Standard chemotherapy with vorinostat improves survival in AML, MDS
MedWire News: Patients with newly diagnosed acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) show high induction response rates when treated with vorinostat in addition to standard idarubicin and cytarabine therapy, suggest phase II trial findings presented at the 2011 annual meeting of the American Society of Hematology.
"The overall response rates are encouraging, and most higher risk patients did very well," said lead study author Guillermo Garcia-Manero (MD Anderson Cancer Center, Houston, Texas, USA) in a press release.
In total, 75 patients aged an average of 52 years with newly diagnosed AML or high risk MDS were assigned to receive induction therapy with vorinostat 500 mg orally three times per day (days 1-3) followed by intravenous idarubin 12 mg/m2 daily for 3 days (days 4-6) and intravenous cytarabine 1.5 g/m2 as a continuous infusion daily for 3 or 4 days (days 4-7).
Patients in remission were treated with five cycles of consolidation therapy using lower doses of the combination and up to 12 months of maintenance with vorinostat on its own.
Combination therapy was well tolerated, with no excess vorinostat-related toxicity observed and an induction mortality rate of 4%.
The most commonly reported toxicities in the study included diarrhea (72%), nausea and vomiting (65%), and skin toxicity (38%). No cardiac toxicity was observed.
Overall, 57 patients achieved complete remission (CR), and another seven had CR with incomplete platelets (CRp), amounting to an overall response rate of 85%. Median overall survival (OS) was 82 weeks and median event-free survival (EFS) was 47 weeks.
All of the 11 enrolled patients with the high-risk Flt-3 ITD mutation responded to treatment, with 10 achieving CR. In this group of patients, median OS and EFS were 91 and 66 weeks, respectively.
A slightly lower remission rate was observed among the 29 patients who were diploid, with 25 showing CR for an overall response rate of 93%. Median OS was 105 weeks and EFS was 68 weeks.
Patients with -5/-7 cytogenetic alterations showed the worst outcomes, with a 64% overall response rate and a median OS and EFS of 34 and 14 weeks, respectively.
In addition, 25% of patients with a CR or CRp received blood stem cell transplants. However, OS and EFS were not reached for these patients.
Further analysis revealed that levels of two proteins, NRF2 and CYBB, were significantly associated with longer survival.
Current plans for a phase III trial comparing standard 7-day treatment of cytarabine and anthracycline, idarubicin and cytarabine, and the proposed regimen are under way.
By Ingrid Grasmo