Oral decitabine plus cedazuridine versus intravenous decitabine

Two DNA methyltransferase inhibitors have been available for parenteral treatment of people with myelodysplastic syndromes and chronic myelomonocytic leukaemia for several decades. Treatment with either decitabine 1 Lubbert M Suciu S Baila L et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011; 29: 1987-1996 Crossref PubMed Scopus (469) Google Scholar or azacitidine 2 Fenaux P Mufti GJ Hellstrom-Lindberg E et al. 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. Lancet Oncol. 2009; 10: 223-232 Summary Full Text Full Text PDF PubMed Scopus (2191) Google Scholar requires frequent visits to hospitals or care units. These DNA methyltransferase inhibitors are effective in about 50% of people with higher risk (as defined in the standard International Prognostic Scoring System) myelodysplastic syndromes or chronic myelomonocytic leukaemia, with short response durations and usual prolongation of survival of less than 1 year. Oral formulations of both DNA methyltransferase inhibitors have reduced bioavailability, 3 Garcia-Manero G Gore SD Cogle C et al. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011; 29: 2521-2527 Crossref PubMed Scopus (207) Google Scholar , 4 Issa JP Garcia-Manero G Giles FJ et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004; 103: 1635-1640 Crossref PubMed Scopus (745) Google Scholar mainly due to rapid inactivation by cytidine deaminase in the gut and liver. However, addition of the cytidine deaminase inhibitor, cedazuridine, to oral decitabine resulted in an improved bioavailability and reported efficacy of this combination in a dose-finding study. 5 Savona MR Odenike O Amrein PC et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019; 6: e194-e203 Summary Full Text Full Text PDF PubMed Scopus (83) Google Scholar Decitabine blood concentrations of the oral combination and pharmacodynamics were similar to the blood concentrations of intravenously administered decitabine obtained in the same patient when the oral combination contained the 30 mg or 40 mg doses of decitabine combined with 100 mg of cedazuridine. 5 Savona MR Odenike O Amrein PC et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019; 6: e194-e203 Summary Full Text Full Text PDF PubMed Scopus (83) Google Scholar The ASCERTAIN trial, 6 Garcia-Manero G McCloskey J Griffiths EA et al. Oral decitabine–cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover pharmacokinetics, phase 3 study. Lancet Haematol. 2024; 11: e15-e26 Summary Full Text Full Text PDF Google Scholar a registrational, multicentre, open-label, crossover trial compared intrapatient the safety and pharmacokinetics of oral decitabine–cedazuridine versus intravenous decitabine over 5 days. Oral decitabine–cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 studyOral decitabine–cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine–cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. Full-Text PDF