For Acute Lymphoblastic Leukemia Patients, New Hope from an Old Treatment

More than 50 years ago, renowned cancer researcher Sidney Farber, MD, began using methotrexate to treat children and young adults with acute lymphoblastic leukemia (ALL), a disease that was almost always fatal. Methotrexate inhibits leukemia cell proliferation by blocking its ability to use folate, an essential vitamin. Today, with methotrexate used in various combinations and dosages, survival rates are above 80 percent.

ALL begins in the bone marrow and spreads rapidly. For the last two decades, ALL patients were treated with methotrexate and asparaginase (known as the Capizzi regimen), starting with a low dose of methotrexate that was gradually increased as patients grew more tolerant. Capizzi successfully prevented relapses of ALL in the bone marrow. Yet relapses of the disease occurred, particularly in the central nervous system, prompting scientists to search for more effective regimens.

New research has shown that high-dose methotrexate—50 times higher than the initial dose in standard treatment—improved five-year event-free survival with no significant differences in toxicities.

In a randomized phase 3 study of 2,426 patients with high-risk B-precursor ALL, researchers showed that a high dose of methotrexate, accompanied by leucovorin to help control side effects, was "clearly superior to the standard treatment," according to Eric Larsen, MD, of Maine Medical Center in Portland, Me. In fact, the researchers stopped enrolling new patients and encouraged eligible patients to switch to the new regimen after a planned interim analysis showed that those receiving high doses had a five-year event-free survival of 82 percent compared with 75.4 percent for the Capizzi regimen.

Larson added that the researchers were surprised to learn that patients in the high-dose arm also had lower rates of febrile neutropenia: 5.2 percent compared with 8.2 percent in the Capizzi arm.