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CHICAGO -- There's new life in an old drug for high-risk acute lymphoblastic leukemia (ALL).

Methotrexate has long been used in a staged fashion to treat children and young adults with ALL and cures about three-quarters of them, according to Eric Larsen, MD, of Maine Medical Center in Portland, Me.

But in a randomized trial, giving high doses of the drug improved five-year survival even more than the standard therapy, Larsen told reporters at the annual meeting of the American Society of Clinical Oncology.

The difference was sufficiently striking enough so that the trial -- Children's Oncology Group Study ALL0232 -- was halted early and patients in the standard therapy arm were offered the experimental treatment, Larsen said.

It is also likely that clinical practice is already changing in reaction to the results, given that most doctors treating pediatric ALL patients are members of the Children's Oncology Group, he said.

"I think most people would be adopting this," Larsen told 番茄社区app. The investigators said they "feel that this is now pretty much standard of care."

Indeed, the results were an open secret within the pediatric ALL community before this week's formal presentation, commented Richard Schilsky, MD, of the University of Chicago Pritzker School of Medicine, who moderated the ASCO press conference at which the results was discussed.

"I'm not sure it has caught on yet in the adult population," he told 番茄社区app.

The so-called Capizzi regimen has been a standard treatment for high-risk ALL for many years, Larsen said.

In that regimen, patients get an initial dose of 100 mg/m² of methotrexate, which is titrated upward over five doses depending on the patient's tolerance, to a maximum of 300 mg/m².

The drug is accompanied by asparaginase (Elspar).

The regimen improves overall event-free survival for children and young adults with the condition, but is less effective at preventing central nervous system (CNS) relapse.

The researchers hypothesized that higher doses might better penetrate the CNS and improve outcomes.

To test the idea, they enrolled 3,154 patients in the trial and randomly assigned them to receive the Capizzi regimen or the investigational therapy (four doses biweekly of 5,000 mg/m² ).

In other words, Larsen noted, each dose was 50 times the initial dose under the Capizzi regimen. Patients were given leucovorin to help control side effects.

The study was halted after a planned interim analysis showed that those getting the high doses had a five-year event-free survival of 82% compared with 75.4% for the Capizzi regimen, Larsen reported. The difference was significant at P=0.006.

He said rates of relapse were significantly lower in both the marrow and CNS with the high dose, at P<0.05 for both comparisons.

At the same time, the investigators found, there was no increased toxicity associated with the high-dose regimen. Indeed, Larsen said, the only significant difference was a lower rate of febrile neutropenia in the high-dose arm: 5.2% versus 8.2% with the Capizzi regimen.

Larsen told 番茄社区app that he and his colleagues are still crunching numbers to see if the high-dose regimen is cost-effective, given that it uses more of the drug and requires inpatient care.

The need for inpatient care is what will drive up the cost, not the cost of the generic drug itself, Schilsky said. On the other hand, the higher incidence of febrile neutropenia in the Capizzi arm might wash out the difference, he added.

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