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High-Dose Methotrexate Improves Survival in High-Risk B-Cell Precursor Acute Lymphoblastic Leukemia

August 2011 Vol 4, No 4, Special Issue - Leukemia

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 B-cell precursor ALL.

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.

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Last modified: August 30, 2021