Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents (Continued)

  • Classification⁸

    • Non-Classical Agents (Nitrogen Mustard Compound):

      • Bendamustine (Treanda)^1,4

        • Bendamustine (Treanda)

        • Some agents are classified as Nonclassic Alkylating Agents.⁴ 

          • These include bendamustine (Treanda, Bendeka)  procarbazine (Matulane) and dacarbazine (DTIC).

        • Bendamustine is a bifunctional alkylating drug.⁴  

          • Bendamustine was first synthesized in 1963 but only more recently has had its contribution to the management of hematologic cancers affirmed by clinical trials.² 

            • Bendamustine is related to the agent chlorambucil (N-methylbenzimidazole analog).²  

              • The substitution of the "purine-like" aromatic ring was added to provide an antimetabolite mechanism in addition to DNA alkylation.

              • DNA damage secondary to bendamustine exposure appears both more extensive and less likely to be repaired compared to damage caused by other alkylating drugs.

                • Furthermore, bendamustine appears unique in its ability to stimulate P21 and p53-induced apoptosis, S-phase cell cycle arrest and "mitotic catastrophe."²

              • Bendamustine administration, while causing DNA intra-and interstrand cross-links,  tends to induce more DNA double-strand breaks at equitoxic doses compared to other alkylating drugs.⁷  

                • Bendamustine also causes a concentration-dependent apoptosis,  using changes in Bcl-2 and Bax expression profiles as indicators (in chronic B-cell lymphocytic leukemia).

                • DNA damage associated with bendamustine is repaired using a base-excision repair mechanism.⁷  

                  • This mechanism may be a basis for the lack of or limited cross-resistance exhibited by bendamustine compared to other alkylating drugs.⁷

          • Bendamustine forms cross-links with DNA,  inducing inhibition of DNA synthesis and function by means of causing single-and double-stranded breaks.⁴  

            • Other mechanisms that contribute to its anticancer effects include mitotic checkpoint inhibition and induction of "mitotic catastrophe."

              • Only partial cross-resistance between bendamustine another alkylating drugs has been noted; this finding may explain bendamustine clinical effects even in the presence of resistance development to other alkylating drugs.⁴

        • Absorption, Distribution, Metabolism, Excretion:

          • Following administration, bendamustine is degraded both by sulfhydryl interaction and by adduct formation with macromolecules.¹ 

            • Only about 5% of parent compound is excreted in the urine.

            • Mean steady-state volume of distribution (Vss) is about 20-25L.⁵

            • Drug clearance is about 700 mL/min.⁵

            • Metabolites resulting from N-demethylation and oxidation exhibit antitumor activity, although metabolite activity tends to be less than that observed the parent compound.

              • Metabolism appears to involve the cytochrome P450 isoform, CYP1A2.²

            • Bendamustine plasma half-life is about 30 min.

            • With respect to toxicity, bendamustine exhibits a toxicity profile comparable to those of other alkylating agents.

              • Notably, toxicity includes a rapidly reversible myelosuppression and mucositis.¹ 

            • Reactions to drug infusion may be reduced by pretreatment with corticosteroids and antihistamines.²  

              • Drug infusion reactions have been described as an important factor for drug discontinuation.²

        • Some Clinical Uses:

          • Bendamustine has been approved for treating non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL).¹  

            • Bendamustine has also been used in treatment of Hodgkin's lymphoma, breast cancer and multiple myeloma.⁴  

            • In the case of CLL, bendamustine was approved for treating patients in 2008.⁵  

              • At that time a phase III clinical trial noted superior bendamustine efficacy compared to chlorambucil, using response rate in progression free survival (PFS) as endpoints.

              • In this setting, bendamustine appeared  better tolerated compared to fludarabine yet resulted in significant myelosuppression which, particularly in elderly and infirmed patients, required a reduction in dosage.

                • This agent is relatively well tolerated in patients with impaired renal function given that drug excretion occurs mainly through feces.⁵

                 

          • "Obinutuzumab plus bendamustine in rituximab-refractory indolent non-Hodgkin lymphoma"⁶

            Attribution: Sehn LH Chua NS Mayer J, et al. GadoLin: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. https://www.youtube.com/watch?v=WV7ay2HF1zM Chicago ASCO Annual Meeting 2015. Oncoletter: May 30, 2015. Oncoletter Youtube Channel:  https://www.youtube.com/channel/UCScuWa-C47mTYLeGwD5Iqkg

          • When considering patients with indolent non-Hodgkin lymphoma who show drug refractory disease, bendamustine exhibits particular effectiveness.⁷  

            • Combination treatment in which bendamustine is administered along with rituximab resulted in response rates of about 90% with complete remission in about 57% in follicular mantle cell lymphoma.

          • Bendamustine can be administered both as monotherapy and in combination with other agents including etoposide, fludarabine, mitoxantrone, methotrexate, prednisone, rituximab and vincristine.⁷  

            • With respect to lymphomas, based on a multicenter phase II trial, an overall response rate of about 90% was reported (35% complete remission; 54% partial response).

              • For previously treated patients, the response rate was about 75%.

            • Estimated median progression-free survival was about 19 months.

          • Bendamustine (Treanda) in combination with mitoxantrone and rituximab point may be a standard of care for indolent lymphoma.⁷