IPSS-Molecular but Not Individual Mutations Predicts Outcomes of Patients with Myelodysplastic Syndrome (MDS) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT): A Mayo Clinic Cohort

Abstract

The decision to offer Allo-HCT in MDS relies on prognostic scoring models which include clonal cytogenetic (CG) abnormalities, blood counts (cytopenias), and % of marrow blasts (i.e. revised international prognostic scoring system, IPSS-R). Recently, an updated clinical-molecular prognostic model combining genomic profiling with hematologic and CG parameters, namely IPSS-Molecular (IPSS-M), showed better prognostic discrimination across all clinical endpoints and re-stratified almost one-half of patients (pts) vs. IPSS-R. Hence, we evaluated the impact of IPSS-M, CG risk group and individual mutations on Allo-HCT outcomes. The analysis included 191 consecutive MDS pts undergoing Allo-HCT who had available next generation sequencing (NGS) analysis performed at Mayo Clinic (at diagnosis (Dx, n=164 or prior to Allo-HCT, n=162) between 11/2015 and 1/2022. Median age at Allo-HCT was 64 (18-75) yrs, and 112 (58.6%) were male. At Dx, 126 (77%) pts had at least one pathogenic genetic alteration, including (>5% incidence) ASXL1 (28.0%), TP53 (18.9%), TET2 (14.6%), SRSF2(12.2%), U2FA1 (12.2%), DNMT3A (8.5%), BCOR (7.9%), RUNX1 (6.7%), and SF3B1 5.5%; a similar mutational pattern was present at Allo-HCT: ASXL1 (28%),TET2 (15.2%) U2AF1 (13.4%), TP53 (12.2%), SRSF2 (11%), RUNX1(9.8%), DNMT3A (7.3%), SETBP1 (7.3%), SF3B1 (6.7%), BCOR (6.7%), STAG2 (5.5%), and JAK2 (5.5%). Most pts (156, 81.7%) received at least 1 line of therapy, and 45 (23.6%) had >5% marrow blasts at Allo-HCT. The majority (134, 70%) received reduced intensity conditioning. Graft versus host disease (GVHD) prophylaxis consisted of methotrexate/tacrolimus in 138 (77.5%) and post-transplant cyclophosphamide in 40 (22.5%). HCT comorbidity index was >3 in 113 (59%). IPSS-M risk group was calculated and reclassified from IPSS-R into very low (1, 0.6%), low (24, 14.7%), moderate low (34, 20.9%), moderate high (41, 25.2%), high (29, 17.8%), very high (34, 20.9%), mainly for IPSS-R intermediate and high-risk groups (Fig. 1). Median F/U after Allo-HCT was 18.8 (0.4-76.8) months. The 100-day and 1-year non-relapse mortality (NRM) were 7.9% and 18.1%, respectively. The 2-year incidence of death and relapse were 40.1% (95% confidence intervals (CI) 33.5-48%) and 21.6% (95%CI 16.4-28.4%), respectively. Cumulative incidences of grade III-IV acute GVHD was 10% and 1-year cumulative incidence of extensive chronic GVHD was 12%. In multivariable analysis, IPSS-M predicted mortality [Hazard ratio (HR) (per 1 risk category) 1.21, 95%CI 1.00-1.47, p=0.049] and relapse (HR=1.47, 95%CI 1.13-1.92, p=0.004), but not NRM (HR 0.95, 95%CI 0.74-1.22). The 1-year mortality rates for very low/low, moderate-low, moderate-high, high/very high risks were 21%, 24%, 32%, and 37%, respectively (Fig. 1). Individual mutations had minimal independent association with outcome in the multivariable model. For mortality, only ASXL1 at Dx (HR 0.48, 95%CI 0.26-0.91, p=0.024) and SF3B1 at Allo-HCT (HR 2.51, 95%CI= 1.06-5.96, p=0.037) were significant. TP53 at Dx had a borderline association (HR 0.46, 95% CI= 0.942.69, p=0.086). Also, there was no significant association of individual mutation with relapse (including TP53 at Allo-HCT, HR 1.77, p=0.085). Only SF3B1 at Allo-HCT correlated with NRM (HR 3.16, 95%CI= 1.22-8.17, p=0.018). Conversely, CG risk group remained strongly associated with mortality (p=0.007) and relapse (p=0.003), particularly poor/very poor (P/VP) risk CG (Mortality: HR 2.46, 95%CI 1.44-4.19, p=0.001; Relapse: HR 3.46, 95%CI 1.70-7.05, p=0.0006). There was no association of CG risk with NRM. We demonstrate value of IPSS-M risk stratification in predicting outcomes after Allo-HCT for MDS, re-stratifying pts into more discrete prognostic groups that predict mortality and relapse risk. Hence, IPSS-M could inform post allo-HCT decision including future maintenance strategies to prevent relapse in high/very high IPSS-M. CG risk group (esp. P/VP risk), a core component of IPSS-M, independently contributes to outcome prediction both within the model and individually. Disease risk does not predict NRM, and individual mutations have limited association with outcome, suggesting allo-HCT may mitigate the poor prognostic impact of high-risk oncogenic mutations present at Dx, including TP53 and ASXL1. An updated analysis on mutational complexity will be shown at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal