HLA-a*0101 Expression Correlates with Increased Risk of Severe Cutaneous Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Fonseca Maira , Jakubowski Ann A. , Devlin Sean M , Young James W. , Fatmi Samira A , Maloy Molly , Giralt Sergio , Ponce Doris , Markova Alina 
Published: October 2019

Abstract
Introduction: Acute graft-versus-host disease (aGVHD) remains a substantial cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT). aGVHD most commonly affects the skin, for which there is a high treatment response after both unmodified and ex-vivo CD34+ selected/T-cell depleted (TCD) alloHSCT grafts. We identified a cluster of patients, however, who developed severe refractory cutaneous aGVHD and expressed MHC class I HLA-A*0101 allele. Although the effect of HLA polymorphisms on cutaneous aGVHD is unknown, we hypothesized that HLA-A*0101 expression correlates with worse cutaneous aGVHD after alloHSCT.
Methods: We evaluated 831 patients who underwent either an unmodified or TCD allograft at a single institution between 03/2010 and 02/2017. We excluded patients who received <8/8 HLA-matched grafts or cord blood transplant. For each patient with cutaneous aGVHD, we assessed donor-recipient HLA-typing (confirming HLA-A*0101 status), as well as time of onset, grade at onset, and highest overall grade of cutaneous aGVHD.
Results: Most of the patients underwent alloHSCT after myeloablative conditioning for the treatment of hematologic malignancies or high-risk non-malignant hematologic disorders. A similar proportion received a TCD or an unmodified allograft. Because all patients had 8/8 HLA-identical donors, both donor and recipient either expressed HLA-A*0101 or did not. HLA-A*0101 was expressed in 206 (25%) patients (98 TCD, 108 unmodified) who had similar demographics to patients lacking HLA-A*0101 (Table 1). At day 180, patients expressing HLA-A*0101 had a higher incidence of grade II-IV cutaneous aGVHD when compared to patients lacking HLA-A*0101 expression in both the TCD (12% vs. 5%, p=0.02) and unmodified (16% vs. 9%, p=0.046) cohorts. Similarly, incidence of severe grade III-IV cutaneous aGVHD was higher in the HLA-A*0101 expressing group when compared to the non-expressing group after TCD (8% vs. 3%, p=0.027) and unmodified (11% vs. 4%, p=0.01) alloHSCT (Fig 1). In a multivariate cause-specific Cox model, HLA-A*0101 expression in the TCD alloHSCT cohort correlated with increased risk of grade III-IV cutaneous aGVHD [HR=2.79 (95% CI: 1.07-7.28), p=0.036] after adjusting for whether the donor was related or unrelated. In the unmodified alloHSCT cohort, HLA-A*0101 expression also correlated with an increased risk of grade III-IV cutaneous aGVHD [HR=2.68 (95% CI: 1.24-5.79), p = 0.012)] after adjusting for relationship status of the donor and the type of conditioning regimen. There was no statistically significant difference in OS or transplant-related mortality between HLA-A*0101 expressing vs. non-expressing patients after TCD or unmodified alloHSCT.
Conclusions: Donor/recipient expression of HLA-A*0101 correlates with an increased incidence and severity of cutaneous aGVHD after both TCD and unmodified alloHSCT, including severe grade III-IV cutaneous aGVHD. These findings have potential practical implications in the development of cutaneous aGVHD prophylaxis or early therapeutic strategies targeting the skin in this high-risk population. These findings merit further investigation in a larger patient/donor population.

Disclosures
No relevant conflicts of interest to declare.