Clinical trial of valproic acid and all‐trans retinoic acid in patients with poor‐risk acute myeloid leukemia

Abstract

BACKGROUND Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induced in vitro differentiation of primary acute myeloid leukemia (AML) blasts, an effect enhanced by all‐trans retinoic acid (ATRA). Clinical responses to VPA were recently observed in patients with myelodysplastic syndrome (MDS). Herein, the authors have described results of a clinical trial with VPA plus ATRA in 26 patients with poor‐risk AML. METHODS VPA (5–10 mg/kg starting dose) and ATRA (45 mg/m2) were administered orally. Low‐dose AraC or hydroxyurea were permitted to control leukocytosis. Biologic activity of VPA was confirmed by serial analysis of HDAC2 protein levels in peripheral blood (PB) mononuclear cells. RESULTS Nineteen of 26 patients completed at least 4 weeks of VPA/ATRA treatment; 7 patients were withdrawn prematurely because of rapidly progressive disease (n = 3) or unacceptable neurologic and cardiovascular toxicity (n = 4). Additional cytoreductive treatment was required in 58% of patients enrolled. Median treatment duration was 3 months. No patient achieved complete remission, one with de novo AML had a minor response, and two patients with secondary AML arising from myeloproliferative disorder (MPD) achieved a partial remission and clearance of PB blasts, respectively. The latter responses were accompanied by profound granulocytosis and erythrocytosis in both patients, reminiscent of the response pattern known from ATRA treatment of acute promyelocytic leukemia. However, cytogenetic analysis of isolated CD34+ cells and granulocytes did not reveal terminal differentiation of leukemic blasts. CONCLUSIONS Treatment with VPA/ATRA results in transient disease control in a subset of patients with AML that has evolved from a myeloproliferative disorder but not in patients with a primary or MDS‐related AML. Cancer 2005. © 2005 American Cancer Society.

Valproic Acid: Second Generation

“…53 These findings underscore the potential of novel epigenetic approaches in transplantation, gene, and neurological therapies. Bug et al 54 reported that the combination of VPA with all-trans retinoic acid is effective in patients with advanced acute myeloid leukemia, leading to blast cell reduction and improvement of hemoglobin. Investigation of the effect of VPA on normal hematopoietic stem cells (HSC) shows that the drug increases both proliferation and selfrenewal of HSC.…”

Histone deacetylase inhibitors: molecular mechanisms of action

“…HDACi, for example, the hydroxamic acid-based vorinostat (SAHA, Zolinza), are promising drugs for cancer treatment (Richon et al, 1998;Marks and Breslow, 2007). Several HDACi are in phase I and II clinical trials, being tested in different tumor types, such as cutaneous T-cell lymphoma, acute myeloid leukemia, cervical cancer, etc (Bug et al, 2005;Chavez-Blanco et al, 2005;Kelly and Marks, 2005;Duvic and Zhang, 2006) (Table 2). Although considerable progress has been made in elucidating the role of HDACs and the effects of HDACi, these areas are still in early stages of discovery.…”

Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells

“…Selection of the respective DACi doses was based on previously proven inhibition of deacetylase activity in primary AML progenitor cells and clinical relevance. 4,19 DACi treatment efficiently inhibited proliferation of LAFP-as well as mock-transduced 32D cells by the factor 5-21 compared with untreated controls (Fig. 1C).…”

“…DACi additionally induce selective proteasomal degradation of histone decetylase 2 (HDAC2), DNA methyltransferases and other proteins responsible for aberrant gene repression and signaling. [4][5][6] This effect equally alters the cellular program, but to date, the underlying mechanisms remain elusive and have not yet been studied in the leukemic stem and progenitor compartment.…”