Bendamustine

Myelosuppression (neutropenia, thrombocytopenia, and anemia) is a common toxicity; may require therapy delay and/or dose reduction; monitor blood counts frequently (nadirs typically occurred in the third week of treatment). Complications due to febrile neutropenia and severe thrombocytopenia have been reported (some fatal). ANC should recover to ≥1,000/mm3 and platelets to ≥75,000/mm3 prior to cycle initiation.

Serious and fatal dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), bullous exanthema, and rash have been reported. Skin reactions have been reported with monotherapy and in combination with other antineoplastic agents or allopurinol and may be progressive or worsen with continued treatment. The risk for severe skin toxicity is increased with concurrent use of allopurinol and other medications known to cause skin toxicity. Monitor closely for dermatologic toxicity. Withhold or discontinue treatment for severe or progressive skin reaction.

Bendamustine is an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. Erythema, marked swelling, and pain have been reported with extravasation.

Bendamustine is associated with a moderate emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting.

Serious and fatal cases of liver injury have been reported, usually within the first 3 months of treatment initiation. Confounding factors in some patients included combination therapy, progressive disease, and/or hepatitis B reactivation. Monitor liver function tests.

Infusion reactions, which may include chills, fever, pruritus, and rash, are common. Rarely, anaphylactic and anaphylactoid reactions have occurred, particularly with the second or subsequent cycle(s). Patients who experienced grade 3 or higher allergic reactions should not be rechallenged. Consider premedication with antihistamines, antipyretics and corticosteroids for patients with a history of grade 1 or 2 infusion reaction. Discontinue for severe allergic reaction or grade 4 infusion reaction; consider discontinuation with grade 3 infusion reaction.

Has been reported with use; monitor potassium closely in patients with cardiac disease.

Pneumonia, hepatitis, sepsis, and septic shock have been reported. Fatalities due to infection have occurred. Patients with myelosuppression are more susceptible to infection; monitor closely. Reactivation of hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster infection may occur in patients receiving bendamustine. Monitor; may require infection prophylaxis and/or treatment prior to bendamustine administration.

Malignancies (including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial cancer) and premalignant diseases have been reported in patients who have received bendamustine.

Tumor lysis syndrome (usually occurring in the first treatment cycle) may occur as a consequence of antineoplastic treatment, including treatment with bendamustine. May lead to life-threatening acute renal failure (without intervention); vigorous hydration and prophylactic measures (eg, antihyperuricemic therapy) should be instituted prior to treatment in high-risk patients; monitor closely. Note: Allopurinol may increase the risk for bendamustine skin toxicity. Disease-related concerns:

Use with caution in patients with mild hepatic impairment. A pharmacokinetic study showed only slight differences in bendamustine AUC and Cmax in patients with mild hepatic impairment (defined in the study as total bilirubin 1 to 1.5 × ULN or AST > ULN), as compared to patients with normal hepatic function (Owen 2010). Use is not recommended in patients with moderate (AST or ALT 2.5 to 10 × ULN and total bilirubin 1.5 to 3 × ULN) or severe (total bilirubin >3 × ULN) hepatic impairment.

Use with caution in patients with mild to moderate renal impairment. According to the manufacturer, use is not recommended in patients with CrCl max in patients with mild (CrCl >50 to ≤80 mL/minute) and moderate (CrCl >30 to ≤50 mL/minute) renal dysfunction, compared to patients with normal renal function (Owen 2010). A retrospective safety study found higher rates of grades 3 and 4 BUN increases and thrombocytopenia, and grades 1 and 2 fatigue, nausea, and alopecia in patients with renal impairment (CrCl Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Bendamustine solution (Treanda: 45 mg/0.5 mL and 180 mg/2 mL) contains N,N-dimethylacetamide, which is incompatible with closed-system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS). When used to prepare or transfer the concentrated bendamustine solution into the infusion bag, the plastic components of these devices may dissolve, resulting in subsequent leakage and potential infusion of dissolved plastic into the patient (ISMP [Smetzer 2015]). Do not use the liquid solution formulation if CSTDs, adapters, and syringes containing polycarbonate or ABS are used prior to dilution in the infusion bag. According to the Treanda manufacturer, after dilution into the infusion bag, devices containing polycarbonate or ABS (including infusion sets) may be used.

Several formulations of bendamustine are available: a liquid solution (45 mg/0.5 mL and 180 mg/2 mL [Treanda] and 100 mg/4 mL [Bendeka]) and a powder for reconstitution (5 mg/mL after reconstitution [Treanda]). Concentrations, storage, and compatibility differ between formulations. Use caution when selecting bendamustine formulation for preparation and administration. Do not mix or combine the formulations.

Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.