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BREN

Cancer Type: Hematologic, Lymphoma - Non-Hodgkin's Intermediate Grade  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Brentuximab - Systemic Anaplastic Large Cell Lymphoma
A - Regimen Name

BREN Regimen
Brentuximab


Disease Site
Hematologic - Lymphoma - Non-Hodgkin's Intermediate Grade

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

Treatment of CD30+ systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen, in patients who have an ECOG performance status of 0 or 1. Treatment beyond 16 cycles may be funded (documentation showing continued evidence of benefit is required).

Not funded for use in the first-line setting or as a bridge to allogeneic stem cell transplant. Not funded for retreatment after disease progression or relapse.


Supplementary Public Funding

brentuximab vedotin
New Drug Funding Program (Brentuximab - Systemic Anaplastic Large Cell Lymphoma) (NDFP Website )

 
B - Drug Regimen

brentuximab vedotin
1.8* mg /kg IV Day 1

*Cap at 180mg for patients who are ≥ 100 kg

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C - Cycle Frequency

REPEAT EVERY 21 DAYS

For up to 16 cycles unless disease progression or unacceptable toxicity occurs

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Low

Premedication (prophylaxis for infusion reactions):

  • Routine pre-medication is not recommended.
  • May consider pre-medication with acetaminophen, H1-receptor antagonist and corticosteroid if an IR has occurred in the past.

Other supportive care:

  • Antiviral and antibiotic prophylaxis post-ASCT should be followed per institutional guidelines.
 
E - Dose Modifications

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

 

 

 

Dosage with toxicity

Toxicity

Type / Grade

Recommendation
Peripheral neuropathy
 
New or worsening Grade 2 or 3

Hold until neuropathy improves to Grade 1 or baseline, then restart at 1.2 mg/kg

Grade 4
Discontinue
Neutropenia
 
Grade 3 or 4

Hold until resolution to baseline or Grade 2 or lower. Consider growth factor support for subsequent cycles.

Recurrent Grade 4 despite the use of growth factors

Discontinue or reduce dose to 1.2 mg/kg

Platelets Grade 3 or 4 Monitor closely and consider platelet transfusions or dose delays
SJS, TEN
 
Any
Discontinue and manage appropriately
PML
Suspected, any grade
Hold and investigate; discontinue if confirmed
 
Pancreatitis Suspected, any grade Hold and investigate; discontinue if confirmed
Pulmonary symptoms Any grade Hold and investigate; consider discontinuing if pneumonitis confirmed
Tumour lysis syndrome
Suspected, any grade

Hold and manage aggressively. May continue therapy after resolution with adequate preventative measures.

 

Management of Infusion-Related Reactions:

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

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

Restart:

  • The infusion may be restarted at a slower rate once symptoms have resolved.
Consider pre-medication with acetaminophen, H1-receptor antagonist and a corticosteroid for subsequent infusions
3
  • Stop treatment.
  • Aggressively manage symptoms.

Restart:

  • The infusion may be restarted at a slower rate once symptoms have resolved.
4
  • Stop treatment.
  • Aggressively manage symptoms.
Permanently discontinue (do not re-challenge).



Hepatic Impairment

The liver is a known route of clearance for brentuximab. MMAE exposure approximately doubled in patients with hepatic impairment; a reduced starting dose should be used (see table below). 

 

Hepatic Impairment Dose
Mild (Child-Pugh A) Start at 1.2 mg/kg and monitor closely
Moderate (Child-Pugh B) Avoid use
Severe (Child-Pugh C) Avoid use

Renal Impairment

Avoid use in patients with severe renal impairment (CrCl <30mL/min). The kidneys are a known route of clearance for brentuximab vedotin. MMAE exposure approximately doubled and severe adverse effects were more frequent in patients with severe renal impairment.

 


Dosage in the Elderly

Efficacy and safety in elderly patients aged 65 and older have not been established.

 


 
F - Adverse Effects

Refer to brentuximab vedotin 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

  • Peripheral neuropathy (may be severe)
  • Myelosuppression +/- infection and bleeding (may be severe, includes anemia, opportunistic infections) 
  • Fatigue
  • Nausea, vomiting
  • Diarrhea
  • Fever
  • Abdominal pain
  • Anorexia, weight loss
  • Constipation
  • Cough, dyspnea
  • Musculoskeletal pain
  • Headache
  • Rash, pruritus
  • Infusion-related reaction (may be severe)
  • Arterial / venous thromboembolism
  • Hypotension
  • Arrhythmia
  • GI perforation
  • Pancreatitis
  • Hepatotoxicity
  • Tumour lysis syndrome
  • Leukoencephalopathy (PML)
  • Pneumonitis
  • Renal failure
 
G - Interactions

Refer to brentuximab drug monograph(s) for additional details.


  • CYP3A4 inducers may reduce exposure to MMAE metabolite; caution and monitor for reduced efficacy
  • CYP3A4 and P-gp inhibitors may increase exposure to MMAE metabolite; caution and monitor for increased adverse reactions
  • Avoid concomitant use of bleomycin given increased risk of pulmonary toxicity 
 
H - Drug Administration and Special Precautions

Refer to brentuximab vedotin drug monograph(s) for additional details


Administration:

  • DO NOT administer as an IV push or bolus
  • Reconstitute each 50 mg vial with 10.5 mL of Sterile Water for Injection to yield a single-use 5 mg/mL solution. Gently swirl the vial to aid dissolution; do not shake.
  • After reconstitution, immediately add to an infusion bag containing at least 100 mL volume to achieve a final concentration of 0.4-1.8 mg/mL and use within 24 hours.
  • Can be diluted into normal saline, 5% dextrose or lactated ringer's injection.
  • Infuse IV over 30 minutes
  • Do not mix with, or administer as an infusion with, other medicinal products.
  • Store vials at 2-8 degrees Celsius in the original carton to protect from light.
  • Store reconstituted solution at 2-8 degrees Celsius for up to 24 hours

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
  • Concomitant use with bleomycin due to increased risk of pulmonary toxicity
  • Patients who have, or have had progressive multifocal leukoencephalopathy (PML)

Warnings/Precautions:

  • Patients with significant pre-existing cardiovascular disease should be monitored closely as the potential cardiotoxicity of brentuximab vedotin is unknown.
  • Use live vaccines with caution

Pregnancy/Lactation:

  • Brentuximab is not recommended for use in pregnancy unless possible benefits to the mother outweigh risks to the fetus. Fetotoxicity has been documented in animals. Adequate contraception (including a barrier method) should be used by both sexes during treatment, and for at least 6 months after the last dose.
  • It is not known if brentuximab is excreted into breast milk. The decision to breastfeed while on the drug should consider potential benefits vs. risks.
 
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 prior to each dose and more frequent monitoring should be considered for patients with grade 3 or 4 neutropenia or thrombocytopenia
  • Liver functions tests; baseline and before each cycle; also as clinically indicated in patients with liver impairment
  • Renal function tests; baseline and before each cycle; also as clinically indicated in patients with renal impairment
  • Clinical toxicity assessment for TLS, PML, infusion-related reactions, infections, neuropathy, pneumonitis, pancreatitis; 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
Pharmacy Workload (average time per visit)
19.589 minutes
Nursing Workload (average time per visit)
47.5 minutes
 
K - References

Brentuximab drug monograph, Cancer Care Ontario.

Deng C, Pan B, O'Connor OA. Brentuximab vedotin. Clin Cancer Res 2012;19(1):22-27.

Minich SS. Brentuximab vedotin: a new age in the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma. Ann Pharmacother 2012;46:377-83.

Pro B, Advani R, Brice P et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 2012;30(18):2190-6.

Younes A, Yasotham U, Kirkpatrick P. Brentuximab vedotin. Nat Rev Drug Discov 2012;11:19-20.

November 2019 Updated infusion reaction information in Premedication and Supportive Measures and Dose Modifications 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.