title: Optimal chemotherapy for leukemia: a model-based strategy for individualized treatment.
abstract: Acute Lymphoblastic Leukemia, commonly known as ALL, is a predominant form of cancer during childhood. With the advent of modern healthcare support, the 5-year survival rate has been impressive in the recent past. However, long-term ALL survivors embattle several treatment-related medical and socio-economic complications due to excessive and inordinate chemotherapy doses received during treatment. In this work, we present a model-based approach to personalize 6-Mercaptopurine (6-MP) treatment for childhood ALL with a provision for incorporating the pharmacogenomic variations among patients. Semi-mechanistic mathematical models were developed and validated for i) 6-MP metabolism, ii) red blood cell mean corpuscular volume (MCV) dynamics, a surrogate marker for treatment efficacy, and iii) leukopenia, a major side-effect. With the constraint of getting limited data from clinics, a global sensitivity analysis based model reduction technique was employed to reduce the parameter space arising from semi-mechanistic models. The reduced, sensitive parameters were used to individualize the average patient model to a specific patient so as to minimize the model uncertainty. Models fit the data well and mimic diverse behavior observed among patients with minimum parameters. The model was validated with real patient data obtained from literature and Riley Hospital for Children in Indianapolis. Patient models were used to optimize the dose for an individual patient through nonlinear model predictive control. The implementation of our approach in clinical practice is realizable with routinely measured complete blood counts (CBC) and a few additional metabolite measurements. The proposed approach promises to achieve model-based individualized treatment to a specific patient, as opposed to a standard-dose-for-all, and to prescribe an optimal dose for a desired outcome with minimum side-effects.
authors.affiliation: School of Chemical Engineering, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Devaraj
authors.initials: D
authors.lastname: Jayachandran
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Rundell
authors.affiliation: School of Chemical Engineering, Purdue University, West Lafayette, Indiana, United States of America; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hannemann
authors.affiliation: Riley Hospital for Children, Indianapolis, Indiana, United States of America.
authors.forename: Terry A
authors.initials: TA
authors.lastname: Vik
authors.affiliation: School of Chemical Engineering, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Doraiswami
authors.initials: D
authors.lastname: Ramkrishna
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D004909:Erythrocyte Indices / Q000187:drug effects; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D066230:Patient-Specific Modeling; D057285:Precision Medicine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D017741:Survivors
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine