Results of a phase I/II study of the combination of 5-aza-2’-deoxycytidine and valproic acid in patients with acute myeloid leukemia and myelodysplastic syndrome

Kantarjian, H.; Sánchez‐González, Blanca; Verstovsek, S.; Ravandi, Farhad; Ryttling, M.; Cortés, Javier; Yang, Hong-Le; Fiorentino, Jackie; Rosner, Gary L.; Issa, Jean-Pierre

doi:10.1200/jco.2005.23.16_suppl.6544

Cited by 13 publications

(7 citation statements)

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“…41 According to our clinical data, VPA has beneficial effects but is not sufficiently active to be useful as single-agent therapy for AML. In elderly patients who are medically unfit for standard chemotherapy, VPA may be combined with inhibitors of important pathways involved in AML pathogenesis, like FLT3-or FTI-inhibitors, or with demethylating agents, which, based on theoretical grounds as well as in vitro findings and preliminary clinical data, 42 should be capable of augmenting the reexpressor strategy.…”

Section: Tablementioning

confidence: 99%

The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia

Kuendgen

Schmid

Schlenk

et al. 2005

Cancer

210

163

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BACKGROUNDValproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all‐trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro.METHODSWe used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy (32 AML secondary to myelodysplastic syndrome [MDS], 22 de novo AML, 4 AML secondary to myeloproliferative syndrome). VPA serum concentrations were 50–100 μg/mL. Thirty‐one patients received VPA monotherapy. ATRA was added later in 13 patients who did not respond or who relapsed. Another 27 patients received VPA plus ATRA from the start. Median treatment duration was 93 days for VPA and 88 days for ATRA.RESULTSThe response rate was only 5% according to International Working Group (IWG) criteria for AML but was 16% when IWG response criteria for MDS were used, which capture hematologic improvement and stabilization of the disease. These endpoints, which are not necessarily correlated with diminishing blast counts, are relevant for the patients' quality of life. Among 23 patients with a peripheral blast count > 5%, 6 (26%) showed a diminishing blast count, and 5 of these had a complete peripheral blast clearance.CONCLUSIONSFuture trials should combine VPA with chemotherapy or demethylating agents. Cancer 2006. © 2005 American Cancer Society.

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Section: Tablementioning

confidence: 99%

The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia

Kuendgen

Schmid

Schlenk

et al. 2005

Cancer

210

163

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“…125 In 40 patients with AML and MDS, combination therapy produced 8 CR and 1CRp (22%) that was associated with changes in histone acetylation and DNA hypomethylation. 126 Another pilot study of combined 5-azacytidine and PB was performed in patients with AML. Combination therapy was well tolerated and a reduction in bone marrow blasts and increased myeloid maturation was observed.…”

Section: Hdacis In Clinical Trialsmentioning

confidence: 99%

Histone Deacetylase Inhibitors for Cancer Therapy

Kim¹,

Bang²,

Robertson³

2006

Epigenetics

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The epigenome of cancer cells is determined by DNA methylation and an array of post-translational modifications of the core histones. Epigenetic abnormalities are commonly found in human tumors and importantly, they can be reversed by pharmacologic inhibitors. Histone deacetylase inhibitors (HDACIs) represent one of the most promising epigenetic treatments for cancer. HDACIs have emerged as promising targets for cancer therapy because they reactivate the transcription of multiple genes that are silenced in human tumors and they show pleiotropic anti-tumor effects selectively in cancer cells. HDACIs are well-tolerated and several show promising anti-tumor activity. While gene transcription has been considered to be the major target of HDACIs, inhibition of acetylation of non-histone proteins is now emerging as a novel basis for their anti-tumor effects. In this review, we discuss new insights into the molecular mechanism of HDACIs, their current status of clinical development, and possible future uses in cancer therapy.

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“…Of 40 evaluable for response, an overall response rate of 22% (8 PR and 1 CR) was observed. Interestingly, the response rates according to the valproic acid dose were 33% for 20 mg, 11% for the 35 mg and 25% for the 50 mg/Kg dose level [39]. Finally, in a third phase I study for metastatic solid tumors valproic acid was administered as an IV loading dose followed by 5 doses of oral doses given every 12 hours followed by a dose of epirubicin at day 3.…”

Section: Discussionmentioning

confidence: 99%

Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study

et al. 2005

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Results of a phase I/II study of the combination of 5-aza-2’-deoxycytidine and valproic acid in patients with acute myeloid leukemia and myelodysplastic syndrome

Cited by 13 publications

References 0 publications

The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia

The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia

Histone Deacetylase Inhibitors for Cancer Therapy

Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study

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