Predictive Value of Detectable Somatic Mutations By Next Generation Sequencing (NGS), at Day +100 (D100) Post-Allogeneic Hematopoietic Cell Transplantation (allo-HCT) on Survival Outcomes in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Background Outcomes of relapsed AML post allo-HCT remain poor. There is a need to develop prognostic markers to identify patients at high risk of relapse. Patients who achieve complete remission with persistent allelic burden detected by NGS post induction chemotherapy have been shown to have a high risk of relapse. We aim to assess the feasibility of standard of care NGS panel in risk stratification for post allo-HCT outcomes. Methods A single center analysis of adult patients who received the first allo-HCT for AML and/or MDS at Mayo Clinic, FL from 2014-2018 was undertaken. Patients allografted at any time point in their disease course were included. A targeted OncHeme NGS panel for myeloid neoplasms was performed prior to allo-HCT. DNA was extracted from the bone marrow sample and following library preparation by hybrid capture, was subjected to NGS with post-sequencing analysis of tumor-associated mutations. The panel was retested on the D100 post allo-HCT bone marrow sample. Outcome data was analyzed using fisheru0027s exact test, cox proportional hazard models and Kaplan-Meier analysis. Results A total of 92 patients were identified, of whom 29 (32%) were tested on D100. 23 of the 29 patients had also been tested pre-allografting with NGS, and represent study population. Median age was 66 (72-22) years. Detailed demographics are shown in Figure 1. Median follow-up was 16 (9-24) months. Fifteen (65%) of 23 had evidence of somatic mutations pre allo-HCT. Only 5 of 15 (33%) who had prior evidence of somatic mutations were found to have detectable mutations on D100. IDH-2 mutations were mostly commonly detected prior to allo-HCT whereas TP53 mutations were most common detected after allo-HCT (Figure 2). Three of 4 patients with baselineTP53 mutations had persistent TP53 mutation at day D100. Eighty percent of patients who had mutations detected by NGS at D100 experienced disease relapse compared to 11% who did not have any detectable mutation (RR=10.32, 95% CI 1.82-58.2, p=0.0082). Patients who had mutations detected by NGS at D100 had a higher mortality rate compared to those who did not have any detectable mutation (80% vs 22%, RR=5.08, 95% CI 1.25-20.68, p=0.0230) (Figure 3). Conclusions Our results show that testing for MRD with NGS is feasible and predicts outcome post allo-HCT. While allo-HCT is effective in preventing relapse in AML, the procedure has limited benefit in AML/MDS with detectable TP53 mutations. As we have demonstrated, persistence of detectable TP53 in remission after allo-HCT is associated with dismal outcome. Patients with detectable NGS mutations prior to allo-HCT should be considered for enrollment in clinical trials evaluating novel conditioning regimens including targeted and/or post-transplant maintenance strategies. One limitation of our study is the use of different gene panels as practice evolved. These results will be validated in larger cohorts.