The bispecific T-cell engager (BiTE®) antibody blinatumomab can produce complete responses (CRs) in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to a phase 1/2 study published in the Journal of Clinical Oncology.
Of the patients who received the recommended dosage of blinatumomab, 39% achieved a CR within the first 2 treatment cycles.
And 52% of these patients achieved a complete minimal residual disease (MRD) response.
“This study showed that [blinatumomab] can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL,” said study author Lia Gore, MD, of University of Colorado Anschutz Medical Campus in Aurora, Colorado.
However, most of these remissions did not last. Although a few of the complete responders were still alive and in CR at the study’s 2-year follow-up, more than half had relapsed, and two-thirds had died.
This trial, known as Study ‘205, was supported by Amgen.
Study ‘205 included 93 pediatric patients with relapsed or refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
Toxicities and recommended dose
There were 4 dose-limiting toxicities during the phase 1 portion of the trial, and 2 of these events were fatal. One patient treated at 15 μg/m2/day developed grade 4 cytokine release syndrome (CRS), which was deemed related to grade 4 gastrointestinal hemorrhage.
Two patients treated at 30 μg/m2/day had grade 4 CRS. One case was attributed to grade 5 cardiac failure, and the other was treated successfully with tocilizumab.
One patient treated at 15 μg/m2/day had grade 5 respiratory failure with cardiac arrest after hypotonia and muscle weakness after 7 days of infusion with blinatumomab. This patient experienced febrile neutropenia and pneumonia shortly before the start of the infusion.
Based on these toxicities, the maximum-tolerated dose of blinatumomab was 15 μg/m2/day, but a step-wise dosage was recommended to reduce the risk of CRS.
So the recommended dose was 5 μg/m2/day on days 1-7 and 15 μg/m2/day on days 8-28 for cycle 1, and 15 μg/m2/day on days 1-28 for subsequent cycles.
Dose adjustment was possible in case of adverse events. Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.
Treatment at recommended dose
Seventy patients received at least 1 infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).
The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease. Four patients had less than the 25% bone marrow blasts required for protocol entry but had more than 5% blasts.
Adverse events
The most common adverse events among the patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).
The most frequent grade 3 or higher events were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).
Eight patients developed CRS. Three had grade 3 and 1 had grade 4 CRS. Two of these patients had treatment interruptions, and 2 discontinued treatment permanently. All 4 patients achieved a CR.
Ten patients (14%) had treatment interruptions due to adverse events, and 4 (6%) discontinued treatment permanently because of adverse events.
Six patients had fatal adverse events. Three died after they went on to allogeneic transplant—1 of multiorgan failure, 1 of sepsis, and 1 of respiratory failure. The 3 other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.
Response and follow-up
Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a CR within the first 2 cycles. Fourteen of these patients (52%) achieved complete MRD response.
CRs were achieved across subgroups, and complete MRD response rates were similar across subgroups.
Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.
At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.
Two of the patients had relapsed but were still alive, 3 had withdrawn consent (1 in CR and 2 after relapse), 3 had died in CR after transplant, and 15 had relapsed and died.
Of the 43 patients who did not achieve a CR within the first 2 treatment cycles, 8 were still alive at the end of the 2-year follow-up.
