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. |