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blinatumomab

( blin-a-too-moo-mab )
Funding:
New Drug Funding Program
  • Blinatumomab – Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia
  • Blinatumomab - Relapsed or Refractory Acute Lymphoblastic Leukemia (Ph+ BCP-ALL)
  • Blinatumomab - Relapsed or Refractory Acute Lymphoblastic Leukemia (Ph- BCP-ALL)
Other Name(s): Blincyto®
Appearance: solution mixed into larger bags of fluids
A - Drug Name

blinatumomab

COMMON TRADE NAME(S):   Blincyto®

 
B - Mechanism of Action and Pharmacokinetics

Blinatumomab binds the CD3/T-cell receptor complex with CD19 on malignant B-cells, including precursor ALL cells. Activation of the T-cell receptor signaling cascade results in lysis of CD19-expressing cells.



Absorption

With continuous intravenous infusion (CIV), mean steady state serum concentrations increased proportionally to dose (over range 5 to 90 mcg/m2/day).


Distribution

Mainly distributed in the vascular space

Metabolism

Catabolized to small peptides and amino acids

Elimination
Half-life

(terminal): 2.1 hours

Urine

0.2% (60 mcg/m2/day CIV)

 
C - Indications and Status
Health Canada Approvals:

For the treatment of adults patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).



Health Canada Conditional Approvals
(pending the result of studies to verify the drug’s clinical benefit. Patients should be advised of the nature of the marketing authorization granted.)

For the treatment of pediatric patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL*.

Note:

*Approval was based on a single-arm phase I/II study.



 
D - Adverse Effects

Emetogenic Potential:  

Low

Extravasation Potential:   None

The following adverse effects were reported in the Phase III study in adults with refractory B-cell precursor ALL.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Hypertension (7%) E
Hypotension (12%) E
Dermatological Rash (14%) E
General Edema (17%) E
Fever (60%) (7% severe) E
Hematological Myelosuppression ± infection, bleeding (27%) ( 21% severe) E
Other - hematophagic histiocytosis (1%) E
Hepatobiliary ↑ LFTs (17%) (10% severe) E
Pancreatitis (rare; may be severe) E  D
Hypersensitivity Hypersensitivity (2%) I
Infusion related reaction (34%) (3% severe) I  E
Immune Antibody response (2%) E
Other - cytokine release syndrome (14%; may be severe) I  E
Metabolic / Endocrine Tumor lysis syndrome (4%) E
Musculoskeletal Musculoskeletal pain (13%) E
Nervous System Cranial neuropathy (rare; may be severe) E
Dizziness (7%) E
Encephalopathy (1%) E  D
Headache (29%) E
Insomnia (10%) E
Peripheral neuropathy (5%) E
Seizure (2%) E
Somnolence (5%) E
Tremor (10%) E
Ophthalmic Visual disorders (6%) (blurred vision) E
Respiratory Cough, dyspnea (15%) E
Vascular Capillary leak syndrome (<1%) (maybe severe) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for blinatumomab include fever, infusion related reaction, headache, myelosuppression ± infection, bleeding, ↑ LFTs, edema, cough, dyspnea, rash, musculoskeletal pain and hypotension.

Infusion reactions are common and may not be distinguishable from cytokine release syndrome (CRS). Patients should be closely monitored for these, especially during the first infusion of the first 2 cycles.  It is important to start at the recommended lower dose (for Cycle 1, days 1 to 7). 

CRS may be severe and sometimes fatal with a median time to onset of 2 days. It may be accompanied by disseminated intravascular coagulation (DIC) and/or capillary leak syndrome (CLS). Premedication with dexamethasone is recommended.  Hematophagocytic histiocytosis/macrophage activation syndrome (MAS) is uncommonly reported.

Patients at risk of tumour lysis syndrome (i.e. high tumour burden) should have appropriate prophylaxis and be monitored closely. Patients with moderate renal impairment are at increased risk.

Severe infections, including atypical ones, have been reported and may be fatal. Patients with an ECOG performance status of 2 or higher are at increased risk. Grade 3 or 4 febrile neutropenia was reported in 25% of patients.

Neurologic events were reported in approximately 50% of adult and 25% of pediatric patients. The median time to onset was within the first 2 weeks of therapy and was generally reversible. Severe events, which may be fatal, for adult patients included encephalopathy, seizures, speech disorders, cognitive disturbances, co-ordination and balance disorders.  There is limited experience with blinatumomab in patients with active ALL in the CNS or a history of neurologic events.

Leukoencephalopathy has been reported rarely, especially in patients who received prior cranial irradiation and chemotherapy (i.e. high dose methotrexate or intrathecal cytarabine). Patients should be closely monitored given the risk of progressive multifocal leukoencephalopathy (PML).

Life-threatening, sometimes fatal pancreatitis has been reported in the clinical trial and post-market setting; in some cases high dose steroids may have been a contributing factor.  The diagnosis of pancreatitis should be considered in patients who have severe upper abdominal pain accompanied with nausea, vomiting or abdominal tenderness.  If pancreatitis is suspected, blinatumomab should be held or discontinued.

Less than 2% of blinatumomab treated adult patients tested positive for anti-blinatumomab antibodies; these antibodies in the majority of these patients had in-vitro neutralizing activity. Contact the manufacturer to discuss antibody testing if anti-blinatumomab antibodies with a clinically significant effect is suspected.

 
E - Dosing

Refer to protocol by which patient is being treated. 

Premedication with dexamethasone and CNS prophylaxis with intrathecal chemotherapy (before and during treatment) are recommended. Patients at risk of tumour lysis syndrome should have appropriate prophylaxis.

Hospitalization is recommended at minimum for the first 9 days of cycle 1 and the first 2 days of cycle 2.



Adults:

Pre-medications (prophylaxis for infusion reaction):

  • Dexamethasone 20mg IV given 1 hour before infusion is recommended.
  • An antipyretic is recommended during the first 48 hours of each cycle.


Other Supportive Care:

For patients with ≥ 50% leukemic blasts in bone marrow or > 15 x 109/L peripheral blood leukemic blast count, treat with dexamethasone up to 24 mg/day for up to 4 days before the first dose of blinatumomab.


Blinatumomab is given as an IV continuous infusion for 28 days, repeated every 6 weeks.  Patients should have 2 induction cycles followed by 3 consolidation cycles. Maintenance therapy of up to 4 additional cycles may be given following consolidation treatment.

Patient Weight

Treatment Cycle 1*

Subsequent Cycles*

Days 1-7
(as IV continuous infusion)

Days 8-28 
(as IV continuous infusion)

Days 29-42

Days 1-28
(as IV continuous infusion)

Days 29-42

≥ 45kg (fixed-dose)

9 mcg/day

28 mcg/day

14-day treatment-free interval

28 mcg/day

14-daytreatment-free interval

< 45 kg, (BSA-based dose)

5 mcg/m2/day

15 mcg/m2/day

15 mcg/m2/day

*Each cycle is separated by a 2-week treatment-free interval


Dosage with Toxicity:

Dose should be withheld or discontinued for toxicity as recommended.

Toxicity

Grade

Patients ≥ 45kg

Patients < 45kg

Neurotoxicity

Grade 3

Hold until recovery to ≤ Grade 1 for at least 3 days.

Restart at 9 mcg/day.  Increase to 28 mcg/day after 7 days if toxicity does not recur.

Pre-medicate with up to 24mg dexamethasone with a 4-day taper.

Consider appropriate anticonvulsant medication.

Discontinue if toxicity occurred at 9 mcg/day, or if toxicity takes more than 7 days to resolve. 

Hold until recovery to ≤ Grade 1 for at least 3 days.

Restart at 5 mcg/m2/day.  Increase to 15 mcg/m2/day after 7 days if toxicity does not recur.

Pre-medicate with at least 0.2-0.4 mg/kg/day dexamethasone (maximum of 24mg) and taper the dose by 25% per day.

Consider appropriate anticonvulsant medication.

Discontinue if toxicity occurred at 5 mcg/m2/day, or if toxicity takes more than 7 days to resolve.

Grade 4

Discontinue.

Seizure

If >1 seizure, Discontinue.

Other clinically relevant toxicity

Grade 3

Hold until recovery to ≤ Grade 1.

Restart at 9 mcg/day.  Increase to 28 mcg/day after 7 days if toxicity does not recur.

Discontinue if toxicity does not resolve within 14 days.

Hold until recovery to ≤ Grade 1.

Restart at 5 mcg/m2/day.  Increase dose to 15 mcg/m2/day after 7 days if toxicity does not recur.

Discontinue if toxicity does not resolve within 14 days.

 

Grade 4


Consider discontinuing

Suspected Pancreatitis

 

Hold and investigate.

Consider discontinuing if confirmed.

Suspected leukoencephalopathy

 

Hold and consider neurologist consultation, brain MRI and examination of CSF.

Discontinue if confirmed.

Capillary leak syndrome, Disseminated intravascular coagulation, infusion reaction

 

Hold until recovery.

Weight benefit vs. risk to discontinue or restart.

* If dose held for less than 1 week, resume same cycle. If dose held for more than 1 week, start a new cycle.

 

Management of Infusion-related reactions (including Cytokine Release Syndrome (CRS)):

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 

Grade Management Re-challenge
1 or 2
  • Stop or slow the infusion rate.
  • Manage the symptoms.


Restart:

  • After resolution of all symptoms, treatment can be resumed.
See restart
3
  • Stop treatment.
  • Aggressively manage symptoms.
     

Restart:

After resolution of all symptoms, treatment can be resumed.

If patient is ≥ 45 kg:

  • Resume at 9 mcg/day, with an escalation to 28 mcg/day after 7 days if the infusion reaction does not recur

If patient is < 45 kg:

  • Resume at 5 mcg/ m2/ day, with an escalation to 15 mcg/ m2 /day after 7 days if the infusion reaction does not recur
 

 

See restart

 

4
  • Stop treatment.
  • Aggressively manage symptoms
Permanently discontinue (do not re-challenge).


Dosage with Hepatic Impairment:

No formal pharmacokinetic studies have been conducted in patients with hepatic impairment. Hepatic impairment does not appear to have an effect on blinatumomab clearance.



Dosage with Renal Impairment:

No formal pharmacokinetic studies have been conducted in patients with renal impairment. A 2-fold difference in mean blinatumomab clearance was found in patients with moderate renal dysfunction (CrCl 30-59 ml/min) compared to those with normal renal function. No information is available in severe renal impairment (CrCl < 30 ml/min) or in patients on hemodialysis.



Dosage in the elderly:

Age does not appear to change the pharmacokinetics of blinatumomab. Patients over age 65 experienced a higher rate of serious neurological events compared to younger patients, including encephalopathy, confusion and cognitive disorders. Serious infections were also more common in older patients.



Dosage based on gender:

Gender does not appear to influence the pharmacokinetics of blinatumomab.



Children:

Refer to the product monograph for comprehensive pre-medication and dosing information in this population.

In general, adverse reactions in pediatric patients treated with blinatumomab were similar in type to those seen in adult patients.  The preservative benzyl alcohol has been associated with potentially fatal toxicity ("gasping syndrome") in neonates. Avoid dosage forms or diluents containing benzyl alcohol in neonates and infants.



 
F - Administration Guidelines

Refer to the Product Monograph for detailed administration and reconstitution information

  • Medication errors have been reported with blinatumomab. Instructions for preparation and administration should be strictly followed.

  • Patients receiving blinatumomab infusions are recommended to be hospitalized for the first 9 days of the first cycle and the first 2 days of the second cycle to monitor for infusion reactions that are clinically indistinguishable from CRS.

  • In patients < 45 kg, blinatumomab must be dosed based on body surface area calculations (mcg/m2/day) and not at the fixed mcg/day dosing regimen.

  • 7-day bags of blinatumomab solution for infusion, which contain benzyl alcohol as a preservative, are not recommended for use in neonates, infants, or patients weighing < 22 kg, due to potential serious and fatal adverse reactions (eg. gasping syndrome).

  • Blinatumomab is administered by continuous IV infusion using an infusion pump.

  • Infuse through a dedicated lumen; DO NOT flush infusion lines into the patient, inadvertent excess dosage may be given as the infusion bag contains overfill (10-30ml) to account for tubing priming volume.

  • IV tubing should contain an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 micron filter.

  • An in-line filter is NOT required for a 7-day bag (based on preparation procedure in product monograph).

  • Blinatumomab is compatible with polyolefin, PVC (non-DEHP), or EVA infusion bags/pump cassettes and tubing sets and incompatible with DEHP equipment due to possibility of particle formation.

The following are possible infusion rates. The infusion pump should be programmable, lockable, non-elastomeric and have an alarm:

Infusion rate (mL/hr)

Duration of infusion (hr)

Total dose volume (mL)

Overfill in bag (mL) based on preparation instructions in product monograph

10

24

240

30

5

48

240

30

3.3

72

240

30

2.5

96

240

30

0.6

168

100.8

9.2

Storage / stability:

  • Refrigerate unopened vials in original package between 2-8oC.

  • Intact vials may be stored for up to 8 hours at room temperature. Reconstituted vials are stable at room temperature for up to 4 hours or for up to 24 hours between 2-8oC.

  • Prepared IV solution (preservative-free) is stable at room temperature for up to 96 hours, or for up to 10 days between 2-8oC.

  • Prepared IV solution (with preservative) are stable at room temperature for up to 7 days or for up to 14 days at 2°C to 8°C.

  • Protect from light. Do not freeze.

  • Storage times include infusion time. If IV bag of solution for infusion is not administered within the time frames and temperatures indicated, discard; do not refrigerate again.


Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
 

 
G - Special Precautions
Contraindications:

  • Patients who are hypersensitive to this drug or any of its components.

Other Warnings/Precautions:

  • Patients with high leukocyte counts and/or high tumour burden as well as those with moderate renal impairment are at risk of tumour lysis syndrome. Prophylaxis and close monitoring should be considered.

  • There is limited experience with blinatumomab in patients with a history of neurological events. Due to the potential for neurological events, including seizures, patients should refrain from driving and engaging in hazardous activities while receiving blinatumomab.

  • Patients who have received prior cranial irradiation and chemotherapy (i.e. high dose methotrexate or intrathecal cytarabine) are at increased risk of encephalopathy and should be monitored closely.


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Mutagenicity: Unknown
  • Embryotoxicity: Unknown
  • Teratogenicity: Unknown

    It is not known if blinatumomab can cause fetal harm, but animal studies have demonstrated that the drug crosses the placental barrier. The risk associated with the fetal exposure to the preservative benzyl alcohol through maternal drug administration is unknown. Blinatumomab is not recommended for use in pregnancy and adequate contraception should be used by both sexes during treatment, and for at least 48 hours after the last dose. If blinatumomab exposure occurred during pregnancy, the infant’s B lymphocytes should be monitored and deemed within the normal range prior to administration of live vaccines.

  • Excretion into breast milk: Unknown

    Given the potential for blinatumomab to cause adverse effects in infants, breastfeeding is not recommended while receiving the drug and for at least 48 hours after the last treatment.

  • Fertility effects: Unknown
 
H - Interactions

No formal drug interaction studies have been conducted. Blinatumomab causes a transient release of cytokines that may suppress CYP450 enzymes, especially during the first 9 days of the first cycle and the first 2 days of the second cycle. Patients receiving concomitant substrates of CYP450, especially those with a narrow therapeutic index, may be at risk of substrate toxicity.

Vaccination with live viral vaccines is not recommended for at least 2 weeks prior to the start of treatment, during treatment, and until recovery of the B lymphocytes to normal range following the last cycle.

 

AGENT EFFECT MECHANISM MANAGEMENT
CYP 2C9 substrates (e.g. warfarin, meloxicam, fluvastatin) increased risk of substrate toxicity blinatumomab treatment may suppress CYP450 monitor and adjust dose of narrow therapeutic range substrates (e.g. warfarin)
CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) increased risk of substrate toxicity blinatumomab treatment may suppress CYP450 monitor and adjust dose of narrow therapeutic range substrates (e.g. cyclosporine)
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and at each visit

Liver function tests

Baseline and at each visit

Signs and symptoms of TLS, including renal function and fluid balance

In the first 48 hrs of the first infusion; thereafter as clinically indicated

Neurological exam

Baseline and as clinically indicated

Clinical toxicity assessment for infusion reactions (including cytokine release syndrome), infections, bleeding, GI effects, pancreatitis, edema, neurological events

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Blinatumomab – Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia
  • Blinatumomab - Relapsed or Refractory Acute Lymphoblastic Leukemia (Ph+ BCP-ALL)
  • Blinatumomab - Relapsed or Refractory Acute Lymphoblastic Leukemia (Ph- BCP-ALL)

 
K - References

Blinatumomab (Blincyto) product monograph. Amgen Canada Inc. June 2018.

Kantarjian H, Stein A, Gokbuget N, at al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017; 376:836-47.

Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66.

Von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Journal of Clinical Oncology. 2016 Dec 20; 34(36):4381-4389.


June 2020 Updated NDFP forms

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.