Table 6 Clinical studies of valproic acid in the treatment of human acute myeloid leukemia (AML); a summary of the previous clinical results from studies of valproic alone, valproic acid + all-trans retinoic acid (ATRA) used alone and in combination with other pharmacological agents

Valproic acid monotherapy

Kuendgen [12]

N = 31

This study included 31 patients receiving valproic acid alone and 40 patients receiving valproic acid plus continuous ATRA. Hematological improvement according to the myelodysplastic syndrome (MDS) criteria was also seen with valproic acid alone for a minor subset of patients.

Valproic acid + ATRA

Kuendgen [12]

N = 40

Based on the overall results the following conclusions can be made:

Bellos [8]

N = 22

• This is a nontoxic treatment, the most frequent side effects being dose-dependent and thereby reversible fatigue and gastrointestinal discomfort. ATRA syndrome is very uncommon and has only been reported in one of these studies.

Bug [9]

N = 26

Cimino [10]

N = 8

• The two drugs can be combined with initial low-toxicity chemotherapy to control hyperleukocytosis (hydroxyurea, cytarabine, 6-mercaptopurin).

Raffoux [14]

N = 11

Pilatrino [13]

N = 20

• Complete remissions are uncommon, probably < 2 to 3%.

• Hematological improvement as defined by the MDS criteria is seen for 20 to 40% of patients; platelet responses seem most common but erythroid and neutrophil responses may also be seen.

• Responses can be seen even with valproic acid levels lower than the therapeutic serum level commonly used for this drug.

• ATRA is usually used as 45 mg/m²/day; continuous ATRA therapy has been used in most studies but intermittent treatment for 14 days at intervals up to 12 weeks may also be used.

• It is uncommon for responses to last for more than one year.

• Median age in most studies is 65 to 75 years; the treatment has been used for patients up to 90 years of age.

Valproic acid + ATRA + theophylline

Ryningen [15]

N = 24

Continuous valproic acid + theophylline was combined with intermittent ATRA 22.5 mg/m² twice daily for 15 days with 12 weeks intervals; 18% of patients had hematological improvement according to the MDS criteria, 2 patients developed atrial fibrillation and the most common side effects were dose-dependent nausea and fatigue.

Valproic acid +ATRA + low-dose cytarabine

Lane [56]

N = 19

Lane: no complete or partial remissions

Corsetti: the study included 25 AML and 6 high-risk MDS patients; 8 patients obtained a complete remission and 3 additional patients obtained hematological improvement.

Fredly: two complete remissions and 9 patients with hematological improvement.

Corsetti [16]

N = 31

Fredly (present study)

N = 36

Valproic acid + ATRA + decitabine

Raffoux [57]

N = 65

Raffoux: six cycles were given; 34 patients were then alive and among these 38% achieved complete remission, 6% partial remission and 41% stable disease. There were 76 events of infections.

Soriano [58]

N = 53

Soriano: 42% overall response rate with 22% complete remissions. The most important nonhematological toxicity was 13 events of grade III/IV neurotoxicity.