blinatumomab

bli-ni-TOO-moe-mab

Therapeutic Classification: antineoplastics

Pharmacologic Classification: T-cell engagers, monoclonal antibodies

High Alert

Relapsed or refractory CD-19 positive, B-cell precursor acute lymphoblastic leukemia (ALL).
CD-19 positive B-cell precursor ALL in first or second complete remission with minimal residual disease ≥0.1%.
CD-19 positive Philadelphia chromosome-negative B-cell precursor ALL in the consolidation phase of multiphase chemotherapy.

Acts as a T-cell engager, binding to and activating T-cells binding them to tumor cells resulting in facilitated lysis of malignant cells.

Therapeutic effects:

Depletion of B-cells, including malignant ones.

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism/Excretion: Catabolized into small peptides and amino acids.

Half-Life: 2.11 hr.

(depletion of B-cells)

ROUTE	ONSET	PEAK	DURATION
IV	rapid	unknown	persists during treatment free interval

Contraindicated in:

Hypersensitivity;
Severe renal impairment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Rep: Women of reproductive potential;
Pedi: risk of potentially fatal “gasping syndrome” in very low-birth-weight neonates born weighing 1500 g and early preterm neonates (born less than 34-wk gestational age); safety and effectiveness not established in children 1 mo;
Geri: risk of neurologic toxicity in older adults.

CV: chest pain, hypotension, peripheral edema, hypertension, tachycardia

Derm: rash

Endo: hyperglycemia

F and E: hypokalemia, hypomagnesemia, hypophosphatemia

GI: abdominal pain, constipation, diarrhea, pancreatitis, vomiting, ↑liver enzymes, hypoalbuminemia

Hemat: anemia, neutropenia, leukocytosis, lymphopenia, thrombocytopenia

Metab: ↓appetite

MS: arthralgia, back pain, bone pain, extremity pain

Neuro: altered consciousness, balance disorder, confusion, coordination disorder, disorientation, dizziness, encephalopathy, fatigue, headache, insomnia, speech disorders, tremor, aphasia, cognitive disorder, IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS), SEIZURES, weakness

Resp: cough, dyspnea

Misc: chills, cytokine release syndrome (CRS), fever, infection , HYPERSENSITIVITY REACTIONS, infusion reactions, TUMOR LYSIS SYNDROME

Drug-drug:

May suppress activity of CYP450 drug-metabolizing enzymes (especially first 9 days of 1st cycle and first 1 days of 2nd cycle); careful monitoring of CYP450 substrates, including cyclosporine and warfarin, is recommended.
May ↓ antibody response to and ↑ risk of adverse reactions from live-virus vaccines; do not administer live vaccines for ≥2 wk before starting therapy, during therapy, and until immune system recovers after completion of therapy.

Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia

Treatment course consists of up to 2 cycles for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy.
IV (Adults and Children ≥1 mo and ≥45 kg): Induction cycle 1: 9 mcg/day as a continuous infusion for days 1–7, followed by 28 mcg/day as a continuous infusion for days 8–28, followed by a 2-wk treatment-free interval. Induction cycle 2: 28 mcg/day as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval. Consolidation cycles 3–5: 28 mcg/day as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval. Continued therapy cycles 6–9: 28 mcg/day as a continuous infusion for days 1–28, followed by an 8-wk treatment-free interval.
IV (Adults and Children ≥1 mo and <45 kg): Induction cycle 1: 5 mcg/m²/day (not to exceed 9 mcg/day) as a continuous infusion for days 1–7, followed by 15 mcg/m²/day (not to exceed 28 mcg/day) as a continuous infusion for days 8–28, followed by a 2-wk treatment-free interval. Induction cycle 2: 15 mcg/m²/day (not to exceed 28 mcg/day) as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval. Consolidation cycles 3–5: 15 mcg/m²/day (not to exceed 28 mcg/day) as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval. Continued therapy cycles 6–9: 15 mcg/m²/day (not to exceed 28 mcg/day) as a continuous infusion for days 1–28, followed by an 8-wk treatment-free interval.

Minimal Residual Disease-Positive B-cell Precursor Acute Lymphoblastic Leukemia

Treatment course consists of 1 cycle for induction followed by up to 3 additional cycles for consolidation.
IV (Adults and Children ≥1 mo and ≥45 kg): Induction cycle 1: 28 mcg/day as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval. Consolidation cycles 2–4: 28 mcg/day as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval.
IV (Adults and Children ≥1 mo and <45 kg): Induction cycle 1: 15 mcg/m²/day (not to exceed 28 mcg/day) as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval. Consolidation cycles 2–4: 15 mcg/m²/day (not to exceed 28 mcg/day) as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval.

B-Cell Precursor Acute Lymphoblastic Leukemia in the Consolidation Phase

IV (Adults and Children ≥1 mo and ≥45 kg): 28 mcg/day as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval.
IV (Adults and Children ≥1 mo and <45 kg): 15 mcg/m²/day (not to exceed 28 mcg/day) as a continuous infusion for days 1–28, followed by a 2-wk treatment-free interval.

Lyophilized powder for injection: 35 mcg/vial (IV solution stabilizer provided with package)

Monitor for signs and symptoms of CRS (fever, headache, nausea, asthenia, hypotension, ↑ AST, ↑ ALT, ↑ bilirubin, disseminated intravascular coagulation) during and following infusion. Median time to onset was 2 days after start of infusion and to resolution was 5 days. May be similar to infusion reactions. If symptoms are Grade 3, hold blinatumomab until resolved and administer dexamethasone 8 mg for patients ≥45 kg or 5 mg/m²for patients <45 kg every 8 hr IV or PO for up to 3 days; then taper over 4 days. Restart at 9 mcg/day for patients ≥45 kg and 5 mcg/m²/day for patients <45 kg. Escalate to 28 mcg/day for patients ≥45 kg and 15 mcg/m²/day in patients <45 kg, after 7 days if toxicity does not recur. If Grade 4 symptoms occur, discontinue blinatumomab permanently and administer dexamethasone as for Grade 3 CRS.
Monitor for signs and symptoms of neurological toxicity (encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion, disorientation, loss of balance and coordination) during therapy. Discontinue blinatumomab permanently if more than 1 seizure occurs. If Grade 3 symptoms occur, hold blinatumomab until no more than Grade 1 (mild) and for at least 3 days; then restart blinatumomab at 9 mcg/day for patients ≥45 kg and 5 mcg/m²/day for patients <45 kg. Escalate dose to 28 mcg/day for patients ≥45 kg and 15 mcg/m²/day in patients <45 kg after 7 days if toxicity does not recur. If toxicity occurred at 9 mcg/day for patients ≥45 kg and 5 mcg/m²/day for patients <45 kg or takes >7 days to resolve, discontinue blinatumomab permanently. If Grade 4 symptoms occur, discontinue blinatumomab permanently.
Assess for signs and symptoms of infection (fever, chills, sepsis, pneumonia, bacteremia, opportunistic infections, catheter site infections) during therapy. Treat with anti-infectives as needed.
Monitor for signs and symptoms of tumor lysis syndrome (abdominal pain and distension, dysuria, oliguria, flank pain, hematuria, anorexia, vomiting, cramps, seizures, spasms, altered consciousness) during therapy. May use prophylactic nontoxic cytoreduction and on-treatment hydration. May require temporary interruption or discontinuation.
Monitor for signs and symptoms of pancreatitis (severe and persistent stomach pain, with or without nausea and vomiting) during therapy.

Lab Test Considerations:

Verify negative pregnancy status prior to starting therapy.
Monitor CBC periodically during therapy. May cause neutropenia. Interrupt therapy if neutropenia is prolonged.
- Monitor ALT, AST, GGT, and total serum bilirubin prior to starting and during therapy. If AST and ALT ↑ to ≥5 times the upper limit of normal (ULN) or if bilirubin ↑ to >3 times the ULN, hold therapy.
- May cause hypokalemia, hypomagnesemia, hyperglycemia, and hypophosphatemia.

If an interruption due to an adverse reaction is <7 days, continue same cycle to a total of 28 days inclusive of days before and after interruption. If interruption >7 days, start a new cycle.

Intrathecal chemotherapy prophylaxis is needed before and during therapy to prevent CNS ALL relapse.
MRD-positive B-cell Precursor ALL: Premedicate adults 1 hr prior to 1st dose, in each cycle, with prednisone 100 mg IV or dexamethasone 16 mg IV. Premedicate pediatric patients prior to 1st dose in 1st cycle and when restarting infusion after an interruption of ≥4 hr in 1st cycle with 5 mg/m₂of dexamethasone IV or PO (max dose = 20 mg). Patient must be hospitalized for 1st 3 days of 1st cycle and 1st 2 days of 2nd cycle. If treatment is interrupted for ≥4 hr, supervision by a health care professional or hospitalization is needed.
Relapsed or Refractory B-cell Precursor ALLPremedicate adults with 20 mg of dexamethasone IV or PO 1 hr before 1st dose of each cycle and before step dose (e.g., Cycle 1 Day 8), and when restarting infusion after interruption of ≥4 hr. Premedicate pediatric patients with 5 mg/m₂of dexamethasone IV or PO (max dose = 20 mg) before 1st dose in 1st cycle, before a step dose, and when restarting infusion after an interruption of ≥4 hr in 1st cycle. Patient must be hospitalized for 1st 9 days of 1st cycle and 1st 2 days of 2nd cycle. If treatment is interrupted for ≥4 hr, supervision by a health care professional or hospitalization is needed
B-cell Precursor ALL in the Consolidation PhasePremedicate adults with dexamethasone 20 mg IV 1 hr before 1st dose of each cycle. Premedicate pediatric patients with 5 mg/m₂of dexamethasone IV or PO (max dose = 20 mg) before 1st dose in 1st cycle and when restarting infusion after interruption of ≥4 hr in 1st cycle. Patient must be hospitalized for 1st 3 days of 1st cycle and 1st 2 days of 2nd cycle. If treatment is interrupted for ≥4 hr, supervision by a health care professional or hospitalization is needed.

IV Administration:

Wear gloves, gown, and mask while handling medication. Discard IV equipment in specially designated containers.
Do not flush line, especially when changing bags or at completion of infusion; may result in excess or overdose. To prime IV tubing, use only the solution in the bag containing the FINAL prepared blinatumomab solution. Do not prime with 0.9% NaCl. Aseptically add 270 mL of 0.9% NaCl to polyolefin, DEHP-free PVC, or ethyl vinyl acetate (EVA) infusion bags/pump cassettes. Use polyolefin, DEHP-free PVC, or EVA intravenous tubing sets.
- Add 5.5 mL IV solution stabilizer to IV bag. Stabilizer is used to coat prefilled IV bag; do not use for reconstitution. Gently mix; avoid foaming. Discard remaining stabilizer.
- Entire volume of admixed blinatumomab will be more than 240 mL volume administered to patient to account for priming and ensure patient received full dose. Remove air from infusion bag. Add or remove 0.9% NaCl from bag if needed to adjust volume to 265 to 275 mL.
- Reconstitution: Reconstitute blinatumomab using 3 mL preservative-free sterile water for injection/vial. 12.5 mg/mL. Direct solution toward side of vial; gently swirl to avoid foaming. Do not shake. Solution is clear to opalescent, colorless to slightly yellow; do not infuse solutions that are cloudy, discolored, or contain a precipitate. Vials are stable at room temperature for 4 hr or 24 hr if refrigerated. Patients weighing ≥45 kg:For 9 mcg/day infused over 24 hr at a rate of 10 mL/hr, transfer 0.83 mL of reconstituted solution into IV bag. For 9 mcg/day infused over 48 hr at a rate of 5 mL/hr, transfer 1.7 mL of reconstituted solution into IV bag. For 28 mcg/day infused over 24 hr at a rate of 10 mL/hr, transfer 2.6 mL of reconstituted solution into IV bag. For 28 mcg/day infused over 48 hr at a rate of 5 mL/hr,transfer 5.2 mL of reconstituted solution (2.7 mL from one vial and 2.5 mL from a second vial) into IV bag. Patients weighing <45 kg:See package insert for volumes to add to IV bag for 5 mcg/m²/day and 15 mcg/m²/day dose. Diluted solution is stable for 48 hr at room temperature or for 8 days if refrigerated. May also be infused over 24 or 48 hr.
- For 7-day infusion:Transfer 90 mL bacteriostatic 0.9% NaCl into empty IV bag. Transfer 2.2 mL IV solution stabilizer into IV bag containing saline solution. For patients weighing ≥45 kg: transfer 16.8 mL reconstituted blinatumomab into IV bag. Mix gently to avoid foaming. Add 1 mL 0.9% NaCl for final volume of 110 mL. Mix gently to avoid foaming. Remove air from IV bag; prime tubing with prepared solution, not with 0.9% NaCl. For patients weighing 22–<45 kg: See package insert for volumes to add to IV bag for 15 mcg/m²/day dose. Not recommended for patients weighing <22 kg.
Rate: Infuse via programmable, lockable, nonelastomeric infusion pump with an alarm. Infuse 240 mL over 24 or 48 hr based on pharmacy label, at a rate of 10 mL/hr for 24 hr or 5 mL/hr for 48 hr. Use tubing that is sterile, nonpyrogenic, and low protein-binding, with a 0.2 micron in-line filter. Ensure tubing is compatible with infusion pump. If using a multilumen catheter, infuse blinatumomab through a dedicated lumen.
- For 7-day infusion:Do not use an in-line filter for a 7-day bag. Infuse final infusion solution according to instructions on pharmacy label on the prepared bag at an infusion rate of 0.6 mL/hr for 7 days.

Explain schedule for blinatumomab administration. Instruct patient to read Medication Guide before starting therapy and before each cycle in case of changes.
Instruct patient in how to keep area around IV catheter clean to reduce infections. Advise patient not to change settings of infusion pump.
May cause seizures and loss of consciousness. Caution patient to avoid driving or other activities requiring alertness until response from medication is known.
Advise patient to notify health care professional immediately if signs and symptoms of CRS (fever, tiredness or weakness, dizziness, headache, low BP, nausea, vomiting, chills, facial swelling, wheezing or difficulty breathing, rash) or neurological problems (seizures, difficulty speaking or slurred speech, loss of consciousness, confusion, disorientation, loss of balance) occur or if side effects occur that are bothersome or persistent.
Caution patient to avoid receiving live vaccines for 2 wk before and during therapy and until immune recovery following last cycle of blinatumomab therapy.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, or herbal products.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception and avoid breastfeeding during therapy and for at least 48 hr after last dose and to notify health care professional immediately if pregnancy is planned or suspected. Monitor infant’s B lymphocytes before initiation of live-virus vaccination due to the potential for B-cell lymphopenia in infants following blinatumomab exposure in utero. Monitor neonates receiving blinatumomab (with preservative) for new or worsening metabolic acidosis. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known. The 7-day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL.

Depletion of B-cells, including malignant ones.

Blincyto

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