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Expression of HLA-B35 Is Associated with an Increased Risk of CMV Viremia and Clinically Significant CMV Infection in Patients Receiving Ptcy-Based Hematopoietic Cell Transplantation

Year: 2025

Type: article

Abstract: Hematopoietic cell transplant (HCT) with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis carries a higher risk of cytomegalovirus (CMV) infections despite letermovir prophylaxis. T cell immune responses are crucial for controlling viral infections like CMV, but PTCy may reduce TCR repertoire diversity. A prior study (Hasan A, et al. Blood Adv 2022) showed impaired CMV control by CMVpp65 CTLs restricted by HLA-B35 alleles. We hypothesized that HLA-B35 expression could be a risk factor for CMV infections post-PTCy-based HCT with in-vivo T cell depletion. In this single-center retrospective study, we included consecutive adults at risk for CMV reactivation (recipient and/or donor seropositive) undergoing HCT with PTCy from February 2015 to February 2022. CMV viremia and clinically significant CMV infection (CS-CMVi; CMV viremia/disease requiring CMV therapy) were assessed. Letermovir prophylaxis through D100 was used for CMV-seropositive recipients after 2017. Fine-Gray sub-distribution hazards models identified risk factors for CS-CMVi and CMV viremia, with disease relapse, repeat HCT, or death as competing risks. Cytokine release syndrome (CRS), neutrophil recovery, and acute/chronic GVHD were included as time-varying covariates. The Dana-Farber Harvard Cancer Center (DF/HCC) Institutional Review Board approved the study. Of 211 patients included, 59% were male, with a median age of 60 years (19.4 – 78.3). Acute myeloid leukemia (39%) and myelodysplastic syndrome/myeloproliferative neoplasms (29%) were the most common diseases. Donor were haploidentical (55%), HLA-mismatched unrelated (26%), and HLA-matched unrelated (19%). The majority of recipients were CMV seropositive (78%) and 60% received letermovir prophylaxis. HLA-B35 was carried by 18% patients. Transplant-related complications included CRS (47%), acute GVHD (42%), and chronic GVHD (27%). The one-year cumulative incidence of CS-CMVi was 29.9% (95% CI 23.8 - 36.1%). CMV end-organ disease occurred in 1.4% patients. On multivariable analysis, letermovir use was associated with a lower risk of CS-CMVi (HR 0.19, 95% CI 0.1 – 0.38, p<0.001). Recipient CMV seropositivity and recipient HLA-B35 positivity were associated with higher risks of CS-CMVi (HR 5.57, 95% CI 2.14 – 14.5, p<0.001 and HR 2.81, 95% CI 1.1 – 7.2, p=0.03, respectively) and CMV viremia (HR 4.87, 95% CI 2.35 – 10.1, p<0.001 and HR 2.28, 95% CI 1.15 – 4.55, p=0.02, respectively). Recipients of PT-Cy-based HCT bearing HLA-B35 had a higher risk of CMV viremia and CS-CMVi, suggesting potential defect in CMV antigen presentation by HLA-B35. This may serve as a novel tool to identify patients at risk of CMV infection post-HCT despite letermovir use. Future studies should investigate the mechanism and explore its potential for improving high-risk patients management.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.825