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Refining prognosis in early-stage CLL
mutations and/or del(11q) [TP53abn/SF3B1mut/del(11q)] were positive in 146 cases (42% of the evaluated cohort with available data for all 3 parameters) (Figure 2C) and exhibited a similar TTFT (median TTFT for TP53abn, SF3B1mut, del(11q): 1.8, 2.8 and 2.1 years, respectively; P=0.47) (Figure 2D). The co-occurrence of these aberra- tions was not found to aggravate the prognosis when compared to single aberrations alone (Online Supplementary Figure S3). Male sex was associated with a shorter TTFT (median TTFT: 3.9 years, 95%CI: 0.1-5.9 years) amongst non-TP53abn/SF3B1mut/del(11q) U-CLL cases (Online Supplementary Figure S4).
Similar to M-CLL, we applied recursive partitioning (Figure 3B) which highlighted TP53abn, del(11q) and male sex as the most important variables within Binet A U-CLL.
SF3B1 mutations did not reach significance, potentially due to the low number of cases with isolated SF3B1 muta- tions at the stage of the final nodes. In short, the evaluated U-CLL Binet A cohort was allocated to subgroups with differing TTFT, from shorter to longer, as follows: males with TP53abn; males with del(11q)/females with TP53abn and/or del(11q); males without TP53abn/del(11q); and, females without TP53abn/del(11q).
Two somatic hypermutation categories of chronic lymphocytic leukemia patients, two prognostic indices for time-to-first-treatment
Based on the above, we developed two prognostic indices for assessing TTFT, tailored to each SHM category. Within M-CLL, we defined 4 groups based on their clini-
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Figure 4. Prognostic index for time-to-first-treatment (TTFT) for mutated chronic lymphocytic leukemia (M-CLL) and unmutated chronic lymphocytic leukemia (U- CLL). (A) Prognostic index for TTFT within M-CLL: i) very high risk: Binet C; ii) high risk: Binet B; iii) intermediate risk: Binet A with at least one of the following: TP53abn or +12 or assignment to subset #2 and; iv) low risk: non-TP53abn/+12/#2 Binet A. (B) Prognostic index for TTFT within U-CLL: i) very high risk: Binet C; ii) high risk: Binet B; iii) intermediate risk: Binet A with at least one of the following: TP53abn or +SF3B1 mutations or del(11q) membership; iv) low risk: non-TP53abn/SF3B1mut/del(11q) male Binet A and; v) very low risk: non-TP53abn/SF3B1mut/del(11q) female Binet A.
Figure 5. Kaplan-Meier curves for time-to-first-treatment (TTFT) in the validation cohort. (A) Within mutated chronic lymphocytic leukemia (M-CLL), Binet A cases positive for TP53abn, trisomy 12 (+12) and stereotyped subset #2 assignment display similar TTFT. (B) No difference regarding TTFT among Binet A and unmutated chronic lymphocytic leukemia (U-CLL) cases carrying TP53abn, SF3B1 mutations or del(11q) in the validation cohort.
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