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Higher Methotrexate Dose Fends Off Pediatric Leukemia Recurrence


 

FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY

CHICAGO — A new chemotherapy regimen that starts children and young adults on 50 times the standard dose of methotrexate for high-risk B-precursor acute lymphoblastic leukemia leads to significantly fewer recurrences five years after treatment without an increase in toxicity.

A randomized phase III trial comparing the high-dose regimen to standard therapy was halted in January 2011 after an interim analysis found the 5-year event-free survival rate reached 82% with the new regimen vs. 75% with the old (P = .0006).

Richard Schilsky

Pediatric oncologists began using the new high-dose regimen as standard practice "as soon as we stopped the protocol," Dr. Eric C. Larsen, principal investigator of the study, said at a press briefing June 3, on the opening day of the annual meeting of the American Society of Clinical Oncology. He will present the results June 5 in a plenary session featuring the most important research at the meeting.

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Children with high-risk ALL have a high white blood count at diagnosis and/or are 10 years or more of age.

Although pediatric ALL has a high cure rate and the standard regimen had reduced relapses in the bone marrow over time, investigators were concerned that relapses in the central nervous system had not declined as much. Therefore, they sought a regimen with the potential for greater penetration of tumor cells in the central nervous system.

When the study was conceived 10 years ago, the investigators did not have a new drug or targeted therapy, however, said Dr. Larsen, 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. Therefore, "rather than trying something brand new," they decided to try to optimize treatment with a drug that "had been around for awhile."

One of the earliest chemotherapy drugs, methotrexate promotes cancer cell death by preventing leukemia cells from using folate, an essential vitamin. Its use dates to 1947 when Dr. Sidney Farber induced the first remissions in children with ALL by giving them an early form of methotrexate called aminopterin. It is an essential component of treatment for pediatric ALL, but the optimal regimen was not resolved.

Dr. Richard Schilsky, a professor of medicine and chief of the section of hematology-oncology at the University of Chicago Pritzker School of Medicine, suggested oncologists treating adults have much to learn from how the investigators focused on an existing therapy. "The pediatric oncologists have recognized that to get optimal results in treating cancer you have to optimize the way cancer treatment is given," said Dr. Schilsky, a former ASCO president and moderator of the press briefing.

The Children’s Oncology Group AALL0232 trial started in 2004 and enrolled 3,154 newly diagnosed patients ages 1 to 30. Most pediatric ALL trials do not enroll patients older than 21 years of age, Dr. Larsen said in an interview, but current thinking suggests that young adult patients may do better on pediatric protocols.

At the time of the interim analysis, 2,426 patients had been randomized. About half the population in the interim analysis, 1,217 patients, was treated with a standard Capizzi regimen in which intravenous methotrexate is delivered at a starting dose of 100 mg/m2 and escalated by 50 mg/m2 every 10 days up to a maximum of 5 doses depending on the child’s ability to tolerate the medication. In this regimen methotrexate is followed by a second chemotherapy drug called asparaginase.

The other 1,209 patients were assigned to the high-dose arm, and received 5 g/m2 – that is, 5,000 mg/m2 of methotrexate biweekly in four doses.

Despite concerns that the high-dose regimen would lead to more toxicity, febrile neutropenia occurred less in the experimental arm of the trial: 5.2% vs. 8.2% in the standard arm (P = .005). Leucovorin rescue was available for patients on high-dose methotrexate, which may partially explain the lower incidence of neutropenia in this group. Acute neurotoxicity, osteonecrosis, and other clinically relevant side effects were not significantly different.

Investigators are not sure why the high-dose regimen is less toxic, but side effects with standard therapy may be more the result of the combination of drugs in the Capizzi regimen than of methotrexate itself, Dr. Larsen said.

A substudy is looking at the comparative costs of the two regimens, he added. Methotrexate is inexpensive, but the high-dose regimen requires hospitalization. This needs to be balanced against the cost of hospitalizing and treating with antibiotics the greater proportion of children developing febrile neutropenia, a serious toxicity, on the Capizzi regimen.

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