Study raises questions about value of high-dose methotrexate for young patients with ALL
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NEW ORLEANS — A shorter initial course of higher-dose dexamethasone failed to reduce toxicity vs. the standard regimen among children and young adults with acute lymphoblastic leukemia and lymphoblastic lymphoma, according to study results.
The findings of the randomized phase 3 UKALL 2011 trial, presented at ASH Annual Meeting and Exposition, also showed high-dose methotrexate did not reduce risk for central nervous system relapse when administered with the standard dexamethasone regimen. However, it may lower bone marrow relapse risk for some subgroups of patients with B-type ALL.
Researchers also found that pulses of dexamethasone and vincristine, a common maintenance strategy, may not confer additional benefit for patients who receive high-dose methotrexate.
Background
The multicenter UKALL 2011 trial sought to reduce toxicity of induction therapy and CNS relapse risk among children and adults aged younger than 25 years with ALL or acute lymphoblastic lymphoma (LBL).
In the two-part trial’s first randomization, which included 1,902 patients, researchers observed no decrease in toxicity with a short (14-day) high-dose vs. standard 28-day course of dexamethasone during induction. The results, reported in 2017, also indicated the short course could have slightly less efficacy.
During an ASH press conference, Ajay Vora, MD, of Great Ormond Street Hospital for Children in London, presented results of the second phase, which evaluated the impact of high-dose methotrexate on CNS relapse risk and vincristine and dexamethasone pulses on maintenance morbidity among 1,570 patients.
“For 50 years, [high-dose methotrexate] has been thought to be important to prevent relapses within the central nervous system, although it hasn’t been standard custom in practice within the United Kingdom protocols,” Vora said. “We decided to test that against our standard interim maintenance to reduce the rate of relapse involving the nervous system 4% to 1.5%.”
Researchers also tested whether the pulses added to the standard chemotherapy backbone could result in the same bone marrow relapse rate with less toxicity.
Trial participants had a median age of 5 years (interquartile range, 3-11). Most (83%) had B-ALL, whereas 12% had T-ALL, 4% had T-LBL and 1% had B-LBL. In addition, 43% had NCI high-risk disease.
Methodology
Researchers stratified patients based on NCI and minimal residual disease (MRD) risk among other factors and, for the second phase, randomly assigned them to one of four groups: high-dose methotrexate with dexamethasone and vincristine pulses, high-dose methotrexate without pulses, standard-dose methotrexate with pulses (standard of care) or standard-dose methotrexate without pulses.
CNS relapse rate served as the primary endpoint for the high-dose methotrexate randomization, and bone marrow relapse rate in ALL only served as the primary endpoint for the pulses randomization. Researchers considered EFS as a primary endpoint for both randomizations.
Median follow-up was 76 months.
Key findings
Results of the methotrexate randomization showed no difference in CNS relapse (HR = 0.99; 95% CI, 0.65-1.51; 5-year rates, 5.6% vs. 5.6%) or most other endpoints. However, researchers observed significant interaction with the dexamethasone regimen in the first phase.
“This has made analysis of the results very difficult,” Vora said.
When researchers limited analyses to patients who received the standard dexamethasone course (n = 995), they observed a significant reduction in bone marrow relapse rate with high-dose methotrexate (HR = 0.62; 95% CI, 0.4-0.95), as well as a trend toward improved EFS (HR = 0.75; 95% CI, 0.53-1.04) and OS (HR = 0.61; 95% CI, 0.37-1.03), but no difference in CNS relapse. Subgroup analyses showed no significant interactions, but a more robust effect for B-lineage, NCI high-risk and MRD low-risk patients.
However, high-dose methotrexate appeared to be associated with toxicity, Vora said, with 60% of patients demonstrating delayed clearance and 1.7% experiencing grade 3 to grade 4 acute kidney injury.
Results of the pulses randomization indicated they could be omitted with no negative impact on bone marrow relapse. Researchers reported a noninferior increase in bone marrow relapse of 2.1% (95% CI, 1.4 to 4.7) at 5 years for patients with ALL (HR = 1.22; 95% CI, 0.89-1.67). The group that received standard-dose methotrexate without pulses had shorter EFS overall, whereas pulses demonstrated no appreciable benefit among patients who received high-dose methotrexate with regard to 5-year EFS (difference, 2.8%; 95% CI: 7.4 to 4.4%) and bone marrow relapse rate in patients with ALL (difference, 0.4%; 95% CI, 6.7 to 4.3%).
“We saw a higher rate of secondary cancers in the children who did not receive pulses, which we are struggling to explain a biological basis for,” Vora said.
Next steps
Researchers plan to examine whether omitting dexamethasone and vincristine pulses could result in improved quality of life among the other possible benefits.
“There was an excess of toxicity, primarily infections and neurological toxicity, associated with the pulses, and we had an add-on study looking at patient-reported quality of life and burden of care outcomes which we have yet to analyze, but I’m pretty sure it will show that the pulses and high-dose methotrexate are associated with an impact on quality of life.
“In conclusion, the trial did not give us the answers we were looking for, but that’s why we do randomized trials,” Vora added. “At least we have one clear answer, which is that high-dose methotrexate does not seem to have benefit in reducing the risk [for] CNS relapse.”
References:
- Goulden NJ, et al. Blood. 2017;doi:10.1182/blood.V130.Suppl_1.141.141.
- Kirkwood AA, et al. Abstract 214. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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Kirkwood AA, et al. Abstract 214. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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