Zantrene (bisantrene)

Anthracyclines, particularly doxorubicin and idarubicin, together with cytarabine, have comprised standard of care induction chemotherapy in acute myeloid leukemia (AML) for almost 4 decades...Hypomethylating agents (HMA; azacytidine, decitabine) provide a less toxic alternative and have improved treatment options for the unfit...Approaches that reduce the toxicity of induction therapy and improve the efficacy of HMA treatment are emerging, e. g. combinations with Venetoclax...These data support that addition of bisantrene to HMA backbone therapy may provide an important new treatment strategy in AML. A prospective Phase Ib/II trial is being planned to evaluate this new therapeutic approach.

Background: Bisantrene (Bis), is a topoisomerase-II inhibitor with anthracycline-like activity, lower cardiotoxicity, and activity in patients (pts) with relapsed (rel)/primary refractory (PR) acute myeloid leukemia (AML) (Am J Hematol, 2021). In this Phase II study in a very advanced group of relapsed refractory AML pts resistant to multiple previous lines of chemotherapy including transplantation and with a median of 50% blasts at study initiation, Bis/Clo/Flu combination therapy was found to be safe and well tolerated without cardiac toxicity or tumor lysis syndrome. The maximum length of Bis/Clo/Flu administration was 4 days due to rapidly reversible liver toxicity, and transaminitis. As expected in this highly pretreated population, the infection rates were high.

The SAPK/JNK signaling pathway was strongly activated by the combination treatments, whereas the PI3K/mTOR and Wnt/β-catenin pro-survival pathways were inhibited. These drug combinations may be used in cytoreductive clinical trials for AML patients.