Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial

Kirsten Fischer, Jasmin Bahlo, Anna Maria Fink, Valentin Goede, Carmen Diana Herling, Paula Cramer, Petra Langerbeins, Julia von Tresckow, Anja Engelke, Christian Maurer, Gabor Kovacs, Marco Herling, Eugen Tausch, Karl-Anton Kreuzer, Barbara Eichhorst, Sebastian Böttcher, John F Seymour, Paolo Ghia, Paula Marlton, Michael Kneba, Clemens-Martin Wendtner, Hartmut Döhner, Stephan Stilgenbauer, Michael Hallek

Despite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC) and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the CLL8 trial reporting safety and efficacy of FC and FCR treatment for untreated CLL. In this prospective, randomized phase-III trial, 817 treatment-naïve patients with good physical fitness and CD20-positive, treatment requiring CLL received six courses of either FCR or FC. The primary endpoint was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio (HR), 0.59 (95% confidence interval (CI), 0.50-0.69), p<0.001). Median OS was not reached for the FCR group and 86.0 months for the FC group (HR, 0.68 (95% CI, 0.54-0.89), p=0.001). In patients with mutated IGHV (IGHV MUT) FCR improved PFS and OS compared to FC (PFS HR, 0.47 (95% CI, 0.33-0.68), p<0.001; OS HR, 0.62 (95% CI, 0.34-1.11), p=0.1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% versus 8.8% (p=0.007)). Secondary malignancies including Richter's transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (p=0.1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. www.clinicalTrials.gov NCT00281918.