EARLY IN 2018, blinatumomab (Blincyto) was granted accelerated approval for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease ≥ 0.1%.1,2
Supporting Efficacy Data
APPROVAL WAS BASED on the findings of the multicenter single-arm BLAST trial, which included 86 patients aged ≥ 18 years who had received at least 3 chemotherapy courses of standard ALL therapy, were in complete hematologic remission (defined as < 5% blasts in bone marrow, absolute neutrophil count > 1 G/L, platelets > 100 G/L), and had minimal residual disease at a level ≥ 0.1% on an assay with minimum sensitivity of 0.01%.2 Patients received a fixed dose of blinatumomab at 15 μg/m2/d (equivalent to the recommeded dose of 28 μg/d). Patients received up to four cycles of treatment. Following blinatumomab treatment, 45 of 61 patients (74%) in first complete remission (CR1) and 14 of 25 (56%) in second complete remission (CR2) underwent allogeneic hematopoietic stem cell transplantation in continuous hematologic complete remission.
Efficacy was based on both achievement of undetectable minimal residual disease within one cycle of blinatumomab treatment and hematologic relapse–free survival. The assay used to assess minimal residual disease response had a sensitivity of 0.01% for 6 patients and ≤ 0.005% for 80 patients. Overall, undetectable minimal residual disease was achieved in 52 patients in CR1 (85%) and 18 patients in CR2 (72%). The median estimated hematologic relapse–free survival, with the majority of patients having undergone transplantation, was 35.2 months (range = 0.4– 53.5 months) in patients in CR1 and 12.3 months (range = 0.7–42.3 months) in patients in CR2.
How It Works
BLINATUMOMAB IS a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor complex with CD19 on benign and malignant B cells. Blinatumomab mediates the formation of a synapse between the T-cell and the tumor cell, upregulation of cell-adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, resulting in redirected lysis of CD19-positive cells.
How It Is Used
FOR TREATMENT of minimal residual disease–positive B-cell precursor ALL, a treatment course consists of one cycle of blinatumomab for induction followed by up to three additional cycles for consolidation. A single cycle of induction or consolidation consists of 28 days of continuous intravenous (IV) infusion followed by a 14-day treatment-free interval (total of 42 days). Patients weighing ≥ 45 kg should receive a fixed dose of 28 μg/d. Patients weighing < 45 kg should receive 15 μg/m2/d, not to exceed 28 μg/d. Detailed instructions on the preparation of blinatumomab administration are provided in the product labeling.
Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and reinitiations (eg, if treatment is interrupted for 4 or more hours), supervision by a health-care professional or hospitalization is recommended. Adult patients should be premedicated with prednisone at 100 mg IV or its equivalent (eg, dexamethasone at 16 mg) 1 hour prior to the first dose of blinatumomab in each cycle. Pediatric patients should be premedicated with 5 mg/m2 of dexamethasone (to a maximum dose of 20 mg) prior to the first dose of blinatumomab in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
For dose modifications, if treatment interruption after an adverse event is no longer than 7 days, the same cycle should be continued, to a total of 28 days of infusion inclusive of days before and after treatment interruption in that cycle. If treatment interruption due to an adverse event is longer than 7 days, a new cycle should be started. Labeling provides specific instructions for withholding and modifying doses for patients weighing ≥ 45 kg and < 45 kg for grade 3 cytokine-release syndrome, grade 3 neurologic toxicity, and other clinically relevant adverse events of grade 3. Blinatumomab should be permanently discontinued for grade 4 cytokine-release syndrome and occurrence of more than one seizure or any grade 4 neurologic toxicity, and permanent treatment discontinuation should be considered for other clinically relevant grade 4 adverse events.
THE SAFETY OF blinatumomab in patients with minimal residual disease–positive B-cell precursor ALL was evaluated in 2 single-arm trials including 137 patients (median age = 45 years, range = 18–77 years). The most common adverse events of any grade were pyrexia (91%), infusion-related reactions (77%), headache (39%), infections (pathogen unspecified; 39%), and tremor (31%). Grade ≥ 3 adverse events occurred in 64% of patients, with the most common being neutropenia (15%), leukopenia (9%), and infections (pathogens unspecified; 8%). Serious adverse events occurred in 61%, with those occurring in ≥ 2% of patients including pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device-related infection, seizure, and staphylococcal infection. Discontinuation of therapy due to adverse events occurred in 17% of patients, with neurologic events being the most common cause. Adverse events led to death in 2 patients within 30 days of stopping treatment, with the causes consisting of atypical pneumonia and subdural hemorrhage.
Blinatumomab carries boxed warnings for cytokine-release syndrome and neurologic toxicity, both of which may be life-threatening or fatal. It also carries warnings/precautions for infections, effects on ability to drive and use machines, pancreatitis, preparation and administration errors, and risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative. Instructions for preparation (including admixing) and administration should be strictly followed. Blinatumomab prepared with preservative-free saline should be used for patients weighing < 22 kg. ■
1. U.S. Food and Drug Administration: FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm603171.htm. Accessed August 6, 2018.
2. Blincyto (blinatumomab) for injection prescribing information, Amgen Inc, March 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/ label/2018/125557s013lbl.pdf. Accessed August 6, 2018.