BLINCYTO

Blinatumomab is a

BiTE-class (bi-specific T-cell engager) constructed monoclonal antibody formed by the recombinant fusion of an anti-CD3 single-chain variable fragment (scFV) and an anti-CD19 scFV through a short peptide linker. 5, 6 CD3 is an antigen expressed on the surface of T-cells, while CD19 is mostly expressed on the surface of malignant B-cells.

Since blinatumomab has an affinity to both antigens, it redirects T-cells to tumor cells expressing CD19 and promotes tumor cell lysis and apoptosis. 1, 2, 4 Blinatumomab is It was first approved by the FDA in December for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in relapsed and refractory patients.

In March 2018, it was approved under the FDA's accelerated approval program for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children.

Full approval for this indication was granted in June 2023. 7, 8 Blinatumomab has a short half-life, requiring patients to receive a continuous infusion over 4-week cycles using a portable mini-pump for optimum delivery.

Blinatumomab is indicated for the treatment of adults and children with relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL).

It is also indicated in adults and children for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.

When used in the consolidation phase of a multi-phase chemotherapy regimen, blinatumomab is also indicated for the treatment of CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL).

Blinatumomab promoted peripheral

T-cell redistribution at the start of infusion or dose escalation.

In most patients, T-cell counts were lower in the first 1-2 days of treatment and returned to baseline levels within 7-14 days.

An increase in

T-cell levels, also known as T-cell expansion, was observed in a few patients.

In the first treatment cycle, blinatumomab doses higher than ≥ 5 mcg/m2/day or ≥ 9 mcg/day decreased peripheral B-cell counts to 10 cells/microliter or less.

During the blinatumomab-free period between treatment cycles (2 weeks), peripheral B-cell counts did not recover.

The use of blinatumomab may lead to an elevation of IL-6, IL-10, and IFN-γ; however, cytokine levels return to baseline within 24-48 hours.

Blinatumomab may lead to the development of cytokine release syndrome, neurological toxicities, infections, tumor lysis syndrome, neutropenia and febrile neutropenia, pancreatitis, leukoencephalopathy and transient elevations in liver enzymes.

The use of blinatumomab can also affect a patient's ability to drive and use machines.

B-lymphocyte antigen

CD19 Antibody Activator Regulator T-cell surface glycoprotein CD3 delta chain Antibody Activator.

In adult patients, the pharmacokinetic profile of blinatumomab appears to be linear between 5-90 mcg/m 2 /day (equivalent to 9-162 mcg/day).

The steady-state serum concentration (C ss ) of blinatumomab was achieved within a day of continuous intravenous infusion, and in the range tested, the mean C ss was approximately dose-proportional.

At the clinical doses for the treatment of relapsed or refractory acute lymphoblastic leukemia (9 mcg/day and 28 mcg/day), the C ss was 228 pg/mL and 616 pg/mL, respectively.

Blinatumomab has a volume of distribution based on terminal phase of 4.35 L.

The metabolic pathway of blinatumomab has not been characterized.

As a monoclonal antibody, blinatumomab is expected to be metabolized into small peptides and amino acids via catabolic pathways.

At clinical doses, negligible amounts of blinatumomab were excreted in the urine.

Blinatumomab has a half-life of 2.10 hours.

In pediatric patients, the half-life was 2.19 hours in the first cycle of blinatumomab at the recommended dose.

Blinatumomab has an estimated systemic clearance of 3.11 L/hour in patients receiving blinatumomab with continuous intravenous infusion.

There is a 2-fold difference in clearance values between patients with normal renal function and those with moderate renal impairment.

Pediatric patients had an estimated clearance of 1.88 L/hour/m in the first cycle of blinatumomab at the recommended dose.

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Blinatumomab overdose cases have been reported, including a patient that received 133-fold the recommended therapeutic dose over a short period of time.

In a study that included pediatric and adolescent patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a patient receiving 30 mcg/m2/day of blinatumomab (higher than the maximum tolerated dose) experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS).

The adverse reactions observed during blinatumomab overdoses included fever, tremors, and headache, consistent with those observed at the recommended dose.

If a patient is experiencing an overdose, the blinatumomab product label recommends to interrupt the infusion, monitor the patient for signs of adverse reactions, and provide supportive care.

Re-initiating blinatumomab at the recommended dose should be considered after all adverse reactions have been resolved and no earlier than 12 hours after the infusion is interrupted.

The carcinogenic, genotoxic, and fertility effects of blinatumomab have not been evaluated.

is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation.

Known hypersensitivity to blinatumomab or to any component of the product formulation.

For the treatment of MRD-positive B-cell Precursor ALL.

• See Full Prescribing Information for recommended dose by patient weight and schedule.

• Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle.

• Premedicate with prednisone or equivalent dexamethasone.

For the treatment of Relapsed or Refractory B-cell Precursor ALL.

• Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle.

• Premedicate with dexamethasone.

For the treatment of B-cell Precursor ALL in the Consolidation Phase.

Information for important preparation and administration information.

Administer as a continuous intravenous infusion at a constant flow rate using an infusion pump.

• See Instructions for Use for infusion over 24 hours or 48 hours.

• See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol).

This option is not recommended for patients weighing less than 5.4 kg. 2.1 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).

Table for the recommended dose by patient weight and schedule.

Patients weighing 45 kg or more receive a fixed-dose.

For patients weighing less than 45 kg, the dose is calculated using the patient's body surface area (BSA).

Table 1.

Recommended BLINCYTO Dose and Schedule for the Treatment of MRD-positive B-cell Precursor ALL Cycle Patients Weighing 45 kg or More (Fixed-dose) Patients Weighing Less Than 45 kg (BSA-based dose) Induction Cycle 1 Days 1-28 28 mcg/day 15 mcg/m 2 /day (not to exceed 28 mcg/day) Days 29-42 14-day treatment-free interval 14-day treatment-free interval Consolidation Cycles 2-4 Days 1-28 28 mcg/day 15 mcg/m 2 /day (not to exceed 28 mcg/day) Days 29-42 14-day treatment-free interval 14-day treatment-free interval Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle.

For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.

Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.

Premedicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL: For adult patients, premedicate with prednisone 100 mg intravenously or equivalent (e.g., dexamethasone 16 mg) 1 hour prior to the first dose of BLINCYTO in each cycle.

For pediatric patients, premedicate with 5 mg/m of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.

For administration of BLINCYTO

See Instructions for Use for infusion over 24 hours or 48 hours.

See Instructions for

Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol).

The administration of

BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg. 2.2 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.

BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days).

Patients weighing 45 kg or more receive a fixed-dose and for patients weighing less than 45 kg, the dose is calculated using the patient's BSA.

Table 2.

Recommended BLINCYTO Dose and Schedule for the Treatment of Relapsed or Refractory B-cell Precursor ALL Cycle Patients Weighing 45 kg or More (Fixed-dose) Patients Weighing Less Than 45 kg (BSA-based dose) Induction Cycle 1 Days 1-7 9 mcg/day 5 mcg/m 2 /day (not to exceed 9 mcg/day) Days 8-28 28 mcg/day 15 mcg/m 2 /day (not to exceed 28 mcg/day) Days 29-42 14-day treatment-free interval 14-day treatment-free interval Induction Cycle 2 Days 1-28 28 mcg/day 15 mcg/m 2 /day (not to exceed 28 mcg/day) Days 29-42 14-day treatment-free interval 14-day treatment-free interval Consolidation Cycles 3-5 Days 1-28 28 mcg/day 15 mcg/m 2 /day (not to exceed 28 mcg/day) Days 29-42 14-day treatment-free interval 14-day treatment-free interval Continued Therapy Cycles 6-9 Days 1-28 28 mcg/day 15 mcg/m 2 /day (not to exceed 28 mcg/day) Days 29-84 56-day treatment-free interval 56-day treatment-free interval Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle.

Premedicate with dexamethasone

For adult patients, premedicate with 20 mg of dexamethasone intravenously or orally 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours.

For pediatric patients, premedicate with 5 mg/m of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours in the first cycle.

BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg. 2.3 Treatment of B-cell Precursor ALL in the Consolidation Phase A single cycle of BLINCYTO monotherapy in consolidation is 28 days of continuous infusion followed by a 14-day treatment-free interval (total 42 days) .

Patients weighing 45 kg or more receive a fixed-dose, and for patients weighing less than 45 kg, the dose is calculated using the patient's BSA.

Table 3.

Recommended BLINCYTO Dose and Schedule in the Consolidation Phase of Treatment of B-cell Precursor ALL BLINCYTO Consolidation Cycle Patients Weighing 45 kg or More (Fixed-dose) Patients Weighing Less Than 45 kg (BSA-based dose) Days 1-28 28 mcg/day 15 mcg/m 2 /day (not to exceed 28 mcg/day) Days 29-42 14-day treatment-free interval 14-day treatment-free interval Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle.

For adult patients, premedicate with dexamethasone 20 mg intravenously within 1 hour prior to the first dose of BLINCYTO of each cycle.

For pediatric patients, premedicate with 5 mg/m of dexamethasone intravenously or orally, to a maximum dose of 20 mg prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.

BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg. 2.4 Dosage Modifications for Adverse Reactions If the interruption after an adverse reaction is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle.

If an interruption due to an adverse reaction is longer than 7 days, start a new cycle.

Table 4.

Dosage Modifications for Adverse Reactions Adverse Reaction Grade Based on the Common Terminology Criteria for Adverse Events (CTCAE).

Grade is severe, and Grade is life-threatening.

Weighing 45 kg or More Patients Weighing Less Than 45 kg Cytokine Release Syndrome (CRS) Grade 3 Interrupt BLINCYTO.

Administer dexamethasone 8 mg every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.

CRS is resolved, restart BLINCYTO at 9 mcg/day, and escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.

Administer dexamethasone 5 mg/m 2 (maximum 8 mg) every 8 hours intravenously or orally for up to 3 days and taper thereafter over 4 days.

CRS is resolved, restart BLINCYTO at 5 mcg/m 2 /day, and escalate to 15 mcg/m 2 /day after 7 days if the adverse reaction does not recur.

Grade 4 Discontinue BLINCYTO permanently.

Administer dexamethasone as instructed for

Grade 3 CRS.

BLINCYTO permanently if more than one seizure occurs.

Grade 2 ICANS Interrupt BLINCYTO until ICANS resolves.

Administer corticosteroids and manage according to current practice guidelines.

ICANS is resolved, restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.

Interrupt BLINCYTO until

ICANS resolves.

ICANS is resolved, restart BLINCYTO at 5 mcg/m 2 /day. Escalate to 15 mcg/m 2 /day after 7 days if the adverse reaction does not recur.

Grade 3 Neurologic Events including ICANS Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur.

If the adverse reaction occurred at 9 mcg/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.

Withhold BLINCYTO until no more than

Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m 2 /day. Escalate to 15 mcg/m 2 /day after 7 days if the adverse reaction does not recur.

If the adverse reaction occurred at 5 mcg/m 2 /day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently.

If ICANS, administer corticosteroids and manage according to current practice guidelines.

Neurologic Events including ICANS If

ICANS, adminis.

BLINCYTO package (NDC 55513-160-01, NDC 55513-160-21) 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.

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.

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.

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.

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.

Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman.

There are no available data on the use of BLINCYTO in pregnant women to evaluate for a drug-associated risk.

In animal reproduction studies, a murine surrogate molecule administered to pregnant mice crossed the placental barrier.

Blinatumomab causes

T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance.

In addition, based on expression of CD19 on B-cells and the finding of B-cell depletion in non-pregnant animals, blinatumomab can cause B-cell lymphocytopenia in infants exposed to blinatumomab in-utero.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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.

Animal reproduction studies have not been conducted with blinatumomab.

In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis.

The surrogate molecule crossed the placental barrier and did not cause embryo-fetal toxicity or teratogenicity.

The expected depletions of B and

T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses.

The safety and efficacy of

BLINCYTO in pediatric patients less than 1 month of age have not been established for any indication.

Disease (MRD)-Positive B-cell Precursor ALL The safety and efficacy of BLINCYTO for the treatment of CD19-positive 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% have been established in pediatric patients one month and older.

Use of

BLINCYTO is supported by evidence from two randomized, controlled trials (Study AALL1331, NCT02101853 and Study 20120215, NCT02393859) in pediatric patients with first relapsed B-cell precursor ALL.

Both studies included pediatric patients with MRD-positive B-cell precursor ALL.

The studies included pediatric patients treated with BLINCYTO in the following age groups: 6 infants (1 month up to less than 2 years), 165 children (2 years up to less than 12 years), and 70 adolescents (12 years to less than 17 years).

In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those seen in adult patients with MRD-positive ALL, and no differences in safety were observed between the different pediatric age subgroups.

Relapsed or Refractory B-cell Precursor ALL The safety and efficacy of BLINCYTO have been established in pediatric patients one month and older with relapsed or refractory B-cell precursor ALL.

BLINCYTO is supported by a single-arm trial in pediatric patients with relapsed or refractory B-cell precursor ALL.

This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years).

No differences in efficacy were observed between the different age subgroups.

In general, the adverse reactions in BLINCYTO-treated pediatric patients with relapsed or refractory ALL were similar in type to those seen in adult patients with relapsed or refractory B-cell precursor ALL.

Adverse reactions that were observed more frequently (≥ 10% difference) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).

In pediatric patients less than 2 years old (infants) with relapsed or refractory ALL, the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability.

Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).

B-cell Precursor ALL in the Consolidation Phase The safety and efficacy of BLINCYTO for the treatment of Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase have been established in pediatric patients one month and older.

BLINCYTO for this indication is supported by extrapolation from a randomized controlled study in adults (Study E1910, NCT02003222) and evidence from two randomized, controlled studies in pediatric patients (Study and Study AALL1331) .

Serious and fatal adverse reactions, including "gasping syndrome," can occur in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) treated with benzyl alcohol-preserved drugs intravenously.

The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

In these cases, benzyl alcohol dosages of to 234 mg/kg/day produced high concentrations of benzyl alcohol and its metabolite in the blood and urine (blood concentration of benzyl alcohol were 0.61 to 1.378 mmol/L).

Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known.

Use the preservative-free formulations of

BLINCYTO where possible in neonates.

When prescribing

BLINCYTO (with preservative) in neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative).

BLINCYTO 72-Hour bag (with preservative) and 96-Hour bag (with preservative) contain 2.5 mg of benzyl alcohol per mL, and the 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL.

The administration of

BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg.

Benzyl alcohol administration may contribute to metabolic acidosis in pediatric patients, particularly those with immaturity of the metabolic pathway for alcohol, or those with underlying conditions or receiving concomitant medications that could predispose to acid base imbalance.

Monitor these patients during use of

BLINCYTO (with preservative) for new or worsening metabolic acidosis.

There were 158 (7%) patients 65 years and older in clinical studies of BLINCYTO for patients with MRD positive, CD19-positive B-cell precursor ALL in first or second complete remission, relapsed or refractory CD19-positive B-cell precursor ALL, and CD19-positive, Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase.

Of the total number of

BLINCYTO-treated patients in these studies, 123 (8%) were 65 years of age and older and 21 (1%) were 75 years of age or older.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

However, elderly patients experienced a higher rate of serious infections and neurological toxicities, including cognitive disorder, encephalopathy, and confusion.