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Chemotherapy regimens for non-Hodgkin lymphoma: Bendamustine and rituximab[1,2]

Chemotherapy regimens for non-Hodgkin lymphoma: Bendamustine and rituximab[1,2]
Cycle length: 28 days.
Drug Dose and route Administration Given on days
Rituximab 375 mg/m2 IV Dilute in normal saline (NS) or 5% dextrose in water to a final concentration of 1 to 4 mg/mL. Initial infusion: Start at 50 mg/hour; escalate in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour, as tolerated. In the absence of an initial infusion reaction, patients without clinically significant cardiovascular disease may receive subsequent infusions over 90 minutes.* For the 90-minute infusion, administer 20% of the total dose over the first 30 minutes and the remaining 80% over 60 minutes, as tolerated.[3] Day 1
Bendamustine 90 mg/m2 IVΔ Dilute◊ in 500 mL NS or 2.5% dextrose/0.45% sodium chloride to a final concentration of 0.2 to 0.6 mg/mL.§ Administer over 60 minutes. Days 1 and 2
Pretreatment considerations:
Emesis risk
  • MODERATE.
  • Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions
  • Premedicate with acetaminophen and diphenhydramine, with or without an H2 receptor blocker, 30 minutes prior to at least the first and second infusions of rituximab.[4] There is no standard premedication for the initial bendamustine dose. Consider premedication with antihistamines, antipyretics, and corticosteroids for patients with a previous grade 1 or 2 infusion reaction to bendamustine.[5-7]
  • Refer to UpToDate topics on infusion reactions to therapeutic monoclonal antibodies used for cancer therapy.
Vesicant/irritant properties
  • Bendamustine is an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation (particularly by avoiding use of closed system transfer devices, adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene [ABS] with Treanda injection solution◊); monitor IV site for redness, swelling, or pain.
  • Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
Infection prophylaxis
  • The specific incidence of febrile neutropenia was not reported, however, the incidence of grade 3 or 4 neutropenia was 29 to 49% and the incidence of grade 3 or 4 infection was 7 to 12%.[1,2] Primary prophylaxis with hematopoietic growth factors should be considered on an individual basis. Antiviral prophylaxis and Pneumocystis jirovecii prophylaxis are also individualized.
  • Refer to UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.
Dose adjustment for baseline liver or kidney dysfunction
  • Treanda should not be used in patients with a creatinine clearance <40 mL/min. Bedenka should not be used in patients with a creatinine clearance <30 mL/min. Bendamustine should be used with caution in patients with mild hepatic and kidney impairment. Bendamustine should not be used in patients with moderate to severe (AST or ALT >2.5 times the ULN and total bilirubin >1.5 times the ULN) hepatic impairment.[5-7]
  • Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and chemotherapy nephrotoxicity and dose modification in patients with kidney insufficiency, conventional cytotoxic agents.
Hepatitis screening
  • Patients should be screened for hepatitis B and C prior to starting rituximab, and if positive, considered for antiviral prophylaxis.
  • Refer to UpToDate topics on hepatitis B virus reactivation associated with immunosuppressive therapy.
Monitoring parameters:
  • Obtain CBC with differential weekly (initially).[5-7]
  • Assess electrolytes and liver and kidney function prior to each treatment.
  • Carriers of hepatitis B or C virus should be monitored for clinical and laboratory signs of active infection during and following completion of therapy. Rituximab should be discontinued if reactivation occurs.
  • Refer to UpToDate topics on hepatitis B virus reactivation associated with immunosuppressive therapy.
  • Monitor IV infusion site for redness, swelling, pain, infection, and necrosis during and after the bendamustine infusion.
Suggested dose modifications for toxicity:
Myelotoxicity
  • Delay treatment if absolute neutrophil count <1000/microL, platelet count <75,000/microL, or if there is an active infection.[4-7] If grade 4 hematologic toxicity occurs, reduce dose to 60 mg/m2 on days 1 and 2 of each cycle.[2,5-7] Further dose reductions or dose re-escalation may be done at the discretion of the physician.
Other toxicity
  • For grade 3 or greater nonhematologic toxicity, reduce bendamustine dose to 60 mg/m2 on days 1 and 2 of the treatment cycle.[5-7] If toxicity resolves, doses may be cautiously re-escalated on subsequent cycles. Further dose reductions or dose re-escalation may be done at the discretion of the physician.
If there is a change in body weight of at least 10%, doses should be recalculated.
This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

ALT: alanine aminotransferase; AST: aspartate aminotransferase; CBC: complete blood count; IV: intravenous; ULN: upper limit of normal.

* In the absence of an initial reaction, an alternative schedule for subsequent rituximab infusions is to start at 100 mg/hour and escalate in 100 mg/hour increments every 30 minutes to a maximum of 400 mg/hour as tolerated.[4] If there is an infusion reaction to any dose, follow the initial infusion guidelines described above.

¶ A subcutaneous formulation (rituximab-hyaluronidase) that uses a fixed dose and a shorter administration time is an acceptable alternative for patients who have tolerated at least one full dose of intravenous rituximab.[8] Dosing varies by histology and clinicians should refer to the United States Prescribing Information for details.

Δ Increased deaths have been reported in older patients (eg, >70 years) treated with bendamustine plus rituximab;[9] we modify the treatment plan for these patients by lowering the dose of bendamustine (to 70 mg/m2), limiting the number of cycles, or offering an alternative chemotherapy backbone.

◊ Standard bendamustine solution (Treanda injection[5]) is not compatible with closed system transfer devices, adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS), since these plastics can dissolve upon contact.

§ Concentration and infusion length recommendations for Treanda are for lyophilized powder, which is available as 25 mg/vial or 100 mg/vial.[6] If using Treanda injection solution (which is available as a 45 mg/0.5 mL or 180 mg/2 mL solution), the recommended final concentration is 0.2 to 0.7 mg/mL, infused over 60 minutes.[5] If using Bendeka 25 mg/mL solution, dilute in 50 mL NS to a final concentration 1.85 to 5.6 mg/mL and infuse over 10 minutes.[7]
References:
  1. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: The BRIGHT study. Blood 2014; 123:2944.
  2. Rummel MJ, Niederle N, Maschmeyer G, et al. 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; 381:1203.
  3. Sehn LH, Donaldson J, Filewich A, et al. Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting. Blood 2007; 109:4171.
  4. Rituxan - rituximab injection, solution. US Food and Drug Administration (FDA) approved product information. Revised June 2023. US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b172773b-3905-4a1c-ad95-bab4b6126563 (Accessed on April 2, 2024).
  5. Treanda - bendamustine hydrochloride injection, solution, concentrate. United States Prescribing Information. Revised October 2022. US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39d53698-57fa-7c99-fc5b-f52a55684826 (Accessed on April 2, 2024).
  6. Treanda - bendamustine hydrochloride injection, powder, lyophilized, for solution. United States Prescribing Information. Revised October 2022. US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39d53698-57fa-7c99-fc5b-f52a55684826 (Accessed on April 2, 2024).
  7. Bendeka - bendamustine hydrochloride injection, solution. United States Prescribing Information. Revised January 2024. US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ace9a43b-f9bd-4896-abfe-0ef4fec67ddf (Accessed on April 2, 2024).
  8. Rituxan Hycela - rituximab and hyaluronidase injection, solution. US Food and Drug Administration (FDA) approved product information. Revised November 2022. US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e5b7e82-f018-4eaf-ae78-d6145a906b20 (Accessed on April 2, 2024).
  9. Hiddemann W, Barbui AM, Canales MA, et al. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: Influence of chemotherapy on efficacy and safety. J Clin Oncol 2018; 36:2395.
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