Blincyto

Antineoplastic Bispecific Antibodies Targeting CD19 and CD3

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.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

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 InjectionBSA of 1.4 to 1.49 m2: 13.1 mL of blinatumomab (5 vials); add 4.7 mL of 0.9% Sodium Chloride InjectionBSA of 1.3 to 1.39 m2: 12.2 mL of blinatumomab (5 vials); add 5.6 mL of 0.9% Sodium Chloride InjectionBSA of 1.2 to 1.29 m2: 11.3 mL of blinatumomab (5 vials); add 6.5 mL of 0.9% Sodium Chloride InjectionBSA of 1.1 to 1.19 m2: 10.4 mL of blinatumomab (4 vials); add 7.4 mL of 0.9% Sodium Chloride InjectionBSA of 1 to 1.09 m2: 9.5 mL of blinatumomab (4 vials); add 8.3 mL of 0.9% Sodium Chloride InjectionBSA of 0.9 to 0.99 m2: 8.6 mL of blinatumomab (4 vials); add 9.2 mL of 0.9% Sodium Chloride InjectionBSA of 0.8 to 0.89 m2: 7.7 mL of blinatumomab (3 vials); add 10.1 mL of 0.9% Sodium Chloride InjectionBSA of 0.7 to 0.79 m2: 6.8 mL of blinatumomab (3 vials); add 11 mL of 0.9% Sodium Chloride InjectionBSA of 0.6 to 0.69 m2: 5.9 mL of blinatumomab (3 vials); add 11.9 mL of 0.9% Sodium Chloride InjectionBSA of 0.5 to 0.59 m2: 5 mL of blinatumomab (2 vials); add 12.8 mL of 0.9% Sodium Chloride InjectionBSA of 0.4 to 0.49 m2: 4.1 mL of blinatumomab (2 vials); add 13.7 mL of 0.9% Sodium Chloride InjectionNOTE: 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.

infection / Delayed / 0-15.0
cytokine release syndrome / Rapid / 0-15.0
bradycardia / Rapid / 0-14.0
atrial fibrillation / Early / 0-14.0
neurotoxicity / Early / 0-13.0
elevated hepatic enzymes / Delayed / 0-8.0
fever / Early / 0-7.0
hyperbilirubinemia / Delayed / 0-5.0
tremor / Early / 0-4.0
headache / Early / 0-4.0
encephalopathy / Delayed / 0-4.0
supraventricular tachycardia (SVT) / Early / 0-2.0
sinus tachycardia / Rapid / 0-2.0
weight gain / Delayed / 0-1.0
back pain / Delayed / 0-1.0
dizziness / Early / 0-1.0
insomnia / Early / 0-1.0
aphasia / Delayed / 0-1.0
edema / Delayed / 0-1.0
fluid retention / Delayed / 0-1.0
peripheral edema / Delayed / 0-1.0
rash / Early / 0-1.0
contact dermatitis / Delayed / 0-1.0
erythema / Early / 0-1.0
maculopapular rash / Early / 0-1.0
hypotension / Rapid / 0-1.0
cranial nerve palsies / Delayed / Incidence not known
seizures / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
erythema multiforme / Delayed / Incidence not known
hypertensive crisis / Early / Incidence not known
tumor lysis syndrome (TLS) / Delayed / Incidence not known
leukoencephalopathy / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
suicidal ideation / Delayed / Incidence not known
capillary leak syndrome / Early / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
macrophage activation syndrome / Delayed / Incidence not known

infusion-related reactions / Rapid / 27.0-72.0
antibody formation / Delayed / 0-2.0
lymphadenopathy / Delayed / Incidence not known
confusion / Early / Incidence not known
paresis / Delayed / Incidence not known
tachypnea / Early / Incidence not known
atopic dermatitis / Delayed / Incidence not known
hyperthermia / Delayed / Incidence not known
depression / Delayed / Incidence not known

chills / Rapid / 0-28.0
paresthesias / Delayed / Incidence not known
hypoesthesia / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
flushing / Rapid / Incidence not known
nausea / Early / Incidence not known
asthenia / Delayed / Incidence not known
myalgia / Early / Incidence not known

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.[58559]

Neurotoxicity has been reported with blinatumomab therapy (e.g., encephalopathy, seizures, speech disorders, cranial nerve disorders, disturbances in consciousness, confusion, disorientation, and coordination and balance disorders); some cases were life-threatening or fatal. The median time to onset of neurological toxicity was within 2 weeks; specific toxicity varied by patient age. Monitor patients for signs and symptoms of neurotoxicity. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe neurological toxicity. Advise patients against driving or operating machinery due to a risk of seizures or loss of consciousness during blinatumomab therapy. 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.

Blincyto

Rx

Bispecific CD19-directed CD3 T-cell engager monoclonal antibody
Used for certain types of CD19-positive B-cell precursor ALL in patients 1 month of age or older
Cytokine release syndrome and severe neurological toxicities have been reported; treatment may need to be interrupted or discontinued

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.

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.

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.

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.

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.

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.

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.

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.

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.
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.
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.
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.
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.
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.
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.
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.
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.

Blincyto Intravenous Inj Pwd F/Sol: 35mcg

45 kg or greater: 28 mcg/day
Less than 45 kg: 15 mcg/m2 per day (not to exceed 28 mcg/day)

45 kg or greater: 28 mcg/day
Less than 45 kg: 15 mcg/m2 per day (not to exceed 28 mcg/day)

45 kg or greater: 28 mcg/day
Less than 45 kg: 15 mcg/m2 per day (not to exceed 28 mcg/day)

15 mcg/m2 per day (not to exceed 28 mcg/day)

15 mcg/m2 per day

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.

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.

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.

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.