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Arsenic Compounds Effective Against APL

Arsenic Compounds Effective Against APL

NEW ORLEANS—Two forms of arsenic are effective for inducing remissions in people with acute promyelocytic leukemia (APL), according to data presented at the ASH meeting.

Used medically for more than 2,000 years, arsenic had been largely abandoned in the 20th century until two Chinese research teams reported in 1996 that they had obtained remissions in APL patients with arsenic, reported Steven Soignet, MD, of the Developmental Chemotherapy Service at Memorial Sloan-Kettering Cancer Center in New York. Inspired by these results, Dr. Soignet began studying the use of arsenic trioxide (As2O3)in APL.

He reported results of a study begun in April 1998 among 40 people with relapsed or refractory APL. They received arsenic trioxide at a dose of 0.15 mg/kg in an infusion over 1 to 2 hours.

Report Treatments

Treatment was repeated each day until visible leukemic cells disappeared from the bone marrow or until day 60, whichever came first. Patients who achieved complete remission were eligible for further arsenic trioxide treatments.

Treatment lasted a median of 34 days. Complete remission (defined as all normal blood results) was achieved by 34 (85%) patients at 28 to 85 days, with a median of 53 days. Cumulative arsenic trioxide dose ranged from 115 to 1,014 mg and averaged 410 mg.

Of patients who did not achieve remission, two seemed to be resistant, three died before evaluation of the effect of the drug, and one patient continued to have residual acute myelogenous leukemia, although her previously positive reverse transcriptase polymerase chain reaction test for the fusion gene PML-RAR-alpha became negative.

Dose-Limiting Effects

Dose-limiting adverse effects were weight gain and fluid retention (as much as 10 kg of fluid) and neuropathy. The most common side effects of the arsenic treatment were high glucose concentrations, prolonged QTc interval, skin rash, fatigue, and dizziness during the infusion.

Dr. Soignet concluded that arsenic trioxide is safe and very effective for inducing complete remission in people with APL, even those who’ve been heavily pretreated and have limited options. He pointed out that arsenic trioxide seems to be more potent than retinoic acid, and the two drugs may be synergistic. He said that the combination of arsenic trioxide and retinoic acid deserves investigation.

The study was conducted jointly with researchers from Georgetown University in Washington, D.C., Northwestern University in Chicago, University of Southern California in Los Angeles, the M.D. Anderson Cancer Center in Houston, the Dana Farber Cancer Center in Boston, the University of Washington in Seattle, the Cleveland Clinic, Stanford University in California, and PolaRx Biopharmaceuticals, Inc., in New York.

Another Arsenic Compound

Arsenic trioxide is not the only arsenic compound being used to treat APL. Dao-pei Lu, MD, chairman of Beijing Medical University in China, reported on a study of tetra-arsenic tetra-sulfide (TATS or As4S4). Dr. Lu and his collaborators have treated 100 APL patients with TATS from 1994 to 1998.

The researchers administered 0.5 g of TATS orally three times a day. Patients were treated for 2 to 4 weeks, then had a rest period of 2 to 3 weeks. This alternation of treatment and rest periods continued for 3 to 4 years. Starting in 1998, the researchers used high-purity TATS produced in-house. Patients receiving this high-purity TATS received 1 g orally three times a day. They also had an alternating treatment-rest schedule like that of the other TATS group, except that rest periods were longer in the fourth year of treatment.

Ninety-three patients were evaluable. These included 79 patients who were in remission when they started TATS, 10 patients who had not yet received any treatment for APL, and 4 patients who were in relapse. All patients achieved complete remission. Of the 93 patients, only 4 patients later on relapsed.

Most patients had no side effects from TATS. Adverse effects that did occur tended to do so with the high-purity preparation. The most common adverse effect was a mild elevation in liver enzymes.

Dr. Lu concluded that TATS by mouth is highly effective both for inducing complete remission and in maintaining it in patients with APL. In addition, it is well tolerated.

 
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