Photo by Bill Branson
High-dose methotrexate (MTX) is more effective than escalating doses of MTX for young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), according to a study published in the Journal of Clinical Oncology.
Patients who received high-dose MTX during interim maintenance 1 had significantly better event-free survival (EFS) than those who received escalating MTX.
In addition, the study showed that substituting dexamethasone for prednisone during induction was beneficial for younger—but not older—patients.
The high-dose MTX protocol outlined in this study, and the use of dexamethasone in younger patients, has become the standard practice for the treatment of high-risk ALL patients in North America.
Prior to the release of the initial study results, which were first presented last year at the ASCO Annual Meeting, the standard of care for high-risk ALL patients in North America was escalating MTX.
“One of the improvements in outcome for ALL overall has been using methotrexate in a more intense fashion, by giving higher doses,” said study investigator William L. Carroll, MD, of NYU Langone Medical Center in New York, New York.
“We designed this study to compare high-dose and escalating methotrexate to determine the best way to use this drug to increase the survival of high-risk ALL patients.”
Treatment
Between January 2004 and January 2011, Dr Carroll and his colleagues enrolled 3154 patients, ages 1 to 30, with newly diagnosed, high-risk B-ALL. After exclusions, 2914 patients were randomized to treatment.
Using a 2 × 2 factorial design, the patients were randomized to receive dexamethasone for 14 days or prednisone for 28 days during induction and high-dose MTX or Capizzi escalating-dose MTX plus pegaspargase during interim maintenance 1.
So the treatment groups were as follows:
- Prednisone and escalating MTX (n=926)
- Prednisone and high-dose MTX (n=926)
- Dexamethasone and escalating MTX (n=535)
- Dexamethasone and high-dose MTX (n=527).
MTX results
At the planned interim analysis, the 5-year EFS was 82% among patients who received high-dose MTX and 75.4% among those who received escalating MTX (P=0.006).
The final data showed 5-year EFS rates of 79.6% and 75.2%, respectively (P=0.008) and 5-year overall survival rates of 88.9% and 86.1%, respectively (P=0.025).
There was a higher rate of febrile neutropenia during interim maintenance 1 among patients who received escalating MTX than among those who received high-dose MTX—8.3% and 5.1%, respectively (P=0.003).
There were 5 cases of ischemic cerebrovascular toxicity among patients who received high-dose MTX and none among the patients who received escalating MTX (P=0.03).
But there were no other significant differences in adverse events between the high-dose and escalating-dose MTX groups.
Corticosteroid results
Patients age 10 and older saw no benefit from dexamethasone, and, in fact, were at much higher risk of developing osteonecrosis. Because of this risk, the corticosteroid induction arm of this study was closed early, in 2008.
However, the investigators found that patients younger than age 10 did benefit from dexamethasone exposure.
Specifically, patients under 10 who received dexamethasone and high-dose MTX had significantly better EFS than patients who received the other 3 treatment regimens.
The 5-year EFS rate was 91.2% in the dexamethasone and high-dose MTX arm, 83.2% in the dexamethasone and escalating MTX arm, 80.8% in the prednisone and high-dose MTX arm, and 82.1% in the prednisone and escalating MTX arm (P=0.015).
For patients of all ages, there was a higher rate of febrile neutropenia during induction among patients who received dexamethasone than among those who received prednisone—18.2% and 11.0%, respectively (P<0.001).
Patients who received dexamethasone also had a higher rate of infections/infestations—29.4% and 20.3%, respectively (P<0.001).
However, there was no significant difference in induction death rate—1.9% and 1.8%, respectively (P=0.87). The same was true when the investigators looked only at patients younger than 10 (P=0.71) or at patients 10 and older (P=0.69).
Among patients ages 10 and older who participated in the induction corticosteroid randomization before it was closed, the 5-year cumulative incidence of osteonecrosis was 24.3% for patients who received dexamethasone and 15.9% for those who received prednisone (P=0.001).
There were no other significant differences in adverse events between the 2 corticosteroid regimens.
