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.