During a plenary session of the 66th American Society of Hematology Annual Meeting and Exposition, Rachel Rau, MD, associate professor of pediatrics at Seattle Children’s Hospital in Washington, presented findings on the addition of blinatumomab as a new standard treatment for children with both average- and higher-risk newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).
“Despite the conduct of many large, well-designed clinical trials, outcomes in pediatric B-ALL have remained largely the same over more than two decades,” Dr. Rau said. To improve disease-free survival (DFS) in children with National Cancer Institute standard risk (SR) B-ALL with average or higher relapse risk, the phase III randomized Children’s Oncology Group (COG) study, AALL1731, sought to determine the efficacy of two nonsequential cycles of the bispecific T-cell engager blinatumomab in conjunction with chemotherapy.
Researchers randomized 1,440 patients ages 1 to 10 years into four arms: 418 SR-average patients and 304 SR-high patients were randomized to the control arm to receive risk-adapted standard intensity (SI) chemotherapy alone, while 417 SR-average patients and 301 SR-high patients were randomized to receive SI chemotherapy plus two cycles of blinatumomab.
In intent-to-treat analysis, the three-year DFS was greater for patients randomized to blinatumomab arms versus control arms (96.0±1.2% vs. 87.9±2.1%; p<0.0001). When stratified by risk group, DFS remained superior in both SR-average and SR-high blinatumomab-randomized patients at three years versus their counterparts in the control arms (97.5±1.3% vs. 90.2±2.3% and 94.1±2.5% vs. 84.8±3.8%, respectively).
The blinatumomab arms showed fewer relapses (19 vs. 56), of which fewer were isolated bone marrow (iBM) or combined BM/central nervous system (CNS; 52.6% vs. 69.6%) than patients in the control arm. “We know that blinatumomab does not have activity in the CNS, so we must consider preventing that CNS number from creeping up,” said coauthor Sumit Gupta, MD, of the Hospital for Sick Children in Toronto.
Additionally, researchers examined the efficacy of the blinatumomab groups with known prognostic implications stratifying patients by sex, race, ethnicity, CNS status at diagnosis, genetic risk group, and measurable residual disease status. “Blinatumomab improved outcomes in virtually every subgroup, including ones that we considered high risk in the past,” Dr. Rau said.
On June 30, 2024, these outcomes prompted the COG Data Safety and Monitoring Committee to recommend early termination of randomization.
Regarding safety, rates of grade 4 or 5 infections were rare and not different between randomized arms. Rates of grade 3 or higher sepsis or catheter-related infection were observed in 14.8% of SR-average patients randomized to receive blinatumomab versus 5.1% of patients receiving chemotherapy alone; much of this difference was due to increased rates of these infections during subsequent cycles of chemotherapy that followed blinatumomab. Overall, blinatumomab was well tolerated, and 0.3% of first courses were associated with grade 3 or greater cytokine release syndrome and 0.7% with seizures.
“While more work is needed to determine the reasons for these increased rates of infections, we think that because blinatumomab attacks the normal B cells while it is attacking the malignant ones, infection may follow from a prolonged period of reduced normal B-cell numbers, and therefore, reduced immunoglobulin levels,” Dr. Rau said.
“If blinatumomab is effective, the next step is to take away some of the toxic chemotherapy; which components to take away will require a lot of thoughtful design,” she added.
Researchers cite the short follow-up time (median 2.5 years) as a limitation. “While we suspect these improved outcomes will hold up over time, because ALL can relapse late, we intend to follow patients to ensure that we maintain the same superior outcomes,” Dr. Rau said.
Nevertheless, “the vast majority of children with ALL live in places where they can’t access standard chemotherapy,” Drs. Rau and Gupta emphasized. “It’s incumbent upon us as a community of hematologists to ensure that this paradigm-shifting treatment is actually available to patients.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Rau R, Gupta S, Kairalla JA, et al. Blinatumomab added to chemotherapy improves disease-free survival in newly diagnosed NCI standard risk pediatric B-acute lymphoblastic leukemia: results from the randomized Children’s Oncology Group study AALL1731. Abstract 1. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 8, 2024; San Diego, California.
