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Treatment with the bispecific CD19-directed CD3 T-cell engager blinatumomab (Blincyto) resulted in significant improvements in overall survival compared with chemotherapy alone in pediatric patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) after first relapse, according to the results of two international studies.

In one randomized phase III study, patients with B-ALL ages 18 and younger treated with blinatumomab had a 2-year estimated event-free survival rate that was twice that of patients treated with chemotherapy (66.2% vs 27.1%; HR 0.33, 95% CI 0.18-0.61) after a median follow-up of 22.4 months.

This improvement in the primary endpoint was seen in all subgroups and in patients who relapsed within 18 months of diagnosis (HR 0.21, 95% CI 0.07-0.59). There were half as many deaths in the blinatumomab group compared with the chemotherapy group (14.8% vs 29.6%; HR 0.43, 95% CI 0.18-1.01), reported Franco Locatelli, MD, PhD, of University of Rome, and colleagues in .

In a second randomized phase III trial, blinatumomab was compared with chemotherapy in patients up to age 30. The 2-year overall survival rate was significantly improved for patients assigned to blinatumomab versus chemotherapy (71.3% vs 58.4%; HR 0.62, 95% CI 0.39-0.98, 1-sided P=0.03) over a median follow-up of 2.9 years.

The disease-free survival rate -- the primary endpoint -- was also higher for blinatumomab compared with chemotherapy, but did not reach statistical significance (54.4% vs 39.0%; HR 0.70, 95% CI 0.47-1.03), possibly due to early termination of the study, reported Patrick Brown, MD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues in .

Both studies were stopped early. The first study was stopped for benefit of blinatumomab. The second study was recommended for closure because of concerns about loss of clinical equipoise due to a combination of higher disease-free and overall survival rates, lower rates of serious toxicity, and higher rates of minimal residual disease (MRD) negativity with blinatumomab.

In an , Neerav Shukla, MD, and Maria Luisa Sulis, MD, both of Memorial Sloan Kettering Cancer Center in New York City, wrote that the results of these two studies "show a clear benefit of blinatumomab for children with high-risk relapsed B-ALL" and that several conclusions supporting a change in clinical practice can be drawn.

First, they noted, blinatumomab was significantly less toxic than chemotherapy. Specifically, in the trial by Locatelli and colleagues, the incidence of serious adverse events with blinatumomab was almost half that of chemotherapy (24.1% vs 43.1%); incidence of adverse events of grade 3 or higher was 57.4% for blinatumomab compared with 82.4% for chemotherapy.

"Second, the MRD negativity rates in the blinatumomab groups in both studies were greater than the chemotherapy-only groups," Shukla and Sulis wrote. "This is a critical end point because the posttransplant survival outcome is highly dependent on the extent of disease control at time of transplant."

In the first study, MRD remission occurred in 90% of patients assigned to blinatumomab compared with 54% of patients assigned to chemotherapy. In the second study, twice as many patients treated with blinatumomab were MRD negative after two cycles (66% vs 32%).

Finally, Shukla and Sulis noted that the studies demonstrated that patients who received blinatumomab as consolidation were more likely to proceed to transplant. In the first study, 88.9% of patients in the blinatumomab group underwent allogeneic hematopoietic stem cell transplant while in second continuous complete remission compared with 70.4% of patients in the chemotherapy group. In the second study, 70% of patients assigned to blinatumomab proceeded to transplant compared with only 43% of the chemotherapy group.

Shukla and Sulis said that questions remain, including the optimal timing to introduce blinatumomab and how many cycles are needed. However, these trial results "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."

Study Details

Locatelli and colleagues enrolled 108 patients (median age 5 years, 52% girls) from 47 centers in 13 countries from November 2015 to July 2019. Patients had high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts; 97.2% of patients) or with M2 marrow (blasts ≥5% and <25%) at randomization. Patients received induction therapy and two blocks of consolidation and were then randomly assigned to one cycle of blinatumomab or chemotherapy.

Brown and colleagues enrolled 208 patients with high- and intermediate-risk B-ALL in first relapse (median age 9 years, 47% female) from 155 hospitals from December 2014 to September 2019. All patients received a 4-week re-induction chemotherapy course and were then randomly assigned to two cycles of blinatumomab or two cycles of multiagent chemotherapy.