  Acute lymphoblastic leukemia is the most common malignancy in childhood.
Successful treatment requires initial high-intensity chemotherapy, followed by
low-intensity oral maintenance therapy with oral 6-mercaptopurine (6MP) and
methotrexate (MTX) until 2-3 years after disease onset. However, intra- and
interindividual variability in the pharmacokinetics (PK) and pharmacodynamics
(PD) of 6MP and MTX make it challenging to balance the desired antileukemic
effects with undesired excessive myelosuppression during maintenance therapy. A
model to simulate the dynamics of different cell types, especially neutrophils,
would be a valuable contribution to improving treatment protocols (6MP and MTX
dosing regimens) and a further step to understanding the heterogeneity in
treatment efficacy and toxicity. We applied and modified a recently developed
semi-mechanistic PK/PD model to neutrophils and analyzed their behavior using a
nonlinear mixed-effects modeling approach and clinical data obtained from 116
patients. The PK model of 6MP influenced the accuracy of absolute neutrophil
count (ANC) predictions, whereas the PD effect of MTX did not. Predictions
based on ANC were more accurate than those based on white blood cell counts.
Using the new cross-validated mathematical model, simulations of different
treatment protocols showed a linear dose-effect relationship and reduced ANC
variability for constant dosages. Advanced modeling allows the identification
of optimized control criteria and the weighting of specific influencing factors
for protocol design and individually adapted therapy to exploit the optimal
effect of maintenance therapy on survival.
