Evaluating Day +90 Donor Chimerism as a Prognostic Marker of Clinical Outcomes Among Allogeneic Hematopoietic Cell Transplant Recipients Who Received Myeloablative Conditioning.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for hematologic malignancies. However, relationships between donor chimerism and clinical outcomes remain poorly characterized.

OBJECTIVE: The purpose of this study was to evaluate associations between D+90 unfractionated and CD3+ donor chimerism and clinical outcomes, as well as associations between D+90 donor chimerism and myeloablative conditioning (MAC) regimens.

STUDY DESIGN: This single-center, retrospective cohort study included allo-HCT recipients from 5/4/2011-2/18/2025. Subjects received MAC regimens prior to allo-HCT for hematologic malignancy diagnoses. Full donor chimerism was defined as >95% donor cells by D+90. The primary endpoint was 5-year overall survival (OS) among subjects who achieved D+90 full versus mixed unfractionated donor chimerism. Secondary endpoints included 5-year relapse-related mortality (RRM), non-relapse related mortality (NRM), and cumulative incidence of relapse (CIR) for both unfractionated and CD3+ chimerism, and 5-year OS for CD3+ chimerism. Additional secondary outcomes included differences in clinical outcomes based on D+90 donor chimerism among subjects diagnosed with a myeloid malignancy, differences in achieving full D+90 donor chimerism among subjects who received busulfan-containing conditioning versus cyclophosphamide plus total body irradiation with or without fludarabine (Cy/TBI or Flu/Cy/TBI), and differences in achieving full D+90 donor chimerism based on first-dose area under the curve (AUC0-inf) among subjects who received PK-guided busulfan dosing.

RESULTS: A total of 256 subjects were included in the final analyses (n = 213 full; n = 43 mixed). Full unfractionated D+90 donor chimerism was associated with improved 5-year OS, CIR, RRM, and NRM (adj. HR 0.36, 95% CI 0.23 to 0.57, P < .0001; HR 0.45, 95% CI 0.21 to 0.99, P = .04; adj. HR 0.29, 95% CI 0.16 to 0.52, adj. P < .0001; adj. HR 0.48, 95% CI 0.24 to 0.94, adj. P = .03, respectively). Differences in OS, RRM, CIR, and NRM were not observed between CD3+ study groups (all P > .05). Subjects from the myeloid malignancy subgroup who achieved full unfractionated donor chimerism had significantly improved 5-year OS (HR 0.32, 95% CI 0.16 to 0.63, P < .0001), lower 5-year CIR (HR 0.50, 95% CI 0.21 to 0.98, P = .04), RRM (HR 0.27, 95% CI 0.11 to 0.67, P < .0001), and NRM (HR 0.39, 95% CI 0.18 to 0.85, P = .01) compared to those with mixed donor chimerism. Allo-HCT recipients who received Cy/TBI or Flu/Cy/TBI had an 18% reduced risk of mixed unfractionated donor chimerism by D+90 compared to those who received a busulfan-containing regimen (RR 0.82, 95% CI 0.73 to 0.98, P = .03). First-dose busulfan AUC0-inf did not predict whether subjects would achieve full versus mixed unfractionated donor chimerism (P = .83), but greater busulfan AUC0-inf was associated with a higher likelihood of achieving full CD3+ donor chimerism (P = .02).

CONCLUSION: These data suggest unfractionated donor chimerism by D+90 may be a prognostic marker of clinical outcomes post-allo-HCT.