Driver Somatic Mutations and Transplantation Decision Making in Patients with Myelodysplastic Syndrome

The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various somatic mutations are associated with different phenotypes and clinical outcomes. The only curative treatment for MDS patients is allogeneic hematopoietic stem cell transplantation (HSCT) which is considered as a therapeutic option until the age of 65-70 in eligible patients. Whether the genetic basis influences the outcome of HSCT is currently unclear. Recently, we observed that mutations on ASXL1, RUNX1 and TP53 genes are independent predictors of relapse and overall survival in MDS patients after HSCT, and that the integration of these mutations into currently available predictive models increases the capability to capture prognostic information at individual patient level (Della Porta MG et al. J Clin Oncol, 2016 in press).

In this study, we explored the possibility of developing a clinical/molecular predictive model to specifically estimate the outcome after HSCT in patients with MDS or acute myeloid leukemia evolving from MDS (MDS/AML). We studied 401 patients undergoing allogeneic HSCT for primary MDS or MDS/AML between 1997 and 2013 and reported to the GITMO registry. We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms.

In multivariable analysis with probability of relapse as endpoint the following factors showed independent prognostic value: percentage of marrow blasts (>10% vs. ≤10%, HR 1.43, P=0.04), cytogenetic risk according to IPSSR (poor/very poor vs. very low/low/intermediate risk, HR 1.85, P=.002), disease status at transplant (refractoriness to induction chemotherapy vs. complete remission, HR 2.4, P<.001), type of conditioning (reduced intensity vs. standard conditioning, HR 1.35, P=.034) and mutational status of ASLX1/RUNX1/TP53 genes (present vs absent, HR 1.49, P=.021). Recipient age (>40 vs. ≤40 years, HR 1.68, P=.001), comorbidity risk according to HCT-CI (high vs. low/intermediate risk 2.10, P<.001) type of conditioning (reduced intensity vs. standard conditioning, HR 0.53, P=.033) and HLA matching (≤7/8 vs. 8/8 match, HR 1.97, P=.001) were significant risk factors for transplant-related mortality (TRM).

Based on regression coefficients, we developed a clinical/molecular model predictive for the risk of relapse after transplantation in MDS and MDS/AML. Accordingly, a score value of 1 was assigned for each of the following risk factors: marrow blasts >10%, poor/very poor cytogenetic risk according to IPSSR, refractoriness to induction chemotherapy, and driver mutations in ASLX1/RUNX1/TP53 genes. A relapse risk index was calculated as the sum of these weighted scores, and was then categorized into 4 risk groups: low (score=0), intermediate (score=1-2), high (score=3), and very high (score=4). The cumulative incidence of relapse was estimated by a competing risks approach with TRM. In patients receiving standard conditioning, 5-year probability of survival after allogeneic HSCT was 61%, 43%, 39% and 19% for low, intermediate, high and very high risk (P<.001), while cumulative incidence of relapse were 9%, 19%, 24% and 35%, respectively (P=.001). In patients receiving reduced intensity conditioning, 5-year probability of survival was 55%, 42%, 33% and 15% for low, intermediate, high and very high risk (P=.003), while cumulative incidence of relapse were 12%, 25%, 39% and 58%, respectively (P<.001).

This model serves as a proof of concept that the integration of somatic mutations significantly increase the capability to capture prognostic information in MDS and MDS/AML patients receiving allogeneic HSCT, and may provide a basis for improving clinical decision-making. Possible interventions in patients with high risk of disease relapse after HSCT according to genotype may include the anticipation of the transplant procedure in early disease phase, the use of innovative conditioning regimens to increase the probability to eradicate MDS clone, and prophylaxis of disease recurrence after transplantation by donor leukocyte infusions and targeted/novel therapies