Expression of HLA-B*35 is Associated With an Increased Risk of CMV Viremia and Clinically Significant CMV Infection following PTCy-Based Hematopoietic Cell Transplantation

Abstract

Introduction: HLA-B*35 expression has previously been associated with impaired immunologic control of viral infections including 1 study demonstrating impaired control of CMV by CMVpp65 CTLs restricted by HLA-B*35 alleles. We hypothesized that expression of HLA-B*35 may be a risk factor for CMV infections after PTCy-based HCT.

Methods: In this single-center retrospective study, we included consecutive adults at risk for CMV reactivation (R+ and/or D+) undergoing HCT with PTCy-based GVHD prophylaxis from February 2015 to February 2022. CMV viremia and clinically significant CMV infections (CS-CMVi) were assessed. Letermovir prophylaxis through Day 100 was used for CMV-seropositive recipients after 2017. Fine-Gray sub-distribution hazards models assessed risk factors associated with CS-CMVi and CMV viremia using disease relapse, repeat HCT, or death as competing risks.

Results: The overall 1-year cumulative incidence of CS-CMVi was 29.9% (95% CI 23.8% to 36.1%) and decreased significantly in the post-letermovir era (52.3% vs. 24.0%; P ≤ .001). On multivariable analysis, recipient CMV seropositivity and HLA-B*35 expression were associated with an increased risk of CS-CMVi (HR 5.57 (95% CI 2.14 to 14.5), P < .001 and HR 2.81 (95% CI 1.1 to 7.2), P = .03, respectively) and CMV viremia (HR 4.87 (95% CI 2.35 to 10.1), P < .001 and HR 2.28 (95% CI 1.15 to 4.55), P = .02, respectively).

Discussion: In this study, HLA-B*35 expression was associated with an increased risk of CMV viremia and CS-CMVi suggesting a possible defect in CMV antigen presentation by HLA-B*35 bearing targets. This may represent a novel immunogenetic factor that can be utilized to identify patients at higher risk of post-HCT CMV infections and potentially inform clinical management. Future studies are needed to elucidate the mechanism and investigate clinical applications.

Keywords: CMV infection; HLA-B*35; Post-transplant cyclophosphamide.