TY - JOUR
T1 - Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide
AU - Takahashi, Koichi
AU - Hu, Boyu
AU - Wang, Feng
AU - Yan, Yuanqing
AU - Kim, Ekaterina
AU - Vitale, Candida
AU - Patel, Keyur P.
AU - Strati, Paolo
AU - Gumbs, Curtis
AU - Little, Latasha
AU - Tippen, Samantha
AU - Song, Xingzhi
AU - Zhang, Jianhua
AU - Jain, Nitin
AU - Thompson, Philip
AU - Garcia-Manero, Guillermo
AU - Kantarjian, Hagop
AU - Estrov, Zeev
AU - Do, Kim Anh
AU - Keating, Michael
AU - Burger, Jan A.
AU - Wierda, William G.
AU - Andrew Futreal, P.
AU - Ferrajoli, Alessandra
N1 - Funding Information:
This study was supported by the Cancer Prevention Research Institute of Texas (R120501) (P.A.F.), the Welch Foundation (G-0040) (P.A.F.), the University of Texas System STARS Award (PS100149) (P.A.F.), the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer Award (K.T.), an institutional research grant from the MD Anderson Cancer Center (K.T.), a National Institutes of Health, National Cancer Institute Leukemia SPORE Career Enhancement Grant (K.T.), a Khalifa Scholar Award (K.T.), Charif Souki Cancer Research Fund (H.K.), MD Anderson’s Cancer Center Support Grant (P30 CA016672), and generous philanthropic contributions to MD Anderson’s Moon Shot Program (M.K., W.G.W., P.A.F.).
Publisher Copyright:
© 2018 by The American Society of Hematology
PY - 2018/4/19
Y1 - 2018/4/19
N2 - Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutations than did TN patients. Among all lenalidomide-treated patients, del(17p) (P £ .001), del(11q) (P 5 .032), and complex karyotype (P 5 .022), along with mutations in TP53 (P £ .001), KRAS (P 5 .034), and DDX3X (P £ .001), were associated with worse overall response (OR). R/R patients with SF3B1 and MGA mutations had significantly worse OR (P 5 .025 and .035, respectively). TN and R/R patients with del(17p) and TP53 mutations had worse overall survival (OS) and progression-free survival (PFS). In R/R patients, complex karyotype and SF3B1 mutations were associated with worse OS and PFS; DDX3X mutations were associated with worse PFS only. Weibull regression multivariate analysis revealed that TP53 aberrations (del(17p), TP53 mutation, or both), along with complex karyotype and SF3B1 mutations, were associated with worse OS in the R/R cohort. Taken together, cancer gene mutations in CLL contribute to the already comprehensive risk stratification and add to prognosis and response to treatment. The related trials were registered at www.clinicaltrials.gov as #NCT00267059, #NCT00535873, #NCT00759603, #NCT01446133, and #NCT01002755.
AB - Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutations than did TN patients. Among all lenalidomide-treated patients, del(17p) (P £ .001), del(11q) (P 5 .032), and complex karyotype (P 5 .022), along with mutations in TP53 (P £ .001), KRAS (P 5 .034), and DDX3X (P £ .001), were associated with worse overall response (OR). R/R patients with SF3B1 and MGA mutations had significantly worse OR (P 5 .025 and .035, respectively). TN and R/R patients with del(17p) and TP53 mutations had worse overall survival (OS) and progression-free survival (PFS). In R/R patients, complex karyotype and SF3B1 mutations were associated with worse OS and PFS; DDX3X mutations were associated with worse PFS only. Weibull regression multivariate analysis revealed that TP53 aberrations (del(17p), TP53 mutation, or both), along with complex karyotype and SF3B1 mutations, were associated with worse OS in the R/R cohort. Taken together, cancer gene mutations in CLL contribute to the already comprehensive risk stratification and add to prognosis and response to treatment. The related trials were registered at www.clinicaltrials.gov as #NCT00267059, #NCT00535873, #NCT00759603, #NCT01446133, and #NCT01002755.
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U2 - 10.1182/blood-2017-11-817296
DO - 10.1182/blood-2017-11-817296
M3 - Article
C2 - 29358183
AN - SCOPUS:85047608280
SN - 0006-4971
VL - 131
SP - 1820
EP - 1832
JO - Blood
JF - Blood
IS - 16
ER -
