Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia.
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.
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;
Philip A
PA
Thompson
Department of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia;
Constantine S
CS
Tam
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;
Susan M
SM
O'Brien
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;
William G
WG
Wierda
Department of Biostatistics, and.
Francesco
F
Stingo
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX.
William
W
Plunkett
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;
Susan C
SC
Smith
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;
Hagop M
HM
Kantarjian
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;
Emil J
EJ
Freireich
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;
Michael J
MJ
Keating
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002423:Cause of Death; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015994:Incidence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D018365:Neoplasm, Residual; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000209:etiology / Q000401:mortality; D011379:Prognosis; D012008:Recurrence; D012074:Remission Induction; D019233:Retreatment; D000069283:Rituximab / Q000008:administration & dosage; D016019:Survival Analysis; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
D007143:Immunoglobulin Heavy Chains; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine