Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia

Epigenetic therapies demonstrate significant clinical activity in acute myeloid leukemia (AML) and myelodysplasia (MDS) and constitute an important new class of therapeutic agents. However hematological responses are not durable and disease relapse appears inevitable. Experimentally, leukemic stem/p...

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Bibliographic Details
Published in:	Leukemia Vol. 27; no. 5; pp. 1028 - 1036
Main Authors:	Craddock, C, Quek, L, Goardon, N, Freeman, S, Siddique, S, Raghavan, M, Aztberger, A, Schuh, A, Grimwade, D, Ivey, A, Virgo, P, Hills, R, McSkeane, T, Arrazi, J, Knapper, S, Brookes, C, Davies, B, Price, A, Wall, K, Griffiths, M, Cavenagh, J, Majeti, R, Weissman, I, Burnett, A, Vyas, P
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-05-2013 Nature Publishing Group
Subjects:	692/699/67/1059 692/699/67/1990/1673 692/699/67/1990/283/1897 692/699/67/71 Acute myeloid leukemia Adult Aged Aged, 80 and over Animal diseases Animal models Antimetabolites, Antineoplastic - pharmacology Azacitidine - pharmacology Biomarkers Cancer Research Cells (biology) Chemical compounds Chemotherapy Critical Care Medicine Disease resistance Drug therapy Epigenetics Female Genetic aspects Granulocytes Hematology Hospitals Humans Immunology Immunophenotyping Induction Chemotherapy Intensive Internal Medicine Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - mortality Leukemia, Myeloid, Acute - pathology Male Medicine Medicine & Public Health Middle Aged Morphology Myelodysplastic syndrome Myelodysplastic syndromes Myelodysplastic Syndromes - drug therapy Myelodysplastic Syndromes - mortality Myelodysplastic Syndromes - pathology Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - immunology Oncology original-article Patients Pharmacology Population Progenitor cells Prognosis Quantitation Remission Remission (Medicine) Sodium valproate Stem cells Valproic acid United Kingdom United Kingdom > UK leukemic stem cell myelodysplasia acute myeloid leukemia epigenetic therapies azacitidine disease relapse
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Summary:	Epigenetic therapies demonstrate significant clinical activity in acute myeloid leukemia (AML) and myelodysplasia (MDS) and constitute an important new class of therapeutic agents. However hematological responses are not durable and disease relapse appears inevitable. Experimentally, leukemic stem/progenitor cells (LSC) propagate disease in animal models of AML and it has been postulated that their relative chemo-resistance contributes to disease relapse. We serially measured LSC numbers in patients with high-risk AML and MDS treated with 5'-azacitidine and sodium valproate (VAL–AZA). Fifteen out of seventy-nine patients achieved a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) with VAL–AZA therapy. There was no significant reduction in the size of the LSC-containing population in non-responders. While the LSC-containing population was substantially reduced in all patients achieving a CR/CRi it was never eradicated and expansion of this population antedated morphological relapse. Similar studies were performed in seven patients with newly diagnosed AML treated with induction chemotherapy. Eradication of the LSC-containing population was observed in three patients all of whom achieved a durable CR in contrast to patients with resistant disease where LSC persistence was observed. LSC quantitation provides a novel biomarker of disease response and relapse in patients with AML treated with epigenetic therapies. New drugs that target this cellular population in vivo are required.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0887-6924 1476-5551
DOI:	10.1038/leu.2012.312