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P. Baliakas et al.
AB
Figure 6. Kaplan-Meier curves for time-to-first-treatment (TTFT) for mutated chronic lymphocytic leukemia (M-CLL) and unmutated chronic lymphocytic leukemia (U-CLL) cases carrying trisomy 12 (+12). (A) +12 is an unfavorable prognosticator in M-CLL. (B) +12 is associated with a more indolent clinical course in U-CLL.
co-biological profiles at the time of diagnosis: i) very high risk: Binet C with identical 5- and 10-year treatment-prob- ability (TP) of 92%; ii) high risk: Binet B, 5y-TP and 10y- TP: 64% and 84%, respectively; iii) intermediate risk: Binet A with one of the following: TP53abn and/or +12 and/or subset #2 membership, 5y-TP and 10y-TP: 40% and 55%, respectively. [Of note, among 18 non-censored cases with no treatment indication for more than 10 years after diagnosis, 5 (30%) carried TP53abn]; and iv) low risk: non-TP53abn/+12/subset #2 Binet A, 5y-TP and 10y-TP: 12% and 25%, respectively (Figure 4A). Harrell’s C Index was calculated for the multivariable Cox model with the prognostic index above being the sole predictor and was found to equal 0.745 (se = 0.013).
In U-CLL, we could define 5 groups: i) very high risk: Binet C with 5- and 10-year TP of 100%; ii) high risk: Binet B, 5y-TP and 10y-TP: 90% and 100%, respectively; iii) intermediate risk: Binet A with one of the following: TP53abn and/or SF3B1mut and/or del(11q), 5y-TP and 10y-TP: 78% and 98%, respectively; v) low risk: non- TP53abn/SF3B1mut/del(11q) male Binet A, 5y-TP and 10y- TP: 65% and 85%, respectively; and iv) very low risk: non-TP53abn/SF3B1mut/del(11q) female Binet A, 5y-TP and 10y-TP: 45% and 65%, respectively (Figure 4B). Harrell’s C Index was calculated for the multivariable Cox model with the prognostic index being the sole predictor and was found to equal 0.753 (se = 0.013).
Internal validation
In order to validate the results mentioned above, a boot- strapping procedure was performed. In early stage M-CLL patients, this showed that the average number of predic- tors included in the multivariable Cox model was 3.2 with three variables exhibiting selection percentages greater than 60%, i.e. TP53abn, +12 and subset #2 (Table 1). In early stage U-CLL patients, bootstrapping showed that the average number of predictors considered significant in the multivariable Cox model was 3.5. Four variables exhibited selection percentages greater than 60%, i.e. TP53abn, SF3B1mut, del(11q) and male sex.
External validation
Application of the above mentioned indices to the vali- dation cohort (n=649) led to the following observations: i) in M-CLL, TP53abn, +12 and subset #2 membership (inter- mediate risk for M-CLL) exhibited similar TTFT, consti- tuting a group (16% of all Binet cases also in the validation cohort) with almost identical 5y-TP (43%) and 10y-TP (60%) to those observed in the training cohort (40% and 55%, respectively) (Figure 5A); ii) similarly, in U-CLL, no difference was observed in TTFT for Binet A cases carry- ing TP53abn and/or SF3B1mut and/or del(11q) (intermedi- ate risk for U-CLL) who exhibited similar 5y-TP and 10y- TP to that of the training cohort (74% vs. 78% and 92% vs. 98%, respectively; P-values: non significant) (Figure 5B); iii) amongst the remaining non- TP53abn/SF3B1mut/del(11q) U-CLL Binet A cases, the dif- ference between male and female patients did not reach statistical significance (P=0.2) (Online Supplementary Figure S5A and B).
Discussion
Chronic lymphocytic leukemia constitutes a rather unique case amongst cancers in that the great majority of patients are asymptomatic at diagnosis and classified as early stage, and thus do not require immediate treatment.42 However, most patients will progress and meet the criteria for treatment initiation albeit at a vari- able time from diagnosis.37,42 Therefore, accurate predic- tion of the TTFT is of major importance for both patients and physicians having to address the challenge of living with and managing this (largely) invisible and incurable disease. In support of this argument, solid prognostica- tion is increasingly recognized as both a priority and an unmet need by CLL patients themselves, who would benefit from accurate prognostic information in order to make educated life choices and, perhaps, also participate more actively in their care.
Several prognostic models have been developed for CLL
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