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Nitrogen mustards and oxazaphosphorinesIn useRational design

Bendamustine

Also known as Treanda, Levact, IMET 3393

A nitrogen mustard with a benzimidazole ring, first synthesised in East Germany in the early 1960s. The FDA first approved it on 20 March 2008 for chronic lymphocytic leukaemia.

From discovery to approval

  1. c. 1963 · Earliest report found

    Reviews credit Ozegowski and Krebs, at the Institute for Microbiology and Experimental Therapy in Jena, East Germany, with synthesising it: one gives the early 1960s, another 1963. The molecule was first called IMET 3393.[2][3][4][5][1][6]

  2. 2008-03-20 · FDA regular · 45 years after first description

    Treatment of patients with chronic lymphocytic leukaemia; efficacy relative to first-line therapies other than chlorambucil has not been established (NDA 022249, new molecular entity, priority review, orphan). The letter (signed 20 March 2008) does not use accelerated-approval wording and says an advisory committee was not convened because improvements in response rate and progression-free survival over chlorambucil were robust; regular is an inference.[6]

How it works

The 2008 US label describes a bifunctional mechlorethamine derivative whose electrophilic alkyl groups form covalent bonds with nucleophilic groups, and says the exact mechanism remains unknown. A 2012 review says it appears to act differently from other alkylating agents.[1]

Where it came from and why

Reviews say it was designed as a bifunctional molecule with both alkylating and antimetabolite properties; a 2011 review notes that its benzimidazole ring resembles that of cladribine.

Bendamustine was first synthesised in the early 1960s at the Institute for Microbiology and Experimental Therapy in Jena, East Germany, by Ozegowski and Krebs [2]; a 2014 review gives 1963 [3]. The molecule, first called IMET 3393, was intended to be a bifunctional molecule with alkylating and antimetabolite properties [2]. Extensive studies were done over about 20 years in East Germany, and it became widely used in the eastern bloc [2].

The 2014 review says it was widely used in Eastern Europe for lymphoma and myeloma in the 1970s and 1980s but was not studied in well-designed clinical trials until the 2000s [3]. After licensing in Europe in the mid-1990s, more than 18,000 patients were studied, mainly in Germany [2]. The FDA approved Treanda for chronic lymphocytic leukaemia on 20 March 2008 [6].

Cancers

  • Chronic lymphocytic leukaemia

    The 2008 US label covers treatment of patients with chronic lymphocytic leukaemia and states that efficacy relative to first-line therapies other than chlorambucil has not been established.[1]

  • Indolent B-cell lymphoma and mantle-cell lymphoma

    In a German randomised non-inferiority trial of first-line treatment, bendamustine plus rituximab was compared with R-CHOP in indolent and mantle-cell lymphomas.[7]

  • Multiple myeloma

    A 2012 review reports a randomised trial in which bendamustine plus prednisone was compared with melphalan plus prednisone in myeloma, in the context of its EU-approved uses.[5]

Family and partners

Derived from: Mechlorethamine

Worth knowing

  • The 2008 approval letter says the application was not referred to an advisory committee because the improvements in response rate and progression-free survival over chlorambucil were clinically and statistically robust.[6]
  • A 2011 review says bendamustine can induce cell death through both apoptotic and non-apoptotic pathways, so it keeps activity in cells without a functional apoptotic pathway.[4]
  • After European licensing in the mid-1990s, more than 18,000 patients were studied with bendamustine, mainly in Germany, according to a 2007 review.[2]
  • In the StiL trial abstract (per-protocol analysis), median progression-free survival was 69.5 months with bendamustine plus rituximab and 31.2 months with R-CHOP (hazard ratio 0.58, 95% CI 0.44 to 0.74).[7]

On this site

References

  1. U.S. Food and Drug Administration. Treanda (bendamustine hydrochloride) for injection, prescribing information, NDA 022249 original approval (revised 03/2008). Source
  2. Forero-Torres A, Saleh MN. Bendamustine in non-Hodgkin lymphoma: the double-agent that came from the Cold War. Clin Lymphoma Myeloma. 2007;8 Suppl 1:S13-7. PubMedDOI
  3. Derenzini E, Zinzani PL, Cheson BD. Bendamustine: role and evidence in lymphoma therapy, an overview. Leuk Lymphoma. 2014;55(7):1471-8. PubMedDOI
  4. Cheson BD, Leoni L. Bendamustine: mechanism of action and clinical data. Clin Adv Hematol Oncol. 2011;9(8 Suppl 19):1-11. PubMed
  5. Hoy SM. Bendamustine: a review of its use in the management of chronic lymphocytic leukaemia, rituximab-refractory indolent non-Hodgkin's lymphoma and multiple myeloma. Drugs. 2012;72(14):1929-50. PubMedDOI
  6. U.S. Food and Drug Administration. NDA approval letter, NDA 22-249, Treanda (bendamustine hydrochloride) for injection, signed 20 March 2008. Source
  7. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, 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(9873):1203-10. PubMedDOI
  8. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 022249 (Treanda, bendamustine hydrochloride). Page read 2026-10-26. Source