The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia

Abstract

BackgroundA large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Previous studies have demonstrated that a subset of these patients can benefit from disease-stabilizing therapy based on all-trans retinoic acid (ATRA) and valproic acid. Even though complete hematological remission is only achieved for exceptional patients, a relatively large subset of patients respond to this treatment with stabilization of normal peripheral blood cell counts.MethodsIn this clinical study we investigated the efficiency and safety of combining (i) continuous administration of valproic acid with (ii) intermittent oral ATRA treatment (21.5 mg/m2 twice daily) for 14 days and low-dose cytarabine (10 mg/m2 daily) for 10 days administered subcutaneously. If cytarabine could not control hyperleukocytosis it was replaced by hydroxyurea or 6-mercaptopurin to keep the peripheral blood blast count below 50 × 109/L.ResultsThe study included 36 AML patients (median age 77 years, range 48 to 90 years) unfit for conventional intensive chemotherapy; 11 patients responded to the treatment according to the myelodysplastic syndrome (MDS) response criteria and two of these responders achieved complete hematological remission. The most common response to treatment was increased and stabilized platelet counts. The responder patients had a median survival of 171 days (range 102 to > 574 days) and they could spend most of this time outside hospital, whereas the nonresponders had a median survival of 33 days (range 8 to 149 days). The valproic acid serum levels did not differ between responder and nonresponder patients and the treatment was associated with a decrease in the level of circulating regulatory T cells.ConclusionTreatment with continuous valproic acid and intermittent ATRA plus low-dose cytarabine has a low frequency of side effects and complete hematological remission is seen for a small minority of patients. However, disease stabilization is seen for a subset of AML patients unfit for conventional intensive chemotherapy.

Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic

“…Nine patients demonstrated hematological improvement, with a CRR of 6%, which is lower than the CRR of another study (18%) that used a higher dose of cytarabine (20mg/m 2 twice daily for 10 days every 4–6 weeks). 142,143 On the other hand, the CRR of Fredly et al study is similar to another trial (7.4%) that used cytarabine alone at 20 mg/m 2 once a day for 10 days on monthly basis. 144,145 …”

An ATRActive future for differentiation therapy in AML

“…Kuendgen et al, 42 for instance, found a 5% response in a study of 58 patients treated with valproic acid and ATRA. Fredly et al, 43 in a study of 36 AML patients treated with valproic acid, ATRA, and ara-C, observed that only two obtained a remission, though nine showed stable disease. Ryningen et al 44 reported hematologic improvement in 4 of 22 patients treated with the combination of ATRA, valproic acid, and theophylline.…”

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

“…However, an alternative strategy could be to combine CDC25 inhibitors with low-toxicity disease-stabilizing strategies in patients that are unfit for the intensive and potentially curative treatment. If this last strategy is considered, CDC25 inhibitors may be combined with all-trans-retinoic acid (ATRA) plus valproic acid [167], low-dose cytarabine [168], hydroxyurea and/or 6-mercaptopurine [167][168][169][170][171].…”