Positive results of a phase III cancer clinical trial in an uncommon form of leukemia were released today. The results showed that adult patients with previously untreated acute promyelocytic leukemia (APL) who had standard chemotherapy to induce remission of their disease, and then received the chemotherapy drug arsenic trioxide to maintain remission, had a significantly better event-free survival (more patients free of leukemia) and better overall survival than those who received only standard chemotherapy . The trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and was led by one of its Cooperative Clinical Trials Groups — the Cancer and Leukemia Group B (CALGB).

“The positive result in a clinical trial of a common element holding an uncommon disease in remission for a significant period of time is very encouraging,” said NIH Director Elias A. Zerhouni, M.D.

Acute promyelocytic leukemia, an uncommon subtype of acute myeloid leukemia (AML), accounts for approximately 10 percent of AML cases, or about 1,500 cases per year, in the United States. It is most often diagnosed in young and middle aged adults, but it also occurs in children and older adults. Standard chemotherapy regimens produce complete remission rates of approximately 70 percent and show a five-year survival without the recurrence of disease in 35 to 45 percent of patients.

"Achieving success in a clinical trial for a rare cancer is a difficult task due to the limited number of patients eligible to enroll in the trial, so this is very encouraging news for all patients with this form of leukemia," said NCI Director John Niederhuber, M.D. "This positive outcome demonstrates, yet again, the benefits of clinical trials and will hopefully serve as encouragement for others to join such trials."

This particular type of leukemia is often accompanied by life-threatening bleeding at diagnosis that typically worsens, even as initial treatment is administered. Treatment has improved dramatically in recent years with the addition of all-trans retinoic acid (ATRA, or tretinoin) to chemotherapy. More recently, arsenic trioxide (Trisenox ®) was shown to be an effective drug for producing a second remission in patients who had a relapse or recurrence of their APL after initial treatment. Both ATRA and arsenic trioxide are approved by the U.S. Food and Drug Administration for the treatment of APL.

The CALGB-coordinated study tested the effectiveness and side effects from adding two 25-day courses of intravenous arsenic trioxide to the combination of ATRA and chemotherapy. Patients with newly diagnosed APL were randomly assigned to receive either (1) the standard remission treatment with ATRA twice daily, daunorubicin for four days, and cytarabine for seven days, both of which are standard chemotherapy drugs for this disease, followed by a standard post-remission regimen with two more courses of ATRA plus daunorubicin, or (2) the experimental treatment where patients received the same standard treatment with the addition of two courses of arsenic trioxide given immediately after the patient entered a complete or partial remission and before the standard post-remission regimen. The arsenic trioxide course was a two hour intravenous infusion, Monday through Friday, on an outpatient schedule for five weeks. Patients who remained free of visible leukemia after completion of the remission therapy then received an additional year of treatment with oral chemotherapy drugs to prevent the leukemia from relapsing.

Between June, 1999 and March, 2005, 582 patients enrolled on this study. Patients participated through one of five NCI-sponsored North American Cooperative Oncology Groups, including CALGB, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group (SWOG), Children's Oncology Group (COG) and the National Cancer Institute of Canada, Clinical Trials Group (NCIC-CTG). By study design, patients less than 15 years of age (11 percent of the entire group) were not assigned to the treatment that contained arsenic trioxide.

The percentage of adult patients who remained alive and in remission — free of relapse of their leukemia — three years after diagnosis was 77 percent on the treatment arm that included arsenic trioxide compared to 59 percent on the standard treatment arm. This difference was highly statistically significant. The greater effectiveness of the experimental combination also resulted in better overall survival after three years of 86 percent for the patients who received the arsenic trioxide compared to 77 percent for patients on the standard treatment arm.

Patients were followed for a median period of 29 months. After reviewing the study results, a data safety monitoring board notified the investigators and the NCI of the positive results, and the findings are being released so that all APL patients will have a chance to benefit from this therapy.

Bayard Powell, M.D., Wake Forest University, Winston-Salem, N.C., principal investigator of the study, said, “The willingness of patients with leukemia and their physicians to participate in this important clinical trial has markedly improved the outcome for these and future patients with APL.”

The side effects from treatment were reported at the annual meeting of the American Society of Hematology in Orlando, Fla., in December 2006. There was no difference in hematologic (blood count) toxicities between the group who received arsenic and those who did not, but there was a slightly higher incidence of headache and infection in the group who received arsenic trioxide. A complete scientific presentation of these study results is planned for the annual meeting of the American Society of Clinical Oncology in Chicago, Ill., in June 2007.

Richard Larson, M.D., University of Chicago, Ill., a co-investigator of the study, noted, “These results indicate that arsenic trioxide should be considered as part of the initial treatment of patients with acute promyelocytic leukemia.”

The study was sponsored by the Division of Cancer Treatment and Diagnosis (DCTD), NCI, under a Clinical Trials Agreement between DCTD, NCI and Cephalon, Inc., Frazer, Pa. (marketers and sellers of Trisenox®) and monitored by an independent Data and Safety Monitoring Board that recommended release of the results.

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The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.