This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of azacitidine, decitabine, or low-dose cytarabine in patients with acute myeloid leukemia unfit to receive intensive induction chemotherapy. Half of the patients (50%) had poor Eastern Cooperative Oncology Group Performance Status (2-3). The coprimary end points were complete remission (19% and 17% of patients for guadecitabine and TC, respectively [stratified P = .48]) and overall survival (median survival 7.1 and 8.5 months for guadecitabine and TC, respectively [hazard ratio, 0.97; 95% confidence interval, 0.83-1.14; stratified log-rank P = .73]). One- and 2-year survival estimates were 37% and 18% for guadecitabine and 36% and 14% for TC, respectively. A large proportion of patients (42%) received <4 cycles of treatment in both the arms. In a post hoc analysis of patients who received ≥4 treatment cycles, guadecitabine was associated with longer median survival vs TC (15.6 vs 13.0 months [hazard ratio, 0.78; 95% confidence interval, 0.64-0.96; log-rank P = .02]). There was no significant difference in the proportion of patients with grade ≥3 adverse events (AEs) between guadecitabine (92%) and TC (88%); however, grade ≥3 AEs of febrile neutropenia, neutropenia, and pneumonia were higher with guadecitabine. In conclusion, no significant difference was observed in the efficacy of guadecitabine and TC in the overall population. This trial was registered at www.clinicaltrials.gov as #NCT02348489.

Astex Pharmaceuticals Inc Pleasanton CA

China Medical University Hospital Taichung City Taiwan

Coriell Institute for Medical Research Camden NJ

Fakultní Nemocnice Brno Česká Republika

GHR Mulhouse Sud Alsace Mulhouse France

Hôpital Lyon Sud Pierre Bénite France

Hôpital Saint Louis Paris France

Hospital St Marina EAD Varna Bulgaria

Medical University of Lodz and Copernicus Memorial Hospital Lodz Poland

Nagasaki University Hospital Nagasaki Japan

Novant Health Cancer Institute Elizabeth Charlotte NC

Ospedale Policlinico San Martino Genova Italy

Princess Margaret Cancer Centre Toronto ON Canada

Roswell Park Comprehensive Cancer Institute Buffalo NY

Samodzielny Publiczny Centralny Szpital Kliniczny Warszawa Poland

Semmelweis Egyetem Budapest Hungary

Severance Hospital Yonsei University Health System Seoul Republic of Korea

Städtisches Klinikum Braunschweig gGmbH Braunschweig Germany

The University of Texas MD Anderson Cancer Center Houston TX

Ulm University Hospital Ulm Germany

University of Alberta Hospital Edmonton Canada

Univerzita Karlova Praha Česká Republika

Weill Cornell Medicine New York NY

Zobrazit více v PubMed

Sasaki K, Ravandi F, Kadia TM, et al. De novo acute myeloid leukemia: a population-based study of outcome in the United States based on the Surveillance, Epidemiology, and End Results (SEER) database, 1980 to 2017. Cancer. 2021;127(12):2049–2061. PubMed PMC

Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed acute myeloid leukemia with >30% blasts. Blood. 2015;126(3):291–299. PubMed PMC

Kantarjian HM, Thomas XG, Dmoszynska A, et al. 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. J Clin Oncol. 2012;30(21):2670–2677. PubMed PMC

DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. PubMed PMC

DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–629. PubMed

DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005) : a single-arm, phase 1b and randomized, phase 2 trial. Lancet Oncol. 2021;22(11):1597–1608. PubMed

Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH-1 mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519–1531. PubMed

Daver N, Konopleva M, Maiti A, et al. Paper presented at American Society of Hematology Annual Meeting & Exposition; 2021. Phase I/II study of azacitidine (AZA) with venetoclax (VEN) and magrolimab (Magro) in patients (pts) with newly diagnosed older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML; pp. 11–14. presentation 371.

Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J Clin Oncol. 2014;32(12):1242–1248. PubMed PMC

Wang ES, Montesinos P, Minden MD, et al. Paper presented at American Society of Hematology Annual Meeting & Exposition; 2021. Phase 3, open-label, randomized study of gilteritinib and azacitidine vs azacitidine for newly diagnosed FLT3-mutated acute myeloid leukemia in patients ineligible for intensive induction chemotherapy; pp. 11–14. abstr 700.

Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med. 2001;134(7):573–586. PubMed

Griffiths EA, Choy G, Redkar S, Taverna P, Azab M, Karpf AR. SGI-110: DNA methyltransferase inhibitor oncolytic. Drugs Future. 2013;38(8):535–543. PubMed PMC

Issa J-P, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16(9):1099–1110. PubMed PMC

Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136(6):674–683. PubMed PMC

Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 2017;18(10):1317–1326. PubMed PMC

Roboz GJ, Kantarjian H, Yee KWL, et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer. 2018;124(2):325–334. PubMed PMC

Ferrara F, Barosi G, Venditti A, et al. Consensus-based definition of unfitness to intensive and non-intensive chemotherapy in acute myeloid leukemia: a project of SIE, SIES and GITMO group on a new tool for therapy decision making. Leukemia. 2013;27(5):997–999. PubMed

Dohner H, Estey EH, Amadori S, et al. European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–474. PubMed

Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642–4649. PubMed

National Comprehensive Cancer Network NCCN clinical practice guidelines in oncology (NCCN guidelines®): acute myeloid leukemia. Version 2. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411

Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcomes in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–1918. PubMed

Jahn N, Jahn E, Saadati M, et al. Genomic landscape of patients with Flt-3-mutated acute myeloid lekemia (AML) treated with the CALGB 10603/RATIFY trial. Leukemia. 2022;36(9):2218–2227. PubMed PMC

Zeidan AM, Fenaux P, Gobbi M, et al. Prospective comparison of outcomes with azacitidine and decitabine in AML patients ineligible for intensive chemotherapy. Blood. 2022;140(3):285–289. PubMed PMC

Maio M, Covre A, Fratta E, et al. Molecular pathways: at the crossroads of cancer epigenetics and immunotherapy. Clin Cancer Res. 2015;21(18):4040–4047. PubMed

Cabrero M, Jabbour E, Ravandi F, et al. Discontinuation of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute myelogenous leukemia in complete remission or partial response: retrospective analysis of survival after long-term follow up. Leuk Res. 2015;39(5):520–524. PubMed PMC

Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer. 2011;117(12):2697–2702. PubMed PMC

Gore SD, Fenaux P, Santini V, et al. A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated with azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica. 2013;98(7):1067–1072. PubMed PMC

Dohner H, Estey EH, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–447. PubMed PMC

Fenaux P, Haase D, Sanz GF, Santini V, Buske C, ESMO Guidelines Working Group Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl 3):iii57–iii69. PubMed

Zobrazit více v PubMed

ClinicalTrials.gov
NCT02348489