Folic acid antagonists were introduced for the treatment of acute leukemia in 1948 by Farber and his associates.1 Early experience with parenteral administration of folic acid analogues was thought to show no advantage over oral administration. Methotrexate evolved as the most commonly used compound. The drug was usually given in daily oral doses of 1 to 5 mg, depending on the age of the patient. Complete remissions were induced in 11 of 48 previously untreated children with acute lymphocytic leukemia and lasted for a median of 17 weeks in a previous study conducted by members of the Acute Leukemia Group B.2 (The diagnosis, as used by the authors, includes stem cell leukemia but excludes acute myelocytic leukemia.) Other authors achieved comparable results.
Goldin et al explored the effect of different dose schedules of methotrexate on the survival of mice with leukemia 1210.3 Drug administration every fourth day
New Treatment Schedule With Improved Survival in Childhood LeukemiaIntermittent Parenteral vs Daily Oral Administration of Methotrexate for Maintenance of Induced Remission. JAMA. 1965;194(1):75–81. doi:10.1001/jama.1965.03090140083021