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.