Use of Retinoic Acid in Acute Promyelocytic Leukemia Patients Triples Overall Survival Rates

PHILADELPHIA--The use of all-trans-retinoic acid (RA, Vesanoid)in-duces a very high incidence of complete remission in patientswith acute promye-locytic leukemia (APL) who have not receivedprevious retinoid therapy.

Raymond P. Warrell, Jr., MD, of Memorial Sloan-Kettering CancerCenter, said that in the approximately 120 patients he has treatedwith RA over the past 6 years, overall survival of newly diagnosedpatients has almost tripled, compared with chemotherapy alone.Dr. Warrell discussed his findings at Fox Chase Cancer Center's12th Annual Toward 2000 Symposium.

Conventional chemotherapy has produced overall survival ratesof only 25% to 30%, Dr. Warrell said. With therapy based on RA,he has achieved a complete remission rate of about 85%. He saysthe only patients who do not go into complete remission are thosewho die early or who were misdiagnosed.

Retinoic acid is used for induction therapy, followed by conventionalconsolidation therapy with a full course of an anthracycline-containingregimen with or without cytarabine, then by two more abbreviatedcourses of the same drugs after the patient has recovered fromtreatment-related myelosuppression.

Dr. Warrell believes RA should be used as first-line therapy,and no patient should be treated with chemotherapy alone.

"It's curious that in the United States the drug is approvedonly for treatment of relapsed patients, in which there reallyis no survival advantage whatsoever," he said, "whereasevery study in which the drug has been employed up front has showna major advantage with respect to chemotherapy alone, and that'swhy it is now generally accepted as the standard of care."

The drug's mechanism of action appears to be differentiation.Based on cellular morphology and surface markers, Dr. Warrellfinds that, "it induces differentiation and maturation ofleukemic cells such that these cells grow up, grow old, and thendie off."

The major adverse effect of RA treatment, he said, is retinoicacid syndrome, with weight gain, fluid retention, pleural effusion,pulmonary infiltrates, and respiratory distress. The condition,once established, is quite serious, he said, but is entirely preventableif high-dose corticosteroids are administered at the first signof a problem.

New Agents in the Pipeline

While results in treating APL have improved tremendously withuse of RA, Dr. Warrell foresees new agents, other than classicchemotherapy, adding to the success.

For the small group of patients who are resistant both to retinoidsand to conventional chemotherapy, two groups in China have achieveda 70% to 90% complete remission rate using arsenic trioxide (As2O3)administered intravenously daily. A clinical study of this formulationhas just begun in Paris as well.

Since this compound is not available for human use in the UnitedStates, Dr. Warrell is trying a novel organic arsenical compound,melarsoprol (Arsobal), which, he said, appears to be the onlyarsenical still formulated for human use according to Westernstandards; it is available from the CDC for use in the treatmentof trypano-somiasis.

In addition to RA, vitamin D analogues may also act as differentiatingagents. Dr. Warrell mentioned work with such compounds that arein early stages of clinical investigation. Although the vitaminD analogues have not yet produced clinical successes, they aregood inducers of myeloid differentiation, he said, and other evenmore potent vitamin D-related compounds may eventually make itinto clinical testing.

Finally, he said, another experimental agent for the treatmentof APL is a mo-noclonal antibody directed against CD33, an earlymyeloid cell surface marker. This humanized antibody can elicitantibody-dependent cellular cytotoxicity.