolled on CALGB first-line studies were evaluated (515 pts <70 years, 148 pts ≥70 years). Treatment regimens included Ch on CALGB 9011(n=193), F on CALGB 9011(n=179), F plus rituximab (FR) on CALGB 9712(n=104), F with consolidation alemtuzumab (A) on CALGB 19901(n=85), and FR with consolidation A on CALGB 10101(n=102). Response rates with exact Clopper-Pearson 95% confidence intervals (CIs) were calculated. Proportional hazards models were used to initially model PFS and OS as a function of treatment regimen, controlling for age (>70 vs <70), gender, log transformed white blood cell count, and stage of disease. Models were then fit with a treatment by age interaction term to determine if treatment efficacy varied by age group. P-values and hazard ratio (HR) estimates with 95% CIs were obtained from the models for specific contrasts of interest.

Results:
Median follow-up was 91 months (range, 16–236). Overall response rate (ORR) was significantly different among the treatment regimens (p<0.0001), with the lowest response rate seen in pts treated with Ch (37% ORR, 95% CI 0.30–0.44). ORR was improved in pts treated with F (60% ORR, 95% CI 0.53–0.68), and further improved with FR (84% ORR, 95% CI 0.75–0.90). Response rates were not significantly higher with A consolidation when compared to ORR achieved with similar regimens without A consolidation (FA: 72% ORR, 95% CI 0.61–0.81 and FRA: 90% ORR, 95% CI 0.83–0.95). In multivariable analysis there was no significant difference in ORR between younger and older patients (p=0.78) and there was no significant treatment by age interaction (p=0.77). Among all pts, F improved progression-free survival (PFS) when compared to Ch (p=0.0001), although there was a moderate interaction with age group (p=0.07). In pts younger than 70, F significantly improved PFS when compared to Ch (HR=0.6, 95% CI 0.4–0.7). However, for pts aged 70 or older, while ORR was higher with F, there was no difference in PFS between the two regimens (HR=0.9, 95% CI: 0.6–1.5). Similarly, there was a significant treatment by age interaction effect with respect to overall survival (OS) (p=0.02). While OS was improved for pts under the age of 70 treated with F versus Ch (HR=0.7, 95% CI: 0.5–0.9), this benefit did not hold for patients 70 years or older (HR=1.3, 95% CI: 0.8–2.0) and trended toward favoring Ch. In contrast, the addition of rituximab to F improved both PFS (HR=0.6, 95% CI: 0.4–0.8) and OS (HR=0.7, 95% CI: 0.5–0.9) over F alone in all pts, with no significant differences in benefit between younger and older pts (p=0.71). Consolidation with A did not improve PFS (FA versus F: p=0.77 and FRA versus FR: p=0.94) or OS (FA versus F: p=0.26 and FRA versus FR: p=0.68), irrespective of age.

Discussion:
These data support chlorambucil as an acceptable treatment for CLL pts age 70 or older, and an appropriate chemotherapeutic backbone for future trials. The addition of rituximab to fludarabine-containing regimens significantly improves both PFS and OS in younger and older pts, confirming the importance of this agent in current front-line CLL regimens. The addition of consolidation alemtuzumab did not improve response rates, PFS, or OS regardless of age, compared to similar regimens that did not include alemtuzumab consolidation, although these data are less mature compared to those derived from the older studies. Collectively, these data suggest that future clinical trials for older CLL pts should incorporate rituximab or other anti-CD20 antibodies with similar or improved efficacy, but not fludarabine or alemtuzumab.

Disclosures:
No relevant conflicts of interest to declare.