FDA Approval for Blinatumomab
Brand Name: Blincyto™
- Approved to treat Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia
Full prescribing information is available, including clinical trial information, safety, dosing, drug–drug interactions, and contraindications.
On December 3, 2014, the Food and Drug Administration (FDA) granted accelerated approval for blinatumomab (Blincyto™, made by Amgen Inc.) for the treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (ALL).
The approval was based on the achievement of durable complete remission and response with a reduction in minimal residual disease to less than 10−4 (that is, less than one leukemia cell in a background of 10,000 normal cells) in a multicenter open-label single-arm phase II trial (Protocol MT103-211) that enrolled 185 patients with relapsed or refractory ALL. Blinatumomab was administered by continuous infusion for 4 weeks of a 6-week cycle. Up to two cycles were used for first-line (induction) therapy and three cycles were used for post-remission (consolidation) therapy.
In the trial, 32 percent (95 percent CI: 26, 40) of patients with relapsed or refractory ALL had a complete remission after two cycles of treatment with blinatumomab; the median duration of the response was 6.7 months (range, 0.46–16.5 months). Furthermore, 31 percent (95 percent CI: 25, 39) of the patients in the study had a complete remission with or without complete hematologic recovery, but with reduction in minimal residual disease to less than 10−4.
Safety was evaluated in 212 patients with relapsed or refractory ALL who were treated with blinatumomab as part of this and other clinical trials. The most common adverse reactions (seen in at least 20 percent of patients) were fever (62 percent), headache (36 percent), swelling of the legs or arms (25 percent), febrile neutropenia (25 percent), nausea (25 percent), low potassium levels in the blood (hypokalemia) (23 percent), rash (21 percent), tremor (20 percent), and constipation (20 percent). Approximately half of the patients treated with blinatumomab experienced a neurological toxicity that often required an interruption of therapy.
Blinatumomab is a bispecific monoclonal antibody that stimulates the immune system and interferes with tumor growth. It binds CD19, a tumor-associated antigen that is overexpressed on the surface of leukemia cells, and CD3, a glycoprotein on the surface of T cells that functions as part of the T-cell receptor. Blinatumomab acts as a link to bring leukemia cells into contact with T cells, resulting in T-cell activation and a cytotoxic T-cell response against CD19-expressing leukemia cells.
Activation of the immune system by blinatumomab increases the levels of several cytokines in the blood, a potentially life-threatening toxicity called cytokine release syndrome. Cytokine release syndrome, including life-threatening or fatal events, was reported in 11 percent of the patients treated with blinatumomab. The product labeling for blinatumomab carries a BOXED WARNING regarding cytokine release syndrome and neurological toxicities. In addition, the FDA approved blinatumomab with a Risk Evaluation and Mitigation Strategy (REMS) that consists of a communication plan to inform health care providers about the serious risks of cytokine release syndrome and neurological toxicicties and the potential for errors in drug preparation and administration.
As a requirement of FDA’s accelerated therapy program, the manufacturer is required to conduct a study to verify that blinatumomab improves survival in participants with relapsed or refractory Philadelphia chromosome–negative precursor B-cell ALL.
For patients weighing at least 45 kg, the recommended dose and schedule for blinatumomab is 9 mcg per day on days 1–7 and 28 mcg per day on days 8–28 of the first 42-day cycle. It should be administered at 28 mcg per day on days 1–28 of later cycles.