Fludarabine Pharmacokinetic Model-Based Dosing Minimizes the Risk of Graft Rejection in Pediatric Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Abstract

Fludarabine is commonly used during conditioning for allogeneic hematopoietic cell transplantation (HCT) to prevent rejection of donor cells, given its profound immunosuppressive effects on T cells, albeit with minimal activity against NK cells. In pediatric patients, traditional body-surface-area (BSA)-based dosing strategies may result in non-optimal exposure. Pharmacokinetic (PK) models have been developed that allow precise targeting of a goal exposure (area-under-the-curve [cAUC] of 20 mg·h/L), which may improve outcomes. We sought to determine whether the use of PK-guided model-based dosing (MBD) results in lower incidences of rejection in the context of other relevant predictors of rejection. We performed a retrospective analysis of 410 patients with a median age of 8 yr (range, 0.1 to 26.5) who underwent first allogeneic HCT for treatment of both malignant and non-malignant conditions between 2008 and 2024 with fludarabine-containing conditioning, including 239 who received BSA-based dosing and 171 who received MBD. The overall 6-mo cumulative incidence of immunologic rejection was 5.8% (95% CI, 3.4% to 8.2%). Factors associated with rejection included: (1) an absolute lymphocyte count obtained prior to start of lymphodepletion (absolute lymphocyte count [ALC]) ≥1.275 × 10^9/L (9.4% versus 1.1% for lower ALCs; P < .001); (2) using a female donor for a male recipient (10.9% versus 4% for other combinations; P = .009); (3) using an HLA-mismatched donor (9.7% versus 1.6% for 10/10 matched donors; P < .001); and (4) positive CMV serostatus of recipient and/or donor (7.3% versus 1.6% for CMV recipient negative/donor negative; P = .02). MBD of fludarabine was also associated with a lower risk of rejection (1.8% versus 8.5% for BSA-based dosing; P = .004) and this association was most apparent amongst those with two or three of the other identified risk factors. Multivariate analysis confirmed all five of these factors are independently associated with rejection; the hazard ratio of rejection for BSA-based dosing of fludarabine was 5.12 (1.51 to 17.28; P = .009). Use of MBD of fludarabine to target a cAUC of 20 mg·h/L is an important component of optimizing conditioning regimens to minimize risk of immunologic rejection. While the potential benefit of MBD with fludarabine was most significant in patients with other risk factors for rejection, the simplicity of this approach allows for its universal incorporation into conditioning regimens for all pediatric allogeneic HCT.

Keywords: Fludarabine; Pharmacokinetics; Rejection.