Long-Term Outcome of B-CLL Patients Treated in a Prospective Trial Evaluating Combination of Oral Fludarabine and Cyclophosphamide As Frontline Therapy

The combination of fludarabine and cyclophosphamide (FC) has become the core combination of modern frontline chemotherapy for fit and young B-CLL patients (pts). Recently the association with rituximab to FC (IV administration) has been shown to increase the response and extend both progression free survival (PFS) and overall survival (OS) in untreated pts (Hallek et al., Lancet 2010). So far few data are available concerning the very long term outcome of pts treated by FC containing regimen. Methods. We previously reported a prospective phase II trial (Cazin et al., BJH 2008) of the oral combination of FC over 5 days in 75 patients with untreated B-CLL and less than 66 years old. The study was conducted between October 1999 and February 2001. Briefly, oral FC then demonstrated high efficacy with overall response rate (ORR) and complete response (CR) rate of 80% and 53% respectively despite the absence of rituximab in this regimen. We here propose to examine 10-year end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN) by updating survival data of all the pts incuded in this trial. Results. With a median follow-up of 10.7 years, the median 10-year OS was 51.7%. Responders presented better 10-year OS than non-responders (57% vs. 38%, p=0.031) but quality of response (CR vs. PR) did not significantly impact 10-year OS. A major prognostic impact of IGVH mutational status could be observed since 10-year OS was 81% for mutated patients vs. 44% for unmutated pts (p=0.012). The median 10-year PFS was 30% and clearly influenced by the mutational status (50% if mutated profile vs. 12% if unmutated profile, p=0.02). However there is no trend of a plateau and even long term responding patients still relapse with time. Finally, only one patient developed t-MN but 9 others presented solid neoplasms. Conclusion. Long-term follow-up of B-CLL patients prospectively treated in a phase II clinical trial demonstrates extended OS and PFS with oral FC without high risk of t-MN.

No relevant conflicts of interest to declare.