Bendamustine

Structural formula
General
Non-proprietary name	Bendamustine
other names	4- [5- [bis (2-chloroethyl) amino] -1-methylbenzimidazol-2-yl] butanoic acid
Molecular formula	C 16 H 21 Cl 2 N 3 O 2
External identifiers / databases
CAS number 16506-27-7 3543-75-7 ( hydrochloride ) 1374784-02-7 (hydrochloride monohydrate) EC number 680-659-4 ECHA InfoCard 100.205.789 PubChem 65628 ChemSpider 59069 DrugBank DB06769 Wikidata Q425745
Drug information
ATC code	L01 AA09
Drug class	Cytostatics
Mechanism of action	Alkylanthium
properties
Molar mass	358.26 g mol −1
solubility	12.5 g L −1 in water (20 ° C)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Hydrochloride hydrate danger H and P phrases H: 301-351-360 P: 201-281-301 + 310-308 + 313
Toxicological data	40 mg kg −1 ( LD 50 ,  rat ,  iv ) 80 mg kg −1 ( LD 50 ,  mouse ,  iv )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Bendamustine is an antitumor chemotherapeutic agent from the group of alkylating agents . Within the alkylating it belongs, such as chlorambucil and melphalan , to the group of N -Lost - even or nitrogen mustard that are already in derivatives World War I as a chemical warfare agents were known.

In 2017, doctors and pharmacists were warned about bendamustine in a red-hand letter because increased mortality was observed in clinical studies in which bendamustine was used in non-approved combination treatments or outside the approved indications . This applies in particular to the initial therapy of previously untreated indolent non-Hodgkin lymphomas, including follicular lymphoma . The increased mortality was mainly caused by (opportunistic) infections . The main area of ​​application is hematology , but the combination of bendamustine with the monoclonal antibody n rituximab or obinutuzumab is not approved in Germany according to the specialist information applicable to bendamustine . In particular, initial therapy for follicular lymphoma in combination with rituximab or obinutuzumab is off-label use ; this is explicitly stated in the S3 guideline on follicular lymphoma published in June 2020 .

Bendamustine was developed in the 1960s at the Institute for Microbiology and Experimental Therapy (IMET) in the GDR and described in 1963 by Werner Ozegowski and Dietrich Krebs. It was initially called IMET ₃₃₉₃ and was marketed as Cytostasan ^® in the GDR at the end of the 1960s . After reunification, it was approved in the Federal Republic of Germany in 1993. Since then there have been several restrictions on drug approval due to insufficient evidence of efficacy and safety.

Effect and properties

Bendamustine is a so-called alkylating agent . It intervenes in a special way in the multiplication of cancer cells. Here, the active ingredient in a sense woven into the tumor - DNA . As a result, the cancer cells can no longer divide. In this way, bendamustine limits or stops tumor growth.

Kinetics and metabolism

Bendamustine distributes itself rapidly into a wide variety of tissues regardless of age (> 70 years) and tumor stage (distribution half-life approx. 7 minutes). The tissue distribution is uneven. 90% of the bendamustine is excreted in the faeces . Less than 10% is found unchanged in the urine. Including the metabolites monohydroxybendamustine, dihydroxybendamustine, M 3 and M 4, a total of 20% of the administered dose is found in the urine within 24 hours. It can therefore be dosed independently of the kidney function . Like other nitrogen mustards, bendamustine is also hydrolyzed non-enzymatically to mono- and dihydroxybendamustine at the bischloroethyl partial structure. The active metabolism of bendamustine takes place in the liver. Phase I metabolism occurs via cytochrome P450 subtype 1A2 (CYP1A2). Active metabolites are γ-hydroxybendamustine (M 3) and N-desmethylbendamustine (M 4). The plasma concentration of these metabolites is 1/10 or 1/100 of the parent substance, so it must be assumed that the unchanged bendamustine has the main cytotoxic effect (overview).

Side effects

After bendamustine had a relatively favorable side effect profile for a long time, study results from the MAINTAIN study were published in 2013, which, based on the evaluation of 947 patients, showed that indolent non-Hodgkin lymphomas (including follicular lymphoma ) in combination with rituximab were used in the primary treatment in over half of the patients there was a massive loss of CD4-positive cells ( median 119 cells / µl) that are otherwise typical for AIDS patients. At the same time there were frequent cases of the usually fatal brain disease progressive multifocal leukoencephalopathy (PML), which is considered to be an AIDS-defining disease . In 2017, after further findings from clinical studies, a warning was issued in a Rote-Hand-Brief that treatment with bendamustine could lead to the prolongation of lymphopenia (<600 cells / µl) or low CD4-positive T cell counts ( T helper cells ) (< 200 cells / µl), which last at least 7–9 months after the end of treatment and which occur especially when bendamustine is combined with rituximab. Patients with lymphopenia and low CD4- positive T-cell counts after treatment with bendamustine are more susceptible to (opportunistic) infections . Bendamustine in combination with rituximab was used as the primary therapy for indolent non-Hodgkin lymphoma or mantle cell lymphoma in the BRIGHT study compared to the standard rituximab chemotherapy combinations rituximab plus cyclophosphamide , doxorubicin , vincristine and prednisone ( CHOP ) or cyclo-rituximab , Vincristine and prednisone (CVP) have been associated with increased mortality and an unfavorable safety profile. Similarly, in a clinical study investigating the efficacy and safety of previously untreated follicular lymphomas (GALLIUM study), the combination of bendamustine with obinutuzumab or rituximab was associated with a high rate of death. The Association of German Hematologists DGHO commented on this as follows: “Most of these deaths were caused by infections. This fact may be based on the rapid and long-lasting reduction of CD3 / CD4 cells observed under bendamustine, which was not seen under CHOP or COP. "

commitment

The main area of ​​application of bendamustine is chronic lymphocytic leukemia . Bendamustine is the drug of choice here if therapy with fludarabine does not bring the desired success or is not possible. As a secondary monotherapy, bendamustine is also an option in the treatment of indolent non-Hodgkin lymphoma if this lymph gland cancer continues to grow despite treatment with rituximab . Bendamustine is sometimes used in advanced stages of multiple myeloma (malignant plasma cell conversion in the bone marrow) in certain patient groups .

According to the specialist information , bendamustine is approved in Germany for the following indications:

1. Primary therapy for chronic lymphocytic leukemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is unsuitable.
2. Monotherapy for indolent non-Hodgkin lymphoma in patients with progression during or within 6 months of treatment with rituximab or with rituximab-containing therapy (secondary therapy).
3. Primary therapy for multiple myeloma (stage II according to Durie-Salmon with progression or stage III) in combination with prednisone in patients who are older than 65 years and are not suitable for an autologous stem cell transplant and who already have clinical neuropathy at the time of diagnosis , which excludes treatment with thalidomide or bortezomib .

Bendamustine is ineffective in melanomas, germ cell tumors, soft tissue sarcomas, squamous cell carcinomas in the head and neck area, in hepatocellular and bile duct carcinomas.

Finished medicinal products

Levact, generics

Individual evidence

1. ↑ ^{a b c} Safety data sheet Ribomustin ( Memento from September 18, 2013 in the Internet Archive ) (PDF; 115 kB), as of March 1, 2007.
2. ↑ ^{a b} Data sheet Bendamustine hydrochloride hydrate from Sigma-Aldrich , accessed on May 5, 2011 ( PDF ).
3. ↑ ^{a b} Rote-Hand-Brief Levact (Bendamustin) 2017. (PDF) bfarm.de; accessed on February 17, 2020
4. ↑ ^{a b} Technical information on bendamustine. (PDF) amazonaws.com; accessed on February 17, 2020
5. ↑ S3 guideline on follicular lymphoma from June 2020 (PDF) Retrieved on August 2, 2020 . 
6. ↑ W. Ozegowski, D. Krebs: ω- [bis- (β-chloroethyl) -amino-benzimidazolyl- (2)] -propionic and -butyric acids as potential cytostatics. In: J Prakt Chem. Volume 20, Number 3-4, 1963, pp. 178-186. doi: 10.1002 / prac.19630200310
7. ↑ Publication. European Medicines Agency (EMA) 2017; accessed on February 17, 2020
8. ↑ ^{a b} Bendamustine application. Yellow list; accessed on February 17, 2020
9. ↑ J. Barth, M. Rummel: Bendamustine - antitumoral nitrogen mustard derivative with clinical features. In: drug therapy . 28, 2010, pp. 114-122.
10. ↑ J. Barth, M. Rummel: Antitumoral therapy with bendamustine. In: Hospital Pharmacy . 31, 2010, pp. 393-404.
11. ↑ Burchardt et al: Interim evaluation of the MAINTAIN study (lecture no. 32). 2013, accessed August 17, 2020 . 
12. ↑ Burchardt et al .: newevidence.com (PDF) 2013 New Evidence, p. 82; accessed on February 17, 2020
13. ↑ “When the CD4 count drops below 200, a person is diagnosed with AIDS” (German: “When the CD4 value falls below 200, the diagnosis is AIDS”) hiv.va.gov accessed on February 17, 2020
14. ^ Statement (PDF) of the DGHO on the benefit assessment of drugs for rare diseases according to § 35a SGB V, obinutuzumab (follicular lymphoma, first-line therapy); accessed on February 17, 2020
15. ↑ M. Schmidt-Hieber, A. Schmittel u. a .: A phase II study of bendamustine chemotherapy as second-line treatment in metastatic uveal melanoma. In: Melanoma Research . Volume 14, Number 6, December 2004, pp. 439-442. PMID 15577312 .
16. ↑ C. Kollmannsberger, A. Gerl u. a .: Phase II study of bendamustine in patients with relapsed or cisplatin-refractory germ cell cancer. In: Anti-Cancer Drugs . Volume 11, Number 7, August 2000, pp. 535-539. PMID 11036955 .
17. ↑ JT Hartmann, F. Mayer u. a .: Bendamustine hydrochloride in patients with refractory soft tissue sarcoma: a noncomparative multicenter phase 2 study of the German sarcoma group (AIO-001). In: Cancer. Volume 110, Number 4, August 2007, pp. 861-866, doi: 10.1002 / cncr.22846 . PMID 17599772 .
18. ↑ D. Bottke, K. Bathe et al. a .: Phase I trial of radiochemotherapy with bendamustine in patients with recurrent squamous cell carcinoma of the head and neck. In: Radiation Therapy and Oncology. Volume 183, Number 3, March 2007, pp. 128-132, doi: 10.1007 / s00066-007-1597-1 . PMID 17340070 .
19. ↑ K. Schoppmeyer, F. Kreth u. a .: A pilot study of bendamustine in advanced bile duct cancer. In: Anti-Cancer Drugs . Volume 18, Number 6, July 2007, pp. 697-702, doi: 10.1097 / CAD.0b013e32803d36e6 . PMID 17762399 .

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