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St. Jude projects 90 percent cure rate for ALL

The cure rate for the once almost universally fatal childhood cancer acute lymphoblastic leukemia (ALL) could reach 90 percent in the near future, thanks to improvements in diagnosis and treatment over the past four decades, according to investigators at St. Jude Children's Research Hospital. Almost 4,000 cases of ALL are diagnosed in the United States each year, about two-thirds of which are in children and adolescents, making this disease the most common cancer in this age group.

A report on the progress in the treatment of ALL authored by two St. Jude investigators appears in the January 12 issue of the New England Journal of Medicine.

The progressive improvement in the cure rate since 1962, when only 4 percent of children with ALL survived, reflects in large part the more effective use of existing drugs and the incorporation of sophisticated genetic technologies to personalize treatments, the authors said. Research findings at St. Jude have enabled clinicians to identify patients for whom standard treatment is most likely to fail, and who should therefore be treated more aggressively; these findings have also allowed clinicians to choose the optimal drugs and drug dosages for individual patients.

The improvements in ALL treatment are also helping to reduce the long-term toxic side effects of therapy by enabling clinicians to reduce or avoid the use of certain drugs or radiation that can damage major organs or cause secondary cancers.

"Our success reflects many years of dedication and research by an experienced team that have paid off substantially," said Ching-Hon Pui, M.D., director of the Leukemia/Lymphoma Division at St. Jude and American Cancer Society F.M. Kirby Clinical Research Professor. "A 90 percent cure rate for ALL is quite possible in the near future if we continue to incorporate the breakthroughs of past decades and successfully overcome the remaining challenges."

The dramatic increase in cure rates for c hildren is especially significant in the case of African-American children, Pui noted. They still have poor outcomes in national studies, but studies at St. Jude have shown African-American children have the same high cure rates as white children when given access to the same effective treatments.

"This reflects the ability of St. Jude to provide free treatment to all children regardless of their ethnic or racial backgrounds or their ability to pay; and to tailor the treatment according to their specific needs," Pui said. "The significant leadership role St. Jude played is due entirely to the enormous contributions made by our extraordinary team of doctors, pharmacists, nurses, and other clinicians and scientists over the years," said William E. Evans, Pharm.D., director and chief executive officer of St. Jude and the paper's co-author. "Their efforts are directly responsible for helping to push up the cure rate for ALL.

"Thanks to their work and the work of other institutions, we can now identify factors putting patients at high risk; and that has enabled us to determine whether treatment failure is due to resistance of leukemic cells to drugs, or merely due to the use of inadequate doses of those agents," Evans said. "By having the tools to precisely assess the risk of relapse in a specific patient, we can design the most effective treatments possible at the start of therapy. That's a key element of our success in raising the cure rate for ALL while limiting toxic effects of therapy."

That success is based to a large extent on the work done at St. Jude and elsewhere in identifying specific mutations in leukemic cells that strongly suggest the likelihood that treatment will fail the child, the authors reported. For example, a chromosomal abnormality called the TEL-AML1 fusion gene, which is an abnormal combination of two separate genes, confers a relatively favorable outlook for patients with this form of ALL. But patients whose leukemic cel ls have another genetic abnormality called the Philadelphia chromosome or a very low number of chromosomes--hypodiploidy--are at increased risk of treatment failure.

Adding to the complexity of the patient's response to treatment are differences in how quickly the body activates, breaks down or eliminates specific cancer drugs.

"Many genetic factors likely interact to influence the response of the patient to treatment," Evans said. "That's why the breakthroughs in pharmacogenomics made at St. Jude and elsewhere are so important. They let clinicians identify the patterns of gene activity and inactivity in both the patient's body and in leukemic cells that influence drug efficacy and toxicity. Without such information we would still be treating ALL using a lot of guesswork instead of good science."

Pharmacogenomics is the study of the effects of different genes on the response to drugs. Such studies often include the analysis of the roles of hundreds or even thousands of genes.

Another significant contribution made by St. Jude researchers is the measurement of minimal residual disease (MRD)--the small populations of leukemic cells that survive initial treatment (induction therapy). These cells can replenish the population of leukemic cells and cause the patient to relapse.

Using highly sensitive techniques, St. Jude researchers developed a technique for identifying abnormal combinations of proteins that appear only on the surface of leukemic cells. This allows scientists to quickly and accurately determine the percentage of such cells in samples taken from the patient. Doctors measure MRD to determine if induction therapy has eliminated enough leukemic cells to ensure a high probability of success. Until now, researchers had to rely on the less-accurate technique of microscopic examination to determine which cells in a child's blood sample were leukemic.

"MRD measurements help us to predict the ultimate response of each patient to treatment," Pui said. "That information helps us to determine how intensive the rest of the therapy should be. Our goal is the complete eradication of leukemic cells with the least toxicity to the children."

The continued improvement in diagnosis and treatment made possible by MRD, pharmacogenomics and new drug therapies has shifted the focus in ALL therapy toward reduction of both the immediate and long-term side effects of treatment. For example, a St. Jude team lead by Evans demonstrated that patients who lack the enzyme TPMT are more sensitive to thiopurine chemotherapy drugs and are more likely to suffer damage to the body's blood-producing cells. Evans subsequently discovered the genetic cause and developed a gene-based test that permits clinicians to identify children who should be treated with lower doses of this class of drugs while still receiving full therapeutic benefit. The overall improvements have led to more skilled use of cancer drugs, stem cell transplantation and treatment of ALL that invades the central nervous system, according to Pui.

"We are now testing the feasibility of omitting irradiation for all patients and reserving this treatment for only those children who suffer a relapse," he noted. "Irradiation of the brain can cause second cancers, hormonal disturbances and disruption of intellectual development as the child grows. So our omission of the use of irradiation should further reduce acute and long-term toxic side effects and improve outcome."

Coupled with the successes of the recent past, future treatment improvements promise to continually improve the survival rate of ALL, Evans said. For example, new drugs directed against the proteins made by genes linked to ALL will add to the options for treating this disease.

"Multiple breakthroughs at St. Jude and elsewhere have transformed ALL from a virtual death sentence into a disease that children can increasingly be expected to survive with minima l side effects," Evans said. "Surpassing 90 percent is an important step toward our ultimate quest of curing all children with this disease."


Source:St. Jude Children's Research Hospital

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