Association between early promoter-specific DNA methylation changes and outcome in older acute myeloid leukemia patients

Highlights • Very early peripheral blood promoter demethylation of some genes predict response. • Global DNA methylation decreased by one month in older AML patients on treatment. • Early methylation tests could help determine appropriate older AML therapy choice.

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Published in	Leukemia research Vol. 42; pp. 68 - 74
Main Authors	Achille, Nicholas J, Othus, Megan, Phelan, Kathleen, Zhang, Shubin, Cooper, Kathrine, Godwin, John E, Appelbaum, Frederick R, Radich, Jerald P, Erba, Harry P, Nand, Sucha, Zeleznik-Le, Nancy J
Format	Journal Article
Language	English
Published	England Elsevier Ltd 01.03.2016
Subjects	Aged Aminoglycosides - administration & dosage Aminoglycosides - adverse effects AML Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Azacitidine - administration & dosage Azacitidine - adverse effects Decitabine DNA methylation DNA Methylation - genetics Elderly Enzyme-Linked Immunosorbent Assay Female Hematology, Oncology and Palliative Medicine Humans Hydroxyurea - administration & dosage Hydroxyurea - adverse effects Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Male Middle Aged Prognosis Prognostic Promoter Regions, Genetic - genetics Real-Time Polymerase Chain Reaction Risk Factors Transcriptome Treatment Outcome AML DNA methylation Decitabine Elderly Prognostic
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Abstract	Highlights • Very early peripheral blood promoter demethylation of some genes predict response. • Global DNA methylation decreased by one month in older AML patients on treatment. • Early methylation tests could help determine appropriate older AML therapy choice.
AbstractList	Highlights • Very early peripheral blood promoter demethylation of some genes predict response. • Global DNA methylation decreased by one month in older AML patients on treatment. • Early methylation tests could help determine appropriate older AML therapy choice. Treatment options for older patients with acute myeloid leukemia (AML) range from supportive care alone to full-dose chemotherapy. Identifying factors that predict response to therapy may help increase efficacy and avoid toxicity. The phase II SWOG S0703 study investigated the use of hydroxyurea and azacitidine with gemtuzumab ozogamicin in the elderly AML population and found survival rates similar to those expected with standard AML regimens, with less toxicity. As part of this study, global DNA methylation along with promoter DNA methylation and expression analysis of six candidate genes (CDKN2A, CDKN2B, HIC1, RARB, CDH1 and APAF1) were determined before and during therapy to investigate whether very early changes are prognostic for clinical response. Global DNA methylation was not associated with a clinical response. Samples after 3 or 4 days of treatment with azacitidine showed significantly decreased CDKN2A promoter DNA methylation in patients achieving complete remission (CR) compared to those who did not. Samples from day 7 of treatment showed significantly decreased RARB, CDKN2B and CDH1 promoter DNA methylation in responders compared to nonresponders. Gene-specific DNA methylation analysis of peripheral blood samples may help early identification of those older AML patients most likely to benefit from demethylating agent therapy. •Very early peripheral blood promoter demethylation of some genes predict response.•Global DNA methylation decreased by one month in older AML patients on treatment.•Early methylation tests could help determine appropriate older AML therapy choice. Treatment options for older patients with acute myeloid leukemia (AML) range from supportive care alone to full-dose chemotherapy. Identifying factors that predict response to therapy may help increase efficacy and avoid toxicity. The phase II SWOG S0703 study investigated the use of hydroxyurea and azacitidine with gemtuzumab ozogamicin in the elderly AML population and found survival rates similar to those expected with standard AML regimens, with less toxicity. As part of this study, global DNA methylation along with promoter DNA methylation and expression analysis of six candidate genes (CDKN2A, CDKN2B, HIC1, RARB, CDH1 and APAF1) were determined before and during therapy to investigate whether very early changes are prognostic for clinical response. Global DNA methylation was not associated with a clinical response. Samples after 3 or 4 days of treatment with azacitidine showed significantly decreased CDKN2A promoter DNA methylation in patients achieving complete remission (CR) compared to those who did not. Samples from day 7 of treatment showed significantly decreased RARB, CDKN2B and CDH1 promoter DNA methylation in responders compared to nonresponders. Gene-specific DNA methylation analysis of peripheral blood samples may help early identification of those older AML patients most likely to benefit from demethylating agent therapy. Treatment options for older patients with acute myeloid leukemia (AML) range from supportive care alone to full-dose chemotherapy. Identifying factors that predict response to therapy may help increase efficacy and avoid toxicity. The phase II SWOG S0703 study investigated the use of hydroxyurea and azacitidine with gemtuzumab ozogamicin in the elderly AML population and found survival rates similar to those expected with standard AML regimens, with less toxicity. As part of this study, global DNA methylation along with promoter DNA methylation and expression analysis of six candidate genes ( CDKN2A, CDKN2B, HIC1, RARB, CDH1 and APAF1 ) were determined before and during therapy to investigate whether very early changes are prognostic for clinical response. Global DNA methylation was not associated with a clinical response. Samples after 3 or 4 days of treatment with azacitidine showed significantly decreased CDKN2A promoter DNA methylation in patients achieving complete remission (CR) compared to those who did not. Samples from day 7 of treatment showed significantly decreased RARB, CDKN2B and CDH1 promoter DNA methylation in responders compared to nonresponders. Gene-specific DNA methylation analysis of peripheral blood samples may help early identification of those older AML patients most likely to benefit from demethylating agent therapy.
Author	Achille, Nicholas J Zeleznik-Le, Nancy J Othus, Megan Phelan, Kathleen Cooper, Kathrine Godwin, John E Erba, Harry P Nand, Sucha Appelbaum, Frederick R Radich, Jerald P Zhang, Shubin
AuthorAffiliation	b SWOC Statistical Center, Seattle, WA 98109, United States a Oncology Research Institute, Loyola University Health Sciences Division, Maywood, IL 60153, United States e Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States c Division of Hematology & Oncology, Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, United States f Division of Hematology & Oncology, Department of Medicine, University of Alabama, Birmingham, AL 35294, United States d Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR 97213, United States
AuthorAffiliation_xml	– name: f Division of Hematology & Oncology, Department of Medicine, University of Alabama, Birmingham, AL 35294, United States – name: c Division of Hematology & Oncology, Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, United States – name: e Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States – name: d Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR 97213, United States – name: a Oncology Research Institute, Loyola University Health Sciences Division, Maywood, IL 60153, United States – name: b SWOC Statistical Center, Seattle, WA 98109, United States
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Snippet	Highlights • Very early peripheral blood promoter demethylation of some genes predict response. • Global DNA methylation decreased by one month in older AML... •Very early peripheral blood promoter demethylation of some genes predict response.•Global DNA methylation decreased by one month in older AML patients on... Treatment options for older patients with acute myeloid leukemia (AML) range from supportive care alone to full-dose chemotherapy. Identifying factors that...
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SubjectTerms	Aged Aminoglycosides - administration & dosage Aminoglycosides - adverse effects AML Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Azacitidine - administration & dosage Azacitidine - adverse effects Decitabine DNA methylation DNA Methylation - genetics Elderly Enzyme-Linked Immunosorbent Assay Female Hematology, Oncology and Palliative Medicine Humans Hydroxyurea - administration & dosage Hydroxyurea - adverse effects Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Male Middle Aged Prognosis Prognostic Promoter Regions, Genetic - genetics Real-Time Polymerase Chain Reaction Risk Factors Transcriptome Treatment Outcome
Title	Association between early promoter-specific DNA methylation changes and outcome in older acute myeloid leukemia patients
URI	https://www.clinicalkey.es/playcontent/1-s2.0-S0145212616300042 https://dx.doi.org/10.1016/j.leukres.2016.01.004 https://www.ncbi.nlm.nih.gov/pubmed/26818573 https://search.proquest.com/docview/1770878394 https://search.proquest.com/docview/1790948185 https://pubmed.ncbi.nlm.nih.gov/PMC4779662
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