Work

Association of Early Tacrolimus Levels and Outcomes after Post-Transplant Cyclophosphamide in Allogeneic Hematopoietic Cell Transplantation

Year: 2025

Type: article

Abstract: Background In retrospective analyses, higher trough concentrations of calcineurin inhibitors (CNIs – tacrolimus or cyclosporine) early post-allogeneic hematopoietic cell transplantation (alloHCT) were associated with decreased incidence of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM), and improved overall survival (OS). Whether high levels of peri-HCT CNI are beneficial after post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis is not established. Methods Adult alloHCT patients who received PTCy-based GVHD prophylaxis and tacrolimus (TAC) were identified from September 2014 through April 2022. Patients received PTCy 50 mg/kg IV D+3 and D+4 with TAC (0.02 mg/kg/IVCI; goal 5-12 ng/mL) and MMF (15 mg/kg IV Q8H, max 3 g/day) starting D+5. Individual median TAC trough concentration levels were calculated for weeks 2, 3, and 4 post alloHCT. We evaluated associations between these median levels and time-to-event outcomes of interest including the cumulative incidence (CI) at D+100 for aGVHD, 1-year CI of cGVHD, OS, PFS, and toxicity (e.g., hyperbilirubinemia and acute kidney injury). Time-to-event outcomes were landmarked at 2-, 3-, and 4-weeks post alloHCT. Results We included 248 patients transplanted mostly for acute leukemia (N = 103) or MDS (N = 57). Reduced-intensity or nonmyeloablative regimens were more commonly utilized with haploidentical or mismatched donors (Table 1). Median TAC level at 2-, 3-, and 4-weeks post-transplant were 10 ng/mL (5.8-15.2), 9.1 ng/mL (6-13), and 8.9 ng/mL (5.4-12.7) respectively. There was no association between TAC levels and risk of grade III-IV aGVHD at 2 weeks post alloHCT (HR 1.04 [95% CI 0.87, 1.25], p = 0.65) with similar results at weeks 3 (HR 1.06 [95% CI 0.78, 1.43], p = 0.72) and 4 (HR 1.06 [95% CI 0.76, 1.49], p = 0.73) (Figure 1). Similarly, with cGVHD there was no association between observed TAC medians from weeks 2-4 (p = 0.51, 0.57, and 0.21 respectively). When GVHD outcomes using the midpoint of our institutional target range for TAC, no significant difference was observed with TAC levels < 8 ng/mL vs. ≥ 8 ng/mL (Figure 2). Similarly, there did not appear to be a statistically significant impact on OS (HR 1.0 [95% 0.86, 1.17]), RFS (HR 1.02 [95% CI 0.9, 1.17]), or toxicities with increasing TAC levels at week 2 or subsequent time points. Conclusion In the context of PTCy-based prophylaxis, increasing median TAC trough did not appear to confer protection from acute GVHD . Lower target TAC trough < 8 ng/mL may be acceptable to minimize peri-HCT toxicity. These results require confirmation in a prospective cohort analysis .

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.448