High-dose methotrexate improves 5-year event-free survival over the standard regimen of escalating methotrexate plus asparaginase (Elspar; together known as Capizzi methotrexate) as maintenance therapy in children and young adults with high-risk acute lymphoblastic leukemia (ALL), reported Eric C. Larsen, MD, Director, Maine Children’s Cancer Program and the Division of Pediatric Hematology/Oncology, Barbara Bush Children’s Hospital, Maine Medical Center, Portland.
The high-dose methotrexate regimen produced the superior event-free survival with no additional significant side effects compared with the standard regimen in a phase 3 study of 3154 patients with newly diagnosed high-risk
With the advent of novel therapies several years away, investigators were forced to review the history of therapy for ALL, including the intensification of central nervous system (CNS)-directed therapy (ie, radiation therapy), but this option was discarded to reduce the side effects of treatment. They decided to focus on systemic therapies for improving CNS control, including high-dose methotrexate during interim maintenance.
Patients aged <30 years meeting National Cancer Institute high-risk criteria, which include patients aged ≤10 years with a white blood cell count of ≥50,000 cells/μL, were eligible for the study. They were randomly assigned to prednisone or dexamethasone as induction therapy, followed by consolidation for 8 weeks. They were then randomized to high-dose methotrexate or Capizzi methotrexate during a 2-month interim phase.
When the protocol for the study was developed 10 years ago, there was a shift in the pattern of disease recurrence to a relative increase in CNS failure over marrow failure. “The planning group for the protocol focused specifically on strategies that might improve CNS control,” said Dr Larsen.
At a planned interim analysis, the 5-year, event-free survival rate for patients who received high-dose methotrexate was 82% compared with 75.4% for patients receiving the escalating methotrexate regimen. There were also significantly fewer bone marrow relapses (42 vs 68, respectively) and CNS relapses (22 vs 32, respectively) in the high-dose group. The trial was halted early as a result, after 2426 patients completed the interim maintenance phase, and certain patients were eligible to then receive the high-dose methotrexate regimen.
Patients receiving high-dose methotrexate had a lower incidence (5.2%) of febrile neutropenia than those receiving the standard regimen (8.2%). There were no differences in other significant toxicities. Patients with slow early responses to therapy appeared to gain the most benefit from high-dose methotrexate, according to Dr Larsen.
Among the 435 patients with slow early responses, the 5-year event-free survival rate was 79.5% with high-dose methotrexate and 65.4% with Capizzi methotrexate. In the 1843 patients with rapid early responses, there was no significant difference in 5-year event-free survival between the 2 groups (86.6% with high-dose methotrexate vs 82.7% with Capizzi methotrexate).
Given the longer survival with high-dose methotrexate and a superior toxicity profile with this regimen, high-dose methotrexate is “the new standard of care for high-risk ALL,” declared Martin S. Tallman, MD, Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center, and Weill Cornell Medical College, New York City.