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Preliminary results from a large, randomized clinical trial for patients ages 16 to 60 with previously untreated acute myeloid leukemia (AML), a cancer of the blood and bone marrow, show that patients who received a high dose of a commercially available chemotherapy drug, daunorubicin, during initial therapy lived longer than patients who received a standard dose of the same drug. Daunorubicin, a drug originally approved for use by the U.S. Food and Drug Administration in 1979, inhibits DNA replication and repair and leads to cell death. The clinical trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG).

The Data Monitoring Committee overseeing the trial (known as E1900, clinical trial registry number NCT00049517) recommended that the results of a recent interim analysis be made public because the study had met its primary endpoint of demonstrating improved overall survival. Researchers found that the patients in the trial who received the higher dose of daunorubicin (90-milligrams per square meter of body surface area, or 90mg/m², given on each of the first three days of treatment) in combination with standard treatment of a chemotherapy drug used for AML since the 1960s, ara-C (cytarabine), had a median overall survival of 23.7-months compared to patients treated with the standard dose of daunorubicin (45 mg/m² given on each of the first three days of treatment) in combination with ara-C, who had a median overall survival of 15.1-months. This survival difference was highly statistically significant. Also of importance, the frequency of serious treatment toxicities observed in this study was similar between the high-dose and standard-dose daunorubicin treatment groups.

"The findings of this large clinical trial are important because they will likely change practice and improve the outcome for many patients with AML," said Martin Tallman, M.D., chair of the ECOG Leukemia Committee and professor of Medicine at Northwestern University Feinberg School for Medicine and the Robert H. Lurie Comprehensive Cancer Center, Chicago. The trial's study chair was Hugo Fernandez, M.D., associate professor of Medicine and Oncology and associate chief of the Blood & Marrow Transplantation Division at the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.

A total of 633 patients with non-promyelocytic AML who had not previously received chemotherapy were enrolled in this study between December 2004 and September 2008. Patients were randomly assigned to one of two treatment groups to receive initial, or induction, chemotherapy with either high-dose or standard-dose daunorubicin with ara-C. Patients who were assessed as having a complete, positive response to induction therapy were then treated with additional therapy. As of September 2008, 334 patients proceeded to the next, or consolidation step of the study.

Bone marrow transplantation and peripheral blood stem cell transplantation are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy and are common procedures for patients with AML. In this trial, those patients with unfavorable prognostic factors and/or matching sibling donors were treated with an allogeneic (donor) transplant whenever possible. Among those who received standard-dose daunorubicin, 4.7% underwent allogeneic hematopoietic stem cell transplantation (HSCT). For those randomized to high-dose daunorubicin, 5.7% underwent allogeneic HSCT. There were no differences between the treatment groups in terms of subsequent chemotherapy or autologous transplantation that affect the results of the trial.

Because daunorubicin is an FDA-approved drug for AML, patients with this disease can potentially gain immediate benefit from the results of this trial. "This trial is a prime example of a study question that would only have been carried out by an NCI-sponsored oncology Cooperative Group because the agent tested in the trial has been in common use for this disease for more than three decades and there's little incentive for commercial concerns to test an already approved product," said James H. Doroshow, M.D., director of NCI's Division of Cancer Treatment and Diagnosis.

An estimated 13,290 people will be diagnosed with AML in the United States in 2008. Most cases are in adults with half the cases being under 60 years of age. Overall, only about 33% of those with AML survive the disease, and survival is less likely with increasing age. Advances in AML therapy depend in large part on the ability to increase the initial response to induction therapy.