Bendamustine

Bendamustine is a nitrogen oxide derivative that belongs to the group of cytostatic drugs and is used to treat a wide variety of cancers. Due to its function as an alkylating agent, bendamustine causes intra- and interstrand cross-linking between DNA bases, which leads to cell death.

Bendamustine is a bifunctional mechloroethamine derivative that can form electrophilic alkyl groups that bind covalently to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and interstrand cross-linking between DNA bases, which leads to apoptosis of the cell. Bendamustine is active against both active and dormant cells. However, the exact mechanism of action is not fully understood.

Absorption: After a single intravenous dose of bendamustine hydrochloride, Cmax typically occurred at the end of the infusion.

Distribution: The mean steady-state volume of distribution (Vss) of bendamustine is approximately 20-25 l.The steady-state volume of distribution for total radioactivity was approximately 50 l, indicating that neither bendamustine nor total radioactivity is extensively distributed to tissues. In vitro binding of bendamustine to human serum plasma proteins was in the range of 94-96%. The data indicate that bendamustine is unlikely to be displaced by highly protein-bound drugs.

Metabolism: In vitro data indicate that bendamustine is metabolized primarily by hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with little cytotoxic activity. Two active minor metabolites, M3 and M4, are mainly formed via CYP1A2. However, the concentrations of these metabolites in plasma are 1/10 and 1/100 of the parent compound, respectively, suggesting that the cytotoxic activity is mainly due to bendamustine. The results of a mass balance study in humans confirm that bendamustine is extensively metabolized via hydrolytic, oxidative and conjugative metabolic pathways.

Elimination: The mean recovery of total radioactivity in cancer patients after intravenous infusion of [14C]-bendamustine hydrochloride was approximately 76% of the dose. About 50% of the dose was recovered in urine and about 25% of the dose in feces. Urinary excretion was confirmed to be a relatively insignificant route of elimination of bendamustine, with approximately 3.3% of the dose recovered in urine as the parent compound. Less than 1% of the dose was recovered in urine as M3 and M4 and less than 5% of the dose was recovered in urine as HP2. The half-life is about 40 minutes and the clearance is 700 ml/min.

The main indication is chronic lymphocytic leukemia (Binet stage B or C) when fludarabine combination chemotherapy is unsuitable

Bendamustine is also an option in the treatment of indolent non-Hodgkin's lymphoma if this lymphoma continues to grow despite treatment with rituximab.

In addition, bendamustine is used in advanced stages of multiple myeloma (stage II according to Durie-Salmon with progression or stage III) in combination with prednisone, in patients older than 65 years who are not suitable for autologous stem cell transplantation (HDT/ASCT) and who already have clinical neuropathy at the time of diagnosis, which rules out treatment with thalidomide or bortezomib.

Over the last ten years, bendamustine has established itself as an important addition to the therapeutic arsenal for lymphoma. The BR regimen has attracted the interest of hematologists due to its lower toxicity and near-equivalent efficacy compared to the conventional CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone), particularly in low-grade lymphomas. Recently, there have been some reports of bendamustine-related skin toxicity (Nishikori M et al. 2015; Gavini A et al. 2012). Malipatil et al. reported experience with 16 patients in India who received bendamustine. They found that erythematous papular skin lesions occurred in more than 50% of cases, mainly on the exposed areas of the limbs and trunk. However, no correlation was found with the bendamustine dose, the number of cycles, the sex of the patients and the type of chemotherapy protocol.

Similarly, Nishikori et al. (2015) reported that of 34 patients who received BR therapy, 32% (11/34) developed persistent exanthema. These patients showed a higher CD8/CD4 T-cell ratio and higher seropositivity for hepatitis B core antibodies compared to the remaining patients. The authors hypothesized that occult activation of the immune system by latent infections (e.g. occult hepatitis B) could be a triggering event for such rashes (Nishikori M et al. (Nishikori M et al. 2015).

In non-clinical studies, bendamustine has shown embryo/foetal, teratogenic and genotoxic effects. The cytostatic drug must therefore not be used during pregnancy unless clearly necessary.

Lactation: Since it is not known whether bendamustine passes into breast milk, bendamustine is contraindicated during lactation.

A typical dosing regimen for bendamustine is intravenous administration of 100-150 mg/m2 body surface area on days 1 and 2 every four weeks.

UAW -casustic (Sahu KK et al. 2016): A 67-year-old man suffered from persistent fever for 6 months. Clinical examination revealed anemia, hepatosplenomegaly and generalized lymphadenopathy. Lymph node biopsy and bone marrow examination showed features consistent with mantle cell lymphoma (MCL). Treatment was with bendamustine rituximab (B-90 mg/m2 × 2 days and R-375 mg/m2). During the first cycle, after infusion of bendamustine, flaccid to tense blisters and vesicles developed on erythematous skin localized proximal to the injection site on the left hand. The lesions did not affect any other parts of the body. The blisters resolved on their own without the use of medication, but recurred in a similar form shortly after the second cycle, only to heal again spontaneously.

Interactions may occur with the following compounds when used concomitantly with bendamustine:

Myelosuppressive drugs: Enhancement of the effect of bendamustine and/or the concomitantly administered drugs on the bone marrow.

Ciclosporin or tacrolimus: Excessive immunosuppression with the risk of lymphoproliferation possible.

Vaccination: Cytostatic drugs may reduce antibody formation after vaccination with a live vaccine and increase the risk of infection.

CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir and cimetidine: CYP1A2 is involved in the metabolism of bendamustine.

Bendamustine must not be used in the following cases:

• Hypersensitivity to the active substance
• Lactation
• Severe liver dysfunction (serum bilirubin > 3.0 mg/dl)
• Jaundice
• Severe bone marrow suppression and severe changes in the blood count (drop in leukocyte and/or platelet levels to < 3,000/μl or < 75,000/μl)
• Major surgical procedures within 30 days before the start of treatment
• Infections, especially those accompanied by leukocytopenia
• Yellow fever vaccination

Benda ^NC®, 2.5 mg/ml powder for concentrate for solution for infusion, 25 mg Hexal AG

^{Benda-onkovis®} 100 mg/ml concentrate for the preparation of a solution for infusion, 100 mg Onkovis GmbH

Bendamustine ^Accord® 2.5 mg/ml powder for concentrate for solution for infusion, 25 mg

Bendamustine ^AqVida® 100 mg/ml concentrate for solution for infusion, 100 mg AqVida GmbH

Bendamustine ^axios® 2.5 mg/ml, powder for a concentrate for the preparation of a solution for infusion, 100 mg Axionovo GmbH

Bendamustine has a major influence on the ability to drive and operate machinery, as ataxia, peripheral neuropathy and somnolence may occur with the use of the drug.

The use of bendamustine is associated with a risk of tumor lysis syndrome and can also lead to severe/progressive skin reactions. Hematologic malignancies of various forms have also been reported. In the event of severe infusion reactions, use must be discontinued.

Bendamustine may also cause mild to moderate renal dysfunction, hepatic dysfunction and sepsis.

1. Gavini A et al. (2012) Generalized purpuric drug exanthemwithhemorrhagic plaques following bendamustine chemotherapy in a patient withB-prolymphocytic leukemia. Int J Hematol 95:311-314.
2. Malipatil B et al. (2011) Preliminary experience with the use of bendamustine: a peculiar skin rash as the commonest side effect. Hematol Oncol Stem Cell Ther 4:157-160.
3. Nishikori M et al. (2015) Increased number of peripheral CD8+ T cells but not eosinophils is associated with late-onset skin reactions caused by bendamustine. Int J Hematol 102:53-58.
4. Rummel MJ et al. (2013) Bendamustine plus rituximab versus CHOP plus rituximabas first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomized, phase 3 non-inferiority trial. Lancet 381:1203-1210.
5. Sahu KK et al. (2016) Bullae And Blisters: A Rare Case of Bendamustine Skin Toxicity. Indian J Hematol Blood Transfus 32(Suppl 1):368-369.