Acute Myeloid Leukemia Patients Respond to New Combination

Adding a third drug to frontline combination therapy for acute myeloid leukemia resulted in an 85% complete remission rate in a clinical trial at The University of Texas MD Anderson Cancer Center.

Researchers reported study results today at the 53rd Annual Meeting of the American Society of Hematology. The high overall response rate to initial treatment in the Phase II clinical trial will lead to a nationwide Phase III clinical trial of the three-drug combination.

The 75 patients on the study received the drug vorinostat, known commercially as Zolinza, a histone deacetylase inhibitor, in addition to the chemotherapy drug cytarabine and idarubicin, an anthracycline antibiotic commonly used as chemotherapy.

"The overall response rates are encouraging, and most higher risk patients did very well," says study leader Guillermo Garcia-Manero, M.D., professor in MD Anderson's Department of Leukemia. Garcia-Manero will be the principal investigator of the Phase III trial, which will be conducted through the National Cancer Institute's Cooperative Oncology Groups.

Adding a third drug to frontline combination therapy for acute myeloid leukemia resulted in an 85% complete remission rate in a clinical trial at The University of Texas MD Anderson Cancer Center.

Researchers reported study results today at the 53rd Annual Meeting of the American Society of Hematology. The high overall response rate to initial treatment in the Phase II clinical trial will lead to a nationwide Phase III clinical trial of the three-drug combination.

The 75 patients on the study received the drug vorinostat, known commercially as Zolinza, a histone deacetylase inhibitor, in addition to the chemotherapy drug cytarabine and idarubicin, an anthracycline antibiotic commonly used as chemotherapy.

"The overall response rates are encouraging, and most higher risk patients did very well," says study leader Guillermo Garcia-Manero, M.D., professor in MD Anderson's Department of Leukemia. Garcia-Manero will be the principal investigator of the Phase III trial, which will be conducted through the National Cancer Institute's Cooperative Oncology Groups.

Vorinostat activates suppressed genes by protecting acetyl chemical groups that adhere to histone proteins, which are connected to DNA like beads on a string. Acetylated histones make genes more accessible for transcription, so vorinostat presumably works by reactivating blocked tumor-suppressing genes.

According to the NCI's Surveillance Epidemiology and End Results database, about 14,000 new cases of AML are diagnosed annually in the United States and the disease kills about 9,000 people each year. AML is characterized by swift proliferation of immature white blood cells in the blood and bone marrow that crowds out normal cells, leaving patients exposed to infection, severe anemia and bleeding.

Overall, 57 patients achieved complete remission, and another seven had complete remission with incomplete platelets (CRp), for an overall response rate of 85$. Median overall survival was 82 weeks and median event free survival was 47 weeks.

Overall response rate for 10 patients with the high-risk Flt-3 ITD mutation was 100%, with 10 achieving complete remissions and the other a CRp. Their median overall survival was 91 weeks and median event free survival was 66 weeks.

No cardiac toxicities and no excess toxicity related to vorinostat were observed. Common side effects were diarrhea (72%), nausea and vomiting (65%) and skin toxicities (38%).

Phase III clinical trial

There will be three arms for the randomized, blinded Phase III clinical trial:

• Standard frontline therapy of seven days of cytarabine infusion and three days of the anthracycline antibiotic daunirubicin
• MD Anderson standard frontline therapy of three days of idarubicin with high-dose continuous infusion of cytarabine for four days
• Three days of idarubicin, four days of cytarabine plus vorinostat

Additional resources

ASH Abstract 763

MD Anderson news release.