Myelodysplastic syndrome

Prognostic significance of serial molecular annotation in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML)

Abstract

The implementation of next-generation sequencing (NGS) has influenced diagnostic, prognostic, and therapeutic decisions in myeloid malignancies. However, the clinical relevance of serial molecular annotation in patients with myelodysplastic syndrome (MDS) undergoing active treatment is unknown. MDS or secondary acute myeloid leukemia (sAML) patients who had at least two NGS assessments were identified. Outcomes according to mutation clearance (NGS-) on serial assessment were investigated. Univariate and multivariate Cox regression models were used to evaluate the prognostic impact of NGS trajectory on overall survival (OS). A total of 157 patients (MDS [n = 95]; sAML [n = 52]; CMML [n = 10]) were identified, with 93% of patients receiving treatment between NGS assessments. Magnitude of VAF delta from baseline was significantly associated with quality of response to treatment. Patients achieving NGS- had significantly improved OS compared to patients with mutation persistence (median OS not reached vs. 18.5 months; P = 0.002), which was confirmed in multivariate analysis (HR,0.14; 95%CI = 0.03–0.56; P = 0.0064). Serial TP53 VAF evaluation predicts outcomes with TP53 clearance representing an independent covariate for superior OS (HR,0.22; 95%CI = 0.05–0.99; P = 0.048). Collectively, our study highlights the clinical value of serial NGS during treatment and warrants prospective validation of NGS negativity as a biomarker for treatment outcome.

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Fig. 1: Dynamics of VAF changes of dominant clone before and after treatment.
Fig. 2: Mutational spectrum in patients who achieved NGS negativity on serial analyses.
Fig. 3: Prognostic impact of serial NGS results on overall survival.
Fig. 4: Prognostic impact of TP53 VAF changes on overall survival.

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Acknowledgements

This work was supported in part by a research grant from the Graduate Medical Education (GME) at the University of South Florida (SY), Research Training Award for Fellow (RTAF) from the American Society of Hematology (SY), Scholar Award from the American Society of Hematology (SY), NIH grant K08 CA237627 (SY), MDS Foundation Young Investigator Grant (DAS), Early Career Award of the Dresner Foundation (DAS), and Edward P. Evans Foundation Award (DAS).

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Conception and design: SY, DAS. Collection and assembly of data: SY, NHA, MH, KS, JL, JH, AL, EP, RK, DAS. Data analysis and interpretation: SY, SMG, JS, CV, DAS. Manuscript writing: SY, NHA, MH, KS, SMG, JL, JH, AL, EP, RK, DAS.

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Correspondence to David A. Sallman.

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Yun, S., Geyer, S.M., Komrokji, R.S. et al. Prognostic significance of serial molecular annotation in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Leukemia (2020). https://doi.org/10.1038/s41375-020-0997-4

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