Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms

Abstract

The prognostic and predictive value of sequencing analysis in myelodysplastic syndromes (MDS) has not been fully integrated into clinical practice. We performed whole exome sequencing (WES) of bone marrow samples from 83 patients with MDS and 31 with MDS/MPN identifying 218 driver mutations in 31 genes in 98 (86%) patients. A total of 65 (57%) patients received therapy with hypomethylating agents. By univariate analysis, mutations in BCOR, STAG2, TP53 and SF3B1 significantly influenced survival. Increased number of mutations (≥ 3), but not clonal heterogeneity, predicted for shorter survival and LFS. Presence of 3 or more mutations also predicted for lower likelihood of response (26 vs 50%, p = 0.055), and shorter response duration (3.6 vs 26.5 months, p = 0.022). By multivariate analysis, TP53 mutations (HR 3.1, CI 1.3–7.5, p = 0.011) and number of mutations (≥ 3) (HR 2.5, CI 1.3–4.8, p = 0.005) predicted for shorter survival. A novel prognostic model integrating this mutation data with IPSS-R separated patients into three categories with median survival of not reached, 29 months and 12 months respectively (p < 0.001) and increased stratification potential, compared to IPSS-R, in patients with high/very-high IPSS-R. This model was validated in a separate cohort of 413 patients with untreated MDS. Although the use of WES did not provide significant more information than that obtained with targeted sequencing, our findings indicate that increased number of mutations is an independent prognostic factor in MDS and that mutation data can add value to clinical prognostic models.

The evolving role of next generation sequencing in myelodysplastic syndromes

“…Somatic mutation status may, however, predict duration of response to therapy. Mutations in DNA methylation regulators and the presence of 3 or more mutations have been associated with a shorter duration of response to DNMTIs (Montalban‐Bravo et al , ). Recent retrospective data suggests that the duration of response to DNMTIs is significantly shorter in patients with TP53 mutations, roughly 6 months versus 29 months, although this study did not detect a difference in overall response rate based on TP53 mutational status (Takahashi et al , ).…”

Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

“…From the available data, it is known that the presence of a number of somatic mutations can affect the response rates to therapy and the level of overall survival [12]. Mutations in the TET2, DNMT3A, TP53 genes were reported to be associated with a high probability of response to HMA [13,14,15].…”

Are next-generation sequencing results knocking on Heaven’s door for transplantation planning in chronic myelomonocytic leukemia?

“…5 DNMT3A and TP53 mutations, although less common in CMML, have also been associated with poorer OS. 6,7 It is noteworthy that the number of mutations also influences patients' outcomes, as recently demonstrated in a study in which a shorter OS was observed in CMML patients with three or more concomitant mutations. 7 Specific prognostic scoring systems for individual risk assessment are essential in order to provide risk-adapted treatment.…”

“…6,7 It is noteworthy that the number of mutations also influences patients' outcomes, as recently demonstrated in a study in which a shorter OS was observed in CMML patients with three or more concomitant mutations. 7 Specific prognostic scoring systems for individual risk assessment are essential in order to provide risk-adapted treatment. The most commonly used are the CMML-specific prognostic scoring system (CPSS), 8 the MD Anderson Cancer Center prognostic score (MDAPS) 9 and the revised International Prognostic Scoring System (IPSS-R) 10 (the last only being applicable to "dysplastic" CMML).…”