High-Dose Methotrexate May Make Posttreatment Steroids Unnecessary for Some Pediatric Patients With ALL or LBL

Get Permission

The results of a new study answer some questions and raise new ones about the optimal treatment strategy for children and young adults living with acute lymphoblastic leukemia (ALL) or lymphoblastic leukemia (LBL). The randomized study is the first to test whether the use of a shorter, higher-dose course of dexamethasone during the first phase of cancer treatment is associated with reduced toxicity. It also analyzed the effects of using a higher dose of methotrexate and of omitting pulses of dexamethasone along with vincristine monthly following initial treatment. Monthly pulses of vincristine and dexamethasone are commonly used as a maintenance strategy in this setting. Findings from the study were presented by Kirkwood et al at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 214).

The findings indicated that an initial course of daily higher-dose dexamethasone (10 mg/m2) spanning 2 weeks did not reduce toxicity compared to the standard regimen (6 mg/m2), which lasts 4 weeks. The results also showed that, when given with the standard dexamethasone regimen, high-dose methotrexate reduces the risk of relapse in the bone marrow—but not in the central nervous system—for some subgroups of patients with ALL, as well as that pulses of dexamethasone and vincristine may not have added benefit in patients who have received high-dose methotrexate.

“Based on our results, if you give high-dose methotrexate after standard dexamethasone in the induction phase, omission of pulses may not reduce the chance of cure, although that conclusion should be considered tentative given the confounding interactions,” said senior author Ajay Vora, MD, of the Great Ormond Street Hospital for Children in London.

According to initial study findings, pulses were associated with an increased risk of behavior change, muscle weakness, and high blood sugar; the researchers are currently analyzing the data further to assess the effect of the pulses on quality of life.

Study Details

The trial had two main phases and examined three main questions. For the first phase, researchers randomly assigned 1,902 patients to receive either a 2-week, higher-dose course or a 4-week course of dexamethasone during initial treatment. The results for that phase, reported in 2017, indicated the short course of steroids brought no reduction in toxicity and may be slightly less effective.

For the second phase, researchers randomly assigned 1,570 patients into four groups: high-dose methotrexate plus dexamethasone and vincristine pulses, high-dose methotrexate without pulses, standard-dose methotrexate with pulses, and standard-dose methotrexate without pulses. Some patients were enrolled in both phases of the trial, while others only participated in one phase or the other.

Study Findings

Key endpoints for the second phase focused on whether the steroid pulses could be safely omitted without affecting bone marrow relapse or 5-year event-free survival and whether the high-dose methotrexate could improve rates of central nervous system relapse. For high-dose methotrexate, the results showed no significant differences overall for most endpoints. Researchers did find a significant interaction with the dexamethasone regimen given in the first phase, with patients treated with the 4-week schedule showing improvements in bone marrow relapse rates when treated with high-dose methotrexate.

Overall, the results suggested that steroid pulses could be safely omitted without adversely affecting bone marrow relapse. However, omitting the pulses was associated with a decrease in event-free survival overall. This effect was smaller in those treated with 4-week dexamethasone and high-dose methotrexate, suggesting it may be possible to omit pulses with this treatment schedule.

“We found that the interactions are highly significant, which is something nobody expected,” said Dr. Vora. “In addition, we were surprised that high-dose methotrexate seems to bring a benefit with respect to relapses primarily in the bone marrow and not the central nervous system—and we don’t have a biologically plausible explanation for that finding.”

Going forward, researchers will be analyzing quality-of-life outcomes related to the dexamethasone/vincristine pulses for further insights into the possible benefits of skipping this added therapy. They will also study outcomes at longer follow-ups to ensure these results hold. In addition, the researchers noted that other studies are underway to further illuminate optimal treatment strategies for different patient subgroups.

Disclosure: For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.