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

Abstract

Accurate identification of patients likely to achieve long-progression-free survival (PFS) after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high response rate, but continued relapses were seen in initial reports. We reviewed the original 300 patient phase 2 FCR study to identify long-term disease-free survivors. Minimal residual disease (MRD) was assessed posttreatment by a polymerase chain reaction-based ligase chain reaction assay (sensitivity 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS, 6.4 years). The 12.8-year PFS was 53.9% for patients with mutated immunoglobulin heavy chain variable (IGHV) gene (IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD-negativity posttreatment; of these, 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 follow-up 105.4 patient-years). On multivariable analysis, IGHV-UM (hazard ratio, 3.37 [2.18-5.21]; P < .001) and del(17p) by conventional karyotyping (hazard ratio, 7.96 [1.02-61.92]; P = .048) were significantly associated with inferior PFS. Fifteen patients with IGHV-M had 4-color MRD flow cytometry (sensitivity 0.01%) performed in peripheral blood, at a median of 12.8 years posttreatment (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 clinical trials; alternative strategies may be preferred in patients with IGHV-UM, to limit long-term toxicity.

Figure 1

Estimates of PFS and overall survival in the total cohort and PFS according to mutation status, B2M, and posttreatment MRD. (A) PFS and survival in the total cohort. (B) PFS according to mutation status. (C) PFS according to mutation status and baseline B2M. (D) Six-month landmark PFS according to mutation status and achievement of posttreatment MRD-negativity.

Figure 2

Estimates of PFS according to depth of response and number of cycles received. (A) PFS according to IWCLL response criteria and MRD. (B) PFS according to number of FCR cycles received. (C) PFS according to number of FCR cycles received in patients who achieved CR. (D) PFS according to number of FCR cycles received in patients who achieved MRD-negativity posttreatment.

Figure 3

Estimates of overall survival according to pretreatment mutation status, B2M, and posttreatment MRD. (A) OS according to mutation status. (B) OS according to mutation status and baseline B2M. (C) Six-month landmark OS according to the achievement of posttreatment MRD-negativity. (D) Six-month landmark OS from end-of-therapy according to mutation status and the achievement of posttreatment MRD-negativity.

Figure 4

Cumulative incidences of relapse, non–CLL-related death, CLL-related death, and RT. (A) Cumulative incidence of relapse and death in remission. (B) Cumulative incidence of death due to CLL-related causes, second cancers, and RT. (C) Cumulative incidences of relapse and death in remission according to mutation status. (D) Cumulative incidences of death due to CLL, other cancers, or RT according to mutation status.