Age Distribution and Pattern of Myeloid Marrow Mutations in Patients (pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS) after Failure of Hypomethylating Agents (HMAs)

Background: The aging marrow stem cell demonstrates more somatic mutations when compared to younger marrow stem cells. These abnormalities have been noted in pts with MDS, as well as in patients with normal peripheral blood counts (Steensma et al, Blood 2015; Jaiswal et al, N Engl J Med 2014). Mutations are rarely detected in people 1 (Figure 1). Table 1 shows the most frequent clonal myeloid mutations in ONTIME, based on age above and below 75 years (the median age in ONTIME).Table 3.Incidence (%) of Patients with Specific Mutations, Age Above and Below 75 YearsMutation< 75 years (N=60)≥ 75 years (N=51)Total (N=111)Fisher's Exact Test P-valueSRSF22729280.83TP532518220.37ASXL12018190.81SF3B11316140.79U2AF11212121.00TET21216140.59RUNX1814110.38DNMT3A812100.75In a separate analysis, the number of months from diagnosis of MDS and duration of prior HMA treatment did not appear to influence the pattern of mutations (Table 2). Table 2.Mutations by Months Since MDS Diagnosis and Duration of Prior HMAMutationNMonths from MDS Diagnosis median (range)Duration of HMA (mo) median (range)All analyzed pts11118.5 (0.1-116)8.9 (1.2-65)TP532414.9 (0.7-116)13.0 (1.2-36)SF3B11629.4 (7.5-63)13.0 (1.2-36)TET21522.6 (0.1-63)11.4 (2.0-36)SRSF23117.2 (6.6-116)6.4 (3.0-35)ASXL12115.7 (4.9-66)8.2 (2.8-44)DNMT3A1115.1 (7.4-36)6.5 (4.2-30)Conclusions: Somatic mutations are common in marrow stem cells from patients with HR-MDS. Over 45% of patients had 1 mutational abnormality, and 44% had >1. Of note, patients under and over the median age of pts with MDS had a similar mutational pattern, which was not influenced by either length of time since diagnosis of MDS or prior treatment with an HMA. In this analysis, the mutational genomic abnormalities in the MDS marrow stem cell were similar among younger and older patients with MDS, suggesting the underlying pathogenic mechanisms causing these abnormalities are also similar irrespective of patient age. Figure 1. Number of Mutations Per Patient Figure 1. Number of Mutations Per Patient Figure 2. Overall Survival in ONTIME by Number of Marrow Stem Cell Mutations Figure 2. Overall Survival in ONTIME by Number of Marrow Stem Cell Mutations Disclosures Mufti: Onconova Therapeutics Inc: Research Funding. Silverman:Onconova Therapeutics Inc: Honoraria, Patents & Royalties: co-patent holder on combination of rigosertib and azacitdine, Research Funding. Best:Onconova Therapeutics Inc: Research Funding. Fructman:Onconova Therapeutics Inc: Employment. Azarnia:Onconova Therapeutics Inc: Employment. Petrone:Onconova Therapeutics Inc: Employment.