A randomized Phase III Children?s Oncology Group study shows that a high-dose methotrexate regimen is superior to the standard regimen of escalating methotrexate for children and young adults with high risk B-precursor acute lymphoblastic leukemia or ALL. This new regimen improved five-year event-free survival and had no greater significant side effects compared to the standard regimen. The trial establishes a new standard treatment for these patients.

?Pediatric acute lymphoblastic leukemia was once a deadly form of leukemia, and now it?s one of the most curable. This trial helps us address an important need for patients with this disease. With these results, we now have an approach that will raise cure rates even higher,? said Eric C. Larsen, MD, principal investigator of the study and 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. ?Based on the findings from this trial all current and upcoming treatment protocols for children with newly diagnosed high risk B-precursor ALL will use this regimen.?

Methotrexate has been an essential component in the treatment of children with ALL for more than 50 years, but the optimal dose and schedule has been a matter of debate and clinical research. Escalating intravenous methotrexate followed by a second chemotherapy drug called asparaginase (Elspar?, Merck & Co?,/Kidrolase?,SOBI,Swedish Orphan Biovitrum), together known as the Capizzi regimen, has been an effective standard treatment for ALL for approximately two decades. This approach involves starting at a low dose of methotrexate and gradually increasing the dose depending on a patient?s tolerance.

Central nervous system
The escalating methotrexate regimen has led to improved cure rates for ALL, by decreasing relapses in the bone marrow, where the disease initially occurs. Relapse rates in the central nervous system (CNS)have not declined as significantly, representing an ongoing need for better treatment options. To reduce these CNS relapses, this study tested a methotrexate regimen, which delivers a dose 50 times the starting dose of the escalating regimen. The high-dose regimen has a greater potential to reach tumor cells in the central nervous system.

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Trial results
The Phase III study randomized 2,426 patients ages 1 to 30 with newly diagnosed high-risk B-precursor ALL to high-dose methotrexate versus escalating methotrexate plus asparaginase during a two-month interim maintenance phase of therapy following standard induction and consolidation chemotherapy. At a planned interim analysis, the five-year, event-free survival for patients who received high-dose methotrexate was 82%, compared to 75% for patients on the escalating methotrexate regimen. There were also significantly fewer bone marrow and CNS relapses in the high-dose group.

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Enrollment was halted early as a result, and certain patients were eligible to then receive the high dose methotrexate regimen. The investigators were initially concerned that there might be more side effects in the group receiving high-dose methotrexate, however these patients actually had a lower incidence of febrile neutropenia (fever with low white blood cell counts) than those on the standard regimen. There were no differences in other significant toxicities.

ALL, a fast-growing cancer of the white blood cells, is the most common leukemia in children. About 4,000 new cases of ALL are diagnosed in the U.S. each year.

For more information:
Study author: Larsen EC, Salzer WL, Devidas M, Nachman JB, Raetz EA, et al.
Abstract title: High dose methotrexate (HD-MTX) as compared to Capizzi methotrexate plus asparaginase (C-MTX/ASNase) improves event-free survival (EFS) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): a report from the Children?s oncology group study AALL0232.
Sunday, June 5, 2011, 1:00 PM, CDT Maine Medical Center
Hall B1 Portland, ME
Abstract: # 3

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