Combination of vorinostat and low dose cytarabine for patients with azacitidine-refractory/relapsed high risk myelodysplastic syndromes

Thomas Prebet; Thorsten Braun; Odile Beyne-Rauzy; Francois Dreyfus; Aspasia Stammatoullas; Eric Wattel; Shanti Ame; Emmanuel Raffoux; Jacques Delaunay; Aude Charbonnier; Lionel Adès; Pierre Fenaux; Norbert Vey

doi:10.1016/j.leukres.2013.07.023

Combination of vorinostat and low dose cytarabine for patients with azacitidine-refractory/relapsed high risk myelodysplastic syndromes

Leuk Res. 2014 Jan;38(1):29-33. doi: 10.1016/j.leukres.2013.07.023. Epub 2013 Aug 13.

Authors

Affiliations

¹ Hematology Department, Institut PAOLI-CALMETTES and Aix-Marseille Université, Marseille, France.
² Hematology Department, Hôpital Avicenne, Assistance Publique Hopitaux de Paris (AP-HP), Bobigny, France.
³ Hematology Department, Hôpital Purpan, Toulouse, France.
⁴ Hematology Department, Hôpital Cochin, Assistance Publique Hopitaux de Paris (AP-HP), Paris, France.
⁵ Hematology Department, Centre Henri Becquerel, Rouen, France.
⁶ Hematology Department, Hôpital Lyon Sud, Pierre-Bénite, France.
⁷ Hematology Department, Centre Hospitalo universitaire, Strasbourg, France.
⁸ Hematology Department, Hôpital Saint Louis, Assistance Publique Hopitaux de Paris (AP-HP), Paris, France.
⁹ Hematology Department, Centre Hospitalo universitaire, Nantes, France.
¹⁰ Hematology Department, Institut PAOLI-CALMETTES and Aix-Marseille Université, Marseille, France. Electronic address: veyn@ipc.unicancer.fr.

PMID: 23953882
DOI: 10.1016/j.leukres.2013.07.023

Abstract

Outcome of patients with myelodysplastic syndrome after azacitidine failure is poor. In this population, we combined cytarabine (10-20mg/m²/day 14 days) with vorinostat (400mg/day) for escalating durations (7 days, 10 days and 14 days), and starting on day 1 (concomitant arm) or on day 14 (sequential arm) following a 3+3 phase I design. 40 patients were treated. Dose limiting toxicities were all seen in sequential arm. The overall response rate was 15% with 4 responses in concomitant arm (ORR=25%). We conclude that this combination is tolerable and concomitant administration might be less toxic and have better therapeutic effect (clinicaltrials.gov NCT00776503).

Keywords: Azacitidine failure; Epigenetic; HDAC; Myelodysplasia.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Azacitidine / administration & dosage
Cytarabine / administration & dosage
Cytarabine / adverse effects
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Resistance, Neoplasm
Female
Humans
Hydroxamic Acids / administration & dosage
Hydroxamic Acids / adverse effects
In Vitro Techniques
Middle Aged
Myelodysplastic Syndromes / drug therapy*
Myelodysplastic Syndromes / pathology
Nausea / chemically induced
Neutropenia / chemically induced
Recurrence
Risk Factors
Survival Analysis
Thrombocytopenia / chemically induced
Treatment Outcome
Vomiting / chemically induced
Vorinostat

Substances

Hydroxamic Acids
Cytarabine
Vorinostat
Azacitidine

Associated data

ClinicalTrials.gov/NCT00776503