Oncology · 1948
Aminopterin-induced remissions in childhood acute leukemia
In the mid-1940s, acute lymphoblastic leukemia in children was a uniformly lethal diagnosis. Median survival from diagnosis to death was measured in weeks to a few months. Most hematologists and oncologists regarded systemic drug treatment as futile; the prevailing view was that cancer was a local disease requiring local treatment, and that circulating malignancies were beyond the reach of any pharmaceutical agent. Sidney Farber, a pathologist at Children's Hospital in Boston, disagreed, partly on theoretical grounds and partly because he had observed that folic acid supplements appeared to accelerate leukemic proliferation in some patients.
That observation led Farber to test the opposite approach: blocking folate metabolism. Working with Yellapragada Subbarao and colleagues at Lederle Laboratories, who had synthesized a series of folic acid antagonists, Farber obtained aminopterin and began treating children with acute leukemia in 1947. By mid-1948 he had results on 16 patients. Ten entered temporary remission, defined by measurable reductions in circulating blast counts, reduced lymph node enlargement, and clinical improvement. The findings appeared in the New England Journal of Medicine in June 1948.
The remissions were short. None lasted beyond several months, and all patients eventually relapsed and died. Some colleagues at Children's Hospital objected to the trials on the grounds that brief remissions followed by death offered the children and their families false hope. Farber's response was that demonstrating any temporary control of a malignancy by a systemic drug was worth pursuing, because it meant the principle of chemotherapy was sound and the practical limits were a problem of better drugs and combinations, not a flaw in the concept.
That reasoning proved correct. Farber's laboratory continued testing folate antagonists, moving to methotrexate, the more stable successor to aminopterin, and exploring combinations with corticosteroids and other agents. Other investigators at the National Cancer Institute and elsewhere built on the same logic. By the late 1950s and 1960s, combination regimens using multiple agents with different mechanisms were being designed to prevent resistance.
At St. Jude Children's Research Hospital, Donald Pinkel and colleagues introduced the Total Therapy approach in the 1960s, combining multi-drug chemotherapy with central nervous system prophylaxis. By the early 1970s, long-term remission in childhood ALL was being achieved in more than half of treated patients. Current protocols achieve five-year survival rates above 90% in pediatric ALL.
Key People
- Sidney Farber — Boston pediatric pathologist who designed and conducted the aminopterin trials
- Yellapragada Subbarao — Biochemist at Lederle Laboratories who synthesized the folate antagonists Farber tested
- Donald Pinkel — St. Jude oncologist who developed the Total Therapy protocols that achieved long-term ALL remission
N Engl J Med 1948;238:787-793
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