Comparison of Chimerism Kinetics and Associated Outcomes in Patients receiving Post-Transplant Cyclophosphamide vs. Methotrexate based GVHD Prophylaxis following Allogeneic Hematopoietic Cell Transplant.
Background: Post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is now being used beyond haploidentical (HID) allogeneic hematopoietic cell transplant (alloHCT). However, the kinetics of chimerism in patients receiving PTCy and its impact on post-transplant relapse is unknown. In this study we describe the kinetics of donor chimerism in patients receiving PTCy, factors predisposing to mixed donor chimerism, and the associated survival outcomes.
Methods: Patients undergoing alloHCT at Mayo Clinic, Rochester, from January 2018 to June 2023 were included in the study. Full donor chimerism was defined as donor cell fraction ≥95%, and mixed chimerism as donor cell fraction <95%. Analysis of covariance was used to assess the trend of tacrolimus levels in patients with mixed vs. full donor CD3 chimerism. Relapse-free survival (RFS) and overall survival (OS) from transplant were determined using the Kaplan-Meier method. Mixed donor chimerism was considered a time-dependent covariate in multivariate analysis.
Results: A total of 500 patients were evaluated. A total of 189 (37.8%) patients received myeloablative conditioning (MAC); 27 (14.3%) of whom received PTCy and 162 (85.7%) received methotrexate (MTX) for GVHD prophylaxis. Among patients receiving PTCy, HID and mismatched donor transplants were significantly associated with a lower risk of mixed CD3 chimerism. In patients receiving PTCy, myeloablative busulfan/fludarabine (BuFlu), compared to non-busulfan MAC regimens, was associated with an increased risk of day +90 mixed chimerism (OR 10.47, P=0.02). However, reduced intensity (RIC) BuFlu was not associated with an increased risk of mixed CD3 chimerism (OR 0.71, P=0.7). Among patients receiving MAC and PTCy, those with high tacrolimus levels (≥11 mcg/ml) beyond the 2nd week post-transplant period were more likely to have mixed CD3 chimerism (F1,145 = 4.15, P=0.043). In patients receiving MAC and PTCy, day +90 mixed CD3 chimerism was associated with an inferior RFS (1-year RFS: 89.16% vs. 40.0%, P = 0.009). Multivariate analysis showed that mixed donor CD3 chimerism was associated with an inferior RFS in patients receiving MAC and PTCy (HR 6.53, 95% CI 1.18 - 36.15, P=0.032).
Conclusions: Among patients receiving MAC and PTCy, detection of mixed donor CD3 chimerism at any timepoint after transplant portends an inferior RFS. A high tacrolimus level beyond 2nd week of transplant in this subset of patients was associated with mixed CD3 chimerism. The detection of mixed CD3 chimerism provides an opportunity to implement strategies that may help in decreasing the risk of relapse in this subset of patients.