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Clinical Trial
. 2012 Jun 20;30(18):2204-10.
doi: 10.1200/JCO.2011.38.3265. Epub 2012 May 14.

Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome

Guillermo Garcia-Manero  1 , Francesco Paolo Tambaro, Nebiyou B Bekele, Hui Yang, Farhad Ravandi, Elias Jabbour, Gautam Borthakur, Tapan M Kadia, Marina Y Konopleva, Stefan Faderl, Jorge E Cortes, Mark Brandt, Yumin Hu, Deborah McCue, Willie Mae Newsome, Sherry R Pierce, Marcos de Lima, Hagop M Kantarjian
Affiliations
Clinical Trial

Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome

Guillermo Garcia-Manero et al. J Clin Oncol. .

Abstract

Purpose: To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).

Patients and methods: Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m(2) intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m(2) IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely.

Results: After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival.

Conclusion: The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
(A) Overall survival and (B) event-free survival of all patients by molecular cytogenetic subset. −5/−7 cytogenetics. Misc, miscellaneous.
Fig 2.
Fig 2.
Gene expression of genes involved in resistance and reactive oxygen species sequentially during therapy. Gene expression was normalized to glyceraldehyde phosphate dehydrogenase and was measured sequentially during the first course of therapy. D, day.
Fig 3.
Fig 3.
Overall survival based on levels of (A) NRF2 and (B) CYBB.
Fig A1.
Fig A1.
(A) Overall survival and (B) event-free survival from time of transplantation. (C) Overall survival and (D) event-free survival from time of therapy on protocol. NR, not reached.
Fig A2.
Fig A2.
Examples of histone acetylation.
Fig A3.
Fig A3.
Gene expression at baseline.
See this image and copyright information in PMC

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