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 children 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 cells 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.