Roxanne Nelson

June 03, 2011

June 3, 2011 (Chicago, Illinois) — A regimen of high-dose methotrexate appears to be superior to the standard protocol of escalating methotrexate in children and young adults with high-risk B-precursor acute lymphoblastic leukemia (ALL).

In a planned interim analysis, 5-year event-free survival for patients who received the high-dose regimen was 82%, compared with 75% for those receiving the escalation protocol.

The results of this phase 3 trial, which were presented here at the American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting, establish a new standard of treatment for this population.

Dr. Eric Larsen

"We feel that it is the standard of care to receive high-dose methotrexate in this population," said lead author Eric C. Larsen, MD, director of the Maine Children's Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children's Hospital at Maine Medical Center in Portland, adding that he hopes to see it incorporated into practice guidelines.

High-dose methotrexate will be incorporated in current and future Children's Oncology Group trials.

Outcomes were better for patients who received the high-dose regimen than for those who received the dose-escalating Capizzi regimen, he explained. "High-dose methotrexate will be incorporated in current and future Children's Oncology Group trials for children and young adults."

Lower Toxicity in High-Dose Group

Dr. Larsen noted that adverse events were closely monitored, and high-dose methotrexate appeared to be safe with no increase in toxicity. "High-dose methotrexate was actually less toxic than the Capizzi regimen," he said.

There were no statistically significant differences in clinically relevant toxicities between the 2 groups, including acute neurotoxicity and osteonecrosis. The authors note that there were fewer marrow (42 vs 68) and central nervous system (CNS) relapses (22 vs 32) with the high-dose regimen than with the standard protocol. The incidence of febrile neutropenia was also lower with the high-dose regimen (5.2% vs 8.2%; P = .005).

"The lower rates of CNS and marrow relapses in the high-dose group reached statistical significance," said Dr. Larsen.

Optimal Dose Not Yet Established

Even though methotrexate has been used for more than 5 decades and is an essential part of the treatment regimen for children with ALL, the optimal dose and schedule have not been fully established. The Capizzi regimen, which involves the administration of escalating-dose methotrexate and L-asparaginase, has been the standard treatment for ALL for the past 20 years.

Although event-free survival continues to improve for children and young adults with high-risk ALL, CNS disease has become an increasing site of treatment failure, the authors note. AALL0232 was a phase 3 randomized trial for patients 1 to 30 years of age with newly diagnosed National Cancer Institute high-risk B-precursor ALL that evaluated the safety and efficacy of interventions targeted to enhance CNS control.

In their study, Dr. Larsen and colleagues randomized 2426 patients to receive dexamethasone or prednisone during induction, and then to receive high-dose methotrexate (5 g/m2 biweekly for 4 weeks) or escalating-dose methotrexate plus PEG-L-asparaginase during interim maintenance.

Enrollment was stopped early because the survival difference crossed a predefined boundary, explained Dr. Larsen, and patients receiving the escalating-dose regimen were permitted to cross over to the high-dose regimen when feasible.

Old Drugs, New Optimization

One of the remarkable things about pediatric oncology is that pediatric oncologists recognize that to get optimal results, you have to optimize the way you give the treatment," said George W. Sledge Jr., MD, president of ASCO.

You have to optimize the way you give the treatment.

Many advances in pediatrics have not come with new drugs, but with optimizing current therapies, explained Dr. Sledge, who is also the Ballvé-Lantero Professor of Oncology and professor of pathology and laboratory medicine at Indiana University School of Medicine in Indianapolis. "This is something we can think about as we optimize therapies for adults.

The study was funded by the National Institutes of Health. Dr. Larsen has disclosed no relevant financial relationships. Coauthor James B. Nachman reports receiving honoraria from Sigma-Tau. Coauthor Julie M. Gastier-Foster reports receiving research funding from the Children's Oncology Group. Coauthor Michael J. Borowitz reports receiving research funding from Becton-Dickinson. Coauthor Brent L. Wood reports receiving research funding from Becton-Dickinson.

American Society of Clinical Oncology (ASCO®) 2011: Abstract 3. Annual Meeting: Presented June 5, 2011.

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