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

• Published in: Blood Vol. 127; no. 3; pp. 303 - 309
• Main Authors: Thompson, Philip A., Tam, Constantine S., O'Brien, Susan M., Wierda, William G., Stingo, Francesco, Plunkett, William, Smith, Susan C., Kantarjian, Hagop M., Freireich, Emil J., Keating, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-01-2016; American Society of Hematology
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cause of Death; Clinical Trials and Observations; Cyclophosphamide - administration & dosage; Female; Humans; Immunoglobulin Heavy Chains - genetics; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell - diagnosis; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Male; Middle Aged; Mutation; Neoplasm Staging; Neoplasm, Residual; Neoplasms, Second Primary - epidemiology; Neoplasms, Second Primary - etiology; Neoplasms, Second Primary - mortality; Prognosis; Recurrence; Remission Induction; Retreatment; Rituximab - administration & dosage; Survival Analysis; Treatment Outcome; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-09-667675

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.
•FCR-treated chronic lymphocytic leukemia patients with mutated IGHV gene achieve long-term PFS, with a plateau on the PFS curve.•MRD-negativity posttreatment is highly predictive of long-term PFS, particularly in patients with mutated IGHV gene.