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Curing Pediatric Acute Lymphocytic Leukemia

This article was published in December 2008 as part of the special ASH anniversary brochure, 50 Years in Hematology: Research That Revolutionized Patient Care.

The road to curing most children with acute lymphocytic leukemia (ALL), the most common childhood cancer, may be the greatest success story in the history of cancer.

The modern therapy for childhood ALL began in Boston when Dr. Sidney Farber, a pathologist at the Children's Hospital, developed an interest in childhood leukemia. The years before World War II had seen the cure of pernicious anemia, a disorder caused by vitamin B-12 deficiency characterized by the overwhelming presence of immature red blood cells in the bone marrow, a feature that resembled leukemia. At the time, an essential food chemical, folic acid, was found to cure similar anemias seen in infancy and pregnancy.

Farber wondered whether folic acid would also cure ALL because it too featured immature blood cells and anemia. He tried it in some children, and it failed and seemingly made them worse. He then reasoned that folic acid may have stimulated the growth of leukemia cells as well as normal cells and instead tried to block that stimulation with an antagonist of folic acid, aminopterin. Remarkably, this drug produced temporary remission with the return of normal blood cells and health. A new era was born. Farber reported his findings in the June 3, 1948, issue of the New England Journal of Medicine. This laid the groundwork for important advances in the 1950s and beyond.

In 1950, Gertrude Elion and George Hitchings, who subsequently received the Nobel Prize, developed 6-mercaptopurine (6-MP), which was designed to interfere with DNA synthesis and kill rapidly growing cells like leukemia. At about the same time, cortisone-based drugs (corticosteroids) were new and were tried for virtually every disease, including cancer. Both 6-MP and corticosteroids, like methotrexate (another anti-folic-acid drug), resulted in a transient improvement in the duration and quality of survival for children with ALL.

Still, all of the children treated at this time eventually died because resistance to these drugs invariably developed. Nevertheless, these earlier successes generated a great deal of interest and, more importantly, organized action. Because of the relative rarity of childhood leukemia, investigators from several institutions began to work together. Two multi-institution "Leukemia Groups" were developed to speed up the study of new therapies.

Between 1949 and 1954, the first clinical trials that tested combinations of chemotherapy drugs methotrexate, corticosteroids, and 6-MP for childhood ALL were carried out. The latter studies were the first controlled clinical trials in leukemia, perhaps in cancer history, that simultaneously compared two drugs - in this case methotrexate vs. 6-MP. The results were very informative and were accompanied by wide-ranging laboratory research, particularly in animals. Patients lived longer with these new combinations of chemotherapy drugs, but all still died, usually within a year.

A series of trials was performed at St. Jude Children's Research Hospital that used new combinations of drugs to improve response. Because ALL tended to come back in the central nervous system, a major advance was made by aggressively treating the brain and spinal fluid with radiation and drugs that markedly decreased this form of relapse.

These studies proved to be a breakthrough, and, ultimately, one-half of the patients were cured of leukemia. The idea that the cure of ALL was now possible was published in 1971 and again in 1972. Many colleagues thought this was irresponsible and gave false hope; thankfully, they were wrong.

The 1970s were a fertile time for leukemia investigators throughout the U.S. and Europe. Better control of infection and bleeding, better nursing, increasing resources from the National Institutes of Health and the public, and especially the courage and faith of the children and families who participated in studies, made steady progress possible. Work from then to the present has led to a cure rate now approximating 80 percent.

It may be a cliché, but it is nonetheless true: if we all have achieved more, it is because we stand on the shoulders of those early giants. Because of them, the cure of childhood ALL may be the greatest cancer story ever told.