The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia.
BACKGROUND
Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all-trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro.


METHODS
We used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy (32 AML secondary to myelodysplastic syndrome [MDS], 22 de novo AML, 4 AML secondary to myeloproliferative syndrome). VPA serum concentrations were 50-100 mug/mL. Thirty-one patients received VPA monotherapy. ATRA was added later in 13 patients who did not respond or who relapsed. Another 27 patients received VPA plus ATRA from the start. Median treatment duration was 93 days for VPA and 88 days for ATRA.


RESULTS
The response rate was only 5% according to International Working Group (IWG) criteria for AML but was 16% when IWG response criteria for MDS were used, which capture hematologic improvement and stabilization of the disease. These endpoints, which are not necessarily correlated with diminishing blast counts, are relevant for the patients' quality of life. Among 23 patients with a peripheral blast count > 5%, 6 (26%) showed a diminishing blast count, and 5 of these had a complete peripheral blast clearance.


CONCLUSIONS
Future trials should combine VPA with chemotherapy or demethylating agents.
Kuendgen
Andrea
A
Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, Dusseldorf, Germany. kuendgen@med.uni-duesseldorf.de
Schmid
Mathias
M
Schlenk
Richard
R
Knipp
Sabine
S
Hildebrandt
Barbara
B
Steidl
Christian
C
Germing
Ulrich
U
Haas
Rainer
R
Dohner
Hartmut
H
Gattermann
Norbert
N
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage / Q000627:therapeutic use*; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D014212:Tretinoin; D014635:Valproic Acid