Blinatumomab is a bispecific T-cell engaging (BiTE) monoclonal antibody that binds to CD19 expressed on precursor B-cells and CD3 expressed on the surface of T-cells. It is indicated in adult and pediatric patients with CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease of 0.1% or greater and relapsed or refractory CD19-positive B-cell precursor ALL. Blinatumomab has a black box warning for cytokine release syndrome and neurotoxicity; some cases were life-threatening or fatal.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Preparation and administration errors have occurred with blinatumomab resulting in over- or overdosing patients; call 1-800-77-AMGEN (1-800-772-6436) for questions regarding reconstitution and preparation.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 2
-Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Each package contains a 35-mcg lyophilized powder vial of blinatumomab and a 10-mL vial of IV solution stabilizer; do NOT use the IV solution stabilizer for reconstitution of the drug.
-Blinatumomab is administered as a continuous IV infusion; it is prepared in infusion bags or cassettes to be given over 24 hours, 48 hours, or 7 days.
Reconstitution:
-Add 3 mL of preservative-free Sterile Water for Injection toward the side of the lyophilized powder vial and gently swirl to avoid excess foaming (do NOT shake); the final concentration is 12.5 mcg/mL.
-The solution should be clear to slightly opalescent and colorless to slightly yellow.
-Storage following reconstitution: store up to 4 hours at room temperature (23 to 27 degrees C; 73 to 81 degrees F) or up to 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F); protect drug and IV stabilizer vials from light.
Preparation:
-The reconstituted blinatumomab vial must be further diluted prior to IV infusion.
-Use only polyolefin, di-ethylhexylphthalate (DEHP)-free PVC, or ethyl vinyl acetate (EVA) infusion bags/pump cassettes and IV tubing.
-The IV solution stabilizer is used to coat the prefilled IV bag to prevent the adhesion of blinatumomab to IV bags and lines.
24-Hour or 48-Hour Infusions:
-Fill an empty bag or pump cassette with 270 mL of 0.9% Sodium Chloride Injection.
-Add 5.5 mL of the IV solution stabilizer to the prefilled bag/pump cassette and gently mix to avoid foaming; discard contents remaining in the IV solution stabilizer vial.
-Depending on the dose and the infusion duration time (see below), add the appropriate volume of blinatumomab from the reconstituted vial to the bag/pump cassette and gently mix.
9 mcg/day
0.83 mL (24-hour infusion); 1.7 mL (48-hour infusion)
28 mcg/day
2.6 mL (24-hour infusion); 5.2 mL* (48-hour infusion)
5 mcg/m2 per day
BSA of 1.5 to 1.59 m2: 0.7 mL (24-hour infusion); 1.4 mL (48-hour infusion)
BSA of 1.4 to 1.49 m2: 0.66 mL (24-hour infusion); 1.3 mL (48-hour infusion)
BSA of 1.3 to 1.39 m2: 0.61 mL (24-hour infusion); 1.2 mL (48-hour infusion)
BSA of 1.2 to 1.29 m2: 0.56 mL (24-hour infusion); 1.1 mL (48-hour infusion)
BSA of 1.1 to 1.19 m2: 0.52 mL (24-hour infusion); 1 mL (48-hour infusion)
BSA of 1 to 1.09 m2: 0.47 mL (24-hour infusion); 0.94 mL (48-hour infusion)
BSA of 0.9 to 0.99 m2: 0.43 mL (24-hour infusion); 0.85 mL (48-hour infusion)
BSA of 0.8 to 0.89 m2: 0.38 mL (24-hour infusion); 0.76 mL (48-hour infusion)
BSA of 0.7 to 0.79 m2: 0.33 mL (24-hour infusion); 0.67 mL (48-hour infusion)
BSA of 0.6 to 0.69 m2: 0.29 mL (24-hour infusion); 0.57 mL (48-hour infusion)
BSA of 0.5 to 0.59 m2: 0.24 mL (24-hour infusion); 0.48 mL (48-hour infusion)
BSA of 0.4 to 0.49 m2: 0.2 mL (24-hour infusion); 0.39 mL (48-hour infusion)
15 mcg/m2 per day
BSA of 1.5 to 1.59 m2: 2.1 mL (24-hour infusion); 4.2 mL* (48-hour infusion)
BSA of 1.4 to 1.49 m2: 2 mL (24-hour infusion); 3.9 mL* (48-hour infusion)
BSA of 1.3 to 1.39 m2: 1.8 mL (24-hour infusion); 3.7 mL* (48-hour infusion)
BSA of 1.2 to 1.29 m2: 1.7 mL (24-hour infusion); 3.4 mL* (48-hour infusion)
BSA of 1.1 to 1.19 m2: 1.6 mL (24-hour infusion); 3.1 mL* (48-hour infusion)
BSA of 1 to 1.09 m2: 1.4 mL (24-hour infusion); 2.8 mL (48-hour infusion)
BSA of 0.9 to 0.99 m2: 1.3 mL (24-hour infusion); 2.6 mL (48-hour infusion)
BSA of 0.8 to 0.89 m2: 1.1 mL (24-hour infusion); 2.3 mL (48-hour infusion)
BSA of 0.7 to 0.79 m2: 1 mL (24-hour infusion); 2 mL (48-hour infusion)
BSA of 0.6 to 0.69 m2: 0.86 mL (24-hour infusion); 1.7 mL (48-hour infusion)
BSA of 0.5 to 0.59 m2: 0.72 mL (24-hour infusion); 1.4 mL (48-hour infusion)
BSA of 0.4 to 0.49 m2: 0.59 mL (24-hour infusion); 1.2 mL (48-hour infusion)
*requires 2 blinatumomab vials
-Attach the IV tubing containing a sterile, non-pyrogenic, low protein-binding 0.2 micron in-line filter; ensure the tubing is compatible with the infusion pump.
-Remove air from the IV bag and prime the IV tubing with the prepared final solution for infusion; do NOT prime with 0.9% Sodium Chloride Injection.
-Storage of diluted admixture: store up to 48 hours (including infusion time) at room temperature or up to 8 days under refrigeration; discard the prepared admixture if it is not stored properly or given within the designated time frame.
7-day Infusion
-Fill an empty bag or pump cassette with 90 mL of Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol).
-Add 2.2 mL of the IV solution stabilizer to the prefilled bag/pump cassette and gently mix to avoid foaming; discard contents remaining in the IV solution stabilizer vial.
-Depending on the dose (see below), add the appropriate volume of blinatumomab from the reconstituted vial to the bag/pump cassette and gently mix.
-Add the required volume of 0.9% Sodium Chloride Injection (see below) so that the total volume in the bag/pump cassette is 110 mL and gently mix.
28 mcg/day
16.8 mL of blinatumomab (6 vials); add 1 mL of 0.9% Sodium Chloride Injection
15 mcg/m2 per day
BSA of 1.5 to 1.59 m2: 14 mL of blinatumomab (5 vials); add 3.8 mL of 0.9% Sodium Chloride Injection
BSA of 1.4 to 1.49 m2: 13.1 mL of blinatumomab (5 vials); add 4.7 mL of 0.9% Sodium Chloride Injection
BSA of 1.3 to 1.39 m2: 12.2 mL of blinatumomab (5 vials); add 5.6 mL of 0.9% Sodium Chloride Injection
BSA of 1.2 to 1.29 m2: 11.3 mL of blinatumomab (5 vials); add 6.5 mL of 0.9% Sodium Chloride Injection
BSA of 1.1 to 1.19 m2: 10.4 mL of blinatumomab (4 vials); add 7.4 mL of 0.9% Sodium Chloride Injection
BSA of 1 to 1.09 m2: 9.5 mL of blinatumomab (4 vials); add 8.3 mL of 0.9% Sodium Chloride Injection
BSA of 0.9 to 0.99 m2: 8.6 mL of blinatumomab (4 vials); add 9.2 mL of 0.9% Sodium Chloride Injection
BSA of 0.8 to 0.89 m2: 7.7 mL of blinatumomab (3 vials); add 10.1 mL of 0.9% Sodium Chloride Injection
BSA of 0.7 to 0.79 m2: 6.8 mL of blinatumomab (3 vials); add 11 mL of 0.9% Sodium Chloride Injection
BSA of 0.6 to 0.69 m2: 5.9 mL of blinatumomab (3 vials); add 11.9 mL of 0.9% Sodium Chloride Injection
BSA of 0.5 to 0.59 m2: 5 mL of blinatumomab (2 vials); add 12.8 mL of 0.9% Sodium Chloride Injection
BSA of 0.4 to 0.49 m2: 4.1 mL of blinatumomab (2 vials); add 13.7 mL of 0.9% Sodium Chloride Injection
NOTE: The safety of administering blinatumomab 7-day infusion in patients with a BSA of less than 0.4 m2 has not been established.
-Attach the IV tubing; do NOT use an in-line filter and ensure the tubing is compatible with the infusion pump.
-Remove air from the IV bag and prime the IV tubing with the prepared final solution for infusion; do NOT prime with 0.9% Sodium Chloride Injection.
-Storage of diluted admixture: refrigerate if not used immediately; store up to 7 days (including infusion time) at room temperature or up to 14 days under refrigeration; discard the prepared admixture if it is not stored properly or given within the designated time frame.
Continuous Intravenous Infusion:
-Administer blinatumomab as a continuous IV infusion at a constant flow rate using an infusion pump; the pump should be programmable, lockable, non-elastomeric, and have an alarm.
-Do NOT flush the infusion line or IV catheter, especially when changing infusion bags. Flushing when changing bags or at the completion of infusion can result in an overdose.
-Infuse through a dedicated lumen when administering via a multi-lumen venous catheter.
-Properly dispose of any unused portion of blinatumomab in the IV bag or tubing.
24-Hour or 48-Hour Infusions:
-The volume administered to the patient (240 mL) is less than the total starting volume of 270 mL to account for the priming of the IV tubing and to ensure that the patient will receive the full dose.
-Infuse 24-hour bags at a rate of 10 mL/hour and 48-hour bags at a rate of 5 mL/hour.
7-day Infusion:
-The volume administered to the patient (100 mL) is less than the total starting volume of 110 mL to account for the priming of the IV tubing and to ensure that the patient will receive the full dose.
-Infuse at a rate of 0.6 mL/hour for 7 days.
Hematologic toxicity has been reported in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) (n = 267) and minimal residual disease (MRD)-positive ALL (n = 137) who received blinatumomab in clinical trials. Monitor complete blood counts (CBC) with differential during blinatumomab therapy; interrupt therapy in patients who develop prolonged neutropenia. Hematologic toxicity that was reported in clinical trials included anemia (relapsed/refractory ALL: 25%; grade 3 or higher, 19%), leukopenia (relapsed/refractory ALL: 8%; grade 3 or higher, 7%; MRD-positive ALL: 14%; grade 3 or higher, 9%), neutropenia (relapsed/refractory ALL: 31%; grade 3 or higher, 28%; MRD-positive ALL: grade 3 or higher, 15%), thrombocytopenia (relapsed/refractory ALL: 21%; grade 3 or higher, 18%; MRD-positive ALL: 10%; grade 3 or higher, 6%), and grade 3 or 4 decreased lymphocyte count/lymphopenia (relapsed/refractory ALL: 80%). Hematologic adverse events that occurred more often in pediatric patients (age range, 1 month to 17 years) compared with adults with relapsed or refractory ALL were anemia (41% vs. 34%), leukopenia (24% vs. 11%), and thrombocytopenia (34% vs. 21%) in a single-arm trial (n = 70). Other adverse events reported in clinical studies include lymphadenopathy, hematophagic histiocytosis, and leukocytosis.
Serious infection has been reported in approximately 25% of patients with acute lymphoblastic leukemia (ALL) who received blinatumomab in clinical trials; some cases were life-threatening or resulted in death. Monitor patients for signs and symptoms of infection; administer antibiotics including prophylactic antibiotics as clinically appropriate. Infections (pathogen unspecified) (28%; grade 3 or higher, 15%) including bacterial infections (14%; grade 3 or higher, 7%), fungal infections (10%; grade 3 or higher, 5%), viral infections (11%; grade 3 or higher, 1%), sepsis (2% or greater), septic shock (2% or greater), pneumonia (2% or greater), bacteremia (2% or greater), and device-related infection (2% or greater) were reported in adult patients with relapsed or refractory ALL who received blinatumomab (n = 267) in a randomized, phase III trial. Other adverse events reported in clinical studies include decreased immunoglobulin levels (e.g., decreased A, G, and M blood immunoglobulin levels) and systemic inflammatory response syndrome. In a pooled analysis of 2 single-arm trials (n = 137), infection (39%; grade 3 or higher, 8%) and decreased immunoglobulin levels (18%; grade 3 or higher, 5%) occurred in adult patients with minimal residual disease-positive ALL who received blinatumomab therapy. Viral, bacterial, and fungal infections were also reported.
In patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia who received blinatumomab, hypokalemia was reported in 50% of pediatric patients less than 2 years of age compared with 15% to 20% of older pediatric patients and 17% of adult patients in a single-arm trial (n = 70).
Weight gain has been reported in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and minimal residual disease (MRD)-positive ALL who received blinatumomab in clinical studies. In a pooled analysis of 2 single-arm trials (n = 137), weight gain occurred in 10% of adult patients with MRD-positive ALL who received blinatumomab therapy; grade 3 or higher weight gain was reported in less than 1% of patients. In a single-arm trial (n = 70), weight gain occurred more often in pediatric ALL patients compared with adult patients (17% vs. 6%).
Pain, back pain, bone pain, and extremity pain have been reported in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and minimal residual disease (MRD)-positive ALL who received blinatumomab in clinical studies. In a pooled analysis of 2 single-arm trials (n = 137), back pain occurred in 12% of adult patients with MRD-positive ALL who received blinatumomab therapy; grade 3 or higher back pain was reported in less than 1% of patients.
Neurotoxicity has been reported in approximately 65% (grade 3 or higher, 13%) of patients with acute lymphoblastic leukemia (ALL) who received blinatumomab in clinical trials; signs and symptoms consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 7.5% of blinatumomab-treated patients. The median time to onset of neurotoxicity was within 2 weeks. Neurologic toxicities in pediatric patients aged 1 month to less than 2 years old (n = 10) included agitation, headache, insomnia, somnolence/drowsiness, and irritability. Monitor patients for signs and symptoms of neurotoxicity, including ICANS. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe neurological toxicity. Headache was reported in 23% (grade 3 or higher, less than 1%) of adult patients with relapsed or refractory ALL who received blinatumomab (n = 267) in a randomized trial. Other adverse events reported in clinical studies include tremor (e.g., resting tremor, intention tremor, and essential tremor), altered consciousness (e.g., depressed level of consciousness, confusion, disturbance in attention, lethargy, mental status changes/impaired cognition, stupor, and somnolence), dizziness, memory impairment, seizures (e.g., atonic seizure), aphasia, cognitive disorder, speech disorder, hypoesthesia, encephalopathy, paresthesias, and cranial nerve palsies/disorders (trigeminal neuralgia, trigeminal nerve disorder, sixth nerve paralysis, facial nerve disorder, and facial paresis). In a pooled analysis of 2 single-arm trials (n = 137), headache (39%; grade 3 or higher, 4%), tremor (31%; grade 3 or higher, 4%), insomnia (18%; grade 3 or higher, less than 1%), aphasia (12%; grade 3 or higher, less than 1%), dizziness (10%; grade 3 or higher, less than 1%), and encephalopathy (10%; grade 3 or higher, 4%) occurred in adult patients with minimal residual disease-positive ALL who received blinatumomab therapy. In this analysis, encephalopathy included the following terms: cognitive disorder/impaired cognition, depressed level of consciousness, disturbance in attention, lethargy, leukoencephalopathy, memory impairment, and somnolence/drowsiness. Seizures, speech disorder, hypoesthesia, and confusional state were also reported.
Fever has been reported in 55% to 91% of patients with acute lymphoblastic leukemia (ALL) who received blinatumomab in clinical trials. Fever was reported in 55% of adults with relapsed or refractory ALL who received blinatumomab (n = 267) in a randomized, phase III trial; grade 3 or higher fever occurred in 6% of patients. In a pooled analysis of 2 single-arm trials (n = 137), fever (91%; grade 3 or higher, 7%) and chills (28%) occurred in adult patients with minimal residual disease-positive ALL who received blinatumomab therapy. In a single-arm trial (n = 70), fever occurred more often in pediatric patients (age range, 1 month to 17 years) compared with adults with relapsed or refractory ALL (80% vs. 61%).
In a pooled analysis of 2 single-arm trials (n = 137), cough occurred in 13% of adult patients with minimal residual disease-positive acute lymphoblastic leukemia (ALL) who received blinatumomab therapy; dyspnea was also reported. Additionally, respiratory adverse events have been reported in patients with relapsed or refractory ALL who received blinatumomab in clinical studies including dyspnea (e.g., exertional dyspnea, respiratory failure, respiratory distress, bronchospasm, bronchial hyperreactivity, tachypnea, and wheezing), cough, and productive cough.
Edema was reported in 18% of adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who received blinatumomab (n = 267) in a randomized, phase III trial; grade 3 or higher edema occurred in 1% of patients. The term edema includes face edema, fluid retention, peripheral edema or swelling, and face swelling. In a pooled analysis of 2 single-arm trials (n = 137), peripheral edema was reported in adults with minimal residual disease-positive ALL who received blinatumomab.
Rash has been reported in adult acute lymphoblastic leukemia (ALL) patients who received blinatumomab in clinical trials. Rash was reported in 12% of patients with relapsed or refractory ALL who received blinatumomab (n = 267) in a randomized, phase III trial; grade 3 or higher rash occurred in 1% of patients. In this trial, the term rash included erythema, erythematous rash, generalized rash, macular rash, maculopapular rash, pruritus/pruritic rash, skin exfoliation, and toxic skin eruption. Other adverse events reported in clinical studies include hypersensitivity, anaphylactoid reactions, angioedema, allergic/atopic dermatitis, drug eruption, erythema multiforme, and urticaria. In a pooled analysis of 2 single-arm trials (n = 137), rash occurred in 16% of adult patients with minimal residual disease-positive ALL who received blinatumomab therapy; grade 3 or higher rash was reported in less than 1% of patients. In this analysis, rash included contact dermatitis, eczema, erythema, and maculopapular rash. Hypersensitivity was also reported.
Cardiotoxicity has been reported in adult patients with acute lymphoblastic leukemia (ALL) who received blinatumomab in clinical trials. Arrhythmias were reported in 14% of adults with relapsed or refractory ALL who received blinatumomab (n = 267) in a randomized, phase III trial; grade 3 or higher arrhythmias occurred in 2% of patients. The term arrhythmia includes atrial fibrillation, atrial flutter, bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia (SVT), and tachycardia. In a single-arm trial (n = 70), hypertension occurred more often in pediatric patients (age range, 1 month to 17 years) compared with adults with relapsed or refractory ALL (26% vs. 8%). Other adverse events reported in clinical studies include chest pain (unspecified), hypotension (e.g., decrease blood pressure, hypovolemic shock, and circulatory collapse), and hypertension (e.g., increased blood pressure and hypertensive crisis). In a pooled analysis of 2 single-arm trials (n = 137), arrhythmias (12%; grade 3 or higher, 2%) and hypotension (14%; grade 3 or higher, less than 1%) occurred in adult patients with minimal residual disease-positive ALL who received blinatumomab therapy. In this analysis, the term arrhythmia included bradycardia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, tachycardia, and ventricular extrasystoles. Hypertension and chest pain were also reported.
Tumor lysis syndrome (TLS) has been reported in patients with acute lymphoblastic leukemia who received blinatumomab in clinical studies. Preventative measures such as cytoreductive therapy (e.g., allopurinol) and hydration is recommended during blinatumomab therapy. Monitor patients for signs or symptoms of TLS. Therapy interruption or discontinuation may be necessary in patients who develop TLS.
Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving blinatumomab, especially in patients with prior treatment with cranial radiation therapy and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.
Antibody formation to blinatumomab occurred in less than 2% of patients in clinical studies; 78% of patients who tested positive for blinatumomab-binding antibodies also tested positive for neutralizing anti-blinatumomab antibodies in vitro. Anti-blinatumomab antibody formation is unlike to have a clinical impact on the safety or efficacy of blinatumomab.
Pancreatitis has been reported in patients who received blinatumomab in combination with dexamethasone in clinical studies; additionally, fatal pancreatitis has been reported in postmarketing surveillance. Promptly evaluate patients who develop signs and symptoms of pancreatitis such as severe and persistent stomach pain, with or without nausea and vomiting. Therapy interruption or discontinuation may be necessary if pancreatitis occurs.
Hyperthermia was reported in adults with relapsed or refractory acute lymphoblastic leukemia who received blinatumomab in clinical studies.
Disorientation and depression (e.g., depressed mood, depression, suicidal ideation, and completed suicide) were reported in patients with acute lymphoblastic leukemia who received blinatumomab in clinical studies.
Flushing/hot flush was reported in patients with acute lymphoblastic leukemia who received blinatumomab in clinical studies.
Cytokine release syndrome (CRS) has been reported in 15% of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and in 7% of patients with minimal residual disease-positive ALL who received blinatumomab in clinical trials. The median time to CRS onset was 2 days after the infusion; the median time to resolution was 5 days in cases that resolved. Patients should be closely monitored for signs or symptoms of CRS. Therapy interruption or discontinuation may be necessary in patients who develop grade 3 or 4 CRS; in these patients, administer corticosteroids (e.g., dexamethasone) for up to 3 days followed by a taper over 4 days. Adverse events associated with CRS may include fever, headache, nausea, asthenia, hypotension, and increased transaminase and bilirubin levels. Disseminated intravascular coagulation (DIC), capillary leak syndrome, cytokine storm, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome were also reported in patients who had CRS. CRS was reported in 14% of adult patients with relapsed or refractory ALL who received blinatumomab (n = 267) in a randomized, phase 3 trial; grade 3 or higher CRS occurred in 3% of patients.
Transient elevated hepatic enzymes have been reported in patients with acute lymphoblastic leukemia (ALL) who received blinatumomab in clinical trials; the median time to onset of elevated hepatic enzymes was 19 days. Most cases were associated with cytokine release syndrome (CRS). Grade 3 or greater elevated hepatic enzymes occurred in about 7% of patients without CRS. Monitor liver function tests, including gamma-glutamyl transferase and total bilirubin levels, prior to initiating treatment and during blinatumomab therapy. Interrupt therapy in patients who develop increased transaminase levels of greater than 5-times the upper limit of normal (ULN) or increased bilirubin levels of greater than 3-times the ULN. Hypertransaminasemia/increased AST or ALT levels (15%; grade 3 or higher, 8%) and grade 3 or 4 hyperbilirubinemia/increased bilirubin levels (5%) were reported in adults with relapsed or refractory ALL who received blinatumomab (n = 267) in a randomized, phase III trial. Increased alkaline phosphatase levels have also been reported in clinical studies. In a pooled analysis of 2 single-arm trials (n = 137), hypertransaminasemia/increased AST or ALT levels occurred in 9% of adult patients with minimal residual disease-positive ALL who received blinatumomab therapy; grade 3 or higher hypertransaminasemia/increased AST or ALT levels were reported in 7% of patients. Hyperbilirubinemia was also reported.
Infusion-related reactions have been reported in 30% of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) (n = 267) and in 77% of patients with minimal residual disease-positive ALL (n = 137) who received blinatumomab in clinical trials; grade 3 or higher infusion-related reactions occurred in 3% and 5% of these patients, respectively. Blinatumomab infusion-related reaction symptoms may be clinically indistinguishable from cytokine release syndrome and may include eye swelling, hypertension, hypotension, myalgia, periorbital edema, pruritus, fever, acute kidney injury, and rash. Premedication with dexamethasone is required prior to the first dose of each cycle, prior to a dosage escalation, and prior to restarting therapy after stopping the infusion for 4 or more hours. In a single-arm trial (n = 70), infusion reactions (49% vs. 34%) occurred more often in pediatric patients (age range, 1 month to 17 years) compared with adults with relapsed or refractory ALL.
Blinatumomab use is contraindicated in patients who have had a hypersensitivity reaction to blinatumomab or any other component of the product. Blinatumomab is a monoclonal antibody produced in Chinese hamster ovary cells ;it may be advisable to use caution in patients with a hamster protein hypersensitivity to other products derived from Chinese hamster ovary cells.
Cytokine release syndrome (CRS) has been reported in patients receiving blinatumomab; some cases were life-threatening or fatal. Symptoms include asthenia, fever, headache, hypotension, nausea, elevated hepatic enzymes (AST/ALT), and increased total bilirubin levels. Other serious conditions that occurred with CRS were disseminated intravascular coagulation (DIC), capillary leak syndrome, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Blinatumomab infusion-related reactions may also occur and symptoms may be clinically indistinguishable from CRS; premedication with dexamethasone is required prior to the first dose of each cycle, prior to a dosage escalation, and prior to restarting therapy after stopping the infusion for 4 or more hours. Patients should be closely monitored for signs or symptoms of CRS. Therapy interruption or discontinuation may be necessary in patients who develop grade 3 or 4 CRS; in these patients, administer corticosteroids (e.g., dexamethasone) for up to 3 days followed by a taper over 4 days.
Neurotoxicity has been reported with blinatumomab therapy (e.g., immune effector cell-associated neurotoxicity syndrome [ICANS], encephalopathy, seizures, speech disorders, cranial nerve disorders, disturbances in consciousness, confusion, disorientation, and coordination and balance disorders); some cases were life-threatening or fatal. Monitor patients for signs and symptoms of neurotoxicity, including ICANS. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe neurological toxicity. Advise patients against driving or operating machinery during blinatumomab therapy due to the risk of loss of consciousness caused by adverse neurological events, such as seizures or ICANS. Use blinatumomab with caution in patients with neurological disease. There is limited experience using blinatumomab in patients with central nervous system acute lymphoblastic leukemia; these patients were not included in clinical trials.
Neutropenia and febrile neutropenia have been reported in patients receiving blinatumomab; some cases were life-threatening. Monitor complete blood counts (CBC) with differential; interrupt blinatumomab therapy in patients who develop prolonged neutropenia.
Serious infection (e.g., sepsis, pneumonia, bacteremia, opportunistic infection, and catheter-site infection) has been reported in patients receiving blinatumomab; some infections were life-threatening or fatal. Monitor patients for signs and symptoms of infection; administer antibiotics including prophylactic antibiotics as clinically appropriate.
Tumor lysis syndrome (TLS) has been reported in patients receiving blinatumomab. Preventative measures such as cytoreductive therapy (e.g., allopurinol) and hydration is recommended during blinatumomab therapy. Monitor patients for signs (e.g., serum electrolytes, uric acid, creatinine) or symptoms of TLS. Therapy interruption or discontinuation may be necessary in patients who develop TLS.
Hepatotoxicity (i.e., transient elevated hepatic enzymes) has been reported with blinatumomab therapy; most cases were associated with cytokine release syndrome (CRS). Use caution in patients with hepatic disease; blinatumomab has not been studied in this patient population. Monitor liver function tests, including gamma-glutamyl transferase and total bilirubin, prior to initiating treatment and during blinatumomab therapy. Interrupt therapy in patients who develop increased transaminase levels of greater than 5-times the upper limit of normal (ULN) or increased bilirubin levels of greater than 3-times the ULN. The median time to onset was 3 days in clinical trials and 19 days in patients without CRS.
Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving blinatumomab, especially in patients with prior treatment with cranial radiation therapy and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.
Use blinatumomab with caution in geriatric patients. The rates of serious infections and neurological toxicity (e.g., cognitive disorder, encephalopathy, confusion) were higher in patients 65 years of age or older compared with younger adult patients.
Fatal pancreatitis has been reported in patients who received blinatumomab in combination with dexamethasone. Promptly evaluate patients who develop signs and symptoms of pancreatitis; therapy interruption or discontinuation may be necessary.
Vaccination with live virus vaccines is not recommended starting from 2 weeks prior to, during, and until immune recovery following the last cycle of blinatumomab therapy. Due to the potential for B-cell lymphocytopenia with blinatumomab exposure in-utero, monitor B lymphocytes in neonates before administering a live virus vaccine. Gasping syndrome, characterized by central nervous system depression, metabolic acidosis, and gasping respirations, may occur in neonates who receive IV drugs containing benzyl alcohol as a preservative. Therefore, use the preservative-free formulations of blinatumomab whenever possible in neonates. Monitor neonatal patients receiving blinatumomab with preservative for new or worsening metabolic acidosis. Other adverse reactions that may occur with high benzyl alcohol concentrations include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Consider the combined daily metabolic load of benzyl alcohol from all sources including blinatumomab with preservative, other products containing benzyl alcohol, or other excipients (e.g., ethanol, propylene glycol) which compete with benzyl alcohol for the same metabolic pathway. The blinatumomab 7-day infusion bag contains 7.4 mg of benzyl alcohol per mL. Benzyl alcohol dosages of 99 to 234 mg/kg per day produced high concentrations of benzyl alcohol and its metabolite in the blood and urine (benzyl alcohol blood concentration, 0.61 to 1.378 mmol/L). Very low birth weight (less than 1,500 g), early preterm/premature neonates (gestational age of less than 34 weeks), underlying conditions that make patients less able to metabolize benzyl alcohol, or concomitant medications that cause acid base imbalances may increase the risk of gasping syndrome in neonates who receive IV drugs containing benzyl alcohol as a preservative.
Pediatric patients including infants, children, and adolescents had a higher incidence of fever, hypertension, anemia, infusion-related reactions, thrombocytopenia, leukopenia, and weight gain compared with adult patients who received blinatumomab.
Counsel patients about the reproductive risk and contraception requirements during blinatumomab treatment. Pregnancy testing should be performed prior to starting blinatumomab in female patients of reproductive potential. These patients should use effective contraception during and for 48 hours after the last blinatumomab dose. Women who become pregnant while receiving blinatumomab should be apprised of the potential hazard to the fetus.
Blinatumomab may cause fetal harm (e.g., B-cell lymphocytopenia) when administered during pregnancy based on its mechanism of action. A murine surrogate molecule crossed the placental barrier in pregnant mice; however, no embryo-fetal toxicity or teratogenicity was observed. Additionally, T-cell activation and cytokine release by blinatumomab may compromise pregnancy maintenance. Advise pregnant patients of the potential risk to the fetus with blinatumomab use. Avoid giving live vaccines to neonates exposed to blinatumomab in-utero until B-cell function returns.
According to the manufacturer, women should discontinue breast-feeding during blinatumomab therapy and for 48 hours after the last dose because of the potential for serious adverse reactions including B-cell lymphocytopenia in nursing infants. It is not known if blinatumomab is secreted in human milk or if it affects milk production or the breast fed infant.
For the treatment of acute lymphocytic leukemia (ALL):
NOTE: The FDA has designated blinatumomab an orphan drug for this indication.
-for the treatment of relapsed or refractory CD19-positive B-cell precursor ALL:
NOTE: Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle of blinatumomab. For all subsequent cycle starts and re-initiation (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
Intravenous dosage:
Adults: For patients weighing 45 kg or greater, administer blinatumomab 9 micrograms (mcg) IV daily on days 1 to 7 followed by blinatumomab 28 mcg IV daily on days 8 to 28 on cycle 1 only. For patients weighing less than 45 kg, administer blinatumomab 5 mcg/m2 (not to exceed 9 mcg) IV daily on days 1 to 7 followed by blinatumomab 15 mcg/m2 (not to exceed 28 mcg) IV daily on days 8 to 28 on cycle 1 only. For cycles 2 to 9, give blinatumomab 28 mcg IV daily for 28 consecutive days/cycle in patients weighing 45 kg or greater or blinatumomab 15 mcg/m2 (not to exceed 28 mcg) IV daily for 28 consecutive days/cycle in patients weighing less than 45 kg. Repeat induction (cycles 1 and 2) and consolidation (cycles 3 to 5) treatment cycles every 42 days; repeat cycles 6 to 9 (maintenance treatment) every 84 days. Premedicate with dexamethasone 20 mg at 1 hour prior to the first dose of each cycle, prior to a dosage increase (e.g., day 8 of cycle 1), and prior to resuming therapy (after stopping for 4 or more hours). Therapy interruption or discontinuation may be necessary for severe toxicity. At a median follow-up time of 11.7 months, the median overall survival time was significantly improved with blinatumomab compared with standard chemotherapy (7.7 months vs. 4 months; hazard ratio = 0.71; 95% CI, 0.55 to 0.93; p = 0.01) in adult patients with Philadelphia-negative, relapsed or refractory B-cell precursor acute lymphoblastic leukemia in a multinational, randomized, phase III trial (n= 405; The TOWER trial). Additionally, 24% of patients in this study went on to receive an allogeneic stem-cell transplantation.
Adolescents and Children: For patients weighing 45 kg or greater, administer blinatumomab 9 micrograms (mcg) IV daily on days 1 to 7 followed by blinatumomab 28 mcg IV daily on days 8 to 28 on cycle 1 only. For patients weighing less than 45 kg, administer blinatumomab 5 mcg/m2 (not to exceed 9 mcg) IV daily on days 1 to 7 followed by blinatumomab 15 mcg/m2 (not to exceed 28 mcg) IV daily on days 8 to 28 on cycle 1 only. For cycles 2 to 9, give blinatumomab 28 mcg IV daily for 28 consecutive days/cycle in patients weighing 45 kg or greater or blinatumomab 15 mcg/m2 (not to exceed 28 mcg) IV daily for 28 consecutive days/cycle in patients weighing less than 45 kg. Repeat induction (cycles 1 and 2) and consolidation (cycles 3 to 5) treatment cycles every 42 days; repeat cycles 6 to 9 (maintenance treatment) every 84 days. Premedicate with dexamethasone 5 mg/m2 (not to exceed 20 mg) prior to the first dose of each cycle, prior to a dosage increase (e.g., day 8 of cycle 1), and prior to resuming therapy (after stopping for 4 or more hours). Therapy interruption or discontinuation may be necessary for severe toxicity. A complete remission (CR) or CR with partial hematological recovery (CRp) after 1 or 2 cycles of blinatumomab (primary endpoint) was achieved in 32.9% of pediatric patients (median age, 8 years; range, 7 months to 17 years) with relapsed or refractory B-cell precursor ALL in a multicenter, single-arm study (n = 70; prior allogeneic hematopoietic stem-cell transplant (HSCT), 57.1%). The median number of blinatumomab treatment cycles was 1 (range, 1 to 5 cycles). The minimal residual disease response rate was 43.5% and the relapse-free survival time was 6 months in responding patients (CR or CRp); 48% of patients subsequently underwent an allogeneic HSCT in remission. Eligible patients had more than 25% blasts in bone marrow and were in second or later bone marrow relapse, had any marrow relapse after allogeneic HSCT, or were refractory to other treatments.
Infants: 5 mcg/m2 IV daily on days 1 to 7 followed by blinatumomab 15 mcg/m2 IV daily on days 8 to 28 on cycle 1 only. For cycles 2 to 9, give blinatumomab 15 mcg/m2 IV daily for 28 consecutive days/cycle. Repeat induction (cycles 1 and 2) and consolidation (cycles 3 to 5) treatment cycles every 42 days; repeat cycles 6 to 9 (maintenance treatment) every 84 days. Premedicate with dexamethasone 5 mg/m2 prior to the first dose of each cycle, prior to a dosage increase (e.g., day 8 of cycle 1), and prior to resuming therapy (after stopping for 4 or more hours). Therapy interruption or discontinuation may be necessary for severe toxicity. A complete remission (CR) or CR with partial hematological recovery (CRp) after 1 or 2 cycles of blinatumomab (primary endpoint) was achieved in 32.9% of pediatric patients (median age, 8 years; range, 7 months to 17 years) with relapsed or refractory B-cell precursor ALL in a multicenter, single-arm study (n = 70; prior allogeneic hematopoietic stem-cell transplant (HSCT), 57.1%). The median number of blinatumomab treatment cycles was 1 (range, 1 to 5 cycles). The minimal residual disease response rate was 43.5% and the relapse-free survival time was 6 months in responding patients (CR or CRp); 48% of patients subsequently underwent an allogeneic HSCT in remission. Eligible patients had more than 25% blasts in bone marrow and were in second or later bone marrow relapse, had any marrow relapse after allogeneic HSCT, or were refractory to other treatments.
-for the treatment of CD19-positive B-cell precursor ALL in patients in first or second complete remission who have minimal residual disease of 0.1% or greater:
NOTE: Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle of blinatumomab. For all subsequent cycle starts and re-initiation (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
Intravenous dosage:
Adults: 28 micrograms (mcg) IV daily in patients weighing 45 kg or greater OR 15 mcg/m2 (not to exceed 28 mcg) IV daily in patients weighing less than 45 kg for 28 consecutive days/cycle on cycle 1 (induction therapy) and cycles 2, 3, and 4 (consolidation therapy). Repeat treatment cycles every 42 days. Premedicate with dexamethasone 16 mg (or equivalent) at 1 hour prior to the first dose of each cycle. Therapy interruption or discontinuation may be necessary for severe toxicity. The primary endpoint of complete minimal residual disease (MRD) response after 1 cycle of blinatumomab was 81.5% (first complete remission (CR), 85.2%; second CR, 72%) and the median hematologic relapse-free survival time was 22.3 months (first CR, 35.2 months; second CR, 12.3 months) in adult patients (age range, 18 to 76 years) with B-cell precursor acute lymphoblastic leukemia in first (n = 61) or second (n = 25) hematologic CR who had persistent or MRD of 0.1% or higher after a minimum of 3 blocks of intensive chemotherapy in an open-label, nonrandomized, phase II trial (the BLAST trial). Additionally, 69% of patients in this study went on to receive an allogeneic stem-cell transplantation.
Adolescents and Children: 15 micrograms (mcg)/m2 (not to exceed 28 mcg) IV daily in patients weighing less than 45 kg OR 28 mcg IV daily in patients weighing 45 kg or greater for 28 consecutive days/cycle on cycle 1 (induction therapy) and cycles 2, 3, and 4 (consolidation therapy). Repeat treatment cycles every 42 days. Premedicate with dexamethasone 5 mg/m2 (not to exceed 20 mg) prior to the first dose of each cycle and prior to resuming therapy (after stopping for 4 or more hours). Therapy interruption or discontinuation may be necessary for severe toxicity. At a median follow-up time of 2.9 (range, 0 to 5.6) years in living patients, the primary endpoint of 2-year disease-free survival (DFS) rate was not significantly improved with blinatumomab (n = 105) compared with chemotherapy (n = 103) consolidation after 1 cycle of standard re-induction chemotherapy in pediatric patients and young adults aged 1 to 30 years (median age, 9 years) who had intermediate- or high-risk first relapse B-cell ALL and received blinatumomab consolidation in a randomized, phase 3 (AALL1331) trial. The 2-year DFS (54.4% vs. 39%; hazard ratio (HR) = 0.7; 95% CI, 0.47 to 1.03) and overall survival (OS; 71.3% vs. 58.4%; HR = 0.62; 95% CI, 0.39 to 0.98) rates were improved in the blinatumomab compared with chemotherapy consolidation. Of note, this study may not have had enough power to detect a significant difference between arms for the primary endpoint because it was halted early based on favorable (but not statistically significant) DFS and OS results from a planned interim analysis. A hematopoietic stem cell transplant (HSCT) following randomized therapy was given in 70% and 43% of patients in the blinatumomab and chemotherapy arms, respectively. At a median follow-up time of 22.4 months, the primary endpoint of event-free survival (EFS) was significantly improved with 1 cycle of blinatumomab compared with standard multidrug chemotherapy (69% vs. 42%; hazard ratio (HR) = 0.33; 95% CI, 0.18 to 0.61) as a third consolidation course prior to allogeneic HSCT in pediatric patients aged 28 days to less than 18 years (median age, 5 years; range, 1 to 17 years) with high-risk first-relapse B-cell ALL in a randomized, phase 3 trial (Study 20120215; n = 108). This trial was halted early based on favorable EFS in a planned interim analysis. At a median follow-up time of 19.5 months, OS was not significantly improved in the blinatumomab arm (HR = 0.43; 95% CI, 0.18 to 1.01). An allogeneic HSCT occurred in 88.9% and 70.4% of patients who achieved a second complete remission in the blinatumomab and chemotherapy arms, respectively.
Infants: 15 micrograms (mcg)/m2 IV daily for 28 consecutive days/cycle on cycle 1 (induction therapy) and cycles 2, 3, and 4 (consolidation therapy). Repeat treatment cycles every 42 days. Premedicate with dexamethasone 5 mg/m2 (not to exceed 20 mg) prior to the first dose of each cycle and prior to resuming therapy (after stopping for 4 or more hours). Therapy interruption or discontinuation may be necessary for severe toxicity. At a median follow-up time of 2.9 (range, 0 to 5.6) years in living patients, the primary endpoint of 2-year disease-free survival (DFS) rate was not significantly improved with blinatumomab (n = 105) compared with chemotherapy (n = 103) consolidation after 1 cycle of standard re-induction chemotherapy in pediatric patients and young adults aged 1 to 30 years (median age, 9 years) who had intermediate- or high-risk first relapse B-cell ALL and received blinatumomab consolidation in a randomized, phase 3 (AALL1331) trial. The 2-year DFS (54.4% vs. 39%; hazard ratio (HR) = 0.7; 95% CI, 0.47 to 1.03) and overall survival (OS; 71.3% vs. 58.4%; HR = 0.62; 95% CI, 0.39 to 0.98) rates were improved in the blinatumomab compared with chemotherapy consolidation. Of note, this study may not have had enough power to detect a significant difference between arms for the primary endpoint because it was halted early based on favorable (but not statistically significant) DFS and OS results from a planned interim analysis. A hematopoietic stem cell transplant (HSCT) following randomized therapy was given in 70% and 43% of patients in the blinatumomab and chemotherapy arms, respectively. At a median follow-up time of 22.4 months, the primary endpoint of event-free survival (EFS) was significantly improved with 1 cycle of blinatumomab compared with standard multidrug chemotherapy (69% vs. 42%; hazard ratio (HR) = 0.33; 95% CI, 0.18 to 0.61) as a third consolidation course prior to allogeneic HSCT in pediatric patients aged 28 days to less than 18 years (median age, 5 years; range, 1 to 17 years) with high-risk first-relapse B-cell ALL in a randomized, phase 3 trial (Study 20120215; n = 108). This trial was halted early based on favorable EFS in a planned interim analysis. At a median follow-up time of 19.5 months, OS was not significantly improved in the blinatumomab arm (HR = 0.43; 95% CI, 0.18 to 1.01). An allogeneic HSCT occurred in 88.9% and 70.4% of patients who achieved a second complete remission in the blinatumomab and chemotherapy arms, respectively.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
For therapy interruptions of 7 days or less: Continue the same cycle to a total of 28 days of infusion (include days before and after the interruption in that cycle).
For therapy interruptions lasting greater than 7 days: Start a new cycle.
Cytokine Release Syndrome (CRS)
Grade 3 toxicity: Interrupt therapy until CRS is resolved. For patients weighing 45 kg or greater, start dexamethasone 8 mg IV or PO every 8 hours for up to 3 days, then taper over 4 days. In these patients, restart blinatumomab at 9 mcg daily; increase the dosage to 28 mcg daily after 7 days if CRS does not recur. For patients weighing less than 45 kg, give dexamethasone 5 mg/m2 (Max dose, 8 mg) IV or PO every 8 hours for up to 3 days, then taper over 4 days. In these patients, restart blinatumomab at 5 mcg/m2 daily (Max dose, 9 mcg/day); increase the dosage to 15 mcg/m2 daily (Max dose, 28 mcg/day) after 7 days if CRS does not recur.
Grade 4 toxicity: Permanently discontinue therapy. Administer dexamethasone at the same dosage and schedule as recommended with grade 3 toxicity.
Neurological Toxicity
Grade 3 toxicity: Interrupt therapy until toxicity resolves to grade 1 or less and for at least 3 days. For patients weighing 45 kg or greater, restart blinatumomab at 9 mcg daily; increase the dosage to 28 mcg daily after 7 days if toxicity does not recur. If the toxicity recurs at the 9 mcg/day dosage or does not resolve within 7 days, permanently discontinue therapy. For patients weighing less than 45 kg, restart blinatumomab at 5 mcg/m2 daily (Max dose, 9 mcg/day); increase the dosage to 15 mcg/m2 daily (Max dose, 28 mcg/day) after 7 days if toxicity does not recur. If the toxicity recurs at the 5 mcg/m2/day dosage or does not resolve within 7 days, permanently discontinue therapy.
Grade 4 toxicity or more than 1 seizure: Permanently discontinue therapy.
Other Severe or Life-Threatening Adverse Reactions
Grade 3 toxicity: Interrupt therapy until toxicity resolves to grade 1 or less. For patients weighing 45 kg or greater, restart blinatumomab at 9 mcg daily; increase the dosage to 28 mcg daily after 7 days if toxicity does not recur. For patients weighing less than 45 kg, restart blinatumomab at 5 mcg/m2 daily (Max dose, 9 mcg/day); increase the dosage to 15 mcg/m2 daily (Max dose, 28 mcg/day) after 7 days if toxicity does not recur. If the toxicity does not resolve within 14 days, permanently discontinue therapy.
Grade 4 toxicity: Consider permanently discontinuing therapy.
Maximum Dosage Limits:
-Adults
45 kg or greater: 28 mcg/day
Less than 45 kg: 15 mcg/m2 per day (not to exceed 28 mcg/day)
-Geriatric
45 kg or greater: 28 mcg/day
Less than 45 kg: 15 mcg/m2 per day (not to exceed 28 mcg/day)
-Adolescents
45 kg or greater: 28 mcg/day
Less than 45 kg: 15 mcg/m2 per day (not to exceed 28 mcg/day)
-Children
15 mcg/m2 per day (not to exceed 28 mcg/day)
-Infants
15 mcg/m2 per day
Patients with Hepatic Impairment Dosing
Baseline hepatic impairment: Blinatumomab has not been studied in patients with hepatic impairment. Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no initial dosage adjustments are needed.
Hepatic impairment during therapy: Interrupt blinatumomab therapy if transaminase levels increase to greater than 5 times the upper limit of normal (ULN) or if bilirubin levels increase to greater than 3 times the ULN.
Patients with Renal Impairment Dosing
Creatinine clearance (CrCl) of 30 mL/min or higher: Specific guidelines for dosage adjustments in mild to moderate impairment are not available; it appears that no initial dosage adjustments are needed.
CrCl less than 30 mL/min, including patients on dialysis: Blinatumomab has not been studied in this patient population.
*non-FDA-approved indication
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Carbamazepine: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as carbamazepine. The dose of the concomitant drug may need to be adjusted.
Chikungunya Vaccine, Live: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cyclosporine: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as cyclosporine. The dose of the concomitant drug may need to be adjusted.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desogestrel; Ethinyl Estradiol: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Dextromethorphan; Quinidine: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as quinidine. The dose of the concomitant drug may need to be adjusted.
Digoxin: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as digoxin. In addition, Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients.
Drospirenone; Ethinyl Estradiol: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Ethinyl Estradiol; Norelgestromin: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Ethinyl Estradiol; Norgestrel: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Ethosuximide: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethosuximide. The dose of the concomitant drug may need to be adjusted.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Etonogestrel; Ethinyl Estradiol: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Flecainide: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as flecainide. The dose of the concomitant drug may need to be adjusted.
Fosphenytoin: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as phenytoin/fosphenytoin. The dose of the concomitant drug may need to be adjusted.
Intranasal Influenza Vaccine: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Levonorgestrel; Ethinyl Estradiol: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Lithium: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as lithium. The dose of the concomitant drug may need to be adjusted.
Live Vaccines: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Norethindrone; Ethinyl Estradiol: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Norgestimate; Ethinyl Estradiol: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Phenytoin: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as phenytoin. The dose of the concomitant drug may need to be adjusted.
Procainamide: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as procainamide. The dose of the concomitant drug may need to be adjusted.
Quinidine: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as quinidine. The dose of the concomitant drug may need to be adjusted.
Rotavirus Vaccine: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Tacrolimus: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as tacrolimus. The dose of the concomitant drug may need to be adjusted.
Theophylline, Aminophylline: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as aminophylline. The dose of the concomitant drug may need to be adjusted. (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as theophylline. The dose of the concomitant drug may need to be adjusted.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Typhoid Vaccine: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Warfarin: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as warfarin. The dose of the concomitant drug may need to be adjusted.
Yellow Fever Vaccine, Live: (Contraindicated) Do not administer live vaccines to blinatumomab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving blinatumomab. At least 2 weeks before initiation of blinatumomab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Blinatumomab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Blinatumomab is a bispecific T-cell engaging (BiTE) monoclonal antibody that binds to CD19 expressed on precursor B-cells and CD3 expressed on the surface of T-cells. This binding causes cytotoxic T-cells to be close to normal and malignant CD19-positive B cells and triggers the signaling cascade leading to the upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells ultimately resulting in the lysis of CD19+ cells. The mechanism differs from that of conventional monoclonal antibodies. Conventional monoclonal antibodies differ from BiTE antibodies by using antibody-dependent cellular cytotoxicity and engage natural killer T-cells, macrophages, and neutrophils to cause tumor cell death.
Blinatumomab is administered as a continuous intravenous infusion (CIV). Its pharmacokinetic parameters appear to be linear over a dose range of 5 to 90 micrograms (mcg)/m2 per day (approximately 9 to 162 mcg/day) in adults. Following the administration of blinatumomab CIV in clinical studies, the estimated mean terminal phase Vd was 5.27 L (standard deviation (SD) +/- 4.37 L), the estimated mean systemic clearance was 3.1 L/hour (SD +/- 2.94 L/hour), and the mean half-life was 2.2 hours (SD +/- 1.34 hours). Almost no blinatumomab was excreted in the urine. Although the metabolism of blinatumomab is not known, it is likely degraded via catabolic pathways into small peptides and amino acids.
Pharmacodynamics: T-cell activation and initial redistribution, reduction in peripheral B-cells, and transient cytokine elevation occurs following a blinatumomab continuous IV infusion (CIV) over 4 weeks. T-cell counts initially decline within 1 to 2 days and return to baseline levels within 7 to 14 days in most patients. A few patients experienced increased T-cell counts above baseline. Peripheral T-cell redistribution (adhesion to blood vessel endothelium and/or transmigration into tissue) began after initiating the infusion or escalating the dose. Peripheral B-cell counts decreased to 10 cells/microliter or less during the first treatment cycle in most patients at doses of 5 mcg/m2/day or less and 9 mcg/day or less; B-cell counts did not recover in the 2-week rest period. Incomplete B-cell depletion was observed in patients who received a subtherapeutic blinatumomab dosage of 0.5 mcg/m2 per day and 1.5 mcg/m2 per day; some patients had incomplete B-cell depletion at higher doses. Cytokine (i.e., IL-6, IL-10, and IFN-gamma) levels peaked in the first 2 days after initiating the blinatumomab infusion and returned to baseline levels within the next 24 to 48 hours during the infusion. Cytokine peaks were lower and occurred in fewer patients in subsequent cycles.
Affected cytochrome P450 isoenzymes: CYP450 substrates with a narrow therapeutic index (NTI)
Due to a transient release of cytokines, CYP450 enzyme activity may be suppressed when blinatumomab is started. Use CYP450 substrates, particularly those with a NTI, and blinatumomab with caution. If these drugs are used together, monitor patients for drug toxicity or monitor drug concentrations if applicable; adjust the dose of the CYP450 substrate as necessary. The highest risk for drug interactions in patients receiving concomitant CYP450 substrates is during the first 9 days of the first blinatumomab cycle and the first 2 days of the blinatumomab second cycle.
-Route-Specific Pharmacokinetics
Intravenous Route
Mean steady-state concentrations of blinatumomab increase about proportionally to the dose. At clinical adult doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed or refractory ALL, the mean steady-state blinatumomab concentrations were 228 +/- 356 picogram (pg)/mL and 616 +/- 537 pg/mL, respectively. Steady-state concentrations were achieved within 1 day. In adult patients, the pharmacokinetic parameters of blinatumomab were similar in patients with MRD-positive B-cell precursor ALL and patients with relapsed or refractory ALL.
-Special Populations
Renal Impairment
In a population pharmacokinetic analysis, the mean clearance of blinatumomab was increased about 2-fold in adult patients with moderate renal impairment (CrCl, 30 to 59 mL/min; n = 21) compared with patients who had normal renal function (CrCl, greater than 90 mL/min; n = 215); however, the clearance values were highly varied (coefficient of variation up to 96.8%). There is no data for the use of blinatumomab in patients with severe renal impairment (CrCl, 15 to 30 mL/min) or in patients receiving hemodialysis.
Pediatrics
In pediatric patients, the pharmacokinetic parameters of blinatumomab appear to be linear over a dose range of 5 to 30 micrograms (mcg)/m2 per day. The steady-state blinatumomab values were 162 +/- 179 picogram (pg)/mL for the 5 mcg/m2 per day dose and 533 +/- 392 pg/mL for the 15 mcg/m2 per day dose in pediatric patients with relapsed or refractory ALL. The steady-state blinatumomab concentrations were similar in pediatric patients with MRD-positive B-cell precursor ALL and relapsed or refractory ALL. In all pediatric patients with ALL, the estimated mean volume of distribution, clearance, and terminal half-life values were 4.14 +/- 3.32 L/m2, 1.65 +/- 1.62 L/hour/m2, and 2.14 +/- 1.44 hours, respectively.
Geriatric
Age (range, 0.6 to 80 years) does not affect the pharmacokinetic parameters of blinatumomab.
Gender Differences
Sex does not affect the pharmacokinetic parameters of blinatumomab.
Ethnic Differences
When evaluating studies that had predominantly White (72%) and Asian (17%) patients, the pharmacokinetic (PK) parameters of blinatumomab were not affected by race. However, the effect of other races or ethnicities on the PK parameters of blinatumomab are not known.
Obesity
Body surface area (BSA) (range, 0.4 to 2.7 m2) does affect the pharmacokinetic parameters of blinatumomab; therefore, use BSA dosing in patients who weigh less than 45 kg.