Blinatumomab

Blinatumomab is a bispecific T-cell engager (BiTE), a recombinant protein made in Chinese hamster ovary cells. One binding arm recognises CD19, a protein on the surface of normal and malignant B-lineage cells, and the other recognises CD3 on T-cells. By linking the two cell types it directs the patient’s own T-cells against CD19-positive cells.

Mechanism of Action

• Dual binding: blinatumomab connects CD3 in the T-cell receptor complex with CD19 on both normal and malignant B-cells, which activates the patient’s own (endogenous) T-cells.
• Cytolytic synapse: it mediates the formation of a cytolytic synapse between the T-cell and the tumour cell. The T-cell releases proteolytic enzymes that kill both proliferating and resting target cells.
• Independent of T-cell receptor specificity: the anti-tumour activity does not depend on T-cells carrying a particular T-cell receptor, on peptide antigens presented by the cancer cell, or on HLA molecules on the target cell. It is polyclonal in nature.
• Accompanying immune effects: transient upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines and T-cell proliferation, ending in elimination of CD19-positive cells. Cytokines such as IL-6, IL-10 and interferon gamma rise transiently and return to baseline within about 24 to 48 hours.
• Course during the infusion: over the 4-week infusion there is T-cell activation and initial redistribution, rapid depletion of B-cells in the blood, and a transient cytokine rise. T-cell counts fall in the first 1 to 2 days and return to baseline within 7 to 14 days in most patients; in a few they rise above baseline (T-cell expansion).

Pharmacokinetics

• Exposure: blinatumomab is given intravenously, so absorption does not apply. In adults the pharmacokinetics are linear between 5 and 90 mcg/m²/day (about 9 to 162 mcg/day). The steady-state serum concentration is reached within a day of continuous infusion, stays stable and rises roughly in proportion to dose. At the clinical doses of 9 and 28 mcg/day in relapsed or refractory ALL, mean steady-state concentrations were 228 and 616 pg/mL. Values in MRD-positive ALL and in the consolidation phase were similar to those in relapsed or refractory ALL.
• Distribution: mean volume of distribution (terminal phase) about 5.3 L with continuous infusion.
• Metabolism: the pathway has not been characterised. Like other protein therapeutics, blinatumomab is expected to be broken down into small peptides and amino acids by normal catabolic pathways.
• Elimination: mean systemic clearance with continuous infusion about 3.1 L/hour and mean half-life about 2.2 hours, which is why the medicine is given by continuous infusion. Negligible amounts appear in the urine at clinical doses. In children the half-life in the first cycle was similar.
• Special populations: no clinically meaningful differences were seen with age, sex, race, ethnicity, Philadelphia chromosome status, or mild or moderate hepatic impairment. Body surface area (0.4 to 2.9 m²) influences exposure, which supports dosing by body surface area in patients under 45 kg. There have been no formal studies in renal impairment; analyses showed about a 2-fold difference in mean clearance between moderate renal dysfunction and normal renal function, and no dose adjustment is needed in mild to moderate renal dysfunction.

Blinatumomab is used only as monotherapy, for CD19-positive B-cell precursor acute lymphoblastic leukaemia (ALL).

• Adults, relapsed or refractory ALL: CD19-positive relapsed or refractory B-cell precursor ALL. Patients with Philadelphia chromosome-positive disease must have failed treatment with at least 2 tyrosine kinase inhibitors and have no alternative treatment options.
• Adults, MRD-positive ALL: Philadelphia chromosome-negative CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) of 0.1% or more.
• Adults, newly diagnosed ALL: as part of consolidation therapy for newly diagnosed Philadelphia chromosome-negative CD19-positive B-cell precursor ALL.
• Paediatric patients aged 1 month or older, refractory or relapsed ALL: Philadelphia chromosome-negative CD19-positive B-cell precursor ALL that is refractory or in relapse after at least two prior therapies, or in relapse after prior allogeneic haematopoietic stem cell transplantation.
• Paediatric patients aged 1 month or older, high-risk first relapse: high-risk first relapsed Philadelphia chromosome-negative CD19-positive B-cell precursor ALL, as part of consolidation therapy.

• Hypersensitivity to blinatumomab or to any of the excipients.
• Breastfeeding, during treatment and for at least 48 hours after it.

The safety profile comes from 1,045 patients with B-cell precursor ALL. The most serious reactions were infections (22.6%), neurologic events (12.2%), neutropenia or febrile neutropenia (9.1%), cytokine release syndrome (2.7%) and tumour lysis syndrome (0.8%). The most common reactions were pyrexia (70.8%), infections with unspecified pathogen (41.4%), infusion-related reactions (33.4%), headache (32.7%), nausea (23.9%), anaemia (23.3%), thrombocytopenia (21.6%), oedema (21.4%), neutropenia (20.8%) and febrile neutropenia (20.4%).

Very common (≥1/10): bacterial, viral and pathogen-unspecified infections, febrile neutropenia, anaemia, neutropenia, thrombocytopenia, leukopenia, cytokine release syndrome, insomnia, headache, tremor, tachycardia, hypotension, hypertension, cough, nausea, vomiting, diarrhoea, constipation, abdominal pain, rash, back pain, pain in extremity, pyrexia, chills, oedema, increased liver enzymes, decreased immunoglobulins, infusion-related reactions.

Common (≥1/100 to <1/10): sepsis, pneumonia, fungal infections, leukocytosis, lymphopenia, hypersensitivity, tumour lysis syndrome, confusional state, disorientation, encephalopathy, aphasia, paraesthesia, seizure, cognitive disorder, memory impairment, dizziness, somnolence, hypoaesthesia, cranial nerve disorders, ataxia, immune effector cell-associated neurotoxicity syndrome (ICANS), flushing, dyspnoea, productive cough, respiratory failure, wheezing, hyperbilirubinaemia, bone pain, chest pain, pain, weight increase, increased blood alkaline phosphatase.

Uncommon (≥1/1,000 to <1/100): lymphadenopathy, haemophagocytic lymphohistiocytosis, cytokine storm, speech disorder, capillary leak syndrome, exertional dyspnoea, acute respiratory failure, pancreatitis.

Important serious reactions are cytokine release syndrome (which can be life-threatening or fatal), neurologic events including ICANS (some fatal), serious infections, tumour lysis syndrome, neutropenia, pancreatitis and leukoencephalopathy. They are described under Special Instructions.

• No formal interaction studies have been performed. An in vitro test in human hepatocytes suggested that blinatumomab does not affect CYP450 enzyme activities.
• Transient cytokine release: the cytokines released in the first days of treatment may temporarily suppress CYP450 enzymes. Patients taking CYP450 or transporter substrates with a narrow therapeutic index should be monitored during this time for adverse effects (for example with warfarin) or for drug concentrations (for example with ciclosporin), and the dose of the other medicine adjusted as needed.
• Live virus vaccines: vaccination with live virus vaccines is not recommended from at least 2 weeks before treatment starts, during treatment, and until B-lymphocytes have recovered to normal ranges after the last cycle.

Treatment must be started under the direction and supervision of a physician experienced in treating haematological malignancies. Patients receive the Educational Brochure for Patients and Caregivers and the Patient Card. Blinatumomab is given as a continuous intravenous infusion at a constant flow rate by an infusion pump; the powder is reconstituted and diluted before use following the instructions in the SmPC (section 6.6).

Hospitalisation and Supervision

• Relapsed or refractory ALL: hospitalisation is recommended for at least the first 9 days of the first cycle and the first 2 days of the second cycle.
• Philadelphia chromosome-negative MRD-positive ALL: at least the first 3 days of the first cycle and the first 2 days of each later cycle.
• Consolidation phase: the first 3 days of the first cycle and the first 2 days of the second cycle.
• History or presence of clinically relevant central nervous system (CNS) disease: at least the first 14 days of the first cycle and at least 2 days of the second cycle, with clinical judgement based on tolerance in the first cycle. First neurological events can occur late.
• All later cycle starts and any restart, for example after an interruption of 4 hours or more: supervision by a healthcare professional or hospitalisation is recommended.

Premedication and Supportive Treatment

• Relapsed or refractory ALL, adults: dexamethasone 20 mg intravenously 1 hour before the start of each cycle.
• Relapsed or refractory ALL, paediatric patients: dexamethasone 10 mg/m² (not more than 20 mg) orally or intravenously 6 to 12 hours before the start of cycle 1 (day 1), followed by 5 mg/m² orally or intravenously within 30 minutes before the start.
• Relapsed or refractory ALL with high tumour burden (50% or more leukaemic blasts in bone marrow, or more than 15,000/microlitre in peripheral blood): pre-phase treatment with dexamethasone, not more than 24 mg/day.
• MRD-positive ALL: prednisone 100 mg intravenously, or an equivalent such as dexamethasone 16 mg, 1 hour before the start of each cycle.
• Consolidation, adults: dexamethasone 20 mg intravenously within 1 hour before the start of each cycle.
• High-risk first relapse, paediatric patients: dexamethasone 5 mg/m² (not more than 20 mg) before the first dose in the first cycle and when restarting after an interruption of 4 hours or more in the first cycle.
• All indications: an antipyretic such as paracetamol is recommended during the first 48 hours of each cycle, and intrathecal chemotherapy prophylaxis is recommended before and during treatment to prevent CNS relapse.

Relapsed or Refractory B-Cell Precursor ALL

• Up to 2 treatment cycles. Each cycle is 28 days of continuous infusion followed by a 14-day treatment-free interval.
• 45 kg or more (fixed dose): cycle 1, 9 mcg/day on days 1 to 7, then 28 mcg/day on days 8 to 28; later cycles, 28 mcg/day on days 1 to 28.
• Under 45 kg (by body surface area): cycle 1, 5 mcg/m²/day (not more than 9 mcg/day) on days 1 to 7, then 15 mcg/m²/day (not more than 28 mcg/day) on days 8 to 28; later cycles, 15 mcg/m²/day (not more than 28 mcg/day) on days 1 to 28.
• Patients in complete remission (CR), or complete remission with partial haematological recovery (CRh), after 2 cycles may receive up to 3 further consolidation cycles, based on an individual benefit–risk assessment.

MRD-Positive B-Cell Precursor ALL (Adults)

• Quantifiable MRD must be confirmed in a validated assay with a minimum sensitivity of 10⁻⁴, in a qualified laboratory.
• One induction cycle followed by up to 3 consolidation cycles. Each cycle is 28 days of continuous infusion followed by a 14-day treatment-free interval (42 days in total).
• 45 kg or more: 28 mcg/day on days 1 to 28. Under 45 kg: 15 mcg/m²/day (not more than 28 mcg/day) on days 1 to 28.
• Most responders respond after 1 cycle, so the treating physician should reassess the benefit and risk of continuing in patients with no haematological or clinical improvement after one cycle.

Consolidation, Newly Diagnosed ALL (Adults)

• Up to 4 consolidation cycles, each 28 days of continuous infusion followed by a 14-day treatment-free interval.
• 45 kg or more: 28 mcg/day. Under 45 kg: 15 mcg/m²/day (not more than 28 mcg/day).

High-Risk First Relapse (Paediatric Patients)

• One cycle after induction and 2 blocks of consolidation chemotherapy: 28 days of continuous infusion.
• 45 kg or more: 28 mcg/day. Under 45 kg: 15 mcg/m²/day (not more than 28 mcg/day).

Dose Adjustments for Toxicity

• Temporary or permanent discontinuation should be considered for severe (grade 3) or life-threatening (grade 4) cytokine release syndrome, tumour lysis syndrome, neurological toxicity, elevated liver enzymes and any other clinically relevant toxicity.
• If an interruption for an adverse reaction lasts no more than 7 days, the same cycle is continued to a total of 28 days of infusion, counting the days before and after the interruption. If it lasts longer than 7 days, a new cycle is started. If the toxicity takes more than 14 days to resolve, blinatumomab is stopped permanently, except where the SmPC states otherwise.
• Cytokine release syndrome or tumour lysis syndrome: grade 3, interrupt until resolved, restart at 9 mcg/day (5 mcg/m²/day under 45 kg) and escalate to the full dose after 7 days if it does not recur; grade 4, stop permanently.
• Neurological toxicity other than ICANS: grade 3, interrupt until no more than grade 1 and for at least 3 days, then restart at 9 mcg/day (5 mcg/m²/day under 45 kg), escalating after 7 days if it does not recur and with dexamethasone premedication (24 mg, then reduced step by step over 4 days); stop permanently if it occurred at the lower dose or took more than 7 days to resolve. Grade 4, stop permanently.
• ICANS: managed by grade (ASTCT grading). Grade 1, interrupt until it resolves, monitor, and consider a neurologist, dexamethasone and a non-sedating antiseizure medicine such as levetiracetam. Grades 2 and 3, interrupt, give dexamethasone, and restart at the lower dose once resolved, escalating after 7 days; in grade 3, stop permanently if it occurred at the lower dose or took more than 7 days to resolve, or if more than one seizure occurs. Grade 4, stop permanently, give high-dose corticosteroid and supportive care, including intensive care if needed.
• Elevated liver enzymes: grade 3, if clinically relevant interrupt until no more than grade 1, restart at the lower dose and escalate after 7 days; grade 4, consider stopping permanently.
• Other clinically relevant reactions: grade 3, interrupt until no more than grade 1, restart at the lower dose and escalate after 7 days; grade 4, consider stopping permanently.

Method of Administration

• The infusion pump should be programmable, lockable, non-elastomeric and have an alarm. A bag is infused over up to 96 hours at a constant rate: 10 mL/h for 24 hours, 5 mL/h for 48 hours, 3.3 mL/h for 72 hours or 2.5 mL/h for 96 hours. The starting volume (270 mL) is larger than the volume given (240 mL) to allow for priming of the tubing.
• The treating physician chooses the infusion duration, considering how often bags are changed and the patient’s weight; the target dose delivered does not change. The bag must be changed at least every 96 hours by a healthcare professional for sterility.
• Use tubing with a sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter. With a multi-lumen venous catheter, use a dedicated lumen.
• Do not flush the infusion line, especially when changing bags or at the end of the infusion: flushing can result in excess dosage and complications.

Special Populations

• Elderly: no dose adjustment (65 years and over); limited experience from 75 years.
• Renal impairment: no adjustment in mild to moderate impairment; not studied in severe impairment.
• Hepatic impairment: no adjustment of the initial dose; not studied in severe impairment.
• Children: authorised from 1 month of age for the indications above; experience in children under 1 year is limited. Patients under 45 kg are dosed by body surface area.

Hospital Start and Monitoring

Blinatumomab is started in hospital. Cytokine release syndrome and neurological events usually appear early in treatment and can be severe, life-threatening or fatal, so the SmPC recommends hospitalisation for the first days of treatment (see Administration and Dosage for the minimum periods) together with this monitoring:

• A neurological examination before treatment starts, and clinical monitoring for signs and symptoms of neurologic events, including ICANS, throughout treatment. A writing test can be part of the assessment.
• Close observation for cytokine release syndrome and infusion reactions, especially at the start of the first and second cycles.
• Renal function and fluid balance in the first 48 hours after the first infusion, to detect tumour lysis syndrome.
• White blood cell and absolute neutrophil counts routinely during the infusion, especially in the first 9 days of the first cycle.
• ALT, AST, GGT and total bilirubin before and during treatment, especially in the first 48 hours of the first two cycles.
• Clinical monitoring for infection, pancreatitis and signs of progressive multifocal leukoencephalopathy.
• Supervision by a healthcare professional or hospitalisation whenever an infusion is restarted, for example after an interruption of 4 hours or more.

Neurological Events, Including ICANS

Neurologic events, including fatal ones, have been observed. Severe (grade 3 or higher) events included encephalopathy, seizures, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The median time to the first event was within the first 2 weeks; most resolved after the infusion was interrupted and infrequently led to discontinuation. Elderly patients may be more susceptible to serious events such as cognitive disorder, encephalopathy and confusion.

• Patients with a history of neurologic signs and symptoms (such as dizziness, hypoaesthesia, tremor, paraesthesia or memory impairment) had more neurologic events, usually in the first cycle.
• Experience is limited in patients with clinically relevant CNS disease (for example epilepsy, seizures, stroke, severe brain injury, dementia, Parkinson’s disease, cerebellar disease or psychosis), who were excluded from studies. The benefit must be weighed carefully against a possibly higher risk.
• Experience is limited in active ALL of the CNS or cerebrospinal fluid. Treatment can start once the cerebrospinal fluid has been cleared with CNS-directed therapy such as intrathecal chemotherapy.
• Patients with Down syndrome may have a higher risk of seizures, so seizure prophylaxis should be considered before starting. After a seizure, secondary prophylaxis with an anticonvulsant such as levetiracetam is recommended.

Cytokine Release Syndrome and Infusion Reactions

Cytokine release syndrome (CRS) can be life-threatening or fatal. Signs include pyrexia, asthenia, headache, hypotension, raised total bilirubin and nausea, and the median time to onset was 2 days. Disseminated intravascular coagulation and capillary leak syndrome (hypotension, low albumin, oedema, haemoconcentration) are commonly associated with CRS and need prompt management. Haemophagocytic lymphohistiocytosis or macrophage activation syndrome has been reported uncommonly with CRS.

Infusion reactions can look the same as CRS. They usually occur within 48 hours of starting, but delayed onset or onset in later cycles has been reported. Starting at the recommended low dose in cycle 1 (days 1 to 7) is important to reduce the risk of CRS, and an antipyretic such as paracetamol is recommended during the first 48 hours of each cycle. Management may need interruption or discontinuation of blinatumomab.

Haemophagocytic Lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) and the related immune effector cell-associated HLH-like syndrome (IEC-HS) are life-threatening, with fever, very high ferritin, enlarged liver or spleen, low blood counts and clotting abnormalities. They should be considered when CRS looks atypical or lasts longer than expected. If suspected, blinatumomab must be interrupted for investigation, including other causes such as infection, malignancy or autoimmune disease, and treatment started promptly according to guidelines.

Tumour Lysis Syndrome

Tumour lysis syndrome (TLS) can be life-threatening or fatal. Prevention and treatment include aggressive hydration and a uric acid-lowering medicine such as allopurinol or rasburicase, especially in patients with a high white cell count or high tumour burden. Patients with moderate renal impairment had a higher incidence of TLS in studies.

Infections, Neutropenia, Liver Enzymes and Pancreatitis

• Infections: serious infections, including sepsis, pneumonia, bacteraemia, opportunistic infections and catheter-site infections, have occurred, some life-threatening or fatal. Adults with ECOG performance status 2 had more serious infections. Experience is limited in active uncontrolled infection.
• Neutropenia and febrile neutropenia: including life-threatening cases; blood counts are monitored routinely.
• Liver enzymes: transient rises, mostly in the first week of treatment, which rarely needed interruption.
• Pancreatitis: life-threatening or fatal cases have been reported, and high-dose steroids may have contributed in some. Evaluation may include serum amylase and lipase and abdominal imaging.

Leukoencephalopathy

MRI changes of leukoencephalopathy have been seen, especially after cranial irradiation and anti-leukaemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine); their clinical significance is unknown. Because progressive multifocal leukoencephalopathy is possible, patients are monitored for signs. If it is suspected, consultation with a neurologist, brain MRI and examination of the cerebrospinal fluid are considered.

Relapse Without CD19 and Lineage Switch

CD19-negative relapse has been reported, so CD19 expression should be assessed at bone marrow testing. A switch from ALL to acute myeloid leukaemia has been reported rarely in relapsed patients, who should be monitored for AML.

Vaccination

The safety of live virus vaccines during or after blinatumomab has not been studied. They are not recommended from at least 2 weeks before treatment, during treatment, and until B-lymphocytes have recovered after the last cycle.

Medication Errors and Traceability

Medication errors, including underdose and overdose, have occurred. The preparation (reconstitution and dilution) and administration instructions must be followed strictly. The name and batch number of the product given must be clearly recorded, because it is a biological medicine.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for at least 48 hours after it.
• Pregnancy: no reproductive toxicity studies have been done with blinatumomab. In mice, a murine surrogate molecule crossed the placenta without causing embryotoxicity or teratogenicity. There are no data in pregnant women, and blinatumomab should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus. After exposure in pregnancy, B-cell depletion may be expected in the newborn, who should be monitored; live virus vaccines should be postponed until the infant’s B-cell count has recovered.
• Breastfeeding: it is unknown whether blinatumomab or its metabolites pass into human milk, and a risk to the infant cannot be excluded. Breastfeeding is therefore contraindicated during treatment and for at least 48 hours after it.
• Fertility: no human studies have been done. The murine surrogate molecule had no adverse effects on the reproductive organs of male or female mice in 13-week toxicity studies.

Sodium

Over a 24-hour infusion the medicine contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Blinatumomab has a major influence on the ability to drive and use machines. Confusion, disorientation, coordination and balance disorders, seizures and disturbances in consciousness can occur. Patients should not drive, take part in hazardous occupations or activities, or operate heavy or potentially dangerous machinery while blinatumomab is being given.

Store and transport refrigerated at 2–8 °C. Do not freeze. Keep the vials in the original package to protect them from light. Blincyto is a cold-chain product and must stay at 2–8 °C during transport and storage until it is prepared for infusion. For storage after reconstitution and dilution, see Shelf Life.

• Unopened vials: 5 years.
• Reconstituted solution: chemical and physical in-use stability has been shown for 24 hours at 2–8 °C or 4 hours at or below 27 °C. From a microbiological point of view it should be diluted immediately, unless the method of reconstitution excludes the risk of microbial contamination; otherwise in-use storage times and conditions are the responsibility of the user.
• Diluted solution (prepared infusion bag): chemical and physical in-use stability has been shown for 10 days at 2–8 °C or 96 hours at or below 27 °C. From a microbiological point of view the prepared bags should be used immediately.

Prescription only (Rx), subject to restricted medical prescription (Annex II B): treatment is started and supervised by a physician experienced in treating haematological malignancies. Blinatumomab is a refrigerated infusion that is started in hospital, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions (2–8 °C). Patients and carers receive the Educational Brochure for Patients and Caregivers and the Patient Card.