BLINCYTO® (blinatumomab): Bispecific CD19-Directed CD3 T-cell Engager
BLINCYTO is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of adults and children with:
• B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Mechanism of Action:
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 (TCR) 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, the release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells.
During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterized by T-cell activation and initial redistribution, reduction in peripheral B cells, and transient cytokine elevation. Peripheral T-cell redistribution (ie, T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of BLINCYTO infusion or dose escalation. T-cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in the majority of patients. Increase of T-cell counts above baseline (T-cell expansion) was observed in few patients.
Peripheral B cell counts decreased to less than or equal to 10 cells/microliter during the first treatment cycle at doses ≥ 5 mcg/m2 /day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week BLINCYTO-free period between treatment cycles. Incomplete depletion of B cells occurred at doses of 0.5 mcg/m2 /day and 1.5 mcg/m2 /day and in a few patients at higher doses.
Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, and IFN-γ were measured, and IL-6, IL-10, and IFN-γ were elevated. The highest elevation of cytokines was observed in the first 2 days following start of BLINCYTO infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.
INDICATION & USAGES
Treatment of MRD-Positive B-cell Precursor ALL
• A treatment course consists of 1 cycle of BLINCYTO for induction followed by up to 3 additional cycles for consolidation.
• A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• See label for recommended dose by patient weight and schedule
Treatment of Relapsed or Refractory B-cell Precursor ALL
• A treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy.
• A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days). • A single cycle of treatment of BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days). Reference ID: 4241595 5
• See label for the recommended dose by patient weight and schedule.
Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. (2.2)
- Premedicate with dexamethasone. (2.2)
• Administer as a continuous intravenous infusion at a constant flow rate using an infusion pump. (2.5, 2.6) - See Section 2.5 for infusion over 24 hours or 48 hours. - See Section 2.6 for infusion over 7 days using Bacteriostatic 0.9% Sodium Chloride Injection, USP (containing 0.9% benzyl alcohol). This option is not recommended for patients weighing less than 22 kg. --------------------
-DOSAGE FORMS AND STRENGTHS
For injection: 35 mcg of lyophilized powder in a single-dose vial for reconstitution.
Known hypersensitivity to blinatumomab or to any component of the product formulation.
WARNINGS AND PRECAUTIONS
• Infections: Monitor patients for signs or symptoms; treat appropriately.
• Effects on Ability to Drive and Use Machines: Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
• Pancreatitis: Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO.
• Preparation and Administration Errors: Strictly follow instructions for preparation (including admixing) and administration.
• Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative:
The most common adverse reactions (≥ 20%) were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia.