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<0.001) no difference in the PFS was assessed (median PFS time 18.7 mo for F vs. 17.8 mo for Clb; p=0.72). Moreover, 46% of F treated pts in comparison to 34% Clb treated pts died so far, but overall survival (OS) curves showed no significant difference (median OS 45.9 mo vs. 63.6 mo, p=0.21). Analyzing PFS and OS separately for pts <70 years and ≥70 years no difference between both arms was assessed as well. Impaired creatinine clearance did not have any effect on PFS and OS as well as gender. Pts in the Clb arm received rescue treatment more frequently than F recipients (62% vs. 39%). Pts initially treated with Clb received for first relapse treatment Clb in 20%, F in 43%, F-based combinations in 17% and in 20% others. ORR to 2^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.