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DNMT3A mutation predicts adverse outcome in adult T-ALL
We therefore performed bivariate analyses of the effects of DNMT3A mutations and age across a series of outcome measures. These results are shown in Online Supplementary Table S4. In each case, DNMT3A genotype was still asso- ciated with significantly increased cumulative incidence of relapse (HR 2.80, 95% CI: 1.12-6.97, P=0.034), and shorter event-free survival (HR 2.62, 95% CI: 1.45–5.06, P=0.004) and overall survival (HR 2.05, 95% CI: 1.02-4.12, P=0.043).
Since DNMT3A alterations were almost exclusively found in patients >40 years (16/18 cases), we also per- formed survival analyses that were restricted to the >40- year old subgroup, which constituted a quarter of the total cohort of patients (50/198, 25.3%). Consistent with the
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results of the bivariate analyses, DNMT3A mutation was associated with significantly worse 5-year cumulative incidence of relapse (58.3% mutated vs. 21.7% non- mutated, HR 3.90, 95% CI: 1.30-11.68, P=0.015) (Figure 4A), 5-year event-free survival (25.0% mutated vs. 56.7% non-mutated, HR 2.95, 95% CI: 1.37-6.32, P=0.005) (Figure 4B), and 5-year overall survival (37.5% mutated vs. 62.1% non-mutated, HR 2.35, 95% CI: 1.05-5.26, P=0.038) (Figure 4C).
Finally, we carried out multivariate outcome analyses in the whole cohort using the risk factors that were used to stratify treatment during the GRAALL-2003 and -2005 studies, and which were found to significantly predict prognosis in the univariate analyses. Among age, log(WBC),
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Figure 2. Evidence of DNMT3A mutations in non-leukemic DNA. (A) Direct sequencing of DNMT3A exons 14 and 15, NOTCH1 and NRAS in diagnostic (left panels) and remission (right panels) samples. (B) Mutational assessment of DNA extracted from leukemic and non-leukemic fractions of samples from patients with T-cell acute lymphoblastic leukemia. Sequencing results of DNMT3A and NOTCH1 in leukemic (left panels) and non-leukemic (right panels) DNA are shown. Cases are num- bered according to the listing in Online Supplementary Table S3.
haematologica | 2019; 104(8)
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