Blinatumomab Studies Stopped Early for Clinical Benefit in Pediatric Relapsed ALL

David M. Reese, MD

Two clinical trials evaluating blinatumomab (Blincyto) compared with chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL) were stopped early due to treatment benefit with the bispecific T-cell engager, according to its developer Amgen.

In the phase III Study 20120215 trial (NCT02393859), blinatumomab improved event-free survival (EFS) compared with conventional consolidation chemotherapy in pediatric patients with high-risk, B-cell ALL at first relapse. Due to these encouraging data, enrollment was terminated early in the blinatumomab arm based on a recommendation from an independent data monitoring committee (DMC). Follow-up will continue as prescribed per protocol, Amgen stated in a press release.

Moreover, the randomized, phase III AALL1331 trial (NCT02101853), which was conducted by the Children's Oncology Group (COG), showed that blinatumomab showed a trend toward improvement in disease-free survival (DFS) and overall survival (OS), as well as lower toxicity, and better minimal residual disease (MRD) clearance compared with chemotherapy in pediatric patients with B-cell ALL at first relapse. Based on the COG DMC, the intermediate- and high-risk arms were closed for accrual.

In the AALL1331 low-risk group, the COG DMC recommended that this arm should continue to enroll and randomize patients until the enrollment goals are reached.

"Considered together, the results of these studies are remarkable. Children and adolescents who relapse with acute lymphoblastic leukemia face a poor prognosis and there remains a need for additional treatment options, particularly for those that are identified as high-risk. These data have the potential to be practice-changing and may provide a treatment approach to prevent further relapse that is superior to chemotherapy," David M. Reese, MD, executive vice president of Research and Development at Amgen, stated in the press release. "We look forward to discussing these data with regulatory authorities."

Moreover, blinatumomab-associated adverse events (AEs) that were observed in both trials were consistent with the known safety profile of blinatumomab. The interim data of both studies will be submitted for publication and for presentation at an upcoming medical meeting.

In the multicenter, open-label, randomized, controlled phase III Study 20120215 trial, investigators sought to evaluate EFS after treatment with blinatumomab compared with standard consolidation chemotherapy in 202 pediatric patients with high-risk first relapsed B-cell ALL. Key secondary endpoints included incidence of OS and MRD response, AEs, 100-day mortality after allogeneic hematopoietic stem cell transplantation, incidence of anti-blinatumomab antibody formation, and cumulative incidence of relapse.

To be eligible for enrollment, patients had to have Philadelphia chromosome negative (Ph-) high-risk, first relapse B-precursor ALL, have M1 or M2 marrow at the time of randomization, and be <18 years old. Exclusion criteria included but was not limited to those with clinically relevant central nervous system (CNS) pathology requiring treatment, had evidence of current CNS (CNS 2, CNS 3) involvement by ALL, abnormal renal or hepatic function prior to start of treatment, peripheral neutrophils <500/μL prior to start of therapy, peripheral platelets < 50,000/μL prior to starting treatment.

The trial is being conducted as part of the Pediatric Investigation Plan agreed upon between Amgen and the European Medicines Agency. Additionally, it is being conducted in Australia and various countries in the European Union and Latin America.

In the risk-stratified, phase III COG AALL1331 study, investigators evaluated 598 pediatric patients with B-ALL in first relapse. Following induction block one chemotherapy, those with high-risk and intermediate-risk relapse disease were randomized to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab.

To be eligible for enrollment, patients must have had an ECOG performance score of 0 to 2, and had no prior stem cell transplant or rescue or prior treatment with blinatumomab. Those with Philadelphia chromosome—positive disease were excluded from enrollment.

The trial also compares the DFS of patients with low-risk (LR) relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab. Key secondary endpoints include OS of high-risk , intermediate-risk, and low-risk relapsed B-ALL patients.

The international study is being conducted in Australia, Canada, New Zealand, and the United States. AALL1331 is sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI), part of the National Institutes of Health, and is conducted by the NCI-funded COG.

Blinatumomab is currently approved by the FDA for the treatment of adult and pediatric patients with relapsed/refractory B-cell precursor ALL, as well as adult and pediatric patients with B-cell precursor ALL in first or second complete remission with MRD ≥0.1%.

Amgen Announces Positive Results From Two Phase 3 BLINCYTO® (blinatumomab) Studies In Pediatric Patients With Relapsed Acute Lymphoblastic Leukemia. Amgen. Published September 25, 2019. https://bit.ly/2l4RcNU. Accessed September 25, 2019.