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Therapy

Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome

Leukemia volume 20, pages 212–217 (2006)Cite this article

Abstract

Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.

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Acknowledgements

This work was supported in part by National Institutes of Health Grant RO1 CA82740 (PM) and PO1 CA05826 (SN), and CALGB Clinical Cancer Research Award (LHC), and a SCOR grant from the Leukemia Lymphoma Society (SN, pp).

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Author notes

  1. L H Camacho

    Present address: MD Anderson Cancer Center, Houston, TX, USA

  2. S Soignet

    Present address: Arcus Group, New York, NY, USA

  3. R Warrell

    Present address: Genta Corporation, Berkley Heights, NJ, USA

Authors and Affiliations

  1. Department of Clinical Laboratories, New York, NY, USA

    P Maslak

  2. Department of Medicine, Memorial Hospital, New York, NY, USA

    P Maslak, S Chanel, L H Camacho, S Soignet, R Warrell & S Nimer

  3. The Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    P P Pandolfi, I Guernah & S Nimer

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Correspondence to P Maslak.

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Maslak, P., Chanel, S., Camacho, L. et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 20, 212–217 (2006). https://doi.org/10.1038/sj.leu.2404050

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