Blinatumomab Improves Survival Outcomes Over Chemotherapy in High-Risk B-ALL

Blinatumomab (Blincyto) consolidation demonstrated significantly prolonged event-free survival (EFS) in pediatric patients with high-risk first-relapse B-cell precursor acute lymphoblastic leukemia (B-ALL) when compared with chemotherapy before allogeneic hematopoietic stem cell transplantation (HSCT), according to a press release from Amgen.1

The agent demonstrated superiority of survival outcomes over chemotherapy and a manageable toxicity profile in young patients with B-ALL in 2 clinical trials, each published in JAMA.^2,3

"I am thrilled the study results demonstrated that Blincyto was more effective and associated with fewer and less severe toxicities compared to intensive chemotherapy," said study investigator, Franco Locatelli, MD, PhD, of the Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital and University of Rome, Italy, in a statement.

In the open-label, multicenter, randomized, controlled phase 3 Study 20120215 trial (NCT02393859), blinatumomab demonstrated efficacy over chemotherapy in terms of EFS as the primary end point.²

The trial included pediatric patients between the ages of 28 days and 18 years with high-risk first-relapse B-ALL in morphologic complete remission or with M2 marrow and patients were randomized to receive either a cycle of blinatumomab or chemotherapy as a third course of consolidation treatment before allogeneic HSCT. Patients had already received induction therapy and 2 courses of consolidation chemotherapy.

A total of 108 patients were included in the study and enrollment was ended early for benefit of the blinatumomab arm. Patients were followed for a median of 22.4 months (range, 8.1-34.2).

The EFS rate in the blinatumomab arm was 69% at the time of data cutoff versus 43% in the chemotherapy arm (HR, 0.33; 95% CI, 0.18-0.61; log-rank P < .001). Eight patients (14.8%) in the investigational arm and 16 (29.6%) in the control arm died on the trial. The hazard ratio for overall survival (OS) was 0.43.

Minimal residual disease (MRD) negativity was reported in 90% of the evaluable patients in the blinatumomab arm versus in 54% of the evaluable patients in the chemotherapy arm.

In terms of safety, the incidence of serious adverse events (AEs) was lower with blinatumomab at 24.1% versus 43.1% with chemotherapy. The incidence of adverse events of grade 3 or higher in the blinatumomab arm versus the chemotherapy arm was 57.4% versus 82.4%, respectively. No AEs led to death in either treatment arm. Notably, the most common adverse events (AEs) in the blinatumomab arm were pyrexia (81.5%), nausea (40.7%), headache (35.2%), stomatitis (35.2%), and vomiting (29.6%). No fatal AEs were reported; 2 patients discontinued treatment in the blinatumomab arm due to AEs.

The second study exploring blinatumomab versus chemotherapy in first relapse of B-ALL was the risk-stratified, randomized phase 3 AALL1331 study (NCT02101853).3 The trial included 208 pediatric or young adult patients who were in their first relapse of B-ALL and were classified as high or intermediate risk. The patients enrolled were from 155 hospitals in the United States, Canada, Australia, and New Zealand. The patients were eligible to join the study if they were between the ages of 1 and 30 years with B-ALL in first relapse. Patients with Down syndrome and Philadelphia chromosome–positive ALL as well as those who had previously received blinatumomab treatment or had undergone prior HSCT were excluded.

The primary end point of this study was disease-free survival (DFS) and the secondary end point was OS with a statistical significance threshold of a 1-sided P value < .025.

At a median follow-up of 2.9 years, treatment with blinatumomab led to a 54% DFS rate compared with 39% in the chemotherapy arm (HR, 0.70; 95% CI, 0.47-1.03; 1-sided P = .03). Although higher in the blinatumomab arm, the DFS rate observed did not reach the threshold of statistical significance.

The 2-year OS rate shown with blinatumomab in the study was 71.3% compared with 58.4% in the chemotherapy arm (HR, 0.62; 95% CI, 0.39-0.98; 1-sided P = .02).

After the first cycle of treatment, the MRD negativity rate in the blinatumomab group was 75% versus 32% in the chemotherapy group (P < .001), and after the second cycle, the rates were 66% and 32%, respectively (P < .001).

“Chemotherapy has been used as primary consolidation treatment for ALL patients 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,” said Locatelli, in the press release.

Blinatumomab a bispecific CD19-directed CD3 T cell BiTE molecule. It was the first and only FDA-approved treatment for patients with MRD-positive B-cell precursor ALL. Blinatumomab also has regulatory approval for this indication globally.

With the published results of blinatumomab consolidation versus chemotherapy, Amgen sees a promising future for the agent for oncologists treating patients with B-ALL. David M. Reese, MD, executive vice president of Research and Development at Amgen stated in the press release: “Acute lymphoblastic leukemia is the most common type of cancer in children. Unfortunately, approximately 15% of children with high-risk B-ALL relapse after frontline chemotherapy. There remains an urgent need for novel treatment options for these patients, and the study results support Blincyto as a new standard of care consolidation therapy for patients with this aggressive disease."

_References:

_{1. Blincyto® (Blinatumomab) demonstrated significantly prolonged event-free survival compared with consolidation chemotherapy in pediatric patients with relapsed acute lymphoblastic leukemia. News release. Amgen. March 2, 2021. Accessed March 3, 2021. https://bit.ly/382RH0c}

_{2. Locatelli F, Zugmaier G, Rizzari C, et al. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia. JAMA. 2021;325(9):843-854. doi:10.1001/jama.2021.0987}

_{3. Brown PA, Ji L, Xu X, et al. Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of b-cell acute lymphoblastic leukemia. JAMA. 2021;325(9):833-842. doi:10.1001/jama.2021.0669}