A comparative study of two regimens of combination chemotherapy in acute leukemia.

S INCE THE INTRODUCTION of the folic acid antagonists into clinical medicine’ several other agents with an effect on acute leukemia have been employed: purine analogs,2 corticotropin and corticosteroids.3 Despite the number of compounds available, all patients do not derive benefit from them; when improvement does occur it is usually short lasting. Until other more effective antileukemic treatment is discovered, detailed studies of drugs currently in use are important to determine their optimal application. This study describes two approaches to the improvement of current antimetabolite therapy: a combination of two agents each known to be effective (Methotrexate and 6-mercaptopurine) and, within the context of the combination study, modification of the dose regimen of one antimetabolite. The concept of combination chemotherapy is not new. Ample evidence existed in human tuberculosis4 and in mouse neoplasms at the time this study was undertaken to suggest that certain combinations of chemotherapeutic agents increased therapeutic effectiveness. Striking potentiation of chemotherapeutic response was demonstrated by Law in a lymphocytic leukemia of mice when Methotrexate (amethopterin) was given in combination with a purine analog, 8-azaguanine.6 This combination was not used in man because experience with 6-mercaptopurine indicated that it was a better antileukemic agent in human disease than 8-azaguanine.7 Recent studies of Gobdin and co-workers support the conclusion that under special circumstances, a combination of methotrexate and 6-mercaptopurine can induce enhanced antileukemic effect in mice.8 Goldin et a!. have shown that spacing a folic acid antagonist at intervals of two to four days is the most effective schedule for treating mouse leukemia early after transplantation.9 In contrast, for mouse leukemia treated late after transplantation optimal results are achieved when the drug is administered daily.1#{176} In an effort to establish whether or not these e cperimental observations are pertinent to human acute leukemia, the present study was undertaken. Independent observations on small numbers of patients treated with a combination of 6-mercaptopurine and methotrexate have recently been reported,”