Photo by Bill Branson
Child with leukemia
Escalating methotrexate (MTX) may produce better outcomes than high-dose MTX in children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), according to research published in the Journal of Clinical Oncology.
Researchers compared escalating and high-dose MTX given with the augmented Berlin-Frankfurt-Munster regimen in patients with T-ALL.
Disease-free survival (DFS) and overall survival (OS) rates were significantly higher among patients who received escalating MTX.
The improved survival outcomes in this trial, AALL0434, are the “opposite effect” of what was observed in a parallel trial, AALL0232. In that trial, high-dose MTX was superior to the escalating strategy in patients with B-cell acute lymphoblastic leukemia (B-ALL).
The parallel trial design was used because of the known differences between T-ALL and B-ALL in sensitivity to MTX and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Minneapolis Hospital, and his coauthors.
The AALL0434 study included 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia. They were randomized to post-induction therapy that included either escalating intravenous MTX or high-dose MTX.
The escalating regimen was superior to high-dose MTX, according to investigators.
The 5-year DFS rate was 91.5% with escalating MTX and 85.3% with high-dose MTX (P=0.005). The 5-year OS rate was 93.7% and 89.4%, respectively (P=0.036).
In contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose MTX produced superior 5-year event-free survival and OS. This led Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different MTX schedules, due to differences in doses of pegaspargase, mercaptopurine, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated MTX had two additional doses of pegaspargase. Enhanced asparagine depletion in that arm may have prevented relapse events, the investigators said.
They also said differences in adherence could have played a role, as the cost and time burden of the escalating MTX approach are “substantially less” than the high-dose approach.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved DFS.
AALL0434 was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. His coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.