Epigenetics in Clinical Practice: the Examples of Azacitidine and Decitabine in Myelodysplasia and Acute Myeloid Leukemia
Total Page：16
File Type：pdf, Size：1020Kb
Leukemia (2013) 27, 1803–1812 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu SPOTLIGHT REVIEW Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia EH Estey Randomized trials have clearly demonstrated that the hypomethylating agents azacitidine and decitabine are more effective than ‘best supportive care’(BSC) in reducing transfusion frequency in ‘low-risk’ myelodysplasia (MDS) and in prolonging survival compared with BSC or low-dose ara-C in ‘high-risk’ MDS or acute myeloid leukemia (AML) with 21–30% blasts. They also appear equivalent to conventional induction chemotherapy in AML with 420% blasts and as conditioning regimens before allogeneic transplant (hematopoietic cell transplant, HCT) in MDS. Although azacitidine or decitabine are thus the standard to which newer therapies should be compared, here we discuss whether the improvement they afford in overall survival is sufficient to warrant a designation as a standard in treating individual patients. We also discuss pre- and post-treatment covariates, including assays of methylation to predict response, different schedules of administration, combinations with other active agents and use in settings other than active disease, in particular post HCT. We note that rational development of this class of drugs awaits delineation of how much of their undoubted effect in fact results from hypomethylation and reactivation of gene expression. Leukemia (2013) 27, 1803–1812; doi:10.1038/leu.2013.173 Keywords: epigenetics; MDS; azacitidine; AML; decitabine; hypomethylating agents ‘Epigenetics’ refers to changes in gene expression occurring promoting genes. More direct evidence comes from findings without alterations in DNA sequence.1 For this paper, the relevant that AML blasts, particularly those obtained from patients with epigenetic events are DNA methylation and, to a less extent, secondary AML, have DNA methylation patterns distinct from histone modification.2 DNA methylation typically occurs at those seen in normal CD34 þ cells3 and that specific types of AML, the 50-position of cytosine in areas of the genome rich in for example, those associated with AML1-ETO, CBFb-MYH11, PML- CpG dinucleotides (CpG islands), results in silencing of gene RARa and mutated CEBPA or NPM1 have distinctive methylation expression and is fundamental to normal development. DNA patterns.4 Furthermore, an increase in aberrant DNA methylation methyltransferase 1 (DNMT1) maintains existing methylation was uniformly observed in 184 patients in whom MDS patterns following DNA replication, whereas DNMT3A and 3B ‘progressed’ to AML.5 The latter study did not include a group in methylate unmethylated CpGs. In contrast, members of the TET whom such progression did not occur and the above data are (‘10–11 translocation’) family of proteins remove methyl groups consistent with epigenetic changes as secondary, rather than from CpGs, a process requiring a-ketoglutarate, which is derived primary, events. However, experiments transferring leukemia from from isocitrate in a reaction catalyzed by isocitrate dehydrogenase mice with reduced DNMT1 activity suggest that constitutive 1 and 2. Histones undergo many post-translational modifications, methylation is needed for proper renewal of leukemia stem including acetylation (which increases gene expression), cells,6,7 thus suggesting that epigenetic alterations can be primary deacetylation, methylation and demethylation, with different events. SPOTLIGHT combinations of this ‘histone code’ leading, via chromatin Unlike genetic aberrations, epigenetic changes, are reversible, modification, to activation or repression of gene expression.1,2 prompting interest in drugs that affect the ‘epigenome’. The Relative to their normal counterparts, cancer cells generally ‘epigenetic drugs’ that have found widest use and which we will exhibit genome-wide hypomethylation and CpG island hyper- emphasize are the DNMT inhibitors azacitidine and decitabine. methylation.1 The former leads to the genetic instability Here we will first discuss their use in (a) lower-risk MDS and (b) characteristic of cancer, whereas the latter silences tumor higher-risk MDS and AML, recognizing the distinctive therapeutic suppressor genes. There is considerable evidence that abnormal goals in a and b. We will emphasize comparisons between these methylation has an important role in pathogenesis of acute drugs and other therapeutic options and discuss the possibility myeloid leukemia (AML) and myelodysplasia (MDS), the diseases that, although used essentially interchangeably, azacitidine and of interest to us here. Circumstantially, mutations in DNMT3a and decitabine may differ qualitatively. Concluding that neither drug is isocitrate dehydrogenase 1 and 2, and aberrations in the TET 2 on average satisfactory treatment, particularly for high-risk MDS or gene predicted to disturb its normal function, occur not AML, we will discuss means to predict response in individual infrequently in AML and MDS while many commonly observed patients. Of particular relevance, we will examine the strength of abnormal fusions of the mixed lineage leukemia gene affect the evidence that the undoubted clinical activity of DNMT histone methyl transferases presumably activating leukemia inhibitors and histone decateylase inhibitors results from their Division of Hematology, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, USA. Correspondence: Dr EH Estey, Division of Hematology, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, 825 Eastlake Ave East, G3-204, Seattle, WA 98109, USA. E-mail: [email protected] Received 24 April 2013; revised 24 May 2013; accepted 3 June 2013; accepted article preview online 12 July 2013; advance online publication, 23 July 2013 Epigenetics in clinical practice EH Estey 1804 undoubted epigenetic effects, as examining this hypothesis seems patients who received a median of six cycles (up to 32) after a fundamental to rational development of this class of drugs. Lastly, single 75 mg m À 2 dose of s.c. drug. Although, at its maximum we will discuss newer approaches to epigenetic therapy, involving tolerated dose (480 mg daily  7 days every 28 days) exposure to use (a) as post remission therapy, particularly after allogeneic oral azacitidine was less than with s.c. preparation (as was hematopoietic cell transplantation (HCT) (b) of different schedules hypomethylation), clinical activity was observed, which likely of administration, (c) of pharmacologically improved congeners of owed in part to the oral preparation, as responses are unusual decitabine and (d) of combinations with other active agents. after a single dose of s.c. azacitidine.16 More frequent dosing and/or more extended dosing are planned. Although initial studies with decitabine used a three times intravenous daily AZACITIDINE AND DECITABINE IN ‘LOWER-RISK’ MDS schedule, it appears that results are similar with a more By ‘risk’ I refer to overall survival (OS), the outcome of most convenient once daily 5-day schedule.17 interest to patients. Perhaps the most useful means to assess To date, there have been no randomized trials comparing these expected OS in MDS are the revised International Prognostic various means of administration. More striking is the absence of Scoring System (IPSS-R) based on an exceptionally large database randomized trials comparing azacitidine with decitabine, or either (7012 patients with untreated de novo MDS),8 the WPSS (World drug with lenalidomide, which has activity in MDS patients who Health Organization -based Prognostic Scoring System),9 which lack deletion of the long arm of chromosome 5q.18 Suggestion includes patients with secondary MDS and which addresses that the lack of a formal decitabine–azacitidine comparison may changes in prognosis over time, and the MD Anderson prognostic be more than an academic issue comes from an analysis, which, system for lower-risk MDS,10 which removes some such patients using propensity scoring to account for known prognostic factors from the lower-risk category. By lower-risk MDS, I mean an expected (such as age, blast percent, IPSS score and karyotype), found median OS of X3 years corresponding to the IPSS-R or WPSS superior survival (P ¼ 0.02) in patients aged X65 given azacitidine groups ‘very low’, ‘low’ and ‘intermediate’, and the MD Anderson rather than decitabine;19 it was not noted whether as seems category 1. It is generally accepted that the principal therapeutic likely this finding reflected results in the 40% of patients who goal in such patients is to decrease, particularly red blood cell (RBC), were higher risk. Such a finding may reflect observed differences 20,21 SPOTLIGHT transfusions, in the process improving ‘quality of life’. in the epigenetic effects of azacitidine and decitabine. Randomized trials have shown that azacitidine and decitabine Thus, regarding these drugs as interchangeable epigenetic or are superior to a transfusion-only approach (‘best supportive care’, hypomethylating agents may be an oversimplification. BSC) in this regard. RBC transfusion independence for X8 weeks was observed in 45% of 65 RBC transfusion-dependent patients randomized to subcutaneous (s.c.) azacitidine,11 and B35% of a AZACITIDINE AND DECITABINE IN HIGHER RISK MDS OR AML similar number of transfusion-dependent patients