title: Optimized Treatment Schedules for Chronic Myeloid Leukemia.
abstract: Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib) have been developed to treat Chronic Myeloid Leukemia (CML). Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies. However, the design of such combination therapies (timing, sequence, etc.) remains an open challenge. In this work we mathematically model the dynamics of CML response to combination therapy and analyze the impact of combination treatment schedules on treatment efficacy in patients with preexisting resistance. We then propose an optimization problem to find the best schedule of multiple therapies based on the evolution of CML according to our ordinary differential equation model. This resulting optimization problem is nontrivial due to the presence of ordinary different equation constraints and integer variables. Our model also incorporates drug toxicity constraints by tracking the dynamics of patient neutrophil counts in response to therapy. We determine optimal combination strategies that maximize time until treatment failure on hypothetical patients, using parameters estimated from clinical data in the literature.
authors.affiliation: Department of Industrial and Systems Engineering, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Qie
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Industrial and Systems Engineering, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Junfeng
authors.identifier: http://orcid.org/0000-0002-6561-3647
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dingli
authors.affiliation: Department of Mathematics, University of Minnesota, Minneapolis, MN.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Foo
authors.affiliation: Department of Industrial and Systems Engineering, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Kevin Zox
authors.initials: KZ
authors.lastname: Leder
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D020000:Decision Support Systems, Clinical; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods*; D004360:Drug Therapy, Computer-Assisted / Q000379:methods*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents