Safety and Efficacy of Combining Tagraxofusp (SL-401) with Azacitidine or Azacitidine and Venetoclax in a Phase 1b Study for CD123 Positive AML, MDS, or BPDCN

Background: CD123 is a subunit of the interleukin 3 (IL3) receptor and is expressed on the surface of blasts in most cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). CD123 expression is often higher on leukemia cells than normal progenitors and may be enriched in residual cells surviving chemotherapy. Uniformly high CD123 is characteristic of blastic plasmacytoid dendritic cell neoplasm (BPDCN), an uncommon leukemia related to AML. Tagraxofusp (TAG, SL-401) is a recombinant protein drug consisting of IL3 fused to a truncated diphtheria toxin payload that targets CD123. Single agent TAG is approved for treatment of BPDCN. In preclinical models and in patients who received TAG, we previously found that TAG resistance in AML and BPDCN was mediated by DNA methylation and downregulation of diphthamide genes (e.g. DPH1) and subsequent resistance to diphtheria toxin (Togami, JCI 2019). TAG resistance was reversible by the hypomethylating agent azacitidine (AZA), and TAG plus AZA was more effective than either alone in xenograft models. Therefore, we performed a phase 1b trial combining TAG with AZA or with AZA and venetoclax (VEN) in patients with AML, MDS, or BPDCN.