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Somatic variants in CML-CP as predictive biomarker
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Figure 2. Association of occurrence of somatic variants with clinical outcome of chronic-phase chronic myeloid leukemia (CML-CP) patients starting on imatinib (IM) treatment. Kaplan-Meier survival analyses in IM-treated subjects with somatic variants (red dashed line) versus non-variant (black solid line). The end points used were cumulative incidence of major molecular response (3-log reduction in BCRABL1 transcripts from baseline; MR3) at five years (A) and probabilities of event- free survival (EFS) (B), progression-free survival (PFS) (C) and CML-related survival at eight years after start of therapy (D). Hazard R (95%CI) derived from Cox pro- portional hazard regression models and the P-value calculated by the Log Rank test also shown. Number of subjects (N) per group is also shown. Notably, two sub- jects have been excluded from the survival analysis due to non-CML-related deaths, whereas five subjects have been excluded from the EFS and two from the major molecular response (MR3) analyses, because of IM failure due to intolerance.
rates of EFS, PFS and CML-related survival in 2G-TKI- treated subjects: 90% (39, 98%) vs. 100%, P=0.25 for MR3; 61% (41, 91%) vs. 75% (62, 92%), P=0.32 for EFS; 82% (66, 99%) vs. 89% (80, 99%), P=0.46 for PFS; 81% (63, 99%) vs. 93% (85, 99%), P=0.29 for CML-related sur- vival in variant versus non-variant subjects (Figure 3). We found no association of the somatic variants with out- comes in multivariate analysis with Sokal score, ELTS score or type of BCRABL1 transcript (Online Supplementary Table S5A). When combined with molecular response within the 1st year, only BCRABL1/ABL1 transcripts within the 1st year but not somatic variants were predictive for MR3 and EFS. Non-responders with and without variants had no significant difference in rates of EFS: 38% (16, 87%) vs. 48% (27, 85%), respectively; P=0.69 (Online Supplementary Figure S5B).
Excluding the two subjects with somatic pre-leukemia variants did not alter our conclusions (Online Supplementary Table S4B).
To reduce potential heterogeneity conferred by different 2G-TKI, we next investigated the association of somatic variants with outcomes in the dasatinib-treated cohort only (n=55). No association with outcomes was detected (Online Supplementary Table S5B).
Germline variants in chronic-phase chronic myeloid leukemia subjects
We identified 99 missense variants classified as rare germline (with frequency <1% in the general population) (Online Supplementary Results, Online Supplementary Table S6 and Online Supplementary Figure S6), which did not affect clinical outcome in either cohort (data not shown).
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