Prospective Phase III Trial of Valproic acid (VPA) In Combination with All-Trans Retinoic Acid (ATRA) and Intensive Induction Therapy for AML In Older Patients: The German-Austrian AMLSG 06-04 Study

Treatment options in AML patients older than 60 years are limited. In our previous randomized AML HD98B trial, the addition of all-trans retinoic acid (ATRA) to intensive chemotherapy resulted in an increased complete remission (CR) rate, event-free (EFS) and overall survival (OS). Recent reports indicated a synergistic action of the histone deacetylase inhibitor, valproic acid (VPA), and ATRA as differentiating agents. A synergic effect of VPA in combination with cytarabine and anthracyclines was also observed in vitro.

To evaluate VPA in combination with intensive induction therapy and ATRA in older patients with newly diagnosed AML.

Between August 2004 and February 2006 186 patients were randomized (standard arm, n=93; investigational arm, n=93) in the AMLSG 06-04 study (ClinicalTrials.gov Identifier: NCT00151255); median age was 68 years (60-84). The first 77 were randomized to receive 2 induction cycles (idarubicin 12 mg/m² i.v. days 1–3, cytarabine 100 mg/m² cont. i.v. days 1–5, ATRA 45 mg/m² days 3–5 and 15 mg/m² days 6–28) with or without VPA (days 1–28; started at 400 mg twice a day iv for 2 days and then adapted after day 2 po in order to obtain a serum level of 60–150 mg/l). After an interim analysis the study was amended; for the following 109 patients idarubicin was dose-reduced to day 1 and 3 and VPA only added during the first induction cycle. All patients were intended for consolidation.

CR rates after double induction were in trend higher in the standard arm (standard, 51%; investigational, 40%; p=0.18), whereas rates of early death (ED) were significantly higher in the investigational arm (8% versus 24%; p=0.004) of the study. The increased rates of ED in the investigational arm were present before (p=0.06) and after the amendment (p=0.05).

The main observed toxicities attributed to VPA were grade 3/4 infections and delayed hematologic recovery, with differences between the two arms exclusively seen in the second induction cycle and only in the cohort treated before the amendment: grade 3/4 infections 33.3% versus 53% (p=0.0001); median time to WBC count >1.000 /μ L 21 days versus 26 days (p= 0.02); median time to neutrophil count >500/μ L 24 days versus 30 days (p=0.002); median time to platelet count >20.000/μ L, 19 days versus 28 days (p=0.009) in the standard and investigational arm, respectively. Pharmacokinetic studies revealed that the aimed VPA-serum level of above 60mg/l was achieved in only half of the patients at day 8 of treatment. The interrelationship between VPA-dosage and serum level was weak (Spearman's coefficient, 0.35). The correlation between total VPA-serum level and free VPA-serum level evaluated in a subset of patients adjusted for albumin level was strong (p<0.0001).

The median follow up was 47 months; OS and EFS were not significantly different (3-year OS; standard, 16.3%; investigational, 13.2% (p=0.33); EFS; standard, 4.6%; investigational, 8.6% (p=0.77). The cumulative incidence of relapse (CIR) and death at 3 years was 79% and 10% for the standard arm as well as 68% and 5% for the investigational arm (p=0.16, p=0.73), respectively. Multivariate Cox regression analysis on OS revealed a negative impact of age above 70 years (HR, 1.76; p=0.003), high log10(WBC) (HR, 1.59; p=0.0006), adverse cytogenetics (HR, 2.05; p=0.0009) and in trend wild type NPM1 (HR, 1.58; p=0.06), whereas treatment arm was not significant (HR, 1.21; p=0.29).

In older patients with AML, the addition of VPA to standard induction treatment did not improve clinical outcome. VPA was associated with an increased rate ED due to infections and delayed hematologic recovery.

Döhner:Pfizer: Research Funding. Schlenk:Celgene, Pfizer, Novartis, Cephalon, Amgen:.