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Editorials
Figure 1. The 20-year history of IGHV mutations in chronic lymphocytic leukemia (CLL). IGHV: immunoglobulin heavy chain variable region; BCR: B-cell receptor; M: mutated; U: unmutated; CIT: chemoimmunotherapy; PFS: progression-free survival.
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ERIC group, out of a large cohort of 2366 CLL cases, Baliakas et al.18 focused on 1900 stage A CLLs that were divided into the two main CLL immunogenetic subgroups: U-CLL and M-CLL. Considering each of them separately, they analyzed the relative weight of different prognostic markers in determining the TTFT.18 These prognostic mark- ers included: age, sex, CD38, FISH lesions, TP53, SF3B1, NOTCH1, BIRC3, MYD88 gene mutations, and the major BCR subsets #1, #2 and #4.
This IGHV-based prognostic approach suggests that, among stage A M-CLL, cases with trisomy 12 and stereo- typed subset #2 show a short TTFT at five and ten years after diagnosis, similar to those with TP53 abnormalities; within stage A U-CLL, cases with del(11q) and/or SF3B1 mutations experience a TTFT as short as cases with TP53 abnormalities. These markers are almost entirely mutually exclusive. The validity of the model is confirmed also in an external validation cohort of 649 Binet A CLL. Interestingly, male sex comes out as a determinant of disease course within U-CLL, a recurrent observation that has never been truly addressed.19
Overall, considering patients in all stages, within IGHV M-CLL, the lowest risk category (stage A/non-TP53 abnor- malities/+12/subset #2), representing 73% of all M-CLL, shows a TTFT of 12% and 25% at five and ten years, respectively; this means that only 1 out of 4 patients has required treatment after ten years from diagnosis. The intermediate-risk category (stage A/TP53 abnormali- ties/+12/subset #2), representing 14% of all M-CLL, shows a TTFT of 40% and 55% at five and ten years, implying that 1 out of 2 patients still remains untreated after ten years from diagnosis.
On the other hand, within IGHV U-CLL, the very low- risk category (stage A/female/non-SF3B1 mutation/del11q), representing 13% of all U-CLL, shows a TTFT of 45% and 65% at five and ten years, respectively, much shorter (medi- an TTFT 6.1 years) than low-risk M-CLL patients (median TTFT not reached). The U-CLL low-risk (stage A/male/non-SF3B1 mutation/del11q) and intermediate-risk (stage A/SF3B1 mutation/del11q) patients, representing 19% and 24% of all U-CLL, respectively, show a median TTFT of 3.6 and 2.1 years.
haematologica | 2019; 104(2)