Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid.
BACKGROUND
The authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all-trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).


METHODS
Twenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45-100 microg/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for > or = 2 months were considered evaluable.


RESULTS
Hematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63-550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone.


CONCLUSIONS
Differentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life.
Pilatrino
Chiara
C
Department of Clinical and Biological Science, University of Turin, Turin, Italy. chiarapila@yahoo.it
Cilloni
Daniela
D
Messa
Emanuela
E
Morotti
Alessandro
A
Giugliano
Emilia
E
Pautasso
Marisa
M
Familiari
Ubaldo
U
Cappia
Susanna
S
Pelicci
Pier Giuseppe
PG
Lo Coco
Francesco
F
Saglio
Giuseppe
G
Guerrasio
Angelo
A
D000208:Acute Disease; D000368:Aged; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy*; D010976:Platelet Count; D012306:Risk; D014212:Tretinoin / Q000627:therapeutic use*; D014635:Valproic Acid / Q000627:therapeutic use*
D014212:Tretinoin; D014635:Valproic Acid