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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
Open accessAbstract
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.
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“Hypomethylating agents (HMAs), such as azacitidine and decitabine, yield statistically similar complete remission (CR) rates of approximately 15%-20% in patients with either TP53-mutant or wild-type MDS.12-14”
From Eprenetapopt (APR-246) and Azacitidine in TP53 -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).”
From Eprenetapopt (APR-246) and Azacitidine in TP53 -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [14]
Experimental — accuracy not yet measuredIn the citing paper
“Whilst response rates of up to 60% to azacytidine have been reported in MDS 125,129 ,”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [129]
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“Hypomethylating agents (HMAs) including azacitidine [4 – 6] or decitabine [5] are recommended in MDS as low-intensity therapy to reduce disease-associated symptoms and the risk of disease progression and death, thereby improving both quantity and quality of life [7].”
BackgroundResultInfluentialSelf-citationChomiak, A. A., Tiedemann, R. L., Liu, Y., Kong, X., Cui, Y., Wiseman, A. K., Thurlow, K. E., Cornett, E. M., Topper, M. J., Baylin, S. B., et al. (2024) · Science Advances · doi:10.1126/sciadv.adk4423 · Cited by 44
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Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept
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“A second phase III study was performed in patients with advanced MDS (Fenaux et al, 2009).”
BackgroundMa, E., Bonthapally, V., Chawla, A., Lefèbvre, P., Swords, R. T., Lafeuille, M.-H., Fortier, J., Émond, B., Duh, M. S., & Dezube, B. J. (2016) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2016.08.006 · Cited by 42
“60-69 352 (38) 4 (80) 97 (23) 8 (22) 243 (53)”
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Targeting DNA Methyltranferases in Urological Tumors
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“Nevertheless, a large trial with MDS patients treated with lower doses of these agents showed not only a delay in conversion time for leukemia but also an improvement in overall survival (Fenaux et al., 2009).”
Reilly, B. M., Tanaka, T. N., Diep, D. H., Yeerna, H., Tamayo, P., Zhang, K., & Bejar, R. L. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019000192 · Cited by 43
Targeting DNA Methylation for Treating Triple-Negative Breast Cancer
Yu, J., Zayas, J., Qin, B., & Wang, L. (2019) · Pharmacogenomics · doi:10.2217/pgs-2019-0078 · Cited by 42
Komrokji, R. S., Ali, N. H. A., Sallman, D. A., Padron, E., Dezern, A. E., Barnard, J., Roboz, G. J., Garcia‐Manero, G., List, A. F., Steensma, D. P., et al. (2020) · Cancer Medicine · doi:10.1002/cam4.3608 · Cited by 42
Self-citationCETLAM group, Cabezón, M., Malinverni, R., Bargay, J., Xicoy, B., Marcé, S., Garrido, A., Tormo, M., Arenillas, L., Coll, R., et al. (2021) · Clinical Epigenetics · doi:10.1186/s13148-021-01002-y · Cited by 42
“Half of the patients do not respond favorably to the treatment and virtually all responders eventually relapse [32].”
BackgroundLee, E.-J., Podoltsev, N. A., Gore, S. D., & Zeidan, A. M. (2015) · Blood Reviews · doi:10.1016/j.blre.2015.06.004 · Cited by 42
“Unfortunately, only about one-half of patients respond to azacitidine [14,104].”
BackgroundInfluentialSelf-citationSpinner, M. A., Aleshin, A., Santaguida, M. T., Schaffert, S. A., Zehnder, J. L., Patterson, A. S., Gekas, C., Heiser, D., & Greenberg, P. L. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020001934 · Cited by 40
Epigenetic drugs in cancer therapy: mechanisms, immune modulation, and therapeutic applications
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“…azacitidine significantly prolonged overall survival in higher-risk MDS compared with conventional care regimens (median 24.5 vs 15.0 months; hazard ratio 0.58, 95% CI 0.43–0.77; P < 0.001), while also improving complete and partial remission rates and delaying AML transformation [24, 25].”
InfluentialPhase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes
Uchida, T., Ogawa, Y., Kobayashi, Y., Ishikawa, T., Ohashi, H., Hata, T., Usui, N., Taniwaki, M., Ohnishi, K., Akiyama, H., et al. (2011) · Cancer Science · doi:10.1111/j.1349-7006.2011.01993.x · Cited by 41
New nucleoside analogs for patients with hematological malignancies
Robak, T. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.554822 · Cited by 41
“Lower doses of azacitidine were intensively studied in higher risk MDS and the results of the Phase III international multi-center randomized trial have recently been published [56].”
BackgroundStauder, R. (2012) · Annals of Hematology · doi:10.1007/s00277-012-1472-8 · Cited by 41
“Even in elderly high-risk MDS patients (≥75 years), the safety and tolerability of AZA were good when compared with CCR, although in the CCR group 67 % of the patients had received BSC only [41].”
BackgroundInfluentialVoso, M. T., Breccia, M., Lunghi, M., Poloni, A., Niscola, P., Finelli, C., Bari, A., Musto, P., Zambello, R., Fianchi, L., et al. (2013) · European Journal Of Haematology · doi:10.1111/ejh.12079 · Cited by 41
“Azacitidine treatment is also associated with delayed disease progression, reduced transfusion requirements, and enhanced quality of life (1).”
BackgroundSelf-citationUsing Epigenetic Therapy to Overcome Chemotherapy Resistance.
Strauss, J., & Figg, W. D. (2016) · PubMed · Cited by 41
Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter
Kordella, C., Lamprianidou, E., & Kotsianidis, Ι. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.650473 · Cited by 40
Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies
Patel, A. A., Cahill, K. E., Saygin, C., & Odenike, O. M. (2021) · Blood Advances · doi:10.1182/bloodadvances.2020002929 · Cited by 41
New Approaches to Myelodysplastic Syndrome Treatment
Bazinet, A., & Bravo, G. M. (2022) · Current Treatment Options in Oncology · doi:10.1007/s11864-022-00965-1 · Cited by 40
Ocio, E. M., Herrera, P., Olave, M., Castro, N., Pérez‐Simón, J. A., Brunet, S., Oriol, A., Mateo, M., Sanz, M. Á., López, J. L. G., et al. (2015) · Haematologica · doi:10.3324/haematol.2015.129577 · Cited by 40
Vorinostat in acute myeloid leukemia and myelodysplastic syndromes
Prébet, T., & Vey, N. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.542750 · Cited by 40
“Evidence for the therapeutic relevance of targeting epigenetic regulation has been provided by studies of the DNA methyl transferase inhibitors azacitidine [11,12] and decitabine [13], which showed significant clinical activity, leading to their registration for the treatment of MDS by”
MethodMyelodysplastic syndromes: A practical approach to diagnosis and treatment
Barzi, A., & Sekeres, M. A. (2010) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.77a.09069 · Cited by 42
The molecular pathogenesis of myelodysplastic syndromes
Davids, M. S., & Steensma, D. P. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.10.4.12612 · Cited by 40
Refractory anemia with ring sideroblasts
Malcovati, L., & Cazzola, M. (2013) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2013.09.005 · Cited by 40
“More aggressive therapies including hypomethylating agents and allogeneic stem cell transplantation should be considered in case of disease progression [45,46].”
BackgroundPleyer, L., Burgstaller, S., Stauder, R., Girschikofsky, M., Sill, H., Schlick, K., Thaler, J., Halter, B., Machherndl‐Spandl, S., Zebisch, A., et al. (2016) · Journal of Hematology & Oncology · doi:10.1186/s13045-016-0263-4 · Cited by 40
“Although the sum of available data led the WHO to conclude that AML20–30 (formerly MDS-RAEB-t) and AML30+ were essentially the same disease 15 years ago, several relevant groups do not appear to consider the scientific evidence to be strong enough: (i) The National Comprehensive Cancer Network (NCCN) endorses both FAB…”
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“AZA was administered at a dose of 75mg/m(2) subcutaneously or intravenously for seven consecutive days every 28 days analogous to the dosing scheme in major studies for adult patients.(23,25,33) In 7/8 patients, pre-medication with ondansetron was given intravenously or orally prior to starting AZA, and concomitant IV…”
MethodPD-1 signaling and inhibition in AML and MDS
Haroun, F., Solola, S., Nassereddine, S., & Tabbara, I. A. (2017) · Annals of Hematology · doi:10.1007/s00277-017-3051-5 · Cited by 40
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Self-citationA multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia
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“Outside the context of allo-HSCT, DMAs, including 5-azacitidine and decitabine, have emerged as new therapeutic agents that significantly prolong OS and are considered the current standard of care for most patients with intermediate-2 and high-risk MDS, even though they have no curative potential [33,34].”
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Metadata
- Authors
- Fenaux, P., Mufti, G. J., Hellstrom-Lindberg, E., Santini, V., Finelli, C., Giagounidis, A., Schoch, R., Gattermann, N., Sanz, G., List, A., Gore, S. D., Seymour, J. F., Bennett, J. M., Byrd, J., Backstrom, J., Zimmerman, L., McKenzie, D., Beach, C., & Silverman, L. R.
- Affiliations
- Université Sorbonne Paris Nord (FR)
- King's College Hospital (GB)
- Azienda Ospedaliero-Universitaria Careggi (IT)
- University Hospital Schleswig-Holstein (DE)
- Düsseldorf University Hospital (DE)
- Hospital Universitari i Politècnic La Fe (ES)
- Moffitt Cancer Center (US)
- Johns Hopkins University (US)
- Karolinska University Hospital (SE)
- University of Rochester Medicine (US)
- The Ohio State University (US)
- Celgene (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Fenaux, Pierre
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 10
- Issue
- 3
- Pages
- 223-232
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC4086808
- OpenAlex
- W2118771330
- Cited by
- 2,663
- References
- 45
- Citations by year
- 2026: 80 · 2025: 99 · 2024: 103 · 2023: 153 · 2022: 149 · 2021: 182 · 2020: 148 · 2019: 149 · 2018: 132 · 2017: 164 · 2016: 178 · 2015: 173 · 2014: 201 · 2013: 182 · 2012: 178
- FWCI
- 124.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Florence Research (University of Florence) (submittedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Celgene
- National Cancer Institute (K24CA111717)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- azacitidine, myelodysplastic syndrome, high-risk myelodysplastic syndrome, overall survival, low-dose cytarabine, intensive chemotherapy, best supportive care, hypomethylating agents, treatment efficacy comparison, hematologic malignancies
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic, Azacitidine, Female, Humans, Male, Middle Aged, Myelodysplastic Syndromes, Proportional Hazards Models
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