Risk Factors for Early Relapse after Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome

Abstract

Background Relapse is a challenge after allogeneic hematopoietic cell transplantation (alloHCT) in MDS. MHC class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells. There have been conflicting reports in regards to MICA mismatch and relapse after alloHCT in hematologic malignancies (Carapito Blood 2016, Askar BBMT 2017). However, these studies did not assess somatic mutations, which have shown to impact relapse (Coleman NEJM 2017). We first assessed risk factors for relapse within 6 and 12 months after alloHCT. We then assessed for an effect of somatic mutations and MICA dimorphisms on relapse. Methods We conducted a single center, retrospective analysis of adults with MDS who underwent 1st alloHCT with T-cell replete HLA-8/8 matched related (MRD) or unrelated donor (MUD). In addition to cytogenetic risk stratification, a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms of MICA-129 were categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity. Results From 2000 - 2017, 128 adult MDS patients met inclusion criteria. Median age at alloHCT was 56 years (range, 20-76). IPSS-R scores at diagnosis included 2% very good, 42% good, 23% intermediate, 19% poor, and 14% very poor risk. 62% had MUDs and 87% had a myeloablative regimen. Among 78 patients with data, donor/recipient MICA mismatch was present in 8% while donor MICA-129 dimorphisms were 49% V/V, 42% M/V, and 9% M/M In multivariable analysis, the presence of at least 1 of these less favorable mutations (ASXL1, DNMT3A, FLT3, KRAS, NRAS, and TP53) was a risk factor for relapse within 6 mos (HR 4.30, CI 1.40-13.3, P=0.011; Figure 1); 6-mo relapse incidence (CI) was 45% (22-65) for those with at least 1 of the above mutations vs. 15% (9-22) for all others. A MRD graft was a risk factor for relapse within 12 mos (HR 2.27, CI 1.12-4.59, P=0.023); 12-mo relapse incidence was 36% (23-50) for those with a MRD vs. 19% (11-28) for MUDs. In a 41-patient subset with both MICA and mutation data, although not significant, patients with both donor V/V dimorphism and at least 1 of these less favorable somatic mutations had higher relapse incidence (40% at 12 mos) than those with only 1 of these adverse factors (28%) or neither factor (9%) (P=0.12; Figure 2). Conclusion The presence of at least 1 of the 6 less favorable somatic mutations in our cohort was associated with a risk of relapse within 6 mos after alloHCT for MDS. Our data suggest an additive effect of both weak NK cell activation and less favorable somatic mutations in increasing the risk of relapse, but was not statistically significant. Future investigation of larger cohorts and mechanistic studies are needed to better assess potential interactions between these two elements and the risk of relapse.