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Table 2 Valproic acid (VPA) and all- trans retinoic acid (ATRA) in the treatment of acute myeloid leukemia (AML): 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 (range) (years) Diagnosis Treatment Results Common toxicity
Ryningen et al., 2009 [51] 24 71 (47 to 86) AML ATRA 22.5 mg/m2 × 2 day 1 to 15. VPA and theophylline iv day 3 to 7, thereafter, orally indefinitely. Serum levels of theophylline 50 to 100 μM, VPA 200 to 700 μM. MDS criteria: 9/22 patients had increasing cell counts and 4/22 patients (18%) HI [52, 53]. Median survival 64 days (7 to 644 days). Two patients had atrial fibrillation. Fatigue and nausea were most common.
Bellos et al., 2008 [47] 22 71.5 (41 to 89) AML (95%) or MDS VPA 150 to 300 mg/d. ATRA 45 mg/m2/d for 14 days. MDS criteria: four patients HI-P and one patient HI-E. Treatment duration 37 days (4 to 730 days). Usually well tolerated. Two patients had ATRA syndrome and two patients had continuous fever.
Cimino et al., 2006 [19] 8 61.5 (31 to 69) AML (88%) or CML blast crisis VPA 15 to 30 mg/kg/d with serum levels 50 to 110 μg/ml. ATRA 45 mg/m2 from day 14. Cytoreductive drugs if hyperleukocytosis. Two patients (25%) HI and five patients had stable disease. No clinical response according to AML criteria [54]. Survival 119 days (60 to 184 days). One patient had grade III hepatic toxicity, and one patient had vertigo and tremor.
Kuendgen et al., 2006 [40] 58 71 (42 to 86) AML VPA reaching serum levels 50 to 100 μg/ml. ATRA either 80 mg/m2 days 1 to 7 every second week, or ATRA 15 mg/m2/d from day 4. Total of 31 patients received VPA monotherapy. Cytoreductive drugs if hyperleukocytosis. AML criteria: one patient CR, one patient CRi and one patient PR;
5% response. MDS criteria: 16% responses, 34% stable disease and 50% progressive disease. No difference between treatment groups. Median OS 6.74 months.
Seven patients had tremors. Four patients had grade I/II skin toxicity, three patients had grade I/II gastrointestinal toxicity and one patient had pleural effusion.
Bug et al., 2005 [48] 26 69 (59 to 84) AML (92%) or advanced MDS VPA 5 to 10 mg/kg/d, escalating doses to 5 to 64 mg/kg. ATRA 45 mg/m2/d. Cytoreductive drugs if hyperleukocytosis. One patient PR, one patient had minor response (2/19) and no patients CR; 10% responses. Survival not reported. Three patients had grade IV neurological or pulmonary toxicity and there were 21 events with grade III toxicity.
Raffoux et al., 2005 [50] 11 82 (70 to 85) AML VPA reaching serum levels 50 to 100 μg/ml. ATRA 45 mg/m2/d from day 7. Theophylline reaching serum levels 10 to 15 μg/ml. Cytoreductive drugs if hyperleukocytosis. AML criteria: one patient CR and two patients CRi. According to MDS criteria: two additional patients with HI. Survival 6 months (1 to 28 months). Main side effects were tremor, mental confusion and theophylline-related palpitations.
Kuendgen et al., 2005 [39] 75 67 (21 to 84) AML (43%) or MDS VPA reaching serum concentrations 50 to 100 μg/ml. Total of 66 patients received VPA monotherapy. ATRA 80 mg/m2 days 1 to 7 every second week. MDS criteria: 18 patients responded (24%), one patient CR, one patient PR, 16 patients HI and 25 patients had stable disease. Median response duration 4 months (2 to 27 months). Skin and gastrointestinal toxicity.
Pilatrino et al., 2005 [49] 20 70 (63 to 80) AML (65%) or MDS VPA 10 mg/kg/d escalating to 311 to 693 μM. ATRA 45 mg/m2/d. Cytoreductive drugs if hyperleukocytosis. MDS criteria: 30% patients HI and no patients CR. Median duration of response 189 days (63 to 550 days). Neurologic toxicity and bone pain.
  1. AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; CML, chronic myeloid leukemia; CR, complete remission; CRi, complete remission incomplete (peripheral blood criteria not fulfilled); HI, hematological improvement; HI-E, hematological improvement in erythrocytes; HI-P, hematological improvement in platelet counts; MDS, myelodysplastic syndrome; OS, overall survival; PR, partial remission; VPA valproic acid.