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Table 3 Combination of histone deacetylase (HDAC) inhibition and demethylating agents: summary of clinical studies

From: Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents

Study Number of patients Median age (years) Diagnosis Treatment Results Common toxicity
Raffoux et al., 2010 [64] 65 72 AML (85%) or high-risk MDS 5-AZA 75 mg/m2. VPA 35 to 50 mg/kg po day 1 to 7. ATRA 45 mg/m2 po day 8 to 28. Six cycles. After six cycles, 34 patients survived: 13 patients (38%) CR, two patients (6%) PR and 14 patients (41%) had stable disease. Median OS was 12.4 months. Confusion 33 events, infection 76 events.
Blum et al., 2007 [63] 25 70 AML Decitabine 15 to 20 mg/m2/d iv days 1 to 10 every 28 days. VPA 15 to 20 mg/kg days 5 to 21 in ten patients. Response rate was 44%: four patients CR, four patients CRi and three patients PR (AML criteria). Survival not reported. Neutropenic fever (64%), fatigue and infection (both 48%) were most common.
Soriano et al., 2007 [65] 53 69 AML (92%) or high-risk MDS 5-AZA 75 mg/m2/d. VPA 50 to 75 mg/kg/d days 1 to 7. ATRA 45 mg/m2 days 3 to 5. Treatment repeated every 3 weeks. Overall response rate was 42%: 12 patients (22%) CR. Survival not reported. Two events of grade IV and 11 events of grade III non-hematological toxicity; mainly fatigue or other neurotoxicities.
Garcia-Manero et al., 2006 [66] 54 60 AML (89%) or MDS Decitabine 15 mg/m2/d iv. VPA 20 to 50 mg/kg days 1 to 10. Treatment repeated every fourth week. Twelve patients (22%) had responses: 10 patients CR and two patients CRp. OS 6 months (0.6 to 20.2 months). Fatigue, nausea and diarrhoea were the most common non-hematological toxicities.
Maslak et al., 2006 [67] 10 66.5 AML (80%) or MDS 5-AZA 75 mg/m2/d days 1 to 7. Sodium phenylbutyrate 200 mg/kg/d iv days 8 to 12. Treatment repeated every 21 to 28 days. Three patients (30%) PR and two patients (20%) had stable disease. Duration of response was 45 days (37 to 136 days). Survival not reported. Three patients had neutropenic fever. Nausea, dizziness and fatigue were common.
  1. 5-AZA, 5-azacytidine; AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; CR, complete remission; CRi, complete remission incomplete (peripheral blood criteria not fulfilled); CRp, incomplete platelet recovery; MDS, myelodysplastic syndrome; OS, overall survival; PR, partial remission; VPA, valproic acid.