A pilot study of intermediate‐dose methotrexate and cytosine arabinoside, “Spread‐out” or “Up‐front,” in continuation therapy for childhood non‐T, non‐B acute lymphoblastic leukemia a pediatric oncology group study

One hundred six children with newly diagnosed non‐T‐, non‐B‐cell acute lymphoblastic leukemia (ALL) were treated in a Pediatric Oncology Group (POG) pilot study in which six courses of intermediate‐dose methotrexate (MTX) and cytosine arabinoside (Ara‐C) (1 g/m2 each) were added to a “backbone” of standard continuation therapy. The dose and sequence of MTX/Ara‐C administration were based on a preclinical model that demonstrated synergism between MTX and Ara‐C. Poor‐risk patients (n = 49) were assigned to “up‐front” therapy, in which the MTX/Ara‐C courses were administered during the initial 15 weeks of remission. Standard‐risk patients (n = 57) were assigned to “spread‐out” therapy, in which the MTX/Ara‐C courses were interspersed at 12‐week intervals within continuation treatment. Toxicity after intermediate‐dose MTX/Ara‐C, principally neutropenia and fever, was judged significant but manageable. Unexpectedly, the incidence of fever and neutropenia less than 500/mm3 was greater after “spread‐out” therapy (38%) than after “up‐front” therapy (6%). At 4 years, the Kaplan‐Meier estimate of event‐free survival (EFS) is 71% (± 7%) for standard‐risk patients and 53% (± 8%) for poor‐risk patients. The results of this pilot study support the use of intermediate‐dose MTX/Ara‐C in additional studies.