Blinatumomab shows benefit in pediatric B-cell ALL in first relapse
Results of two studies published in JAMA showed the addition of blinatumomab to consolidation chemotherapy improved outcomes for children and young adults with high-risk first relapse of B-cell acute lymphoblastic leukemia.
In the randomized phase 3 20120215 study, Franco Locatelli, MD, PhD, head of the department of pediatric hematology and oncology at Bambino Gesù Children's Hospital in Rome and full professor of pediatrics at University of Pavia, and colleagues found adding a third consolidation course of blinatumomab (Blincyto, Amgen) — a CD3-CD19 bispecific T-cell engager molecule — prior to allogeneic hematopoietic stem cell transplant significantly improved EFS compared with chemotherapy among children with high-risk first-relapse B-cell ALL.
Postreinduction treatment with blinatumomab also showed favorable results in terms of DFS, OS and minimal residual disease (MRD) negativity among children, adolescents and young adults with high- and intermediate-risk first-relapse B-cell ALL in the randomized COG AALL1331 trial. However, the differences did not reach statistical significance, although the study may have been underpowered for DFS due to its early termination, according to the researchers.
“These two randomized clinical trials affirm the benefit of blinatumomab in pediatric patients with high-risk first relapse of B-ALL with chemotherapy-responsive disease, and the findings suggest that blinatumomab provides a more effective and less toxic therapeutic regimen,” Neerav Shukla, MD, and Maria Luisa Sulis, MD, both of the department of pediatrics and Memorial Sloan Kettering Cancer Center, wrote in an editorial accompanying both studies. “Although only the study by Locatelli [and colleagues] demonstrated a statistically significant difference in EFS in favor of blinatumomab, both studies showed an advantage in OS.”
Locatelli and colleagues evaluated data of 108 children aged younger than 18 years (median age, 5 years; 51.9% female) with high-risk first-relapse B-cell ALL in morphologic complete remission (97.2%), indicating fewer than 5% blasts, or with M2 marrow, indicating 5% to less than 25% blasts.
All patients received induction therapy and two blocks of consolidation therapy. As the third consolidation course, researchers randomly assigned patients to receive one cycle of 15 g/m2 daily blinatumomab for 4 weeks (n = 54) or consolidation chemotherapy (n = 54).
EFS served as the study’s primary endpoint.
Median follow-up was 22.4 months (interquartile range, 8.1-34.2).
Results showed 24-month EFS favored the blinatumomab group (66.2% vs. 27.1%), with significantly fewer events occurring among that group at median follow-up (31% vs. 57%; HR = 0.33; 95% CI, 0.18-0.61).
Eight patients (14.8%) died in the blinatumomab group compared with 16 (29.6%) in the chemotherapy group (HR for OS = 0.43; 95% CI, 0.18-1.01).
More patients assigned blinatumomab achieved MRD remission (90% vs. 54%; difference, 35.6%; 95% CI, 15.6-52.5) and proceeded to HSCT while in second continuous complete remission (88.9% vs. 70.4%).
Common adverse events in the blinatumomab group included pyrexia (81.5%), nausea (40.7%), headache (35.2%) and stomatitis (35.2%). In the chemotherapy group, common events included stomatitis (57.4%), anemia (45.1%), thrombocytopenia (39.2%) and neutropenia (35.3%).
Fewer patients in the blinatumomab group experienced serious adverse events (24.1% vs. 43.1%) and grade 3 or worse adverse events (57.4% vs. 82.4%).
“I am thrilled the study results demonstrated that Blincyto was more effective and associated with fewer and less severe toxicities compared [with] intensive chemotherapy," Locatelli said in an Amgen-issued press release. “Chemotherapy has been used as primary consolidation treatment for [patients with ALL] before receiving a stem cell transplant, despite this approach being only partially effective and associated with relevant toxicity. Blincyto has now been shown to be a more effective and safer consolidation therapy option for children with high-risk first-relapse B-ALL.”
COG AALL1331 trial
In the risk-stratified, randomized phase 3 COG AALL1331 trial, Patrick A. Brown, MD, director of the pediatric leukemia program and associate professor of oncology at Johns Hopkins Medicine and Sidney Kimmel Comprehensive Cancer Center, and colleagues evaluated data of 208 children, adolescents and young adults aged 1 to 27 years (median age, 9 years; 47% female) with high- and intermediate-risk first relapse of B-cell ALL.
All patients received a 4-week reinduction course followed by treatment with two 4-week cycles of blinatumomab (n = 105), dosed at 15 g/m2 per day, or multiagent chemotherapy (n = 103) prior to HSCT.
DFS served as the study’s primary endpoint, with OS as a secondary endpoint.
Eighty of 131 planned events occurred at the time the study randomization stopped, per the recommendation of the data and safety monitoring committee.
“Although the DFS efficacy stopping rule was not met, the combination of higher DFS and OS, lower rates of serious toxicity, and higher rates of MRD clearance for blinatumomab relative to chemotherapy prompted the data and safety monitoring committee to recommend closure of the high- and intermediate-risk randomization due to loss of clinical equipoise between the randomized treatments,” the researchers wrote.
Median follow-up was 2.9 years.
A greater proportion of patients in the blinatumomab group achieved 2-year DFS (54.4% vs. 39%; HR = 0.7; 95% CI, 0.47-1.03) and 2-year OS (71.3% vs. 58.4%; HR = 0.62; 95% CI, 0.39-0.98). However, these differences did not reach the study’s threshold for statistical significance of P < .025.
Significantly more patients assigned blinatumomab than chemotherapy demonstrated MRD negativity after the first cycle (75% vs. 32%) and second cycle (66% vs. 32%; P < .001 for both). Further, more patients in the blinatumomab group proceeded to HSCT (70% vs. 43%; P < .001).
Serious adverse events included infection (blinatumomab, 15% vs. chemotherapy, 65%), febrile neutropenia (5% vs. 58%), sepsis (2% vs. 27%) and mucositis (1% vs. 28%).
The results of both studies showed that, compared with chemotherapy, blinatumomab is associated with less toxicity, confers higher rates of MRD negativity, and leads to a greater proportion of patients undergoing HSCT, according to Shukla and Sulis.
Still, the trials and the differences between them also raise unanswered questions, such as the optimal time to blinatumomab in the salvage regimen, the number of blinatumomab cycles patients should receive, and how patients for whom the first cycle or reinduction fails should be treated.
“The studies by Brown [and colleagues] and Locatelli [and colleagues] represent the first randomized trials to show a clear benefit of blinatumomab for children with high-risk relapsed B-ALL,” Shukla and Sulis wrote. “The improved outcomes, coupled with a favorable toxicity profile, support investigating the inclusion of blinatumomab and other immunotherapies in future clinical trials of front-line treatment and therapy for relapse among patients with childhood ALL.”