Letermovir Prophylaxis for CMV DNAemia /Disease after HLA ‐Mismatched HSCT : A Retrospective Real‐World Analysis with Overlap Propensity Score Weighting

Whether letermovir benefits high-risk HLA-mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly with GIAC-based conditioning, is not well studied. In this retrospective real-world analysis, we evaluated the clinical benefits of letermovir in CMV IgG-positive recipients undergoing HLA-mismatched allo-HSCT (year 2011-2022) using overlap propensity score (OPS) weighting, with a prespecified subgroup included haploidentical HSCT (haplo-HSCT) with modified GIAC (mGIAC). Among 411 transplants, 105 received letermovir, including 39 of 132 patients following the mGIAC protocol. Letermovir significantly reduced day + 180 CMV DNAemia (43.4% vs 83.2%; P < 0.001) and CMV DNAemia/disease (44.7% vs 83.4%; HR 0.33; P < 0.001), with a nonsignificant decrease in CMV disease (4.7% vs 14.2%; P = 0.101). Day + 180 and +360 survival did not differ between groups. In mGIAC haplo-HSCT, letermovir likewise lowered day + 180 CMV DNAemia (47.5% vs 82.3%; P = 0.023) and CMV DNAemia/disease (50.9% vs 83.0%; HR 0.40; P = 0.028) without reducing CMV disease. On multivariable analyses, age ≥ 45 years and nonuse of letermovir independently increased CMV DNAemia/disease risk in both the overall and mGIAC haplo-HSCT cohorts. Overall survival and non-relapse mortality (NRM) were unaffected by letermovir, probably reflecting effective preemptive management and the study's overlap-weighted design. Based on our results, letermovir prophylaxis can effectively reduce CMV DNAemia/disease in HLA-mismatched and mGIAC haplo-HSCT, and may serve as a standard of care for these high-risk patients.