BEND+POLA+RITU

^*Polatuzumab vedotin, bendamustine, and rituximab can be administered in any order on Day 1 of each cycle.

REPEAT EVERY 21 DAYS

For a usual total of up to 6 cycles unless disease progression or unacceptable toxicity occurs

Other Supportive Care:

Pre-medication (prophylaxis for infusion reactions):

Pre-medications for rituximab
Administer the following at least 30 minutes prior to rituximab:

• Oral antipyretic (e.g. acetaminophen)
• H1-receptor antagonist / antihistamine (e.g. diphenhydramine)
• Corticosteroid (e.g. methylprednisolone 80 mg IV) in patients with high bulk disease or pulmonary involvement if no corticosteroids are already being given as part of the chemotherapy regimen.

Pre-medications for polatuzumab vedotin:
If not already pre-medicated, administer an antihistamine and anti-pyretic at least 30 to 60 minutes prior to polatuzumab vedotin administration. 

Other supportive care:

• Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
• Prophylaxis for tumour lysis (high bulk disease)
• Consider anti-infective prophylaxis. (e.g., PJP, herpes virus)
• Consider prophylactic G-CSF administration for neutropenia.

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

Hypertension should be controlled prior to starting bendamustine.

Correct for hypokalemia and other electrolyte abnormalities prior to and during treatment, especially in patients with pre-existing cardiac disorders.

Since transient hypotension may occur during rituximab infusion, consideration should be given to withhold antihypertensive medication 12 hours prior to and throughout the rituximab infusion.

Dose levels

¹No dosage reduction recommendation.  Dose is either delayed or discontinued due to toxicity.

²Do not re-escalate once dose is decreased.

Hematological Toxicities

*Do not start new cycle until non-hematologic toxicities have recovered to ≤ grade 1,  ANC ≥ 1 x 10⁹/L and platelets ≥ 75 x 10⁹/L

^†If bendamustine is discontinued, discontinue polatuzumab  and rituximab 

Peripheral Neuropathy

*Do not start new cycle until non-hematologic toxicities have recovered to ≤grade 1,  ANC ≥1 x 10⁹/L and platelets ≥75 x 10⁹/L

Bendamustine - Non-Hematological Toxicities

*Do not start new cycle until non-hematologic toxicities have recovered to ≤ grade 1,  ANC ≥ 1 x 10⁹/L and platelets ≥ 75 x 10⁹/L

Other Non-Hematological Toxicities

Management of Infusion-related Reactions:

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

Rituximab:

Polatuzumab vedotin:

Bendamustine:

No dose adjustment required for polatuzumab vedotin, bendamustine or rituximab. Patients ≥ 65 of age had a higher incidence of adverse events ≥ grade 3 and discontinuation compared with younger patients with polatuzumab vedotin. Exercise caution as older patients are more likely to experience serious adverse events (including cardiac, pulmonary, or other grade 3/4 toxicity) with rituximab.

Refer to riTUXimab, polatuzumab vedotin, bendamustine drug monograph(s) for additional details of adverse effects

Refer to riTUXimab, polatuzumab vedotin, bendamustine drug monograph(s) for additional details

• Consider withholding antihypertensive medication 12 hours prior to and during rituximab administration.

• Ingestion of grapefruit, starfruit, Seville oranges, their juices or products while on polatuzumab therapy may increase MMAE plasma concentrations as these products have CYP3A4 inhibitory activity; monitor closely for signs of toxicity.

Refer to riTUXimab, polatuzumab vedotin, bendamustine drug monograph(s) for additional details

Administration

Rituximab

Note: Different rituximab products are NOT INTERCHANGEABLE. 

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

• 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.

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

• 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:

First infusion:

• Recommended to be administered over a graduated rate:  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:

• If no severe infusion reaction (grade 3 or 4) occurred with the first cycle, a rapid infusion of IV rituximab over a total of 90 minutes can be initiated with cycle 2 (20% of the dose in the first 30 min then the remaining 80% over 60 min).

• OR 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).

When bulky disease present or WBC > 25-50 x 10⁹/L, consider:

• A slower infusion rate, or
• Split dosing over days 1-2, or
• Delaying rituximab treatment until chemotherapy has reduced the lymphocyte count

Polatuzumab vedotin

• DO NOT administer as an IV push or bolus.

• Reconstitute using sterile water for injection, immediately before dilution.

• Dilute into 0.9% sodium chloride, 0.45% sodium chloride or 5% dextrose IV infusion bag with a minimum volume of 50mL. Final concentration must be 0.72-2.7 mg/mL.

• Do not shake vial or IV bag. Agitation can result in aggregation.

• Infuse via dedicated line equipped with a sterile, non-pyrogenic, low-protein binding in-line or addon filter (0.2 or 0.22 µm size) and catheter.

• Administration of polatuzumab vedotin, bendamustine, and rituximab can occur any order on Day 1 of each cycle.

• Initial dose should be administered over 90 minutes. If well tolerated, the subsequent doses may be administered over 30 minutes.

• Patients should be monitored for infusion-related reactions during and for at least 90 minutes following the first infusion, and for at least 30 minutes following subsequent infusions.

• If a polatuzumab vedotin dose is missed, administer as soon as possible. Adjust cycle schedule in order to maintain a 21-day interval between doses.

• No incompatibilities have been observed between polatuzumab vedotin and:

  • IV infusion bags with polyvinyl chloride (PVC), or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP).

  • Infusion sets or infusion aids with PVC, PE, polyurethane (PU), polybutadiene (PBD), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyetherurethane (PEU), or fluorinated ethylene propylene (FEP), or polytetrafluorethylene (PTFE).

  • Filter membranes composed of polyether sulfone (PES) or polysulfone (PSU).

• Store unopened vials at 2-8°C in the original carton to protect from light.
   

Bendamustine:

• DO NOT administer as an IV push or bolus.

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

• Infuse over 30-60 minutes.

• 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.

• Administer bendamustine through a dedicated line.

• Compatible with PVC or polyethylene lined PVC infusion bags.

• Do not admix with other drugs.

• Store unopened vials at 2-25°C, in original package protected from light.
   

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

Contraindications:

• Patients who have a hypersensitivity to polatuzumab vedotin, bendamustine or rituximab or any components of the formulation.

• 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 mannitol.

Other Warnings/Precautions:

• Exercise caution in patients:

  • with ≥ grade 2 peripheral neuropathy or prior allogeneic hematopoietic stem cell transplantation (HSCT) as they were excluded from polatuzumab vedotin clinical trials.

  • 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 treatment.

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

  • who have or 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). 

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

  • with hypertension and and mild renal impairment

• 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.

• 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.

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

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

• An increased risk of severe skin toxicity (including Stevens-Johnson syndrome and toxic epidermal necrolysis) was noted when allopurinol was used concurrently with bendamustine.

• Caution with driving or using machinery as peripheral neuropathy, fatigue, and dizziness may occur with polatuzumab vedotin treatment.

Pregnancy/lactation:

• This regimen is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.

• Breastfeeding is not recommended during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).

• Fertility Effects:

  • Polatuzumab vedotin: Documented in animals

  • Bendamustine: Yes

  • Rituximab: Unknown

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

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

BC Cancer Protocol Summary for Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Not Eligible for Transplant using Polatuzumab Vedotin, Bendamustine and rituximab; April 2022.

Bendamustine Drug Monograph, Ontario Health (Cancer Care Ontario).

Polatuzumab Drug Monograph, Ontario Health (Cancer Care Ontario).

Rituximab Drug Monograph, Ontario Health (Cancer Care Ontario).

Sehn L, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2019; 37. https://doi.org/10.1200/JCO.19.00172.