Valproic Acid as Adjunct to Induction Therapy in Patients with Acute Myeloid Leukemia: First Results of Two Randomized Studies of the AMLSG.

Differentiation arrest in acute myeloid leukemia (AML) results in part from dysregulation of histone acetylation and deacetylation, leading to transcriptional repression of differentiation-inducing genes. Transcriptional repression can be returned by histon deacetylation inhibitors, such as valproic acid (VPA). In September 2004, we initiated two randomized trials [AMLSG 07-04 (age 18–60 yrs), AMLSG 06-04 (age >60yrs)] to evaluate the impact of VPA as adjunct to standard induction therapy (idarubicin and cytarabine; additional etoposide in pts. <60 yrs) in combination with all-trans retinoic acid (ATRA). This report focuses on serum-levels of VPA achieved by mid-fast saturation, correlation between total and free unbound serum levels of VPA, and influence on hematological reconstitution and morphological abnormalities at remission control induced by VPA. Dose schedule of mid-fast saturation is VPA i.v. 400mg bid. day 1+2, followed by serum level adapted p.o. treatment with retard formulation 4 times a day with a target serum level of 50 to 150mg/l. Data on serum levels in correlation to VPA-dose from 42 patients are available. Median serum level after 2 days of intravenous treatment was 34 mg/l (range 1 to 80mg/l). Median serum level at day 10 of induction therapy was 57mg/l (range 1 to 135mg/l) with 65% of patients having a minimum serum level above 50mg/l. Side effects induced by VPA were tremor, confusion and fatigue necessitating dose reduction of VPA in 5 (12%) cases. A linear regression model revealed high correlation between the free unbound fraction of VPA, total VPA-serum level (coef. 0.19 p<0.0001) and albumin serum level (coef. −0.30, p<0.0001). Other variables such as creatinine or total protein serum levels as well as age did not show significant influence on the free unbound fraction of VPA. High total VPA-serum levels during and after induction therapy were associated with morphological particularities at the time of morphological bone marrow assessment between day 21 to 28. In these cases there was morphological synchronization predominantly at the promyelocyte stage and a slightly but not significantly delayed reconstitution of peripheral blood values. In conclusion, VPA as adjunct to intensive induction therapy is feasible and has possible influence on the kinetics and morphology during hematological regeneration.