Chicago, IL—The use of high-dose methotrexate (HD-MTX) has demonstrated a significant improvement in event-free survival in patients with pediatric acute lymphoblastic leukemia (ALL) at 5 years compared with the standard regimen.
The results of this large randomized clinical trial were reported at the ASCO 2011 annual meeting.
“Pediatric ALL was once a deadly form of leukemia, and now it’s one of the most curable,” said the study’s lead investigator, 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, Portland.
“With these results, we now have an approach that will raise cure rates even higher,” he remarked.
Dr Larsen was quick to point out the oddity of finding a new approach to treatment using such an old drug— methotrexate has been available in one form or another for more than 50 years. “To be perfectly honest with you, when this study was conceived 10 years ago, we didn’t have some new targeted therapy to be excited about, so we decided to see if we could optimize an agent that’s been around for a long time.”
Methotrexate blocks the ability of leukemia cells to use the essential B vitamin folate, which leads to the death of leukemia cells. An early form of methotrexate, aminopterin, was used by renowned cancer researcher Sidney Farber, MD, to induce the first leukemia remissions in children in 1947. It later became an essential component of standard treatment in children with ALL; however, there have been longstanding debates regarding the optimization of the methotrexate dosing.
The current clinical trial was designed to test a higher-than-standard dose of methotrexate—the socalled Capizzi regimen—in pediatric patients with high-risk ALL—children with a very high white blood cell count at diagnosis, which indicates poorer cure rates.
A total of 3154 patients (aged 1-30 years) were randomized to either HDMTX or the standard Capizzi escalating methotrexate dose plus asparaginase (C-MTX) during a 2-month interim maintenance phase of therapy after standard induction and consolidation chemotherapy.
The trial began enrolling and treating patients in 2004 and was stopped early in 2011, after a planned interim analysis demonstrated that the HDMTX was clearly superior to the standard regimen. “Results showed that the 5-year event-free survival rate was 82% for HD-MTX versus 75% for CMTX— a statistically significant difference,” said Dr Larsen.
It was thought that the higher dose of methotrexate might incur greater rates of adverse events in patients; however, no significant increases in side effects were observed. In fact, the incidence of febrile neutropenia was significantly lower in the HD-MTX group, although the reason for this finding remains unclear.
The overall impact of these findings was striking. “The implementation of HD-MTX in children with high-risk ALL changed immediately as soon as we stopped the protocol,” said Dr Larsen. “Patients in the trial who had been randomized to Capizzi and were not too far into therapy were given the choice of coming back and switching, and most did,” he said.
“We feel this is now the new standard of care for children with high-risk ALL,” Dr Larsen said. Based on these results, the Children’s Oncology Group will soon be updating its treatment guidelines.
