Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide

Koichi Takahashi, Boyu Hu, Feng Wang, Yuanqing Yan, Ekaterina Kim, Candida Vitale, Keyur P Patel, Paolo Strati, Curtis Gumbs, Latasha Little, Samantha Tippen, Xingzhi Song, Jianhua Zhang, Nitin Jain, Philip Thompson, Guillermo Garcia-Manero, Hagop Kantarjian, Zeev Estrov, Kim-Anh Do, Michael Keating, Jan A Burger, William G Wierda, P Andrew Futreal, Alessandra Ferrajoli, Koichi Takahashi, Boyu Hu, Feng Wang, Yuanqing Yan, Ekaterina Kim, Candida Vitale, Keyur P Patel, Paolo Strati, Curtis Gumbs, Latasha Little, Samantha Tippen, Xingzhi Song, Jianhua Zhang, Nitin Jain, Philip Thompson, Guillermo Garcia-Manero, Hagop Kantarjian, Zeev Estrov, Kim-Anh Do, Michael Keating, Jan A Burger, William G Wierda, P Andrew Futreal, Alessandra Ferrajoli

Abstract

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 = .032), and complex karyotype (P = .022), along with mutations in TP53 (P ≤ .001), KRAS (P = .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 = .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.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Figure 1.
Figure 1.
Cancer gene mutations in 288 CLL patients. (A) Landscape of genetic mutations detected in 288 CLL patients. Each row represents a somatic gene mutation; each column represents a mutation’s occurrences throughout the patient panel. (B) Percentages of the numbers of mutations per patient among patients who had at least 1 detectable mutation. (C) Frequency of mutations detected by targeted gene sequencing, separated by the disease stage.
Figure 1.
Figure 1.
Cancer gene mutations in 288 CLL patients. (A) Landscape of genetic mutations detected in 288 CLL patients. Each row represents a somatic gene mutation; each column represents a mutation’s occurrences throughout the patient panel. (B) Percentages of the numbers of mutations per patient among patients who had at least 1 detectable mutation. (C) Frequency of mutations detected by targeted gene sequencing, separated by the disease stage.
Figure 2.
Figure 2.
Mutational enrichment in CLL patients. (A) Mutational enrichment in TN CLL patients and R/R CLL patients. Red diamond represents logarithmic OD and bar represents 95% confidence interval (CI). Red asterisks indicate statistically significant differences; yellow asterisks indicate trends toward statistical significance. (B) Mutational enrichment in CLL patients with IGHV mutations and CLL patients without IGHV mutations. Red diamond represents logarithmic OD and bar represents 95% CI. Red asterisks indicate adjusted P value of <.05; yellow asterisks indicate adjusted P value of <.1.
Figure 3.
Figure 3.
Heat map of CNAs inferred from targeted gene sequencing in 288 CLL patient samples. Each raw represents patient and column represents chromosome. Red color indicates copy number gain and blue color indicates copy number loss. Abnormalities such as amp(2p) and del(8p) were detected in addition to the chromosomal abnormalities commonly observed in CLL.
Figure 4.
Figure 4.
Pairwise association of cytogenetic abnormalities and mutations in all patients. The degree of logarithmic odds ratio is shown by color and the size of the box. Red color indicates co-occurence and blue color indicates mutually exclusive pattern. Statistically significant association by FDR is marked by asterisk. FDR, false discovery rate.
Figure 5.
Figure 5.
Survival duration for TN CLL patients according to mutations or FISH abnormalities. (A) OS of TN CLL patients. (B) EFS of TN CLL patients. The median survival duration in months is shown next to each survival curve. Only statistically significant mutations and FISH abnormalities were shown.
Figure 6.
Figure 6.
Survival duration of R/R patients according to mutations or FISH abnormalities. (A) OS of R/R patients. (B) EFS of R/R patients. The median survival duration in months is shown next to each survival curve. Only statistically significant mutations and FISH abnormalities were shown.
Figure 7.
Figure 7.
Comparison of the mutational frequency in the present study’s cohort and those in the CLL8 and CLL11 cohorts. Only the data from treatment naïve patients were compared. Red stars indicate mutations detected in all three cohorts at significantly different frequencies. MDACC, MD Anderson Cancer Center.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi