TY - JOUR
T1 - Fludarabine, cyclophosphamide, and rituximab treatment achieves long-Term disease-free survival in IGHV-mutated chronic lymphocytic leukemia
AU - Thompson, Philip A.
AU - Tam, Constantine S.
AU - O'Brien, Susan M.
AU - Wierda, William G.
AU - Stingo, Francesco
AU - Plunkett, William
AU - Smith, Susan C.
AU - Kantarjian, Hagop M.
AU - Freireich, Emil J.
AU - Keating, Michael J.
N1 - Funding Information:
This study is in memory of Susan Lerner, who lovingly cared for our CLL database and without whom much of this work would not have been possible. P.A.T. received funding from the CLL Global Research Foundation and the Haematology Society of Australia and New Zealand.
Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016/1/21
Y1 - 2016/1/21
N2 - 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 patientswith 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 patientswith IGHV-M, with no relapses beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years). Onmultivariable 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];P5.048)were significantly associated with inferiorPFS. Fifteen patients with IGHV-Mhad 4-colorMRDflowcytometry (sensitivity 0.01%) performed in peripheral blood, at amedian 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 strategiesmaybepreferred inpatientswithIGHV-UM, tolimit long-Term toxicity.
AB - 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 patientswith 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 patientswith IGHV-M, with no relapses beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years). Onmultivariable 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];P5.048)were significantly associated with inferiorPFS. Fifteen patients with IGHV-Mhad 4-colorMRDflowcytometry (sensitivity 0.01%) performed in peripheral blood, at amedian 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 strategiesmaybepreferred inpatientswithIGHV-UM, tolimit long-Term toxicity.
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U2 - 10.1182/blood-2015-09-667675
DO - 10.1182/blood-2015-09-667675
M3 - Article
C2 - 26492934
AN - SCOPUS:84958181962
SN - 0006-4971
VL - 127
SP - 303
EP - 309
JO - Blood
JF - Blood
IS - 3
ER -