Book Review

The Cure of Childhood Leukemia: Into the age of miracles

N Engl J Med 1996; 334:275January 25, 1996

Article

The Cure of Childhood Leukemia: Into the age of miracles
By John Laszlo. 287 pp. New Brunswick, N.J., Rutgers University Press, 1995. $29.95. ISBN: 0-8135-2186-6

A remarkable triumph of modern medicine is the cure of most forms of childhood cancer. By the turn of the century, it is estimated that 1 in 900 persons between 21 and 45 years of age will be a survivor of childhood cancer. The defining event that initiated this awesome achievement was the cure of acute lymphocytic leukemia. The principles of treatment learned from research on childhood leukemia were then successfully applied to the treatment of other cancers.

Fifty years ago, acute lymphocytic leukemia in childhood was always fatal, but today over 75 percent of children with this disease are cured. This triumph did not occur on a specific date, nor was it due to the discovery of a specific “wonder drug.” Instead, it was made possible by the tireless efforts of an enthusiastic and dedicated group of researchers who, from the 1950s through the 1970s, followed a set of “plans without blueprints” that yielded steady, stepwise improvements. John Laszlo traces the story of this victory over leukemia through interviews with nine doctors and researchers who had important roles in the story. In one way or another, the efforts of all the key players were intertwined. Several investigators were linked to the National Cancer Institute and the clinical center that it opened in Bethesda, Maryland, in 1953. In its heyday, this facility was the center of cancer research. Its staff consisted of a small group of senior scientists who were assisted by clinical associates, including Laszlo. Currently national vice-president for research at the American Cancer Society, Laszlo knew many of the pioneers well, and he captures their personalities and their stories in a nostalgic, entertaining, and informative manner.

The story unfolds with the landmark discovery by Sidney Farber and his colleagues that the folic acid antagonist aminopterin could induce temporary remission of childhood leukemia. The discovery, reported in the Journal in 1948, was the first well-documented observation of a beneficial effect of chemotherapy in the treatment of leukemia and initiated the quest for a cure. Joseph Burchenal, at Memorial Sloan-Kettering Cancer Center in New York, moved quickly, with Farber's help, to start his own aminopterin trial, which provided confirmatory results. Burchenal then began wide-scale testing of chemical inhibitors of tumor growth in mice. Whenever a product was found effective, it would be used experimentally in patients. A particularly rewarding relationship began between Burchenal and George Hitchings and his assistant, Gertrude Elion, two pharmaceutical chemists who were working at the Burroughs Wellcome Company in Tuckahoe, New York. Hitchings and Elion developed a variety of purine antagonists, which culminated in the discovery in 1951 of 6-mercaptopurine. The drug was immediately tested by Burchenal in children with leukemia and recognized as another major antileukemic agent.

Burchenal's chemotherapeutic successes prompted the development of a strongly coordinated program of research on acute leukemia at the National Cancer Institute. C. Gordon Zubrod, who was appointed clinical director in 1954, recruited a group of young scientists to fulfill the goal of bringing together chemistry, pharmacology, and quantitative clinical trials for an attack on leukemia. Zubrod was charming, serious, and diplomatic. His dedication to the scientific method earned him deep respect among his peers at the National Cancer Institute. He was particularly supportive of two major players in the leukemia initiative who had confusingly similar names. One was Emil Frei III, known as Tom; the other was Emil Freireich, known as “J.” Zubrod, Frei, and Freireich were convinced that leukemia could be cured. Between 1955 and 1968, they had a phenomenal string of successes, which included the improved induction of remissions, the development of combination chemotherapy, refinement of maintenance strategies, central nervous system prophylaxis, and supportive care with platelet transfusions. These clinical landmarks were the outcome of a complex interplay of ideas, philosophies, intellect, and personalities among the three investigators.

Three other scientists had important roles in these successful early years. In the 1960s, Howard Skipper at the Kettering Institute in Birmingham, Alabama, initiated a series of studies of the quantitative biology of leukemia in mice and its perturbation by chemotherapy. Skipper showed that the time of death after treatment in mice was a precise indication of the number of leukemia cells remaining at the end of treatment. These observations led to the understanding of a fundamental principle of chemotherapy — namely, clonal eradication.

Multicenter clinical trials were strongly promoted by James Holland, who had started the leukemia service at the National Cancer Institute and then moved to Roswell Park Memorial Cancer Institute in Buffalo, New York. Holland supervised collaborations between scientists at the National Cancer Institute and an enormous number of investigators at hospitals in the United States and abroad. The establishment of Acute Leukemia Group B, under the direction of Frei initially, and then Holland, made it possible to track results in large numbers of children with leukemia and to document steady patterns of improved survival in successive clinical trials.

The third important investigator was Donald Pinkel, who moved from Roswell Park to become the first director of St. Jude Children's Research Hospital in Memphis, Tennessee. Pinkel and St. Jude's viewed research on childhood leukemia and its treatment as their special mission. Their achievements were mind-boggling. In the 1960s, the central nervous system became a progressively more common initial site of relapse. From this complication emerged the concept of the central nervous system as a pharmacologic “sanctuary.” Pinkel's strategies for the prevention and treatment of central nervous system leukemia were the turning point for the true cures we see today.

This book is historically interesting, poignant at times, and informative. It does not encompass the history of countless other tireless investigators in other parts of North America and abroad who made great contributions, but it is representative of what went on in that era. It is sprinkled with humor and pathos, reflecting the ups and downs and successes and failures of the central characters in their relentless struggle to defeat leukemia. Laszlo gives us an insider's view of the wards, the laboratories, and the back rooms and private offices, as well as the public forum. The target audience for the book is unclear, but lay readers can understand it as readily as professionals. The book ends with a heartwarming chapter called “The Lucky Ones,” which comprises testimonials from five survivors of childhood leukemia, now adults, who received their diagnoses between 1954 and 1977.

Melvin H. Freedman, M.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada