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Journal ArticleDOI

Decitabine improves outcomes in older patients with acute myeloid leukemia and higher blast counts.

TL;DR: Hypomethylating agents such 5-azacytidine (AZA) and decitabine (DAC) have been used as “lower-intensity” therapy in older patients with AML and may be associated with outcomes similar to intensive therapy.
Abstract: The median age at diagnosis of patients with acute myeloid leukemia (AML) is 66 years, and most patients are > 60 years of age.[1] Due to comorbidities and adverse-risk disease, many older patients may not benefit from intensive chemotherapy.[2, 3] Hypomethylating agents such 5-azacytidine (AZA) and decitabine (DAC) have been used as “lower-intensity” therapy in older patients with AML and may be associated with outcomes similar to intensive therapy.[4, 5] In a post-hoc analysis of a randomized phase III trial of AZA vs. conventional care regimens (CCR) in patients with higher-risk myelodysplastic syndrome (MDS) and 20–30% blasts, AZA produced a response rate of 18% and was associated with an improvement in overall survival (OS) compared to CCR (24.5 vs. 16 months, p=0.001).[6] Subsequent reports have confirmed the activity of AZA in older patients with AML and in those unfit for intensive chemotherapy.[4, 7–9]
Citations
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Journal ArticleDOI
13 May 2017-Genes
TL;DR: The current understanding of how MYC regulates chromatin structure in both a site-specific and genome-wide fashion is outlined, and the implications for therapeutic strategies for cancers with high MYC expression are highlighted.
Abstract: Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC's influence on many of these target genes is rather modest and there is little overlap between MYC regulated genes in different cell types, leaving many mechanistic questions unanswered. Recent advances in the field challenge the dogma further, revealing a role for MYC that extends beyond the traditional concept of a sequence-specific transcription factor. In this article, we review MYC's function as a regulator of the cancer epigenome and transcriptome. We outline our current understanding of how MYC regulates chromatin structure in both a site-specific and genome-wide fashion, and highlight the implications for therapeutic strategies for cancers with high MYC expression.

100 citations

Journal ArticleDOI
TL;DR: A literature search was performed using PubMed to find recent major publications, which provide biological and clinical research about epigenetic therapy in AML patients, and some of them, such as AZA plus venetoclax, already show promising results.
Abstract: INTRODUCTION The majority of patients with acute myeloid leukemia (AML) are older and exhibit a poor prognosis even after intensive therapy. Inducing differentiation and apoptosis of leukemic blasts by DNA-hypomethylating agents, like e.g. azacytidine (AZA) and decitabine (DAC), represent well-tolerated alternative treatment approaches. Both agents show convincing response as single agents in AML. However, there is a lack of knowledge regarding molecular mechanisms and predictive biomarkers for these agents. Areas covered: This review will (i) provide an overview of the current knowledge of molecular mechanisms underlying the action of these drugs, (ii) report promising predictive biomarkers, (iii) elude on new combined treatment options, and (iv) discuss novel approaches to improve outcomes. A literature search was performed using PubMed to find recent major publications, which provide biological and clinical research about epigenetic therapy in AML patients. Expert commentary: Numerous studies have demonstrated that HMA therapy with AZA or DAC may lead to significant response rates, even in pre-treated patients. Nevertheless, there is still an unmet need to further improve outcome in elderly AML patients. Therefore, novel treatment combinations are needed and some of them, such as AZA plus venetoclax, already show promising results.

70 citations

Journal ArticleDOI
TL;DR: Some of the most advanced and promising compounds that are currently in clinical trials and may have the potential to be part of the future armamentarium for acute myeloid leukemia are reviewed.

67 citations


Cites background from "Decitabine improves outcomes in old..."

  • ...Both 5-azacytidine and decitabine have also been shown to be effective in older patients with higher blast count AML and associated with a survival benefit when compared with conventional therapy [32, 33]....

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Journal ArticleDOI
TL;DR: The role of bone marrow evaluation and peripheral blood monitoring in the diagnosis, management, and follow up of AML patients is discussed.

62 citations

Journal ArticleDOI
TL;DR: Using as single agents, hypomethylating agents (HMAs) induce only 15 to 25% complete remissions, but current data suggest that median OS observed after HMAs is comparable to that observed after more intensive therapies, suggesting long-term cure may be obtained in some patients treated with HMAs.
Abstract: Acute myeloid leukemia (AML) is predominantly a disease of older adults associated with poor long-term outcomes with available therapies. Used as single agents, hypomethylating agents (HMAs) induce only 15 to 25% complete remissions, but current data suggest that median OS observed after HMAs is comparable to that observed after more intensive therapies. Whether long-term cure may be obtained in some patients treated with HMAs is unknown. Combinations of HMAs to novel agents are now extensively investigated and attractive response rates have been reported when combining HMAs to different drug classes. The absence of reliable predictive biomarkers of efficacy of HMAs in AML and the uncertainties regarding their most relevant mechanisms of action hinder the rational design of the combinations to be tested in priority, usually in untreated older AML patients.

43 citations

References
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Journal ArticleDOI
TL;DR: The magnitude of the decline in cancer death rates from 1991 to 2010 varies substantially by age, race, and sex, ranging from no decline among white women aged 80 years and older to a 55% decline among black men aged 40 years to 49 years.
Abstract: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data were collected by the National Center for Health Statistics. A total of 1,665,540 new cancer cases and 585,720 cancer deaths are projected to occur in the United States in 2014. During the most recent 5 years for which there are data (2006-2010), delay-adjusted cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.4% per year in women. The combined cancer death rate (deaths per 100,000 population) has been continuously declining for 2 decades, from a peak of 215.1 in 1991 to 171.8 in 2010. This 20% decline translates to the avoidance of approximately 1,340,400 cancer deaths (952,700 among men and 387,700 among women) during this time period. The magnitude of the decline in cancer death rates from 1991 to 2010 varies substantially by age, race, and sex, ranging from no decline among white women aged 80 years and older to a 55% decline among black men aged 40 years to 49 years. Notably, black men experienced the largest drop within every 10-year age group. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population.

10,829 citations

Journal ArticleDOI
TL;DR: In older patients with AML, decitabine improved response rates compared with standard therapies without major differences in safety, and an unplanned survival analysis showed a benefit for decit abine, which was not observed at the time of the primary analysis.
Abstract: Purpose This multicenter, randomized, open-label, phase III trial compared the efficacy and safety of decitabine with treatment choice (TC) in older patients with newly diagnosed acute myeloid leukemia (AML) and poor- or intermediate-risk cytogenetics. Patients and Methods Patients (N = 485) age ≥ 65 years were randomly assigned 1:1 to receive decitabine 20 mg/m2 per day as a 1-hour intravenous infusion for five consecutive days every 4 weeks or TC (supportive care or cytarabine 20 mg/m2 per day as a subcutaneous injection for 10 consecutive days every 4 weeks). The primary end point was overall survival (OS); the secondary end point was the complete remission (CR) rate plus the CR rate without platelet recovery (CRp). Adverse events (AEs) were recorded. Results The primary analysis with 396 deaths (81.6%) showed a nonsignificant increase in median OS with decitabine (7.7 months; 95% CI, 6.2 to 9.2) versus TC (5.0 months; 95% CI, 4.3 to 6.3; P = .108; hazard ratio [HR], 0.85; 95% CI, 0.69 to 1.04). An unp...

942 citations


"Decitabine improves outcomes in old..." refers background in this paper

  • ...Since the DACO-016 trial [11] provided a prospective, randomized data set in older patients with AML, we sought to examine the efficacy of DAC in patients with higher...

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  • ...DAC was studied in a randomized phase III trial (DACO-016) compared to treatment choice (TC: SC or LDAC) in older patients with newly diagnosed AML [11]....

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Journal ArticleDOI
TL;DR: In older adult patients with low marrow blast count (20% to 30%) WHO-defined AML, azacitidine significantly prolongs OS and significantly improves several patient morbidity measures compared with CCR.
Abstract: Purpose In a phase III randomized trial, azacitidine significantly prolonged overall survival (OS) compared with conventional care regimens (CCRs) in patients with intermediate-2– and high-risk myelodysplastic syndromes. Approximately one third of these patients were classified as having acute myeloid leukemia (AML) under current WHO criteria. This analysis compared the effects of azacitidine versus CCR on OS in this subgroup. Patients and Methods Patients were randomly assigned to receive subcutaneous azacitidine 75 mg/m 2 /d or CCR (best supportive care [BSC] only, low-dose cytarabine (LDAC), or intensive chemotherapy [IC]). Results Of the 113 elderly patients (median age, 70 years) randomly assigned to receive azacitidine (n 55) or CCR (n 58; 47% BSC, 34% LDAC, 19% IC), 86% were considered unfit for IC. At a median follow-up of 20.1 months, median OS for azacitidine-treated patients was 24.5 months compared with 16.0 months for CCR-treated patients (hazard ratio 0.47; 95% CI, 0.28 to 0.79; P .005), and 2-year OS rates were 50% and 16%, respectively (P .001). Two-year OS rates were higher with azacitidine versus CCR in patients considered unfit for IC (P .0003). Azacitidine was associated with fewer total days in hospital (P .0001) than CCR. Conclusion In older adult patients with low marrow blast count (20% to 30%) WHO-defined AML, azacitidine significantly prolongs OS and significantly improves several patient morbidity measures compared with CCR.

866 citations


"Decitabine improves outcomes in old..." refers result in this paper

  • ...This rate of progression and incidence of new cases are less much than has been reported in a previous study of Kuwaiti SCD patients, not on HU, over a similar span of time [6]....

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Journal ArticleDOI
01 Mar 2006-Cancer
TL;DR: The aim was to develop prognostic models for complete response (CR), induction (8‐week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated.
Abstract: BACKGROUND Elderly patients (age ≥ 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML-type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I–II studies, low-intensity regimens, or ‘targeted’ therapies. However, baseline expectations for outcomes of elderly AML with ‘standard’ AML-type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8-week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated. METHODS A total of 998 patients age ≥ 65 years with AML or high-risk myelodysplastic syndrome (> 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors associated with CR, induction (8-week) mortality, and survival used standard methods. RESULTS The overall CR rate was 45% and induction mortality 29%. Multivariate analysis of prognostic factors identified consistent independent poor prognostic factors for CR, 8-week mortality, and survival. These included age ≥ 75 years, unfavorable karyotypes (often complex), poor performance (3–4 ECOG [Eastern Cooperative Oncology Group]), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates of 10%, and 1-year survival rates above 50%; 2) an intermediate group (about 50–55% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1-year survival rates of 30%; and 3) an unfavorable risk group (about 25–30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1-year survival rates of less than 10%. CONCLUSIONS Prognostic models, based on standard readily available baseline characteristics, were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions. These predictive models, based on a retrospective analysis, will require validation in independent study groups. Cancer 2006. © 2006 American Cancer Society.

559 citations

Journal ArticleDOI
TL;DR: Decitabine given in a low-dose, 5-day regimen has activity as upfront therapy in older patients with AML, and it has acceptable toxicity and 30-day mortality.
Abstract: Purpose Older patients with acute myeloid leukemia (AML) have limited treatment options because of the lack of effectiveness and the toxicity of available therapies. We investigated the efficacy and toxicity of the hypomethylating agent decitabine as initial therapy in older patients with AML. Patients and Methods In this multicenter, phase II study, patients older than 60 years who had AML (ie, > 20% bone marrow blasts) and no prior therapy for AML were treated with decitabine 20 mg/m2 intravenously for 5 consecutive days of a 4-week cycle. Response was assessed by weekly CBC and bone marrow biopsy after cycle 2 and after each subsequent cycle. Patients continued to receive decitabine until disease progression or an unacceptable adverse event occurred. Results Fifty-five patients (mean age, 74 years) were enrolled and were treated with a median of three cycles (range, one to 25 cycles) of decitabine. The expert-reviewed overall response rate was 25% (complete response rate, 24%). The response rate was co...

423 citations

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