No Significant Clinical Benefit of First Line Therapy with Fludarabine (F) in Comparison to Chlorambucil (Clb) in Elderly Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Phase III Study of the German CLL Study Group (GCLLSG).

Introduction: Treatment regimens based on purine analogues as F have become standard in first line therapy of younger or physically fit CLL pts. In these pts purine analogue-based regimens resulted in higher response rates and prolongation of progression free survival (PFS). Because it is not clear if elderly or physically non-fit pts benefit from more intense first line strategies as well, Clb is still widely used in first line therapy of elderly CLL pts. The GCLLSG initiated a phase III study (CLL5 protocol) to evaluate the effect of F versus (vs.) Clb in first line therapy of elderly patients with advanced CLL. Patients: 206 pts (F 101; Clb 105), older than 64 years, were enrolled between July 1999 and September 2004. 13 pts had to be excluded due to violation of exclusion/inclusion criteria. 15% of the pts were in Binet stage A, 47% in stage B, and 38% in stage C. The median pt age was 70 years (range 64 to 80). Pts were randomized to receive either F 25mg/mi.v. d1–5 q 28 days for 6 courses or Clb 0,4mg/kg ideal bodyweight (BW) (dose escalation up to 0.8mg/kg) q15d for up to 12 months. The mean number of administered courses was 4.9 in the F arm, the median duration of Clb treatment was 6.5 months (median dose 0.5 mg/kg). Results: After a median observation time of 41,5 months (mo) (range 1–89 mo) 165 pts (F 78; Clb 87) were evaluable for response and 184 (F 88; Clb 96) for progression free survival (PFS). In spite of a significantly higher complete remission rate (CRR) and overall response rate (ORR) in the F arm (CRR8% vs. 0%; p=0.008; ORR86% vs. 59%; p nd line F was 53% (10 of 19). Pts initially treated with F received in 26% each F-based combinations and CHOP regimen. Retreatment with F was administered in 12%, while 2 pts only received Clb. Conclusion: This long-term follow-up analysis shows that elderly pts have no significant clinical benefit from first line therapy with F in comparison to Clb. Though higher CRR and ORR F failed to show any benefit in terms of PFS and OS. A possible explanation for this phenomenon is the longer treatment period with Clb, that might prevent earlier relapses. Moreover, in case of relapse F treated pts received either no treatment at all or more intense regimen in comparison to Clb. In conclusion, Clb and F are similar potent first-line treatment options for elderly CLL pts.