Chromosome 6 Loss-of-Heterozygosity in Pre-Transplant Blood Samples of Patients with Severe Aplastic Anemia Is Associated with Lower Risk of Acute Graft- Versus -Host Disease

Abstract

Introduction. Recent studies identified a subset of patients with severe aplastic anemia (SAA) with acquired clonal loss-of-heterozygosity of the HLA locus on chromosome 6p (6pLOH), an alteration that could allow escape from immune surveillance. Here, we examined the presence of this alteration in pre-transplant blood samples of patients with SAA and evaluated its effect on patient risk of acute graft- versus -host disease (aG v HD) after unrelated donor hematopoietic cell transplant (HCT).Methods.We used single nucleotide polymorphism (SNP) array genotyping to identify chromosomal alterations in pre-HCT blood samples of 528 SAA patients who received unrelated donor HCT between 1998-2011. Samples and clinical data were provided by the Center for International Blood and Marrow Transplant Research (CIBMTR®) database and biorepository. Findings were validated in a cohort of 161 SAA patients from the Japanese Marrow Donor Program (JMDP) who received unrelated donor HCT between 1993-2011; 6pLOH was identified using digital droplet PCR in the Japanese cohort. Cox proportional hazard models were used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of aG v HD associated with 6pLOH.Results. The median age at HCT was 25.5 and 22.7 years in the CIBMTR and JMDP cohorts, respectively. All the JMDP patients received bone marrow grafts versus 79% for the CIBMTR cohort, and were more likely to receive reduced intensity conditioning (85% vs. 47%, p<0.0001). 6pLOH was identified in 8% and 12% of the CIBMTR and JMDP SAA patients, respectively. The presence of 6pLOH was marginally associated with male sex (67% vs. 52%, p=0.05) and year of HCT (p=0.03) in the CIBMTR cohort and with age at HCT (mean=16 vs. 24 years, p=0.04) and time between AA diagnosis and HCT in the JMDP cohort (14 vs. 57 months, p<0.0001).In the CIBMTR cohort, patients with 6pLOH had statistically significant lower cumulative incidence (CI) of aG v HD grade II-IV (16% vs. 30% at 100 days, p=0.04) and grade III-IV (5% vs. 17%, p=0.001). Multivariable analysis, adjusted for sex and year at HCT showed similar results, although not statistically significant. The HR for aG v HD grade II-IV=0.55 (95% CI=0.24-1.25), for aG v HD grade III-IV= 0.34 (95% CI=0.08-1.40). Multivariable models from the JMDP cohort, adjusted for age and time between AA diagnosis and HCT showed consistent results for aG v HD grade II-IV (HR=0.50, 95% CI=0.11-2.19). We do not report aG v HD grade III-IV because of small event count (n=5). No statistical significant associations in the other tested endpoints (overall survival and chronic G v HD) were observed for either cohorts.In a combined analysis, multivariable models adjusted for degree of HLA matching, time between AA diagnosis and HCT, G v HD prophylaxis, year at HCT, and stratified on stem cell source, showed a statistically significant lower risk of aG v HD II-IV (HR=0.47, 95% CI=0.23-0.96, p=0.04 in all patients, and HR=0.36, 95% CI=0.15-0.89, p=0.02 in patients who received bone marrow grafts).Conclusion. Pre-HCT clonal presence of 6pLOH in patients with SAA is associated with a reduction in risk for acute G v HD. This alteration identifies a subset of SAA patients with potentially lower HCT-risk, and should be further studied to determine whether it could guide therapeutic decisions for those patients. DisclosuresWang:Pfizer: Employment, Equity Ownership. Lee:Mallinckrodt: Honoraria; Kadmon: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Amgen: Other: One-time advisory board member.