Blincyto

— THERAPEUTIC DISORDERS TREATED —
  • Leukemias, lymphomas, and other hematologic cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Blincyto Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Blinatumomab 35mcg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

    Pharmacological Class

    Bispecific CD19-directed CD3 T-cell engager.

    How Supplied

    Pack—1 (single-use vial + IV solution stabilizer)

    How Supplied

    Each Blincyto package contains:  

    • One Blincyto (blinatumomab) for injection 35 mcg single-dose vial containing a sterile, preservative-free, white to off-white lyophilized powder and  

    • One IV Solution Stabilizer 10 mL single-dose glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution.

    Storage

    Store Blincyto and IV Solution Stabilizer vials in the original package refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light until time of use. Do not freeze. 

    Blincyto and IV Solution Stabilizer vials may be stored for a maximum of 8 hours at room temperature [23°C to 27°C (73°F to 81°F)] in the original carton to protect from light.

    Manufacturer

    Amgen, Inc.

    Generic Availability

    NO

    Blincyto Indications

    Indications

    CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) ≥0.1%. Relapsed or refractory CD19-positive B-cell precursor ALL.

    Blincyto Dosage and Administration

    Adults and Children

    Strictly follow preparation and administration instructions. Give by continuous IV infusion at a rate of 10mL/hr over 24hrs, 5mL/hr over 48hrs, or 0.6mL/hr over 7 days (not recommended for patients <22kg). MRD-positive: premedicate with prednisone 100mg IV or equivalent (adults) 1hr prior to 1st dose of each cycle, or dexamethasone 5mg/m2 to max 20mg (pediatrics) prior to 1st dose in the 1st cycle, and when restarting infusion after interruption (≥4hrs). Treat up to 4 cycles (1 cycle for induction, followed by 3 cycles for consolidation). One single cycle = 28 days of continuous IV infusion followed by a 14-day treatment-free interval (during Cycles 1–4). Hospitalization recommended for first 3 days of Cycle 1 and first 2 days of Cycle 2. <45kg (Cycles 1–4): 15mcg/m2/day (max 28mcg/day) on Days 1–28. ≥45kg (Cycles 1–4): 28mcg/day on Days 1–28. Relapsed/refractory: premedicate with dexamethasone 20mg (adults) 1hr prior to 1st dose of each cycle, or dexamethasone 5mg/m2 to max 20mg (pediatrics) prior to 1st dose in the 1st cycle, plus prior to a step dose, and when restarting infusion after interruption (≥4hrs) for both adults and pediatrics. Treat up to 9 cycles (2 cycles for induction, followed by 3 cycles for consolidation, and up to 4 additional cycles of continued therapy). One single cycle = 28 days of continuous IV infusion followed by a 14-day treatment-free interval (during Cycles 1–5) and 56-day treatment-free interval (during Cycles 6–9). Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of Cycle 2. <45kg (Cycle 1): 5mcg/m2/day (max 9mcg/day) on Days 1–7 and 15mcg/m2/day (max 28mcg/day) on Days 8–28; (Cycles 2–9): 15mcg/m2/day (max 28mcg/day) on Days 1–28. ≥45kg (Cycle 1): 9mcg/day on Days 1–7 and 28mcg/day on Days 8–28; (Cycles 2–9): 28mcg/day on Days 1–28. Dose adjustments, using 24-hr, 48-hr, or 7-day infusion of Blincyto: see full labeling.

    Adults and Children

    Treatment of MRD-positive B-cell Precursor ALL

    • Strictly follow preparation and administration instructions.

    • Give by continuous IV infusion at a rate of 10 mL/hr over 24hrs, 5 mL/hr over 48hrs, or 0.6 mL/hr over 7 days (not recommended for patients <22kg). 

    • 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 IV infusion followed by a 14-day treatment-free interval (total 42 days).  

    • Recommended Dose and Schedule:

      • <45 kg (Cycles 1–4): 15 mcg/m2/day (max 28 mcg/day) on Days 1–28. 

      • ≥45 kg (Cycles 1–4): 28 mcg/day on Days 1–28. 

    • Hospitalization recommended for first 3 days of Cycle 1 and the first 2 days of Cycle 2. Supervision by a healthcare profession or hospitalization is recommended for all subsequent cycle starts and re-initiation (e.g., if treatment is interrupted for 4 or more hours).

    • Premedicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL:

      • For adults: premedicate with prednisone 100 mg IV or equivalent (e.g., dexamethasone 16 mg) 1 hour prior to the first dose in each cycle.

      • For pediatric patients: premedicate with 5 mg/m2 of dexamethasone (max 20 mg) prior to the first dose in the first cycle and when restarting an infusion after interruption of 4 or more hours in the first cycle.

    Treatment of Relapsed or Refractory B-cell Precursor ALL  

    • Strictly follow preparation and administration instructions.

    • Give by continuous IV infusion at a rate of 10 mL/hr over 24hrs, 5 mL/hr over 48hrs, or 0.6 mL/hr over 7 days (not recommended for patients <22kg). 

    • A treatment course consists of up to 2 cycles of Blincyto for induction followed by 3 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 IV 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 IV infusion followed by a 56-day treatment-free interval (total 84 days).

    • Recommended Dose and Schedule:

      • <45 kg (Cycle 1): 5 mcg/m2/day (max 9 mcg/day) on Days 1–7 and 15 mcg/m2/day (max 28 mcg/day) on Days 8–28; (Cycles 2–9): 15 mcg/m2/day (max 28 mcg/day) on Days 1–28. 

      • ≥45 kg (Cycle 1): 9 mcg/day on Days 1–7 and 28 mcg/day on Days 8–28; (Cycles 2–9): 28 mcg/day on Days 1–28. 

    • Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of Cycle 2. Supervision by a healthcare profession or hospitalization is recommended for all subsequent cycle starts and re-initiation (e.g., if treatment is interrupted for 4 or more hours).

    • Premedicate with dexamethasone:

      • For adults: premedicate with dexamethasone 20 mg one hour prior to the first dose in each cycle, prior to a step dose (e.g., Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours.

      • For pediatric patients: premedicate with 5 mg/m2 of dexamethasone (max 20 mg) prior to the first dose in the first cycle prior to a step dose (e.g., Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours.

     

    Other Modifications

    Females and Males of Reproductive Potential 

    • May cause fetal harm when administered to a pregnant woman

    • Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating treatment. 

    • Contraception: Advise females of reproductive potential to use effective contraception during treatment and for 48 hours after the last dose.

    Blincyto Contraindications

    Not Applicable

    Blincyto Boxed Warnings

    Boxed Warning

    Cytokine release syndrome. Neurological toxicities.

    Boxed Warning

    Cytokine Release Syndrome (CRS) and Neurological Toxicities  

    • CRS may be life-threatening or fatal. Interrupt or discontinue Blincyto and treat with corticosteroids as recommended.

    • Neurological toxicities may be severe, life-threatening, or fatal. Interrupt or discontinue Blincyto as recommended. 

    Blincyto Warnings/Precautions

    Warnings/Precautions

    Monitor for cytokine release syndrome, neurological toxicities (eg, seizures, loss of consciousness), tumor lysis syndrome; interrupt or discontinue as recommended (see full labeling). Monitor for infections; give antibiotic prophylaxis as appropriate. Obtain lab tests (including WBC, ANC) during infusion; interrupt if prolonged neutropenia occurs. Monitor ALT, AST, GGT, and total bilirubin prior to and during treatment; interrupt if transaminases rise >5×ULN or if bilirubin rises >3×ULN. Evaluate if signs/symptoms of pancreatitis develop; interrupt or discontinue as appropriate. Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine). Elderly. Neonates/infants: risk of gasping syndrome (due to benzyl alcohol preservative). Pregnancy: exclude status prior to initiation. Advise females of reproductive potential to use effective contraception during and for ≥48hrs after the last dose. Nursing mothers: not recommended (during and for ≥48hrs after the last dose).

    Warnings/Precautions

    Cytokine Release Syndrome (CRS)

    • The median time to onset of CRS was 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved.

    • Monitor patients for signs or symptoms of these events.

    • Advise outpatients on Blincyto to contact their healthcare professional for signs and symptoms associated with CRS. 

    • If severe CRS occurs, interrupt Blincyto until CRS resolves. Discontinue Blincyto permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.

    Neurological Toxicities

    • Monitor for signs and symptoms of neurological toxicities. 

    • Advise outpatients on Blincyto to contact their healthcare professional if they develop signs or symptoms of neurological toxicities.

    • Interrupt or discontinue Blincyto as recommended.

    Infections

    • As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with Blincyto. 

    • Monitor for signs and symptoms of infection and treat appropriately.

    Tumor Lysis Syndrome (TLS)

    • Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during treatment. 

    • Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of Blincyto.

    Neutropenia and Febrile Neutropenia

    • Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during infusion. 

    • Interrupt treatment if prolonged neutropenia occurs. 

    Effects on Ability to Drive and Use Machines 

    • Advise patients to refrain from driving and engaging in hazardous occupations or activities during treatment.

    Elevated Liver Enzymes

    • Monitor ALT, AST, GGT, and total blood bilirubin prior to the start of and during treatment. 

    • Interrupt treatment if the transaminases rise to >5 times the upper limit of normal or if total bilirubin rises to >3 times the upper limit of normal. 

    Pancreatitis

    • Evaluate if signs and symptoms of pancreatitis develop. May require either temporary interruption or discontinuation of Blincyto and dexamethasone.

    Leukoencephalopathy

    • Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown. 

    Preparation and Administration Errors 

    • Strictly follow instructions for preparation (including admixing) and administration to minimize errors.

    Immunization

    • Concomitant live vaccines: not recommended (for ≥2 weeks prior to initiation, during treatment, and until immune recovery after last cycle).

    Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative

    • Risk of gasping syndrome in neonates and infants due to benzyl alcohol preservative.

    • Due to the addition of bacteriostatic saline, 7-day infusion bags of Blincyto solution contain benzyl alcohol and are not recommended for use in any patients weighing less than 22 kg.

    Pregnancy Considerations

    Risk Summary 

    • May cause fetal harm, including B-cell lymphocytopenia, when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus.

    Clinical Considerations

    • Fetal/Neonatal Adverse Reactions: Due to the potential for B-cell lymphocytopenia in infants following exposure to Blincyto in utero, the infant’s B lymphocytes should be monitored before the initiation of live virus vaccination.

    Nursing Mother Considerations

    Risk Summary

    • Advise not to breastfeed during treatment and for 48 hours after the last dose.

    Pediatric Considerations

    • Safety and efficacy of Blincyto have been established in pediatric patients with relapsed or refractory B-cell precursor ALL.

    • Risk of benzyl alcohol toxicity in pediatric patients due to benzyl alcohol preservative. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 

      • Due to the addition of bacteriostatic saline, 7-day infusion bags of Blincyto solution contain benzyl alcohol and are not recommended for use in patients weighing less than 22 kg. Prepare Blincyto solution for infusion with preservative-free saline in 24-hour or 48-hour infusion bags for patients weighing less than 22 kg.

    Geriatric Considerations

    No overall differences in safety or effectiveness were observed between these patients and younger patients.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • May cause fetal harm when administered to a pregnant woman

    • Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating treatment. 

    • Contraception: Advise females of reproductive potential to use effective contraception during treatment and for 48 hours after the last dose.

    REMS

    YES

    Blincyto Pharmacokinetics

    Distribution

    The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.35 (2.45) L with continuous intravenous infusion of blinatumomab. 

    Metabolism

    The metabolic pathway of blinatumomab has not been characterized. Like other protein therapeutics, Blincyto is expected to be degraded into small peptides and amino acids via catabolic pathways.

    Elimination

    The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 3.11 (2.98) L/hour. The mean (SD) half-life was 2.10 (1.41) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses. 

    Blincyto Interactions

    Interactions

    Concomitant live vaccines: not recommended (for ≥2 weeks prior to initiation, during treatment, and until immune recovery after last cycle). Caution with concomitant CYP450 substrates esp. drugs with narrow therapeutic index (eg, warfarin, cyclosporine); monitor and adjust dose as needed.

    Blincyto Adverse Reactions

    Adverse Reactions

    Infections, pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, neutropenia; tremor, encephalopathy, aphasia, sepsis, overdose, septic shock.

    Blincyto Clinical Trials

    Clinical Trials

    MRD-positive B-cell Precursor ALL 

    BLAST Study

    • The efficacy of Blincyto was evaluated in an open-label, multicenter, single-arm study which included 86 patients 18 years of age and older who had received at least 3 chemotherapy blocks of standard ALL therapy, were in hematologic complete remission (defined as <5% blasts in bone marrow, ANC > 1 Gi/L, platelets > 100 Gi/L) and had minimal residual disease (MRD) at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01%.

    • Patients received Blincyto at a constant dose of 15 mcg/m2/day (equivalent to the recommended dosage of 28 mcg/day) intravenously for all treatment cycles. Patients received up to 4 cycles of treatment. The treated population included patients in first or second hematologic complete remission (CR1 or CR2).

    • The efficacy was based on achievement of undetectable MRD within one cycle of Blincyto treatment and hematological relapse-free survival (RFS).

    • 52 of 62 (85.2%; 95%, 73.8-93.0) patients in CR1 achieved complete MRD response. The median hematological relapse-free survival was 35.2 months (range: 0.4 to 53.5). 

    • 18 of 25 (72%; 95% CI, 50.6-87.9) patients in CR2 achieved complete MRD response. The median hematological relapse-free survival was 12.3 months (range: 0.7 to 42.3).

    • Undetectable MRD was achieved by 65 of 80 patients (81.3%; 95% CI, 71.0-89.1) with an assay sensitivity of at least 0.005%. The estimated median hematological RFS among the 80 patients using the higher sensitivity assay was 24.2 months (95% CI: 17.9, NE).

     

    Relapsed/Refractory B-cell Precursor ALL

    TOWER Study

    • The efficacy of Blincyto was compared to standard of care (SOC) chemotherapy in a randomized, open-label, multicenter study in 405 patients 18 years of age and older with relapsed or refractory B-cell precursor ALL. SOC chemotherapy included fludarabine, cytarabine arabinoside, and granulocyte colony-stimulating factor (FLAG); high-dose cytarabine arabinoside (HiDAC); high-dose methotrexate- (HDMTX) based combination; or clofarabine/clofarabine-based regimens. 

    • Patients were randomly assigned 2:1 received Blincyto (n=271) or investigator-selected SOC chemotherapy (n=134). The efficacy was based on overall survival (OS).

    • The study demonstrated a superior improvement in median OS with Blincyto vs. SOC chemotherapy (7.7 months vs. 4 months, respectively; hazard ratio 0.71 [95% CI, 0.55-0.93]; P =.012).

    • Overall response for complete remission plus complete remission with partial hematologic recovery:

      • 42% (95% CI, 37-49) for Blincyto vs 27% (95% CI, 14-28) for SOC Chemotherapy. Treatment difference of 22% (95% CI, 13-31; P <.001).

    • Overall response for complete remission:

      • 34% (95% CI, 28-40) for Blincyto vs 16% (95% CI, 10-23) for SOC Chemotherapy. Treatment difference of 18% (95% CI, 10-26; P <.001).

     

    Study MT103-211 

    • Study MT103-211 was an open-label, multicenter, single-arm study. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL. Blincyto was administered as a continuous intravenous infusion to 185 patients. 

    • Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with Blincyto.

    • CR: 

      • 60 patients (32.4%; 95% CI, 25.7-39.7)

    • CRh: 

      • 17 patients (9.2%; 95% CI, 5.4-14.3)

    • CR/CRh:

      • 77 patients (41.6%; 95% CI, 34.4-49.1)

     

    ALCANTARA Study

    • The efficacy of Blincyto for treatment of Philadelphia chromosome-positive B-cell precursor ALL was evaluated in an open-label, multicenter, single-arm study in 45 patients ≥ 18 years of age with Philadelphia chromosome-positive B-cell precursor ALL, relapsed or refractory to at least 1 second generation or later tyrosine kinase inhibitor (TKI), or intolerant to second generation TKI, and intolerant or refractory to imatinib mesylate. 

    • Blincyto was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with Blincyto.

    • CR: 

      • 14 patients (31%; 95% CI, 18-47)

    • CRh: 

      • 2 patients (4%; 95% CI, 1-15)

    • CR/CRh:

      • 16 patients (36%; 95% CI, 22-51)

     

    Study MT103-205 

    • Study MT103-205 was an open-label, multicenter, single-arm study in 70 pediatric patients with relapsed or refractory B-cell precursor ALL. Blincyto was administered at 5 mcg/m2/day on Days 1-7 and 15 mcg/m2/day on Days 8-28 for Cycle 1, and 15 mcg/m2/day on Days 1-28 for subsequent cycles.

    • 23 out of 70 (32.9%) patients achieved CR/CRh within the first 2 treatment cycles with 17 out of 23 (73.9%) occurring within Cycle 1 of treatment.  The HSCT rate among those who achieved CR/CRh* was 48% (11 out of 23).

    Blincyto Note

    Not Applicable

    Blincyto Patient Counseling

    Patient Counseling

    Cytokine Release Syndrome (CRS) 

    • Advise patients of the risk of CRS and infusion reactions, and to contact their healthcare professional for signs and symptoms associated with CRS or infusion reactions.

    Neurological Toxicities 

    • Advise patients of the risk of neurological toxicities, and to contact their healthcare professional for signs and symptoms associated with this event.

    Infections

    • Advise patients of the risk of infections, and to contact their healthcare professional for signs or symptoms of infection.

    Pancreatitis

    • Advise patients of the risk of pancreatitis and to contact their healthcare provider for signs or symptoms of pancreatitis, which include severe and persistent stomach pain, with or without nausea and vomiting.

    Driving and Engaging in Hazardous Occupations 

    • 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.

    Infusion Pump Errors 

    • Inform patients they should not adjust the setting on the infusion pump. Any changes to pump function may result in dosing errors.

    Cost Savings Program

    Blincyto Support and Resources: https://www.blincyto.com/relapsed-refractory/support-and-resources

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