Azacitidine in CMML: Matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival

Pleyer, Lisa; Germing, Ulrich; Sperr, Wolfgang R.; Linkesch, Werner; Burgstaller, Sonja; Stauder, Reinhard; Girschikofsky, Michael; Schreder, Martin; Pfeilstöcker, Michael; Lang, Alois; Sliwa, Thamer; Geissler, Dietmar; Schlick, Konstantin; Placher-Sorko, Gudrun; Theiler, Georg; Thaler, Josef; Mitrovic, Martina; Neureiter, Daniel; Valent, Peter; Greil, Richard

doi:10.1016/j.leukres.2014.01.006

Cited by 61 publications

(54 citation statements)

References 34 publications

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“…Half of the treated patients were still alive after 2 years in comparison with only 16% in the conventional care regimen group (Fenaux et al, 2010). These results were recently confirmed by Pleyer et al, who showed that 62% of a group of 48 elderly patients (mean 71 years old) survived for 2 years after 5-azaC treatment (Pleyer et al, 2014).Decitabine is clinically effective for the treatment of MDS, and was shown to improve time to AML transformation or death. Indeed, patients treated with Decitabine had a greater median time to AML transformation or death (4.3 months) than patients receiving supportive care alone (Kantarjian et al, 2012).…”

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confidence: 63%

DNA demethylation and invasive cancer: implications for therapeutics

Cheishvili

Boureau

Szyf

2015

British J Pharmacology

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One of the hallmarks of cancer is aberrant DNA methylation, which is associated with abnormal gene expression. Both hypermethylation and silencing of tumour suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. As DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumour suppressor genes. Two cytosine analogues, 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine, were approved by the Food and Drug Administration as antitumour agents in 2004 and 2006 respectively. However, these agents might cause activation of a panel of prometastatic genes in addition to activating tumour suppressor genes, which might lead to increased metastasis. This poses the challenge of how to target tumour suppressor genes and block cancer growth with DNA-demethylating drugs while avoiding the activation of prometastatic genes and precluding the morbidity of cancer metastasis. This paper reviews current progress in using DNA methylation inhibitors in cancer therapy and the potential promise and challenges ahead. LINKED ARTICLESThis article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-11 Abbreviations 5-azaC, 5-azacytidine; 5-azadC, 5-aza-2′-deoxycytidine; FDA, Food and Drug Administration; HDAC, histone deacetylase; SAH, S-adenosyl-homocysteine; SAHA, suberoylanilide hydroxamic acid; SAM, S-adenosyl-methionine Tables of Links DNA methylation overviewDNA methylation is an enzymatically catalysed covalent modification of DNA, occurring typically in the context of cytosine-phosphate-guanine (CpG) dinucleotides. In general, regions with high CpG content, named CpG islands, are demethylated in normal cells, whereas regions with an intermediate or low density of CpGs are differentially methylated in some tissues, but not in others (Bird et al., 1985). Although rarely observed, non-CpG methylation is mainly found in embryonic stem cells (Lister et al., 2009), but its function needs to be further explored. However, non-CpG methylation is abundant in adult brains, and recent data suggest that it plays a role in silencing promoter activity similar to CpG methylation (Guo et al., 2013;Lister et al., 2013). DNA methyltransferases (DNMTs) catalyse the transfer of a methyl group from its donor S-adenosine-methionine (SAM) to the cytosine nucleotide of DNA. Three distinct phylogenic DNMTs were identified in mammals. DNMT1 is a maintenance DNMT, which shows preference for hemimethylated DNA in vitro and faithfully copies DNA methylation in a cytosine-guanine (CG) palindromic dinucleotide from the parental strand to the daughter strand during cell division (Zucker et al., 1985;Flynn et al., 1996;Pradhan et al., 1999;Fatemi et al., 2001). DNMT3a and DNMT3b methylate unmethylated and hemimethylated DNA at an equal rate, which is consistent with a de novo methylation function (Okano et ...

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confidence: 63%

DNA demethylation and invasive cancer: implications for therapeutics

Cheishvili

Boureau

Szyf

2015

British J Pharmacology

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“…Registry design, data collection and monitoring, as well as assessment of efficacy, safety and endpoints within the Austrian Azacitidine Registry were performed as previously described [8, 15]. …”

Section: Patients Design and Methodsmentioning

confidence: 99%

Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group

et al. 2014

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Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n = 302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20–30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53–10.7) months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-014-2126-9) contains supplementary material, which is available to authorized users.

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“…Median overall survival ranged between 12 and 37 months. 106,[110][111][112] AZA is licensed for nonproliferative CMML-2 in many countries; DAC is licensed in the United States only. These drugs are globally well tolerated, with myelosuppression being the major toxicity.…”

Section: Hmasmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 109/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 109/L) and proliferative (white blood cell count ≥13 × 109/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient’s quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.

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Azacitidine in CMML: Matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival

Cited by 61 publications

References 34 publications

DNA demethylation and invasive cancer: implications for therapeutics

DNA demethylation and invasive cancer: implications for therapeutics

Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group

How I treat chronic myelomonocytic leukemia

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