Bisantrene in Combination with Fludarabine and Clofarabine As Salvage Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)- an Open-Label, Phase II, Study
Authors: Danylesko Ivetta , Shimoni Avichai , Avigdor Abraham , Kedmi Meirav , Shem-Tov Noga , Yerushalmi Ronit , Sasson Maya , Dominissini Dan , Andersson Borje S. , Nagler Arnon 
Published: December 2023

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). Bis was also found to synergize with the cytotoxic purine nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in vitro (J Clin Exp Oncol, 2021). We now conducted a phase II study combining Bis with Clo and Flu in pts with Rel/PR AML (NCT04989335).
Methods:
This was a phase II open-label single-center study with 2 stages: a stage with 3+3 dose escalation to assess the safety and provide phase 2 dose (RP2D, 4 vs 5 days) of infusion (i.v.) with up to 12 pts and an expansion phase with up to 17 pts (Simon 2-stage design 9+8) to assess the primary efficacy and confirm the safety of f Bis/Clo/Flu combination pts with Rel/PR AML. Flu (10 mg/m 2) was administered i.v. over 1 hour (h), followed by a 1-h infusion of Clo (30 mg/m 2), and then a 2-h infusion of Bis at 250 mg/m 2, with a 1-hour break for 4 days. The primary endpoint was achieving a partial response (PR). Efficacy was assessed by bone marrow (BM) examination 21 - 30 days post-therapy. Safety included treatment-emergent adverse events (TEAEs), all-cause mortality, and cardiac monitoring with ECG and troponins Toxicity was assessed as per Common Terminology Criteria for Adverse Events (CTCAE v5.0). Interim analysis was planned after the first 12 pts.
Results:
20 pts were included from August 2021. The median age was 48 (19-69) years and 55% were male.14 pts had de novo AML and 5 had secondary AML, 11 pts were in rel, while 9 had PR disease. Median lines of therapy were 4(3-9), 12 with ≤ 4 and 8 &gt;4 lines of therapy. All pts were refractory to the last line of therapy.15 pts (75%) were in relapse post allogeneic transplantation (HSCT). 5 (25%) pts had active extramedullary disease (EMD, 1 with CNS involvement). Median bone marrow blasts pre-Bis/Clo/Flu treatment was 50%. Cytogenetic was normal in 10 (50%) of the pts, 5 had a complex karyotype, 2 MLL rearrangements, 1 t8; 21 and 2 pts had other chromosomal abnormalities. The maximum tolerated dose of the Bis/Clo/Flu combination was 4 days of infusion due to grade 3 liver toxicity in 2 pts and 1 pt that died from sepsis in the first stage of the study. Overall 10 pts developed liver toxicity with elevated liver enzymes and bilirubin in 9 of them (grade 1-4 pts; grade 2-3 pts and grade 3-3 pts). Liver toxicity was transient and resolved in all pts. Two pts had treatment interruption due to liver toxicity. 4 pts had grade I renal toxicity, 7 had mild fluid retention, and 18 developed neutropenic fever of which 10 pts had verified bacteremia. Five pts had pneumonia, 4 invasive fungal infections, and 2 sepsis (1/2 died).1 additional pt died from cerebral venous sinus thrombosis. Overall 5 pts died early and could not be evaluated for response. Clinical-relevant cardiac toxicity was not observed in any of the pts and no one developed ECG changes Transient grade 1 elevation of troponin levels was observed in 4 pts. Six pts responded (CR-5, PR-1) 3 with EMD, however, responses were short-lived and lasted up to 3 months. Five pts (responding-4, active disease-1, being the second transplant in 4) underwent HSCT 1-3 months post-Bis/Clo/Flu with reduced /intermediate intensity conditioning. Stem cell donors were haploidentical-2, matched unrelated -1, and matched sibling-2, respectively. Three pts died: one from graft versus host disease and the other from relapse within 4 months post-transplant and the third from sepsis 2 years post-HSCT. Two of the transplanted pts are in complete remission with a 2-month follow-up.
Conclusions :
In this Phase II study in a very advanced group of relapsed refractory AML ptsresistant 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. Six /15 evaluable pts (40%) respond, enabling an HSCT in 5 of them. These rather impressive results in such a heavily pretreated population support further studies of Bisantrene-based combinations, including those with venetoclax or hypomethylating agents.