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The Lancet. Oncology Mar 2009Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on... (Comparative Study)
Comparative Study Randomized Controlled Trial
Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.
BACKGROUND
Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens.
METHODS
In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799.
FINDINGS
Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments.
INTERPRETATION
Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Azacitidine; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models
PubMed: 19230772
DOI: 10.1016/S1470-2045(09)70003-8 -
Clinical and Translational Science Aug 2023Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute... (Review)
Review
Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute myeloid leukemia, there remain unanswered questions about DNMTi's mechanism of action and predictors of clinical response. Because patients often remain on single-agent DNMTis or DNMTi-containing regimens for several months before knowing whether clinical benefit can be achieved, the development and clinical validation of response-predictive biomarkers represents an important unmet need in oncology. In this review, we will summarize the clinical studies that led to the approval of azacitidine and decitabine, as well as the real-world experience with these drugs. We will then focus on biomarker development for DNMTis-specifically, efforts at determining exposure-response relationships and challenges that remain impacting the broader clinical translation of these methods. We will highlight recent progress in liquid-chromatography tandem mass spectrometry technology that has allowed for the simultaneous measurement of decitabine genomic incorporation and global DNA methylation, which has significant potential as a mechanism-of-action based biomarker in patients on DNMTis. Last, we will cover important research questions that need to be addressed in order to optimize this potential biomarker for clinical use.
Topics: Humans; Decitabine; Azacitidine; Enzyme Inhibitors; Leukemia, Myeloid, Acute; DNA Methylation; DNA; Methyltransferases
PubMed: 37345219
DOI: 10.1111/cts.13548 -
Cells Aug 2022The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although... (Review)
Review
The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms of action; decitabine interferes primarily with the methylation of DNA and azacytidine with that of RNA. Here, we examine the role of DNA methylation in the lineage commitment of stem cells during normal hematopoiesis and consider how mutations in epigenetic regulators such as and can lead to clonal expansion and subsequent neoplastic progression. We also consider why the efficacy of azanucleoside treatment is not limited to neoplasias carrying mutations in epigenetic regulators. Finally, we summarise recent data describing a role for azacytidine-sensitive RNA methylation in lineage commitment and in the cellular response to stress. By summarising and interpreting evidence for azanucleoside involvement in a range of cellular processes, our review is intended to illustrate the need to consider multiple modes of action in the design and stratification of future combination therapies.
Topics: Azacitidine; DNA Methylation; Decitabine; Myeloid Cells; RNA
PubMed: 36010665
DOI: 10.3390/cells11162589 -
BMJ Case Reports Oct 2020We present a case of azacitidine-induced pneumonitis which is a rare adverse drug reaction and reported in less than 0.1% of cases. Common side effects of azacitidine... (Review)
Review
We present a case of azacitidine-induced pneumonitis which is a rare adverse drug reaction and reported in less than 0.1% of cases. Common side effects of azacitidine are weakness, nausea, vomiting, constipation, injection site reactions, insomnia, among others. Our patient received azacitidine to treat her acute myeloid leukaemia and began to develop shortness of breath which progressed to dyspnoea at rest after completing a 7-day course of azacitidine and venetoclax. Initial chest X-ray revealed severe airspace disease for which the patient began receiving broad spectrum antibiotics, antifungals and antivirals therapy. Although infectious workup revealed invasive aspergillosis she did not clinically and radiologically improve despite being on isavuconazole until high-dose glucocorticoids were initiated. This case illustrates the importance of recognising and understanding the potential side effects of azacitidine and other chemotherapy agents as some adverse drug reactions can be life-threatening.
Topics: Aged; Azacitidine; Enzyme Inhibitors; Female; Humans; Invasive Fungal Infections; Lung; Pneumonia; Radiography, Thoracic; Tomography, X-Ray Computed
PubMed: 33122228
DOI: 10.1136/bcr-2020-236349 -
Cold Spring Harbor Perspectives in... May 2017Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to... (Review)
Review
Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in clinical trials. This review will summarize preclinical and clinical data on DNA hypomethylating drugs as a cancer therapy.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Clinical Trials as Topic; DNA Demethylation; Decitabine; Humans; Neoplasms; Tumor Microenvironment
PubMed: 28159832
DOI: 10.1101/cshperspect.a026948 -
Blood Feb 2013The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and...
The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and Holland reported hematologic improvement in patients with myelodysplastic syndrome (MDS) in 1993. That azacitidine improves survival in patients with high-risk MDS and acute myeloid leukemia with MDS features compared with a combined comparator group of supportive care, low-dose cytarabine, and intensive cytarabine plus anthracycline, while inducing trilineage normalization in approximately 15% of patients makes the development of more potent, more specific drugs that behave like azacitidine imperative. The question is, how do the azanucleosides behave?
Topics: Animals; Azacitidine; Decitabine; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute
PubMed: 23449614
DOI: 10.1182/blood-2013-02-483735 -
Journal of Clinical Oncology : Official... Jul 2012This multicenter, randomized, open-label, phase III trial compared the efficacy and safety of decitabine with treatment choice (TC) in older patients with newly... (Comparative Study)
Comparative Study Randomized Controlled Trial
Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
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/m(2) per day as a 1-hour intravenous infusion for five consecutive days every 4 weeks or TC (supportive care or cytarabine 20 mg/m(2) 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 unplanned analysis with 446 deaths (92%) indicated the same median OS (HR, 0.82; 95% CI, 0.68 to 0.99; nominal P = .037). The CR rate plus CRp was 17.8% with decitabine versus 7.8% with TC (odds ratio, 2.5; 95% CI, 1.4 to 4.8; P = .001). AEs were similar for decitabine and cytarabine, although patients received a median of four cycles of decitabine versus two cycles of TC. The most common drug-related AEs with decitabine were thrombocytopenia (27%) and neutropenia (24%).
CONCLUSION
In older patients with AML, decitabine improved response rates compared with standard therapies without major differences in safety. An unplanned survival analysis showed a benefit for decitabine, which was not observed at the time of the primary analysis.
Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Azacitidine; Choice Behavior; Cytarabine; Decision Making; Decitabine; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Neutropenia; Palliative Care; Patient Participation; Remission Induction; Risk Assessment; Risk Factors; Thrombocytopenia; Treatment Outcome
PubMed: 22689805
DOI: 10.1200/JCO.2011.38.9429 -
Leukemia Jan 2024Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and...
Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce leukemic burden in a subset of JMML patients. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since RAS signaling is known to interfere with the intrinsic apoptosis pathway, we combined various BH3 mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both MCL-1 and BCL-X for survival, and that these proteins can be effectively targeted by azacitidine and BH3 mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic MCL-1 and upregulation of proapoptotic BH3-only. The combination of azacitidine with BCL-X inhibition was superior to BCL-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable MCL-1 or BCL-X inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy.
Topics: Humans; Child, Preschool; Azacitidine; Leukemia, Myelomonocytic, Juvenile; Myeloid Cell Leukemia Sequence 1 Protein; bcl-X Protein; Apoptosis; Cell Line, Tumor
PubMed: 37945692
DOI: 10.1038/s41375-023-02079-5 -
IARC Monographs on the Evaluation of... 1990
Review
Topics: Animals; Azacitidine; Carcinogens; Female; Humans; Male; Molecular Structure; Pregnancy
PubMed: 1705587
DOI: No ID Found -
Current Oncology Reports Nov 2022Treatment of elderly patients with acute myeloid leukemia is a known challenge for hematologists due to patient diversity, heterogeneous disease biology, and a rapidly... (Review)
Review
PURPOSE OF REVIEW
Treatment of elderly patients with acute myeloid leukemia is a known challenge for hematologists due to patient diversity, heterogeneous disease biology, and a rapidly evolving treatment landscape. Here, we highlight the importance of determining fitness, review the latest therapeutic developments, and discuss clinical scenarios to provide guidance on individualized treatment for older AML patients.
RECENT FINDINGS
Several factors, like age, performance status, and comorbidities, play a role in fitness and are associated with outcome. Comorbidity scoring systems and geriatric assessments are tools to help physicians select the most appropriate treatment for each patient. The addition of venetoclax, targeted therapy with IDH1/2 and FLT3 inhibitors, and enhanced formulas of existing drugs like CPX-351 and oral azacitidine have improved responses and outcomes. New drugs and combination therapies have increased the therapeutic options for elderly AML patients but determination of fitness and disease biology is essential to select patient-tailored treatments.
Topics: Humans; Aged; Leukemia, Myeloid, Acute; Protein Kinase Inhibitors; Azacitidine
PubMed: 35653050
DOI: 10.1007/s11912-022-01299-9