A Phase II Study of Bisantrene in Patients with Relapsed/Refractory Acute Myeloid Leukemia
Authors: Canaani Jonathan , Danilesko Ivetta , Shem-Tov Noga , Zlotnick Maya , Lozinsky Kira , Benjamini Ohad , Yerushalmi Ronit , Nagar Meital , Dor Chen , Shimoni Avichai , Avigdor Abraham , Nagler Arnon 
Published: November 2020

Background
Relapsed/refractory acute myeloid leukemia (R/R AML) remains a significant therapeutic challenge and while meaningful therapeutics gains have been achieved with the introduction of novel agents, clinical outcomes remain unsatisfactory. Anthracyclines constitute an essential component of induction chemotherapy for AML patients, however owing in part to the cardiotoxicity concerns, they are not broadly prescribed in R/R AML settings. Bisantrene, an anthracene with anthracycline-like activity, was shown in earlier studies to be an effective salvage therapy in R/R AML with no discernible cardiotoxicity. In this study, we assessed the clinical efficacy of bisantrene in a cohort of heavily pre-treated R/R AML patients.
Aims
To investigate the safety and efficacy of bisantrene in adult patients with R/R AML.
Methods
This phase 2, single center study (NCT03820908) enrolled adult R/R AML to receive bisantrene (250 mg/m2 daily for 7 days) which was administered via an intravenous infusion over 2 hours on days 1-7. Patient therapy was limited to one completed cycle of bisantrene including those who had achieved a partial response. Disease assessment included routine blood work and bone marrow studies which were performed at baseline and subsequently at blood count recovery or suspected disease progression. Next generation sequencing (NGS) was performed at baseline for all patients with adequate pre-study samples.
Results
In all, 10 patients were recruited to the study with a median of 3 lines of prior therapy including 7 patients who had relapsed following allogeneic stem cell transplantation. With regard to disease burden, three patients had an antecedent myeloid disorder while 4 patients had extramedullary disease at study recruitment. The most frequently reported grade ≥3 treatment attributed hematologic AE was thrombocytopenia whereas the most frequently reported grade ≥3 treatment attributed non-hematologic AE was mucositis. Of the ten patients, one (10%) achieved a complete remission and three patients achieved a partial remission resulting in an overall response rate of 40% with one patient being bridged to transplantation. NGS of patient samples identified a wide array of mutations associated with activated signaling, splicing, and epigenetic modification (table 1).
Conclusion
In conclusion, in the present study bisantrene induced clinical responses in 4 of 10 patients with R/R AML with acceptable toxicity. Given its marked activity in patients with leukemia cutis, chroromas and CNS disease, we speculate that bisantrene-based chemotherapy may have a significant applicability in patients with extramedullary disease. In view of the observed efficacy and low related toxicity, a follow-up study combining bisantrene with complementary anti-leukemic therapy is planned.

Disclosures
Canaani: Abbvie: Consultancy, Honoraria, Research Funding. Benjamini:Abbvie Inc: Consultancy, Research Funding. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding.