Arsenic Trioxide Produces High Remission Rates in Patients With Relapsed and Refractory Leukemia

December 1, 2001

Data presented at the Joint International Congress on Acute Promyelocytic Leukemia and Differentiation Therapy demonstrated that patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide achieved an overall survival

Data presented at the Joint International Congress onAcute Promyelocytic Leukemia and Differentiation Therapy demonstrated thatpatients with acute promyelocytic leukemia (APL) treated with arsenic trioxideachieved an overall survival at 24 months of 63%.

"Trisenox is a major medical breakthrough for the thousands of relapsedAPL patients whose previous treatments were unsuccessful," said Steven L.Soignet, MD, principal investigator of the arsenic trioxide pilot and pivotalclinical trials. "The high rate of complete remission and relapse-freesurvival associated with the use of this drug is very encouraging news for thispatient population, which traditionally has had a very poor prognosis."

Study Details

The data on arsenic trioxide presented at this meeting combines the resultsof two clinical studies that enrolled 52 patients with a median age of 39 years.One study was a pilot study in 12 patients with relapsed APL conducted atMemorial Sloan-Kettering Cancer Center, and the other, a 40-patient pivotaltrial conducted at nine medical centers across the United States. The results ofthe larger trial were published in a recent issue of the Journal of ClinicalOncology (9:3852-3860, 2001).

Patients were treated with 1- to 2-hour infusions of arsenic trioxide dailyuntil the time of bone marrow complete remission. Those who experienced acomplete response were offered one consolidation course of arsenic trioxide thatbegan 3 to 4 weeks later. Patients who maintained a complete response wereeligible to receive additional cycles of arsenic trioxide in a maintenancestudy, and some patients underwent transplants.

A total of 45 patients achieved a complete remission, for an overall responserate of 87%, with a 2-year relapse-free survival rate of 49%. Toxicities weremanageable, and there were no treatment-related deaths during the study.

"These results confirm Trisenox as a highly effective therapy forpatients with APL in whom standard treatments have failed," said Martin S.Tallman, MD, associate professor of Medicine at Northwestern University MedicalSchool. "They are particularly important because few treatment options havebeen available for patients with relapsed disease."

Selective Anticancer Agent

The latest findings suggest that arsenic trioxide has a dual mechanism ofaction. On one level, it works by destroying a protein that causes abnormallevels of immature white blood cells, while simultaneously boosting the naturalcell death process.

Researchers believe that an anomalous gene creates the abnormal protein thatprevents cell maturation. When arsenic trioxide is administered, it destroysthis protein, allowing cells to mature and natural cell death to occur. Celldeath occurs because arsenic trioxide acts specifically in the final pathwaythat leads to the death of a cell.

"Future studies will investigate whether this therapy is useful in thetreatment of hematologic malignancies. Existing clinical evidence has shownTrisenox to be an effective therapy that prolongs remissions in APL. In fact,Trisenox as a single agent has been shown to produce a status of molecularremission in these patients. Molecular remission corresponds to clearance of theAPL-specific tumor marker in patient’s blood and bone marrow, below the levelof polymerase chain reaction sensitivity. This represents an advancedtherapeutic goal correlating with more favorable patient outcomes" saidFrancesco Lo Coco, MD, department of cellular biotechnologies and hematology,University of La Sapienza, Rome, Italy.

Adverse Events

Most patients experienced some drug-related toxicity. Acute toxicitiesassociated with arsenic trioxide therapy were well defined and, when monitoredand treated appropriately, were manageable. Serious adverse events includedAPL-differentiation syndrome symptoms (eg, fever, weight gain, shortness ofbreath, and muscoloskeletal pain) in 23% of patients, and hyperleukocytosis in50% of patients. Common toxicities included nausea, vomiting, diarrhea,abdominal pain, fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching,headaches, and dizziness.

Another important adverse event was QT prolongation. One serious case of QTprolongation evolved into an abnormally rapid heartbeat. This episode resolvedspontaneously, and the patient was retreated with arsenic trioxide withoutrecurrence of the event.

In contrast to the side effects prevalent with the use of standardchemotherapy, hair loss and mucositis were uncommon.