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BLIN

Cancer Type: Hematologic, Leukemia - Acute Lymphoblastic (ALL)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Blinatumomab - Relapsed or Refractory Acute Lymphoblastic Leukemia
A - Regimen Name

BLIN Regimen
Blinatumomab


Disease Site
Hematologic - Leukemia - Acute Lymphoblastic (ALL)

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of adult patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL), in patients with a good performance status


Supplementary Public Funding

blinatumomab
New Drug Funding Program (Blinatumomab - Relapsed or Refractory Acute Lymphoblastic Leukemia) (NDFP Website )


Additional Information

The information provided in this document is intended for use in the management of adults with leukemia only and for cancer centres with expertise in treating acute leukemia.

 
B - Drug Regimen

Patients ≥45 kg (fixed dose):

Cycle 1*:

blinatumomab
9 mcg /day IV continuous infusion days 1 to 7 (total of 7 days)
blinatumomab
28 mcg /day IV continuous infusion days 8 to 28 (total of 21 days)

 

Cycles 2 to 5*:

blinatumomab
28 mcg /day IV continuous infusion days 1 to 28

 

OR

 

Patients <45 kg (dose based on BSA):

Cycle 1*:

blinatumomab
5 mcg /m²/day IV continuous infusion days 1 to 7 (total of 7 days)
blinatumomab
15 mcg /m²/day IV continuous infusion days 8 to 28 (total of 21 days)

 

Cycles 2-5*:

blinatumomab
15 mcg /m²/day IV continuous infusion days 1 to 28

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

 

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C - Cycle Frequency

REPEAT EVERY 42 DAYS

For up to 5 cycles, involving up to 2 induction cycles followed by 3 additional consolidation cycles unless disease progression or unacceptable toxicity occurs.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Low

Also refer to CCO Antiemetic Recommendations.

 

Pre-medications (prophylaxis for infusion reaction):
(in adults ≥ 18 years of age)

  • 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.
  • CNS prophylaxis with intrathecal chemotherapy (before and during treatment) is recommended.

  • Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.

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

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. 

The information provided in this document is intended for use in the management of adults with leukemia only and for cancer centres with expertise in treating acute leukemia.

 

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.

Weigh 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).



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.


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.

Children:

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

 


 
F - Adverse Effects

Refer to blinatumomab drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Fever
  • Infusion related reaction (may be severe)
  • Headache
  • Myelosuppression ± infection, bleeding (may be severe) 
  • Edema
  • ↑ LFTs
  • Cough, dyspnea
  • Rash
  • Cytokine release syndrome
  • Musculoskeletal pain
  • Hypotension
  • Insomnia
  • Tremor

 

  • Peripheral neuropathy
  • Encephalopathy
  • Cranial neuropathy
  • Seizure
  • Tumour lysis syndrome
  • Hypersensitivity
  • Hematophagic histiocytosis
  • Pancreatitis
  • Capillary leak syndrome
 
G - Interactions

Refer to blinatumomab drug monograph(s) for additional details


  • Blinatumomab may suppress CYP450 via transient release of cytokines.  Monitor and adjust the dose of narrow therapeutic range CYP 2C9 and 3A4 substrates (e.g. warfarin and cyclosporine).  This is especially important during the first 9 days and the first 2 days of the 2nd cycle.

  • 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. 

 

 

 
H - Drug Administration and Special Precautions

Refer to blinatumomab drug monograph(s) for additional details


Administration

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 (e.g. 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.

 

Contraindications

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

 

Warning / 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.

 

Pregnancy and Lactation

  • 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.

  • 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

 
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

  • CBC; Baseline and at each visit

  • Liver function tests; Baseline and at each visit

  • Neurological exam; Baseline and as clinically indicated

  • Signs and symptoms of TLS, including renal function and fluid balance; In the first 48 hrs of the first infusion; thereafter as clinically indicated

  • Clinical toxicity assessment for infusion reactions (including CRS), 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


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J - Administrative Information

Approximate Patient Visit
0.5 hour (connection to IV pump)
Pharmacy Workload (average time per visit)
35.99 minutes
Nursing Workload (average time per visit)
76.29 minutes
 
K - References

Blinatumomab drug monograph, Cancer Care Ontario.

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.

November 2019 Updated infusion reaction information in Premedication, Dose Modification and Administration sections.


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. 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, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
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.