Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia

Abstract

The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a training-validation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring +12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions.

Figure 1

Decision tree resulting from recursive partitioning analysis and amalgamation in the training series. Disruption of TP53 and BIRC3, mutations of SF3B1 and NOTCH1, and del11q22-q23 were the factors selected by the algorithm to split the patient population in 6 terminal nodes. Presence or absence of the TP53 disruption independent of cooccurring genetic lesions was the most significant covariate for the entire study population. Among patients lacking TP53 abnormalities, the most significant covariate was BIRC3 disruption. Among patients lacking both TP53 and BIRC3 abnormalities, the most significant covariate was SF3B1 mutation status. Among patients lacking TP53, BIRC3, and SF3B1 lesions, the most significant covariate was NOTCH1 mutation status. Among patients lacking TP53, BIRC3, SF3B1, and NOTCH1 lesions, the most significant covariate was del11q22-q23. Based on the application of the amalgamation algorithm to the terminal nodes, patients harboring TP53 abnormalities and those harboring BIRC3 abnormalities were grouped into a single category, as well as patients harboring NOTCH1 mutations, SF3B1 mutations, or del11q22-q23. Genetic lesions are represented from right to left according to their hierarchical order of relevance in splitting the parent node into daughter nodes with significantly different survival probabilities. The P value corresponds to the log-rank test adjusted for multiple comparisons. The right branch of each split represents the presence of the lesion. The left branch of each split represents the absence of the lesion. The Kaplan-Meier curves estimate the OS of patients belonging to each terminal node. N indicates the number of patients in the node; M, mutation; and DIS, disruption.

Figure 2

Kaplan-Meier estimates of OS and treatment-free survival according to the integrated mutational and cytogenetic model in the training series. (A) OS. (B) Probability of progressive disease requiring treatment according to IWCLL-NCI guidelines as indicated by treatment-free interval. Cases harboring TP53 and/or BIRC3 disruption (TP53 DIS/BIRC3 DIS) independent of cooccurring genetic lesions are represented by the red line. Patients harboring NOTCH1 mutations (NOTCH1 M) and/or SF3B1 mutations (SF3B1 M) and/or del11q22-q23 in the absence of TP53 and BIRC3 disruption are represented by the yellow line. Patients harboring +12 in the absence of the TP53 disruption, BIRC3 disruption, NOTCH1 mutations, SF3B1 mutations, and del11q22-q23 and patients wild-type for all genetic lesions (normal) are represented by the green line. Cases harboring del13q14 as the sole genetic lesion are represented by the blue line. nr indicates not reached.

Figure 3

Observed OS in patients from the training series compared with the expected OS in the matched general population. OS in CLL patients stratified according to the FISH cytogenetic model (A) and the integrated mutational and cytogenetic model (B) relative to the expected OS in the age-, sex-, and calendar year of diagnosis–matched general population (black line). (A) Patients harboring del17p13 irrespective of cooccurring cytogenetic lesions are represented by the red line. Patients harboring del11q22-q23 in the absence of del17p13 are represented by the purple line. Patients harboring +12 in the absence of del17p13 and del11q22-q23 are represented by the yellow line. Patients harboring a normal FISH karyotype are represented by the green line. Patients harboring del13q14 deletion in the absence of other cytogenetic abnormalities are represented by the blue line. (B) Patients harboring TP53 and/or BIRC3 disruption (TP53 DIS/BIRC3 DIS) independent of cooccurring genetic lesions are represented by the red line. Patients harboring NOTCH1 mutations (NOTCH1 M) and/or SF3B1 mutations (SF3B1 M) and/or del11q22-q23 in the absence of TP53 and BIRC3 disruption are represented by the yellow line. Patients harboring +12 in the absence of TP53 disruption, BIRC3 disruption, NOTCH1 mutations, SF3B1 mutations, and del11q22-q23, and patients wild-type for all genetic lesions (normal) are represented by the green line. Patients harboring del13q14 as the sole genetic lesion are represented by the blue line.

Figure 4

Cumulative incidence of high-risk clonal evolution. Time to high-risk clonal evolution was defined as the time elapsed from diagnosis to the date of development of TP53 abnormalities, BIRC3 abnormalities, NOTCH1 mutations, SF3B1 mutations, or del1q22-q23 (events) or last follow-up or death (censoring). Analysis was performed using death as a competing risk. Only patients who did not present high-risk abnormalities at diagnosis were included in this analysis. (A-D) Cumulative incidence of clonal evolution according to age > 65 years (hazard ratio [HR] = 4.18; 95% CI, 1.26-13.8; 5-year risk: 17.1%, 10-year risk: 32.9%;), high LDH (HR = 3.15; 95% CI, 1.32-7.55; 5-year risk: 24.8%, 9-year risk: 62.8%), unmutated IGHV genes (HR = 2.89; 95% CI, 1.31-6.39; 5-year risk: 18.5%, 9-year risk: 50.8%), +12 or a normal genetics (HR = 2.29; 95% CI, 1.03-5.10; 5-year risk: 13.8%, 9-year risk: 34.5%).

Figure 5

Landmark analysis of the cumulative probability of OS according to the integrated mutational and cytogenetic model. (A) Diagnosis. (B) Landmark at 1 year. (C) Landmark at 2 years. (D) Landmark at 4 years. Patients harboring TP53 and/or BIRC3 disruption (TP53 DIS/BIRC3 DIS) independent of cooccurring genetic lesions are represented by the red line. Patients harboring NOTCH1 mutations (NOTCH1 M) and/or SF3B1 mutations (SF3B1 M) and/or del11q22-q23 in the absence of TP53 and BIRC3 disruption are represented by the yellow line. Patients harboring +12 in the absence of TP53 disruption, BIRC3 disruption, NOTCH1 mutations, SF3B1 mutations, and del11q22-q23 and patients wild-type for all genetic lesions (normal) are represented by the green line. Patients harboring del13q14 as the sole genetic lesion are represented by the blue line.