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FDA Approves Arsenic Trioxide for Treatment of Acute Promyelocytic Leukemia

FDA Approves Arsenic Trioxide for Treatment of Acute Promyelocytic Leukemia

The injectable form of arsenic trioxide (Trisenox) was recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with a severe form of leukemia—acute promyelocytic leukemia (APL)—whose disease has recurred or who have failed to respond to standard therapy.

In the United States, APL represents 10% to 15% of the more than 10,000 patients who are diagnosed annually with acute myeloid leukemia."For patients with APL whose disease has recurred following initial treatment, the use of salvage therapy is highly toxic and rarely curative," said Carolyn Paradise, md, vice president of clinical development at Cell Therapeutics, Inc, manufacturer of Trisenox.

"Results of the clinical trials using Trisenox demonstrated that a significant number of those patients who suffered multiple relapses were able to achieve a complete remission, or a disappearance of all visible leukemia cells," Dr. Paradise continued. "The majority of patients who achieved complete remission were still alive and disease free with a median follow-up time of 16 months. This new treatment represents a significant advance for patients with this disease."

High Rate of Complete Remissions

A pivotal trial involving 40 patients with relapsed/refractory APL unresponsive to standard therapies was conducted at nine institutions, including Memorial Sloan-Kettering Cancer Center in New York and other leading cancer centers across the United States. A complete remission was seen in 70% of these patients, with the majority achieving molecular eradication of the genetic abnormality associated with APL. Complete remissions were reported on average within 2 months after initiation of therapy with arsenic trioxide.

"We are impressed with both the high rate of complete remission and the relapse-free survival in this high-risk population of APL patients whose previous treatment failed to eradicate their disease," said Steven Soignet, md, investigator in the Developmental Chemotherapy Service at Memorial Sloan-Kettering Cancer Center.

Toxicities Associated With Therapy

Most patients experienced some drug-related toxicity. Acute toxicities associated with arsenic trioxide therapy are well defined and, when monitored and treated appropriately, are manageable. Serious adverse events reported include APL-differentiation syndrome symptoms in 23% of patients, and hyperleukocytosis in 50%. Common toxicities included gastrointestinal, fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects were not permanent or irreversible, and they usually did not require an interruption in therapy.

Another important adverse event was QT prolongation. One serious case of QT prolongation evolved into an abnormally rapid heartbeat. This episode resolved spontaneously, and the patient was re-treated with arsenic trioxide without recurrence of the event. In contrast to the side effects that are prevalent with the use of standard chemotherapy, hair loss and mucositis were uncommon.

Dosing Schedule

Arsenic trioxide is administered intravenously in two phases: induction therapy consisting of daily injections of 0.15 mg/kg until the bone marrow is cleared of leukemic cells, for up to a maximum of 60 days, and consolidation therapy using the same dose for 25 days beginning 3 weeks after bone marrow remission is evident.

 
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