Adding a drug that activates genes to frontline combination therapy for acute myeloid leukemia (AML) resulted in an 85% remission rate after initial treatment, researchers at The University of Texas MD Anderson Cancer Center reported at the 53rd Annual Meeting of the American Society of Hematology.
“Results of the Phase II clinical trial of 75 patients set the stage for a national Phase III clinical trial of the new combination compared to standard-of-care frontline combinations used at MD Anderson and elsewhere,” said study leader Guillermo Garcia-Manero, M.D., professor in MD Anderson’s Department of Leukemia.
Addition to Chemotherapy
Study patients received the drug vorinostat (suberoylanilide hydroxamic acid), known commercially as Zolinza? (Merck Sharp & Dohme), a histone deacetylase inhibitor, in addition to the chemotherapy drug cytarabine and idarubicin, an anthracycline antibiotic commonly used as chemotherapy. Vorinostat,not approved for patients with AML, was first approved by the US FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies as the first in a new class of anticancer agents that inhibit histone deacetylases, which have a key role in the epigenetic regulation of gene expression.
“The overall response rates are encouraging, and most higher risk patients did very well,” Garcia-Manero said. He will be the principal investigator of the Phase III trial, which will be conducted through the National Cancer Institute‘s Cooperative Oncology Groups.
Mechanism of Action
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.
High response for higher risk patients
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 11 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.Of 29 patients who were diploid (a pair of each chromosome, double the usual number), 25 had complete remissions and two achieved CRp, for an overall response rate of 93%. Their median overall survivial was 105 weeks and event-free survival was 68 weeks.Seventeen patients with -5/-7 cytogenetic alterations fared less well, with a 64% overall response rate and median overall survival of 34 weeks and median event free survival of 14 weeks.
Side effects
The researchers did not observe cardiac toxicities or excess toxicity related to vorinostat. Common side effects were diarrhea (72%), nausea and vomiting (65%) and skin toxicities (38%).Nineteen patients who achieved either CR or CRp had blood stem cell transplants. Median overall survival and event free survival had not been reached for those patients.Garcia-Manero said levels of two proteins, NRF2 and CYBB, were associated with longer survival.
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.
763 Final Report of a Phase II Trial of Vorinostat with Idarubicin and Cytarabine for Patients with Newly Diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)
Program: Oral and Poster Abstracts
Abstract: 763
Type: Oral
Session: 615. Acute Myeloid Leukemia – Therapy, excluding Transplantation: Clinical Studies
When: Monday, December 12, 2011: 4:30 PM
Where: Room 30 (San Diego Convention Center)
For more information:
– Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008 Feb 1;111(3):1060-6. Epub 2007 Oct 25.
– Sanchez-Gonzalez B, Yang H, Bueso-Ramos C, Hoshino K, Quintas-Cardama A, Richon VM, Garcia-Manero G. Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor. Blood. 2006 Aug 15;108(4):1174-82. Epub 2006 May 4.
