Population pharmacokinetics (POPPK) of F-araA
Non-linear mixed effects modeling analysis was performed via Monolix (version 5.1.0) using the Stochastic Approximation Expectation-Maximization (SAEM) method. A two-compartment PK model was used to describe the data. The PK parameters estimated included clearance, CL (L/hr/m2) and volume, V (L/m2) along with the inter-compartmental clearance and peripheral compartment volume (Q (L/hr/m2) and V2 (L/m2)). In addition, the individual post-hoc parameter values were used to estimate the area under the concentration curve (AUC). The inter-individual variability of the parameters was assumed to be log-normally distributed. A combined additive and proportional residual error model was used with assumed normal distribution of the residuals.
The relationships between the PK parameters and covariates were described using the following model: θ=θBase*exp (β*covariate). A covariate was considered significant in the Univariate analysis, if the addition of the covariate to the model reduced the objective function value (OFV) at least 3.84 units (p < 0.05, based on the χ2 test for the difference in the -2 log-likelihood between two hierarchical models that differ by 1 degree of freedom).
Clinical Outcome :
HCT outcomes such as RRTs, engraftment, rejection, GVHD, donor-recipient chimerism status, and survival status were documented. The potential factors influencing these outcome parameters were evaluated. An absolute neutrophil count of > 500x106/L on three consecutive days was noted as neutrophil engraftment; day +28 chimerism analysis showing more than 95% of donor genetic marker patterns was considered as achieving complete chimerism (CC). Mixed Chimerism (MC) was defined as the presence of >5% residual host chimerism at any time point post HCT, whereas rejection as >90% residual host chimerism in peripheral blood as described previously 25. The RRTs including mucositis was graded according to NCI-CTCAE V5.0 criteria 26, Hepatic Sinusoidal Obstruction Syndrome (SOS) was graded according to Baltimore criteria 27. GVHD was graded using Glucksberg criteria 27. Any deaths occurring within the first 100-days post HCT was regarded as Transplant Related Mortality (TRM). Early TRM (TRM D+30) and late TRM (TRM+100) are deaths occurring within 30 and 100 days post-transplantation mostly due to RRTs and infections. Event-free survival (EFS) was defined from the time of transplant to an event; an event was primary graft rejection/failure, death. Overall survival (OS) was defined as the percentage of patients who were alive at the last follow-up.