High-Dose Methotrexate Better for ALL

By Jonathan S. Batchelor
Published: Saturday, Jun 04, 2011

Methotrexate has been a go-to treatment for high-risk acute lymphoblastic leukemia (HR-ALL) for more than 60 years, but its full potential is still being mined. Research presented at the Annual Meeting of the American Society of Clinical Oncology on Friday demonstrated that higher doses of this drug delivers superior event free survival (EFS), with no increase in acute toxicity, for children and young adults with the disease.

The drug has enjoyed a long history as a staged treatment, also known as the Capizzi regimen, for children and young adults with HR-ALL, delivering an average 75% EFS to patients, according to Eric C. Larsen, MD, medical director of the Maine Children's Cancer Program at the Barbara Bush Children's Hospital at Maine Medical Center in Portland.

Larsen and colleagues in the Children's Oncology Group (COG) Study AALL02332 conducted a randomized trial that delivered higher doses of methotrexate (approximately 50 times the initial dose of conventional treatment) to 1209 HR-ALL patients in one study arm. They compared this with the standard method, Capizzi escalating methotrexate plus PEG asparaginase, in the other study arm (1217 patients) of the trial.

The protocol, which began in 2004, was closed early (January 2011) due to positive results of the investigative therapy in 5-year interim monitoring.

“Planned interim analysis demonstrated that the high-dose methotrexate treatment was clearly superior to the standard Capizzi methotrexate treatment,” stated Larsen.

He reported that the 5-year EFS rates were 82% for the high-dose methotrexate treatment, compared with 75.4% for the Capizzi treatment. Patients in the Capizzi arm were offered the high-dose treatment at protocol close, Larsen noted.

There were fewer marrow and CNS relapses in the high-dose versus Capizzi arms (42 and 22 vs 68 and 32), he said. In addition, the incidence of febrile neutropenia was lower with high-dose methotrexate compared with the Capizzi treatment; 5.2% vs 8.2%, respectively, with a P value of 0.005.

“Pediatric oncologists have recognized that to get optimal results in treating cancer, you have to optimize the way cancer treatment is given,” commented Richard Schilsky, MD, of the University of Chicago Pritzker School of Medicine, who moderated the press conference at which the COG study was presented. “Many of the major results in pediatric oncology, including this one, have really come without introducing any new drugs at all; they've come from optimizing the way available therapies are used.”

Larsen EC, Salzer WL, Devidas M, et al. Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232. J Clin Oncol 29: 2011 (suppl; abstr 3). 


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