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Molecular analyses of leukemia patients suggest strategies for better treatments


Review article from St. Jude Children’s Research Hospital in New England Journal of Medicine

The cure rate for pediatric acute lymphoblastic leukemia (ALL) might continue to rise with improved use of conventional therapies. But even more effective and less toxic therapies based on genetic and pharmacogenetic studies might one day push the success rate close to 100 percent, according to an article published by investigators at St. Jude Children’s Research Hospital in the April 8 issue of the New England Journal of Medicine.

The St. Jude researchers base their prediction on their review of the current and evolving state of ALL diagnosis and treatment. ALL is a cancer in which an excess number of immature and non-functional white blood cells overwhelm the body’s ability to make normal blood cells in the bone marrow. It is the most common type of cancer in children, with about 3,000 new cases each year in the United States alone. The survival has rate increased from 4 percent--when St. Jude opened in 1962--to 80 percent today, following the development of protocol-based treatment at St. Jude that combined different anti-ALL drugs and revolutionized the treatment of ALL.

"The substantial progress in ALL treatment being made today at St. Jude and other institutions reflects not only a more effective use of combining traditional anti-leukemic drugs, but also significant breakthroughs in genetic studies of ALL patients," said Ching-Hon Pui, M.D., director of the St. Jude Leukemia Lymphoma division and the F.M. Kirby Clinical Research Professor for the American Cancer Society.

A key advantage to the genetic approach to ALL treatment is the increasing ability of physicians to identify which gene mutations are linked to increased or decreased responsiveness to anti-leukemic drugs. This information is helping researchers to identify children who have particularly drug-resistant forms of ALL, as well as patients who are more susceptible to the toxicities of specific treatments. The new approach is also guiding development of new drugs that target specific cell molecules, thus avoiding the toxic side effects caused by chemotherapy.

Clinical trials are underway to test the safety and efficacy of drugs targeting a variety of gene mutations. In addition, St. Jude researchers are conducting Phase I clinical trials with investigational drugs to treat cases of ALL that have resisted previous therapies.

Fueling this surge of genetic studies of ALL is the use of DNA microarrays, a technology that permits researchers to analyze simultaneously the expression of thousands of genes. This technology accurately identifies known variations of ALL and provides key insights into their biology and their responses to therapy.

Microarray studies are disclosing the genes making up specific biochemical events leading to ALL, as well as the changes in gene expression caused by specific treatments. When validated by clinical trials, such information will enable physicians to predict with great accuracy how a specific patient will respond to a particular treatment, and to design treatments that will be the most effective but least toxic.

Breakthroughs in genetic analysis of ALL have also provided evidence that some cases of ALL might be due, in part, to a developmental error or exposure of the fetus to mutagens--chemicals that cause gene mutations. The recognition that environmental factors might play a role in the development of ALL has prompted large-scale epidemiological studies in the United States and Britain to determine the affect, if any, exposure to chemicals, viruses, bacteria or ionizing radiation.

The authors conclude that genetic studies of leukemic cells will disclose the mechanism of ALL development and lead to the identification of targets for specific treatments. Studies of genes involved in the metabolism and the effects of chemotherapy and environmental agents will also help develop optimal treatment, and may even provide important clues for the cause of leukemia. Together, these advances might one day permit physicians to cure all patients, regardless of the type of ALL they have, and might even lead to ways to prevent this disease.

Other authors of this review are Mary Relling, Pharm.D., and James Downing, M.D.

Bonnie Cameron | EurekAlert!
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