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Date: November 28, 1995 
Contact: Public Health Service FDA/NCI (301) 496-6641

FDA Approves All-Trans Retinoic Acid
for Treating a Rare Leukemia

The Food and Drug Administration (FDA) has approved the use of the first successful differentiating agent for the treatment of patients with a rare form of leukemia -- ushering in a novel approach to cancer that has long intrigued cancer researchers. The drug, all-trans retinoic acid, is a vitamin A derivative that works by prodding malignant leukemic cells to differentiate or "mature" into normal blood cells, which subsequently die.

The FDA approved Vesanoid (tretinoin) for patients with acute promyelocytic leukemia (APL) who have failed or are resistant to conventional chemotherapy. The drug is also being studied for its usefulness in the treatment of newly diagnosed patients with this leukemia. Vesanoid will be marketed in the United States by Hoffman-La-Roche Inc., Nutley, N.J.

"This is a dramatic and novel pharmacologic correction of the biological consequences of a molecular genetic abnormality associated with a human cancer" said David Parkinson, M.D., chief of the National Cancer Institute's Investigational Drug Branch. However, Parkinson added, all-trans retinoic acid is not a cure for APL, and may in fact work best in combination with chemotherapy. Most patients treated with all-trans retinoic acid alone, he said, tend to relapse within several months. The National Cancer Institute (NCI) is currently evaluating through its Clinical Trials Cooperative Groups all-trans retinoic acid's role relative to chemotherapy in induction or first-line therapy, and in maintenance therapy. Other trials are examining the integration of this active retinoid in combination with chemotherapy.

First recognized in the 1950s, APL constitutes roughly 10 percent of adult acute myeloid leukemia in the United States, or about 800 patients each year. The disease typically presents with a bleeding condition that is often worsened by chemotherapy, leading to a relatively high rate of early mortality. Nevertheless, long-term survival is somewhat more favorable in APL than that associated with other acute myeloid leukemias, with 35 percent to 45 percent of patients living at least five years. Leukemia is a cancer of the blood-forming cells, which occurs when immature or mature cells multiply in an uncontrolled manner in the bone marrow. The disease is classified as either lymphocytic or myeloid leukemia, depending on which of these white blood cells is multiplying abnormally. When the leukemia is acute, it progresses rapidly and involves primarily immature blood cells; in chronic leukemias, in comparison, the disease progresses more slowly and involves the accumulation of greater numbers of more mature blood cells.

In patients with APL, investigators have discovered that besides a distinctive clinical presentation, there is a characteristic molecular pattern as well. Genetic material from two genes on chromosomes 15 and 17 translocate or swap places, producing abnormal "fusion" genes. Normally, the proteins coded for by these genes (so called "transcription factors") help regulate a number of critical cellular functions including cell proliferation, embryonic development, and cell differentiation. One of these proteins -- the nuclear receptor for retinoids -- is the portal through which all-trans retinoic acid gains access to carry out its numerous functions, but in an individual with APL, it appears that such entry is somehow blocked. However, the drug apparently works by bypassing the obstruction; in fact, virtually all patients with this characteristic genetic abnormality respond to the drug, Parkinson said.

In the United States since 1991, NCI, in cooperation with the FDA, has treated more than 1,500 APL patients with all-trans retinoic acid on a compassionate-use basis. A large percentage of these patients have benefited from the drug, according to Parkinson.

In addition, in summary data involving clinical trials in the United States at the Memorial Sloan-Kettering Cancer Center, N.Y., and in France and China, complete responses were seen in 84 percent of 565 APL patients.

All-trans retinoic acid, which is taken orally in pill form, produces adverse reactions similar to other retinoids. The most common side effects are headaches, though some patients experience transient bone pain, and children appear especially prone to the drug's central nervous system effects.

Approximately 25 percent of patients with APL may develop Retinoic Acid Syndrome, a potentially serious complication characterized by fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions, which has, in some cases, caused patients to expire. Although the cause of Retinoic Acid Syndrome is not yet known, several mechanisms have been proposed, including the release of cytokines by maturing cells. Moreover, in most patients, progression of the syndrome can be halted through early treatment with corticosteroids, so that early recognition by the treating physician is impor-tant.

During the course of its development over the past several years, the APL story is viewed not only as an important model for human cancer, but as an important example of how basic and clinical science work together. From the initial laboratory discovery at NCI in the early 1980s that retinoids can cause differentiation in a human cell line to the market approval today, Parkinson noted, is a "good example of how NCI, by working closely with investigators, pharmaceutical companies, and regulatory authorities internationally, can use its resources and organizational skills to bring a drug more rapidly into regular cancer therapy for the benefit of patients."

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