Food and Drug Administration
U.S. Department of Health and Human Services
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T00-47 Print Media: 301-827-6242
September 26, 2000
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The FDA has approved Trisenox (arsenic trioxide) for the treatment of patients with acute promyelocytic leukemia (APL) who have not responded to, or have relapsed following the use of all trans-retinoic acid and anthracycline-based chemotherapy, which is considered first line therapy.
Development of Trisenox was rapid. The drug was approved for marketing only 3 years after the study of the drug was first started in the U.S.
APL is a cancer of the white blood cells. It is characterized by a rapid accumulation of abnormal white blood cells in the bone marrow and blood resulting in anemia, susceptibility to infections, bleeding, and hemorrhage. Patients who have a relapse or who have APL that doesn't respond to first line therapy are currently retreated with all trans-retinoic acid and anthracycline-based chemotherapy or both. Response to therapy is good if a long time has elapsed since initial treatment but usually not if relapse is rapid or if there is no initial response. Trisenox offers a new alternative.
Trisenox was approved as an orphan drug, a drug intended for the treatment of rare diseases or conditions. An estimated 1500 new cases of APL are diagnosed each year, of which an estimated 400 patients will not respond to, or will relapse from, first line therapy.
Arsenic-containing preparations have been in medical use for more than 2000 years. Arsenic-based therapy was used in the United States and Europe more than 100 years ago for leukemia therapy as well as for treatment of infections, but these treatments were subsequently replaced by modern chemotherapy and antibiotics. More recently, interest in arsenic-based therapy was revived by reports of the anti-leukemic activity of some traditional Chinese preparations. Chinese scientists subsequently found that the active ingredient was arsenic trioxide.
The safety and effectiveness of Trisenox were evaluated in the treatment of relapsed or refractory APL in a multicenter clinical study involving 40 patients who received arsenic trioxide infusions. Twenty- eight of the 40 patients (70%) had a remission of their leukemia and met the study-defined criteria for "response". The median time to remission was 51 days. Arsenic trioxide converts the immature cancerous white blood cells into normal white blood cells, an effect similar to that of all trans-retinoic acid. A consequence of this can be a sudden increase in the white blood cell count. In some cases the increase in white blood cells is accompanied by signs of inflammation and fluid accumulation, particularly in the lining of the heart and lungs. This is termed the "APL differentiation syndrome" and can be fatal. The usual treatment is to temporarily stop the leukemia therapy and treat with high dose steroids. In the study submitted to support the approval of Trisenox, the APL differentiation syndrome appeared in 8 of the 40 patients (20%), but in no cases was there a need to interrupt therapy with arsenic trioxide.
Trisenox can cause an important change in the electrocardiogram, an increase in what is termed the Q- T interval. An increase in the Q-T interval can in some cases lead to irregular heart rhythms that can be fatal. Significant increases of the Q-T interval appeared in 16 of the 40 patients (40%). In those patients, no serious abnormal rhythm developed (one patient had a brief episode) but the risk of the effect required that the ECG and patients be closely monitored. Other adverse effects of Trisenox are abdominal discomfort, nausea, vomiting, headache, fatigue, skin changes, and fluid accumulation. Most of the adverse effects were considered mild and resolved after therapy was completed.
In March 1998 arsenic trioxide was granted orphan designation for the treatment of patients with APL. Cell Therapeutics, Inc., will market the drug.
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