FDA Approves Arsenic Trioxide for Treatment of Acute Promyelocytic Leukemia

January 1, 2001

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.

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—acutepromyelocytic leukemia (APL)—whose disease has recurred or who have failed torespond to standard therapy.

In the United States, APL represents 10% to 15% of the more than10,000 patients who are diagnosed annually with acute myeloid leukemia."Forpatients with APL whose disease has recurred following initial treatment, theuse of salvage therapy is highly toxic and rarely curative," said CarolynParadise, md, vice president of clinical development at Cell Therapeutics, Inc,manufacturer of Trisenox.

"Results of the clinical trials using Trisenox demonstratedthat a significant number of those patients who suffered multiple relapses wereable to achieve a complete remission, or a disappearance of all visible leukemiacells," Dr. Paradise continued. "The majority of patients who achievedcomplete remission were still alive and disease free with a median follow-uptime of 16 months. This new treatment represents a significant advance forpatients with this disease."

High Rate of Complete Remissions

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

"We are impressed with both the high rate of completeremission and the relapse-free survival in this high-risk population of APLpatients whose previous treatment failed to eradicate their disease," saidSteven Soignet, md, investigator in the Developmental Chemotherapy Service atMemorial Sloan-Kettering Cancer Center.

Toxicities Associated With Therapy

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

Another important adverse event was QT prolongation. One seriouscase of QT prolongation evolved into an abnormally rapid heartbeat. This episoderesolved spontaneously, and the patient was re-treated with arsenic trioxidewithout recurrence of the event. In contrast to the side effects that areprevalent with the use of standard chemotherapy, hair loss and mucositis wereuncommon.

Dosing Schedule

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