Treatment with the chemotherapy vincristine plus dexamethasone as pulse therapy for childhood acute lymphoblastic leukemia (ALL) can be safely eliminated for pediatric patients with low-risk disease after the first year of treatment, according to new data from a large phase 3 noninferiority clinical trial.
These findings are the result of an international collaboration between St. Jude’s Children’s Research Hospital, the Chinese Children’s Cancer Group, and other cancer research groups in China. The study was published in The Lancet Oncology.
Optimizing Treatment for Childhood ALL
Vincristine plus dexamethasone pulses have been standard care for childhood ALL since the 1970s, but the treatment is associated with neuropsychological side effects, neuropathy, and other adverse events.
“We wanted to study this issue to provide definitive conclusions about whether we can safely omit prolonged pulse therapy with these two drugs to improve quality of life for patients and lessen the burden to their family,” said corresponding author Ching-Hon Pui, MD, chair of the St. Jude Department of Oncology, via a press release. “That’s why doing this study through the Chinese Children’s Cancer Group was key: a definitive noninferiority randomized trial of a disease with a high cure rate such as ALL requires very large numbers of patients all treated consistently.”
For this open-label phase 3 trial, 5,054 patients with newly diagnosed childhood ALL treated at 20 cancer centers across China between January 2015 and February 2019 were enrolled. The authors note that this is the largest clinical trial ever conducted for this childhood cancer. In total, 2,923 patients had low-risk ALL and 2,131 had intermediate-to-high risk ALL. Patients were included if they were subsequently in continuous remission for one year after initial treatment and did not have secondary malignancy.
Patients were randomized 1:1 either receive (control group) or not receive (experimental group) seven pulses of intravenous vincristine (1.5 mg/m2) plus oral dexamethasone (6mg/m2 daily for seven days) during their second year of treatment. Stratification based on disease risk was conducted. The primary endpoint was five-year difference in event-free survival between groups for both low- and intermediate-to-high risk cohorts. The noninferiority margin was 5%.
No Survival Difference for Low-Risk ALL
Median follow-up was 3.7 years (interquartile range, 2.8–4.7). There was no difference in five-year event-free survival for patients with low-risk childhood ALL in either the control or experimental groups (90.3% versus 90.2%; P = 0.90). The one-sided 95% upper confidence bound for event-free survival was 0.024 (2.4%), which establishes non-inferiority in patients with low-risk ALL.
No difference was found in five-year event-free survival for patients with high-risk ALL either (82.8% versus 80.8%; P = 0.90). However, the one-sided 95% upper confidence bound was 0.055 (5.5%), which did not meet the noninferiority requirement.
There were no differences between the low-risk control or experimental groups regarding rates of infection, symptomatic osteonecrosis, or other complications during the second year of treatment. Patients in the intermediate-to-high risk group receiving pulse therapy were more likely to have grade ≥3 pneumonia (2.4% vs. 0.9%) and neuropathy (1.6% vs. 0.6%) compared to the experimental group. Rates of grade 5 fatal infection were comparable between groups for patients with both low-risk (0.1% vs. 0.3%) and intermediate-to-high risk ALL (0.6% vs. 0.5%).
In conclusion, the authors wrote, “Vincristine plus dexamethasone pulses might be omitted beyond 1 year of treatment for children with low-risk ALL. Additional studies are needed for intermediate-to-high-risk ALL.”
“These findings are very good news for patients and families,” said Dr. Pui, “because shortening this pulse therapy will substantially reduce neuropsychological side effects, emotional disturbances and many other neurological and metabolic late effects.”