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BEND+RITU

Cancer Type: Hematologic, Lymphoma - Non-Hodgkin's Low Grade  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Bendamustine - First Line - Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma
New Drug Funding Program
    Bendamustine - Relapsed_Refractory - Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma
New Drug Funding Program
    Rituximab in Combination with Chemotherapy - Indolent B-cell Lymphoma
New Drug Funding Program
    Rituximab - Retreatment - Indolent Lymphoma
New Drug Funding Program
    Rituximab (SC) in Combination with Chemotherapy - Indolent B-cell Lymphoma
A - Regimen Name

BEND+RITU Regimen
Bendamustine-riTUXimab


Disease Site
Hematologic - Lymphoma - Non-Hodgkin's Low 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
  • First-line treatment of patients with indolent CD20 positive non­-Hodgkin’s lymphoma* or mantle cell lymphoma with ECOG status ≤ 2
  • Treatment of patients with relapsed/refractory indolent CD20 positive non-Hodgkin’s lymphoma* or mantle cell lymphoma, where the combination of fludarabine-rituximab could previously have been a therapeutic option.
*(excluding small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL))
​​​​​​ Patients who previously received rituximab may be eligible for rituximab retreatment, in those who sustained a response and remained disease-free for at least 6 months after the last dose of rituximab

Refer to the NDFP eligibility forms for detailed funding criteria.


Supplementary Public Funding

bendamustine
New Drug Funding Program (Bendamustine - First Line - Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma)

bendamustine
New Drug Funding Program (Bendamustine - Relapsed_Refractory - Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma)

riTUXimab
New Drug Funding Program (Rituximab in Combination with Chemotherapy - Indolent B-cell Lymphoma)

riTUXimab
New Drug Funding Program (Rituximab - Retreatment - Indolent Lymphoma) (with combination chemotherapy)

riTUXimab (subcut)
New Drug Funding Program (Rituximab (SC) in Combination with Chemotherapy - Indolent B-cell Lymphoma)

riTUXimab (subcut)
New Drug Funding Program (Rituximab (SC) - Retreatment - Indolent Lymphoma)

 
B - Drug Regimen

Cycle 1:  All patients must receive their first dose of rituximab by IV infusion

 

riTUXimab
375 mg /m² IV Day 1
bendamustine
90 mg /m² IV Days 1 and 2



Cycle 2 and onwards (For a maximum of 6 cycles including initial IV rituximab cycle(s) )

Rituximab IV:

riTUXimab
375 mg /m² IV Day 1


OR

Rituximab subcutaneous: 

The subcutaneous formulation must only be given at the second or subsequent cycles, and only after at least 1 full rituximab IV dose.

riTUXimab (subcut)
1400 mg Subcut Day 1


Plus BEND chemotherapy:

bendamustine
90 mg /m² IV Days 1 and 2
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C - Cycle Frequency

REPEAT EVERY 28 DAYS for a maximum of 6 cycles in the absence of unacceptable toxicity or disease progression.

For patients who responded to induction therapy, and were rituximab-naïve prior to induction, refer to maintenance rituximab regimen - RITU(MNT) or RITU(MNT-SC).

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

Bendamustine pre-medication (only for patients with Grade 1 or 2 reactions with prior infusion):  

  • Analgesic/antipyretic (e.g. acetaminophen), corticosteroid and an antihistamine (e.g. diphenhydramine) should be considered in subsequent cycles.

Hypertension should be controlled prior to starting treatment.

Rituximab premedication:

  • Acetaminophen 650mg PO
  • Diphenhydramine 50mg PO/IV
  • If high volume disease, consider steroids and prophylaxis for tumour lysis

HBsAg positive patients should receive antiviral prophylaxis during and after rituximab. HBsAg negative, but HBcAb positive patients should be considered for antiviral prophylaxis and be closely monitored for viral reactivation by a HBV expert.

 
E - Dose Modifications

See premedication and monitoring sections for supportive care, screening and monitoring recommendations.

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Dosage with toxicity

Dose levels for bendamustine: 90 mg/m2, 60 mg/m2. Do not re-escalate after reduction for toxicity.

Rituximab:  No dosage reduction recommendation.  Dose is either delayed or discontinued due to toxicity.

Toxicity / Counts (x 109/L) Rituximab (IV) Dose / Infusion Rate Rituximab (Subcut) Dose Bendamustine Dose
Grade 4 neutropenia or  platelets; thrombocytopenic bleeding Hold* Hold* Hold* then ↓ 1 dose level
Grade 2 clinically significant Continue Hold until ≤ grade 1 then reduce by 1 dose level
Other ≥ grade 3 non-hematological/organ toxicity Hold until ≤ grade 1; considering discontinuing if grade 4 Hold until ≤ grade 1 then reduce by 1 dose level; consider discontinuing if grade 4
  • Severe mucocutaneous toxicity
  • Serious/life-threatening cardio-pulmonary events
  • Reactivation of tuberculosis or hepatitis B; evidence of active hepatitis
  • PML / RPLS
Discontinue
*Do not start new cycle until toxicities have recovered to ≤ grade 1, platelets ≥ 75-100 x 109/L, and ANC ≥ 1 x 109/L.
 

Infusion or Administration-Related Reactions:
 
Toxicity Rituximab IV Rituximab Subcut Bendamustine
Grade 1-2 Hypersensitivity/ acute reactions   
or Subcut administration-related reactions (if applicable)
  • Stop or slow infusion; exclude respiratory symptoms; treat symptomatically.
  • Restart at 50% previous rate after resolution of symptoms.
  • Hold administration if intolerable. Exclude respiratory symptoms; treat symptomatically. 
  • Cold compresses and topical steroids may be helpful for local cutaneous reactions
Hold or slow infusion; premedicate with antipyretic, antihistamine, and corticosteroid before re-challenge and subsequent cycles.
Grade ≥3 Hypersensitivity/ acute reactions   
or Subcut administration-related reactions (if applicable)
  • Discontinue
  • Manage appropriately; monitor patient until complete resolution.
  • Hold administration if possible.  Discontinue if hypersensitivity, pulmonary-related or based on physician discretion.
  • Manage appropriately; monitor patient until complete resolution.
  • Discontinue
  • Manage appropriately; monitor patient until complete resolution.



Hepatic Impairment

Bilirubin
AST or ALT or ALP
Bendamustine Dose
Rituximab Dose
≤ 1.5 x ULN
≤ 2.5 x ULN
Caution

No adjustment required; discontinue if evidence of hepatitis

> 1.5 x ULN
> 2.5 x ULN
Do not use

 

 


Renal Impairment

Creatinine Clearance (mL/min)
Bendamustine Dose
Rituximab Dose
>80
100%
No adjustment required
40 - 80
Caution
< 40
Do not use

Dosage in the Elderly

No dose adjustment required for either drug. Exercise caution as older patients are more likely to experience serious adverse events (including cardiac, pulmonary, or other grade 3/4 toxicity) with rituximab.


 
F - Adverse Effects

Refer to riTUXimab, riTUXimab (subcut), bendamustine 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

  • Infusion or hypersensitivity reactions (may be severe; with rituximab IV)
  • Nausea, vomiting
  • Fatigue
  • Myelosuppression and Immunosuppression (including atypical infections, viral/TB re-activation)
  • Diarrhea
  • Flu-like symptoms
  • Constipation
  • Administration-related reactions, including cutaneous (with rituximab subcut)
  • Headache
  • Musculoskeletal pain
  • Mucositis
  • Abdominal pain
  • Anorexia, weight loss
  • Dyspepsia
  • Dysgeusia
  • Cough, dyspnea (may be severe)
  • Dizziness
  • Insomnia
  • Paresthesia
  • Rash (may be severe)
  • Edema
  • Abnormal electrolytes
  • Arterial / venous thromboembolism
  • Arrhythmia, prolonged QTc
  • Cardiotoxicity
  • Hypertension
  • Hepatotoxicity
  • Tumour lysis syndrome
  • Nephrotoxicity
  • Pneumonitis, ARDS
  • GI obstruction / perforation
  • PRES / RPLS, PML
  • Optical and cranial nerve disorder
  • Hemolysis
  • Vasculitis
  • Hyperviscosity
  • Secondary malignancy
 
G - Interactions

Refer to bendamustine, riTUXimab, riTUXimab (subcut) drug monograph(s) for additional details.


  • Consider withholding antihypertensive medication 12 hours prior to and during rituximab administration
  • CYP1A2 inhibitors my increase bendamustine concentration and toxicity; use with caution

  • CYP1A2 inducers (including cigarette smoking) may reduce bendamustine concentration and/or efficacy

 
H - Drug Administration and Special Precautions

Refer to bendamustine, riTUXimabriTUXimab (subcut), drug monograph(s) for additional details.


Administration

Rituximab IV and Subcutaneous formulations are not interchangeable.  The dosing and concentrations of these products are different.

Rituximab and bendamustine should be administered in a setting where full resuscitation facilities are immediately available, and under the close supervision of someone experienced and capable of dealing with severe infusion-related reactions.

Rituximab (IV)

  • DO NOT administer as an IV push or bolus.

  • Dilute to a final concentration of 1-4 mg/mL in normal saline or D5W.

  • To avoid foaming, gently invert the bag to mix the solution.

  • Do not admix with other drugs.

  • Administer rituximab through a dedicated line.

  • Compatible with PVC or polyethylene bags.

  • Keep vials refrigerated; do not freeze.  Protect from light.

  Infusion rates:

  • Consider a slower infusion rate or split dosing over days 1-2 for any cycle where bulky disease present or WBC > 25 x 109/L.

  • First infusion: initial rate of 50 mg/h, then escalate rate in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h (about 4.25 hours in total).

Subsequent infusions:

  • Initial rate of 100 mg/h, then escalate rate in 100 mg/h increments every 30 minutes, to a maximum of 400 mg/h as tolerated (about 3.25 hours in total).

  • Published data suggest that a 90 minute infusion (20% of the dose in the first 30 min then the remaining 80% over 60 min) can be used for second and subsequent infusions, if no reaction occurred with the first infusion.

 

Rituximab (Subcut)

Refer to Safety Considerations for the Implementation of Subcutaneous Rituximab Formulation

  • Rituximab (subcut) must not be self-administered.

  • Rituximab (subcut) is given subcutaneously into the abdominal wall only. Do not give in areas where the skin is red, tender, hard, bruised, or where there are moles or scars.

  • Non-Hodgkin’s lymphoma: Give subcutaneously over approximately 5 minutes

  • Observe for at least 15 minutes after administration.

  • If there are other subcutaneous medications, they should be given at separate sites.

  • Compatible with polypropylene or polycarbonate syringes.

  • Keep vials refrigerated in the outer carton; do not freeze. Protect from light.

 

Bendamustine:

  • Non-Hodgkin lymphoma - infuse over 60 minutes

  • DO NOT administer as an IV push or bolus.

  • Dilute to a final concentration of 0.2 - 0.6 mg/mL in 500 mL infusion bag of 0.9% sodium chloride or 2.5% dextrose/0.45% sodium chloride.

  • Reconstituted solution must be transferred to infusion bag within 30 minutes of reconstitution.

  • Administer bendamustine through a dedicated line.

  • Compatible with PVC or polyethylene bags.

  • Do not admix with other drugs.

 

Contraindications:

  • Patients with known hypersensitivity and anaphylactic reactions to proteins of similar mouse or human origin, to Chinese Hamster Ovary (CHO) cell proteins or to any component of rituximab, bendamustine or mannitol.

  • Patients who have or have had PML, have active and/or severe infections, active hepatitis B, or severely immunocompromised (e.g. AIDS patients with very low CD4 or CD8 counts). 

  • Avoid live or live-attenuated vaccines, since they may result in serious or fatal infections in patients immunocompromised by BEND+RITU.

  • Patients with CrCl < 40 mL/min or moderate/severe hepatic impairment

 

Warnings/Precautions:

  • Exercise caution in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection. Patients may have increased risk of infection following rituximab treatment.

  • Prior to starting rituximab in HBV seropositive patients, consultation with a liver disease expert is recommended to determine ongoing monitoring of HBV reactivation and its management.

  • Exercise caution in patients with neutrophil counts < 1.5 x 109/L and/or platelets < 75 x 109/L due to limited experience with rituximab in this patient group.

  • Use rituximab with extreme caution in patients with pre-existing cardiovascular disease or in patients with high tumour burden. Consider steroids ± slow rituximab infusions or infusions split over 2 days for patients with bulky disease or > 25 x 109/L circulating malignant cells.

  • Use rituximab with caution in patients with pulmonary insufficiency or lung tumour infiltration, and in patients with myelosuppression.

  • Reduced immunogenicity may occur with the use of inactivated vaccines.

  • Avoid bendamustine in patients with relapsed indolent NHL who did not tolerate prior therapies (including other alkylating agents)

  • Use bendamustine with caution in patients with hypertension and patients with mild renal and hepatic impairment

 

Pregnancy/lactation:

  • IgGs are known to pass the placental barrier.  There have been reports of infants with transient B-cell depletion and lymphocytopenia.  BEND+RITU should not be used during pregnancy.  Adequate contraception is recommended for both sexes with childbearing potential, during treatment and up to 12 months after the last dose.

  • Breastfeeding is not recommended during treatment with either drug and until rituximab can no longer be detected in the blood.

 
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

  • Blood pressure; baseline and before each dose

  • CBC; baseline and before each cycle

  • Electrolytes, including sodium, potassium, magnesium and uric acid; baseline and before each cycle

  • Liver function tests; baseline and regular

  • Renal function tests; baseline and regular

  • The Hematology Disease Site group recommends screening patients for hepatitis B surface antigen (HBsAg) and core antibody (HBcAb) prior to starting treatment. If seropositive, consult with an expert in HBV and monitor closely.

  • Monitor patients during and for at least 15 minutes after each rituximab dose, longer in patients at higher risk of hypersensitivity reactions

  • Clinical assessment of hypersensitivity/infusion reactions, tumour lysis syndrome, infection (including viral, opportunistic), bleeding, GI, pulmonary, skin, CNS and cardiovascular side effects, secondary malignancies; at each visit

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

Suggested Clinical Monitoring

  • Monitor closely for cardiovascular symptoms for patients who have cardiac conditions or recurrent cardiac events with rituximab
  • ECG; as clinically indicated; periodic in the setting of cardiac disorders and electrolyte imbalances
  • Blood glucose; baseline and periodic
  • CMV testing in febrile patients; as clinically indicated
  • HIV status; baseline

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J - Administrative Information

Approximate Patient Visit
BEND+RITU - 6 hours (first cycle); 1.5 to 4 hours (subsequent cycles); BEND only: 0.5 to 1 hour
Pharmacy Workload (average time per visit)
24.073 minutes
Nursing Workload (average time per visit)
55.417 minutes
 
K - References

Bendamustine and rituximab drug monographs, Cancer Care Ontario.

Davies A, Merli F, Mihaljević B, et al.  Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial.  Lancet Haematol. 2017 Jun;4(6):e272-e282.

Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 Sep 20;26(27):4473-9.

Rummel MJ, Niederle N, Maschmeyer G, et al.; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. doi: 10.1016/S0140-6736(12)61763-2. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184.


PEBC Advice Documents or Guidelines

February 2019 Updated Adverse Effects section.


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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.