Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes.
OBJECTIVE
Epigenetic changes play a role and cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS). We conducted a phase II multicenter study on the combination of the DNA-methyltransferase inhibitor 5-azacytidine (5-AZA) and the histone deacetylase inhibitor valproic acid (VPA) in patients with higher risk MDS.


METHODS
We enrolled 62 patients with MDS (refractory anemia with excess blasts, 39 patients; refractory anemia with excess blasts in transformation, 19 patients; and chronic myelomanocytic leukemia (CMML), 4 patients) and an International Prognostic Scoring System (IPSS) rating of Intermediate-2 (42 patients) or high (20 patients). VPA was given to reach a plasma concentration of >50 microg/mL, then 5-AZA was added s.c. at 75 mg/m(2) for 7 days in eight monthly cycles.


RESULTS
The median overall survival was 14.4 months. At a median follow-up of 12 months (range, 0.7-21.0), the disease progressed in 20 patients, with 21% cumulative incidence of progression. Of 26 patients who completed eight cycles, 30.7% obtained complete or partial remission, 15.4% had a major hematologic improvement, whereas 38.5% showed stable disease. Drug-related toxicity was mild. Favorable prognostic factors for survival were IPSS Intermediate-2 and plasma VPA of > or =50 microg/mL (log rank = 0.013 and 0.007, respectively). Analysis of polymorphisms important for the metabolism of the drugs used in the trial showed that carriers of the CYP2C19*2 variant of cytochrome P450 required higher VPA doses to achieve the target VPA plasma concentration of 50 microg/mL on day 1 of 5-AZA treatment (P = 0.0021).


CONCLUSIONS
Our data show that the 5-AZA/VPA combination is active and safe in patients with MDS with a poor prognosis. Achievement of VPA therapeutic levels may indeed increase 5-AZA efficacy.
Voso
Maria Teresa
MT
Istituto di Ematologia, Universita Cattolica S. Cuore, Rome, Italy. mtvoso@rm.unicatt.it
Santini
Valeria
V
Finelli
Carlo
C
Musto
Pellegrino
P
Pogliani
Enrico
E
Angelucci
Emanuele
E
Fioritoni
Giuseppe
G
Alimena
Giuliana
G
Maurillo
Luca
L
Cortelezzi
Agostino
A
Buccisano
Francesco
F
Gobbi
Marco
M
Borin
Lorenza
L
Di Tucci
Anna
A
Zini
Gina
G
Petti
Maria Concetta
MC
Martinelli
Giovanni
G
Fabiani
Emiliano
E
Fazi
Paola
P
Vignetti
Marco
M
Piciocchi
Alfonso
A
Liso
Vincenzo
V
Amadori
Sergio
S
Leone
Giuseppe
G
D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001374:Azacitidine / Q000008:administration & dosage / Q000627:therapeutic use*; D065731:Cytochrome P-450 CYP2C19; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D014635:Valproic Acid / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008780:Methyltransferases; D001374:Azacitidine