PURPOSE

Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low-dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. Actinium-lintuzumab ( Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single-agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer.

EXPERIMENTAL DESIGN

Here we investigated the potential for Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML.

RESULTS

We demonstrated that Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models.

CONCLUSIONS

There results suggest that the combination of Ac-lintuzumab with venetoclax is a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML. Clinical trial of this combination therapy (NCT03867682) is currently ongoing.