Addition of vorinostat yields high remission rate in AML study

Researchers observed an 85% remission rate among a group of patients with acute myeloid leukemia (AML) who received the histone deacetylase inhibitor vorinostat in addition to the chemotherapeutic agent cytarabine as well as idarubicin, an anthracycline antibiotic commonly used as chemotherapy. Vorinostat appears to work by reactivating blocked tumor-suppressing genes.

In the phase II clinical trial of 75 patients (median age 52 years), 57 achieved complete remission, and another seven had complete remission with incomplete platelets, for an overall response rate of 85%. Median overall survival was 82 weeks and median event-free survival was 47 weeks.

The 11 participants with the high-risk Flt-3 ITD mutation fared even better: In that subset, overall response rate was 100%, with 10 patients achieving complete remission and the remaining patient a complete remission with incomplete platelets. Median overall survival was 91 weeks and median event-free survival was 66 weeks.

Similarly, of 29 patients who had diploid cytogenetics (possessing double the usual number of chromosomes), 25 had complete remission and two achieved complete remission with incomplete platelets, or an overall response rate of 93%, median overall survival of 105 weeks, and median event-free survival of 68 weeks.

The regimen was less successful for 17 patients with -5/-7 cytogenetic alterations. This group demonstrated an overall response rate of 64%, median overall survival of 34 weeks, and median event-free survival of 14 weeks.

Levels of two proteins—NRF2 and CYBB—were associated with longer survival, according to a statement by Guillermo Garcia-Manero, a professor in the Department of Leukemia at the University of Texas M. D. Anderson Cancer Center in Houston, Texas.

Garcia-Manero's group, which reported its findings at the annual meeting of the American Society of Hematology, held December 10-13, 2011, in San Diego, California, observed no cardiac toxicities and no excess toxicity related to vorinostat use. Common side effects were diarrhea (in 72% of patients), nausea and vomiting (65%), and skin toxicities (38%).

These results have set the stage for a national phase III trial, which will compare three interventions:

  • Standard frontline therapy of 7 days of cytarabine infusion and 3 days of the anthracycline antibiotic daunirubicin.
  • M. D. Anderson standard frontline therapy of 3 days of idarubicin with high-dose continuous infusion of cytarabine for 4 days.
  • 3 days of idarubicin, 4 days of cytarabine plus vorinostat.
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