Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia

Hagop Kantarjian, Yasuhiro Oki, Guillermo Garcia-Manero, Xuelin Huang, Susan O'Brien, Jorge Cortes, Stefan Faderl, Carlos Bueso-Ramos, Farhad Ravandi, Zeev Estrov, Alessandra Ferrajoli, William Wierda, Jianqin Shan, Jan Davis, Francis Giles, Hussain I. Saba, Jean Pierre J. Issa

Research output: Contribution to journalArticle

Abstract

Epigenetic therapy with hypomethylating drugs is now the standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, doseintensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.

Original languageEnglish (US)
Pages (from-to)52-57
Number of pages6
JournalBlood
Volume109
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

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decitabine
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Appointments and Schedules
Epigenomics
Pharmacodynamics
Standard of Care
Random Allocation
Modulation
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. / Kantarjian, Hagop; Oki, Yasuhiro; Garcia-Manero, Guillermo; Huang, Xuelin; O'Brien, Susan; Cortes, Jorge; Faderl, Stefan; Bueso-Ramos, Carlos; Ravandi, Farhad; Estrov, Zeev; Ferrajoli, Alessandra; Wierda, William; Shan, Jianqin; Davis, Jan; Giles, Francis; Saba, Hussain I.; Issa, Jean Pierre J.

In: Blood, Vol. 109, No. 1, 01.01.2007, p. 52-57.

Research output: Contribution to journalArticle

Kantarjian, H, Oki, Y, Garcia-Manero, G, Huang, X, O'Brien, S, Cortes, J, Faderl, S, Bueso-Ramos, C, Ravandi, F, Estrov, Z, Ferrajoli, A, Wierda, W, Shan, J, Davis, J, Giles, F, Saba, HI & Issa, JPJ 2007, 'Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia', Blood, vol. 109, no. 1, pp. 52-57. https://doi.org/10.1182/blood-2006-05-021162
Kantarjian, Hagop ; Oki, Yasuhiro ; Garcia-Manero, Guillermo ; Huang, Xuelin ; O'Brien, Susan ; Cortes, Jorge ; Faderl, Stefan ; Bueso-Ramos, Carlos ; Ravandi, Farhad ; Estrov, Zeev ; Ferrajoli, Alessandra ; Wierda, William ; Shan, Jianqin ; Davis, Jan ; Giles, Francis ; Saba, Hussain I. ; Issa, Jean Pierre J. / Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. In: Blood. 2007 ; Vol. 109, No. 1. pp. 52-57.
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AU - Oki, Yasuhiro

AU - Garcia-Manero, Guillermo

AU - Huang, Xuelin

AU - O'Brien, Susan

AU - Cortes, Jorge

AU - Faderl, Stefan

AU - Bueso-Ramos, Carlos

AU - Ravandi, Farhad

AU - Estrov, Zeev

AU - Ferrajoli, Alessandra

AU - Wierda, William

AU - Shan, Jianqin

AU - Davis, Jan

AU - Giles, Francis

AU - Saba, Hussain I.

AU - Issa, Jean Pierre J.

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N2 - Epigenetic therapy with hypomethylating drugs is now the standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, doseintensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.

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