Fludarabine, cyclophosphamide and rituximab achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia

Philip A. Thompson, Constantine S. Tam, Susan M. O'Brien, William G. Wierda, Francesco Stingo, William Plunkett, Susan C. Smith, Hagop M. Kantarjian, Emil J. Freireich and Michael J. Keating

Key points

  • FCR-treated CLL patients with mutated IGHV gene achieve long-term disease-free survival, with a plateau on the PFS curve.

  • MRD-negativity post-treatment is highly predictive of long-term disease-free survival, particularly in patients with mutated IGHV gene.


Accurate identification of patients likely to achieve long-term disease-free survival after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, Cyclophosphamide and Rituximab (FCR) achieved a high initial response rate, but continued relapses were seen in initial reports. We reviewed the results of the original 300 patient phase II FCR study, to identify long-term disease-free survivors. MRD was assessed post-treatment by a PCR-based ligase chain reaction assay (sensitivity at least 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS 6.4 years). 12.8-year PFS was 53.9% for patients with mutated IGHV gene (IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD-negativity post-treatment; of these patients, PFS was 79.8% at 12.8 years. A plateau was seen on the PFS curve in patients with IGHV-M, with no relapses beyond 10.4 years in 42 patients (total 105.4 patient-years of follow-up). On multivariable analysis, IGHV-UM [HR 3.37 (2.18-5.21), p<0.001] and del(17p) by conventional karyotyping [HR 7.96 (1.02-61.92), p=0.048] were significantly associated with inferior PFS. Fifteen patients with IGHV-M had 4-color MRD flow cytometry (sensitivity at least 0.01%) performed in peripheral blood, at a median of 12.8 years post-treatment (range 9.5-14.7). All were MRD-negative. The high rate of very long term PFS in patients with IGHV-M after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup outside of clinical trials. In contrast, alternative strategies may be preferred in patients with IGHV-UM, to limit long-term toxicity.

  • Submitted September 16, 2015.
  • Accepted October 10, 2015.