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Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia.

ABSTRACT: Decitabine's mechanism of action in chronic myelomonocytic leukemia remains incompletely understood. We studied the dynamics of neoplastic cell clearance during decitabine treatment (100 mg/m(2) per course every 4 weeks) using quantitative monitoring of mutant alleles by pyrosequencing. Patients with chronic myelomonocytic leukemia were first screened for JAK2 and NPM1 mutations, and 3 patients with mutations were identified. Mutant allele percentages in mononuclear cell DNA were followed after treatment, along with methylation of LINE1 and 10 other genes. The clearance of mutant alleles was modest after the first cycle, despite induction of hypomethylation. Delayed substantial clearance was observed after 2 to 4 cycles that correlated with clinical response. Two patients had complete disappearance of mutant alleles and sustained clinical remissions. In another patient, mutant allele was detectable at clinical remission, which lasted for 8 months. Our data suggest a predominantly noncytotoxic mechanism of action for decitabine, leading to altered biology of the neoplastic clone and/or normal cells. This trial was registered at www.ClinicalTrials.gov as #NCT00067808.

SUBMITTER: Oki Y

PROVIDER: S-EPMC2234065 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia.

Oki Yasuhiro Y Jelinek Jaroslav J Shen Lanlan L Kantarjian Hagop M HM Issa Jean-Pierre J JP

Blood 20071130 4

Decitabine's mechanism of action in chronic myelomonocytic leukemia remains incompletely understood. We studied the dynamics of neoplastic cell clearance during decitabine treatment (100 mg/m(2) per course every 4 weeks) using quantitative monitoring of mutant alleles by pyrosequencing. Patients with chronic myelomonocytic leukemia were first screened for JAK2 and NPM1 mutations, and 3 patients with mutations were identified. Mutant allele percentages in mononuclear cell DNA were followed after ...[more]

PMID: 18055864

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Project description:BackgroundHypomethylating agents (HMAs) have shown efficacy in the treatment of hematological malignancies and are indicated for the treatment of chronic myelomonocytic leukemia (CMML). While the HMA decitabine, in its intravenous formulation, has been used since 2006 for the treatment of CMML, use of its oral formulation has been limited by poor bioavailability due to first-pass metabolism by the enzyme cytidine deaminase. The dose of intravenous decitabine is limited by toxicities such as cardiomyopathy and heart failure. Therefore, cedazuridine was developed as an inhibitor of cytidine deaminase. Cedazuridine decreases the first-pass metabolism of oral decitabine allowing therapeutic levels to be achieved at lower doses, and thus, the novel oral combination of cedazuridine with decitabine was developed. While cardiomyopathy and heart failure are well-established adverse effects associated with intravenous decitabine alone, there to our knowledge there have been no documented incidences of reversible cardiomyopathy in the literature or in patients who participated in the phase 2 and phase 3 clinical trials of oral decitabine-cedazuridine.CaseThis case study presents an 85 year-old Caucasian female with CMML who developed cardiomyopathy and heart failure with reduced ejection fraction after completing 5 cycles of therapy with decitabine/cedazuridine. Furthermore, her symptoms and cardiac function recovered upon discontinuation of the drug.ConclusionsWe present an occurrence of reversible cardiomyopathy in a patient who completed 5 cycles of decitabine/cedazuridine, an oral combination therapy developed to enhance oral bioavailability of decitabine thereby limiting its adverse effects. As the decitabine/cedazuridine combination therapy rises in popularity due to its convenient oral formulation, more trials are needed to understand the prevalence of cardiomyopathy with this drug and to discover preventative strategies for cardiotoxic effects.

Dataset Information

Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia.

Publications

Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia.

Similar Datasets

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