Highlights
– In CMV‑seronegative adult AML patients undergoing unrelated donor HCT with post‑transplant cyclophosphamide (PTCy), receipt of a CMV‑seropositive donor was associated with inferior overall survival (multivariable HR 1.51; 95% CI 1.07–2.14).
– Restricted mean survival time (RMST) favored CMV‑seronegative donors by 2.95 months over the study follow‑up (P = .045); restricted mean time lost (RMTL) ratio was 1.34 (P = .037) for CMV‑seropositive donors.
– The observed survival difference was driven primarily by a trend to increased relapse (HR 1.42; 95% CI 0.95–2.08; P = .06) rather than non‑relapse mortality (HR 1.19; 95% CI 0.66–2.13; P = .56).
Background
Donor selection for allogeneic hematopoietic cell transplantation (HCT) weighs multiple factors: HLA match, donor age, donor sex, and infectious serologies such as cytomegalovirus (CMV). CMV is a ubiquitous herpesvirus with well‑established implications after HCT: CMV infection/reactivation contributes to morbidity and mortality and complicates immune reconstitution. The conventional transplant pairing of seronegative recipients (R‑) with seropositive donors (D+) has historically raised concern because donor CMV seropositivity can increase recipient risk for CMV viremia and end‑organ disease after transplant.
Post‑transplant cyclophosphamide (PTCy) has become a widely used graft‑versus‑host disease (GVHD) prophylaxis strategy in haploidentical and unrelated donor HCT platforms. Some observational data suggest PTCy may alter patterns of immune reconstitution and is associated with higher rates of early CMV reactivation in certain cohorts. At the same time, contemporary antiviral prophylaxis options are limited by indications: letermovir, a CMV terminase complex inhibitor, reduces CMV infection in CMV‑seropositive recipients and is licensed for prophylaxis in that population, but its role in CMV‑seronegative recipients is constrained by trial inclusion and cost considerations.
Against this backdrop, Mehta et al. (Transplant Cell Ther. 2025) analyzed registry data to evaluate whether donor CMV serostatus affects outcomes in CMV‑seronegative adult acute myeloid leukemia (AML) recipients undergoing unrelated donor HCT with PTCy.
Study design
This was a retrospective cohort analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. Inclusion criteria were adult CMV‑seronegative patients with AML who received unrelated donor HCT with PTCy between 2017 and 2021. Donor CMV serostatus defined groups: CMV‑seronegative donors (D‑) versus CMV‑seropositive donors (D+). Donor age was dichotomized at ≤32 versus >32 years in stratified analyses. Baseline demographics, disease status at transplant, conditioning intensity, HLA match, donor type (matched versus mismatched unrelated donor), and other transplant variables were recorded and compared.
Primary endpoint: overall survival (OS).
Secondary endpoints: relapse, non‑relapse mortality (NRM), acute and chronic GVHD.
Analytic methods: multivariable Cox proportional hazards models adjusted for known confounders and stratified by donor age; Restricted Mean Survival Time (RMST) and Restricted Mean Time Lost (RMTL) analyses were applied to quantify absolute differences in survival time and relative loss of survival time between groups.
Key findings
Cohort and baseline balance
Among 408 CMV‑seronegative AML recipients, 127 (31%) received grafts from CMV‑seropositive donors and 281 (69%) from CMV‑seronegative donors. Baseline characteristics were reported to be well balanced across most measured covariates, including age, disease status at transplant, conditioning intensity, and HLA matching.
Overall survival
In multivariable analysis, recipients of CMV‑seropositive donors had significantly higher risk of mortality compared with recipients of seronegative donors (HR 1.51; 95% CI 1.07–2.14; P = .019). Donor age (dichotomized at 32 years) and donor type (matched versus mismatched unrelated) did not significantly influence OS in this analysis.
RMST/RMTL
Restricted Mean Survival Time analysis revealed that CMV‑seronegative donor recipients lived on average 2.95 months longer over the observation window compared with recipients of CMV‑seropositive donors (P = .045). The RMTL ratio was 1.34 (P = .037), indicating recipients of CMV‑seropositive donors experienced a 34% higher relative loss of survival time.
Relapse and NRM
The difference in OS appeared to be driven primarily by a trend toward increased relapse in recipients of CMV‑seropositive donors (HR 1.42; 95% CI 0.95–2.08; P = .06). There was no statistically significant increase in NRM (HR 1.19; 95% CI 0.66–2.13; P = .56). Acute and chronic GVHD rates were not identified as primary drivers of the survival difference in the reported multivariable models.
Sensitivity and stratified analyses
Multivariable models were stratified by donor age and adjusted for key clinical variables. The association between donor CMV seropositivity and worse OS persisted after adjustment, suggesting the effect was not simply explained by donor age or donor type. However, as with any registry study, unmeasured confounding is possible; the authors discuss limitations including potential differences in CMV surveillance intensity, antiviral use, and other center‑level practices.
Expert commentary and interpretation
Clinical significance
This study provides robust registry‑level evidence that donor CMV serostatus matters in CMV‑seronegative adult AML recipients undergoing unrelated donor HCT with PTCy. The association with worse OS—and the RMST estimate of nearly 3 months’ shorter average survival time—are clinically meaningful, especially when making fine distinctions among otherwise comparable donors.
Potential mechanisms
The observed survival difference driven by a trend toward higher relapse in the D+ group is biologically intriguing and somewhat counter to prior hypotheses that donor CMV reactivity might augment graft‑versus‑leukemia effects. Several mechanistic explanations merit consideration:
- CMV reactivation in the early post‑transplant period may alter immune reconstitution in a way that diminishes effective anti‑leukemia responses—either via immune exhaustion, skewing of T‑cell repertoires, or cytokine milieu changes.
- In the PTCy context, early depletion of proliferating alloreactive T cells followed by reconstitution dynamics could interact with CMV exposure from a seropositive donor to produce suboptimal anti‑leukemia immunity.
- Antiviral therapy or preemptive interventions triggered by CMV viremia may indirectly affect relapse risk via marrow toxicity, drug interactions, or modulation of immune recovery.
Methodological strengths and limitations
Strengths include the use of a large, multicenter registry dataset, contemporary transplant era (2017–2021), and careful multivariable adjustment with RMST to quantify absolute survival differences. Limitations are inherent to retrospective registry analyses: potential residual confounding, lack of centralized CMV monitoring protocols, scarce granular data on timing and magnitude of CMV viremia, detailed antiviral prophylaxis or preemptive therapy use at patient level, and limited mechanistic immune profiling. Importantly, the study population was restricted to adults with AML receiving PTCy; findings may not extrapolate to pediatric patients, other diagnoses, or non‑PTCy GVHD prophylaxis platforms.
Relation to antiviral prophylaxis
Letermovir reduces CMV infection and related complications among CMV‑seropositive recipients after HCT (Marty FM et al., N Engl J Med 2017), but its clinical indications historically have focused on seropositive recipients, and uptake in the D+/R‑ scenario may be limited by licensing and cost. Because the Mehta et al. cohort spans a period when letermovir was entering clinical practice, variable use could influence outcomes in complex ways. At present, letermovir is not routinely used to prevent donor‑derived CMV exposure in R‑ recipients, so strategies to mitigate D+ risks remain primarily donor selection and close monitoring with preemptive therapy when viremia occurs.
Clinical implications and recommendations
Donor selection
When multiple otherwise comparable unrelated donors are available for a CMV‑seronegative AML recipient in a PTCy HCT platform, donor CMV serostatus should be considered a factor in selection. Given the observed association with worse OS and the trend toward higher relapse, preference for a CMV‑seronegative donor may be reasonable if HLA match, donor age, sex, and other critical variables are equivalent.
CMV surveillance and prophylaxis
Transplant centers using PTCy should maintain vigilant CMV surveillance in D+/R‑ pairs and have clear preemptive therapy pathways. The role of letermovir in R‑ recipients is not established; prospective evaluation would be required before routine adoption. For now, tailored strategies—rapid viral load monitoring, early initiation of preemptive antivirals, and close hematologic and infectious follow‑up—are prudent.
Shared decision‑making
Donor selection often involves tradeoffs (HLA match versus donor age versus CMV serostatus). The Mehta et al. data provide quantitative evidence to inform discussions with patients and donor coordinators. In scenarios where a D+ donor offers a superior HLA match or younger age compared with a D‑ donor, clinicians must weigh the relative risks; the current study suggests D+ status independently increases mortality risk, but absolute differences should be balanced against other donor advantages.
Conclusions and future directions
Mehta and colleagues identify donor CMV seropositivity as an independent adverse prognostic factor for overall survival in CMV‑seronegative adult AML recipients undergoing unrelated donor HCT with PTCy, with effect size manifesting as both a hazard ratio increase and an RMST decrement of roughly 3 months. The association appears driven by relapse rather than non‑relapse mortality, raising biologic questions about how donor CMV exposure interacts with post‑transplant immune recovery and graft‑versus‑leukemia effects in the PTCy setting.
Prospective studies are needed to validate these findings, clarify mechanisms (immune phenotyping, CMV viral load kinetics, and antiviral exposure), and evaluate interventions: (1) formal incorporation of donor CMV serostatus into donor prioritization algorithms, (2) trials of targeted antiviral prophylaxis or alternative immunomodulatory strategies in D+/R‑ pairs, and (3) mechanistic studies of T‑cell reconstitution and antigen specificity after PTCy in the context of donor CMV seropositivity.
Funding and clinicaltrials.gov
The analyzed study used CIBMTR registry data; specific funding sources for the authors were reported in the original manuscript (Mehta RS et al., Transplant Cell Ther. 2025). This was a retrospective registry analysis and not a prospective clinical trial; therefore, no ClinicalTrials.gov identifier applies to the primary analysis reported.
References
1. Mehta RS, Aljawai YM, Al‑Juhaishi T, Saultz J, Milano F, Kanakry JA, Kanakry CG, Lazaryan A. Role of Donor Cytomegalovirus Serostatus in Cytomegalovirus‑Seronegative Recipients of Unrelated Donor Hematopoietic Cell Transplantation with Post‑Transplant Cyclophosphamide Prophylaxis. Transplant Cell Ther. 2025 Sep;31(9):672.e1‑672.e9. doi: 10.1016/j.jtct.2025.05.005. PMID: 40379049.
2. Marty FM, Ljungman P, Papanicolaou GA, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic‑Cell Transplantation. N Engl J Med. 2017;377(25):2433‑2444. doi:10.1056/NEJMoa1714914.
Note: Additional literature regarding CMV, PTCy, and immune reconstitution can inform interpretation but were not directly cited in the primary registry analysis summarized here.
