In High-Risk B-Cell ALL, Swapping Out Chemo for Blinatumomab Improves Outcomes

Replacing two high-dose chemotherapy courses with blinatumomab (Blincyto) significantly improved event-free survival (EFS) in pediatric patients with newly diagnosed high-risk B-cell acute lymphoblastic leukemia (ALL), an interim analysis from a phase III trial showed.

The 4-year EFS rate was 83% for those treated with the bispecific T-cell engager versus 70.3% for those treated with chemotherapy (HR 0.51, 95% CI 0.35-0.73, P=0.0002), thus meeting the trial’s primary endpoint of at least a 10% EFS improvement, reported Martin Schrappe, MD, PhD, of the University Medical Center Schleswig-Holstein in Kiel, Germany, at the European Hematology Association annual congress in Stockholm.

In addition, “both systemic- and central nervous system [CNS]-related relapses have been reduced by replacing chemotherapy in favor of introducing blinatumomab,” Schrappe noted.

Specifically, the 4-year cumulative incidence of relapse was 11.8% in the blinatumomab arm compared with 21.4% in the chemotherapy arm.

“Most striking was the reduction in isolated CNS relapses,” Schrappe observed, with only one in the experimental arm compared with nine in the control arm.

There was no difference in 4-year overall survival rates (93.6% in the blinatumomab arm vs 91% in the chemotherapy arm), which was “not a surprise,” Schrappe pointed out, since patients who were in the chemotherapy group at the time of relapse all received blinatumomab.

Schrappe said he and his team decided to conduct this interim analysis “because we were really stunned” by the results from a previous multicenter trial, which showed that children with newly diagnosed B-cell ALL with a National Cancer Institute (NCI)-defined standard risk of relapse lived significantly longer without disease recurrence when they received blinatumomab in addition to chemotherapy.

Thus, keeping in mind the toxicity associated with chemotherapy, Schrappe and colleagues hypothesized that blinatumomab could offer an option to safely reduce chemotherapy while improving efficacy in newly diagnosed high-risk patients.

The international, investigator-initiated AIEOP-BFM ALL 2017 trial enrolled 5,068 patients, including 709 with high-risk B-cell ALL who, after induction, consolidation, and one intensive course of chemotherapy, were randomized to two highly intensive conventional chemotherapy courses or two 28-day cycles of blinatumomab (plus 2 doses of intrathecal methotrexate per cycle).

Baseline patient characteristics were balanced between the two randomized groups. About 60% of patients were between the ages of 1 and 9 years, one-third were 10 to 17 years of age, and the remainder were under 1 year. Most patients in the blinatumomab and chemotherapy arms met the NCI criteria for high-risk disease (54.2% and 52.4%) and had CNS1 involvement (75.7% and 72.7%).

In a subgroup analysis of patients with minimal residual disease (MRD) positivity before randomization, the 4-year EFS rate was 79.1% in the blinatumomab arm and 58.3% in the chemotherapy arm, while the rates for those with MRD-negative status before randomization were 86.4% and 77.1%, respectively.

During the randomized phase, rates of infections were much higher in the chemotherapy arm versus the blinatumomab arm (69.4% vs 23.9%), and life-threatening infections occurred in 3.2% and 0%, respectively. However, more nervous system disorders were observed in the blinatumomab arm (12% vs 3.2%).

Other toxicities that differed significantly between the two groups included pancreatitis (0.3% in the blinatumomab arm vs 2.1% in the chemotherapy arm) and serious mucositis (0.3% vs 10%, respectively).

After randomization, life-threatening adverse events were similar between the experimental and control arms (6.4% and 7.3%), while fatal adverse events occurred in 2.5% and 2.3%, respectively. The most common life-threatening and fatal adverse event was bacterial sepsis.

“This is the first time that I’ve seen that the patient has a major benefit in the reduction of toxicity,” Schrappe noted. “This must be our goal, not only in pediatric ALL. So, I think this agent, at the moment, is the most promising agent to reduce treatment intensity with regard to chemotherapy.”

Blinatumomab is not without side effects, he added, “but, nevertheless, the side effects are more … let’s say, benign … than the ones we see under chemotherapy.”