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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.

SUBMITTER: He Q

PROVIDER: S-EPMC5072565 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Optimized Treatment Schedules for Chronic Myeloid Leukemia.

He Qie Q Zhu Junfeng J Dingli David D Foo Jasmine J Leder Kevin Zox KZ

PLoS computational biology 20161020 10

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 ...[more]

PMID: 27764087

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Project description:The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.

Dataset Information

Optimized Treatment Schedules for Chronic Myeloid Leukemia.

Publications

Optimized Treatment Schedules for Chronic Myeloid Leukemia.

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