Adaptive Immune Gene Signatures Correlate with Response to Flotetuzumab, a CD123 × CD3 Bispecific Dart® Molecule, in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Background. The therapeutic approach in patients (pts) with acute myeloid leukemia (AML) has not changed substantially in >30 years. The introduction of new treatment strategies, including immunotherapy, remains a priority. Flotetuzumab, a CD123 × CD3 bispecific DART immunotherapy, is being tested in a phase 1/2 study of relapsed/refractory (R/R) AML. We previously showed that AML pts with an immune-enriched and IFN-γ-dominant tumor microenvironment (TME) experience significantly shorter relapse-free survival, suggesting refractoriness to standard induction chemotherapy (Vadakekolathu J, et al. Blood 2017; 130: 3942A). Herein, we report that an IFN-γ-dominant TME, while predicting resistance to standard therapy, is favoring response of AML to flotetuzumab. Methods. Gene expression was analyzed in 78 bone marrow (BM) samples (36 at baseline, 27 post-cycle 1 and 15 post-cycle 2) from 40 pts with relapsed or refractory AML enrolled in a phase 1/2 clinical trial of flotetuzumab (NCT#02152956). Thirty-six baseline BM samples were included in the analysis, of which 34 from pts who were treated at the target dose of ≥500 ng/kg/day. The NanoString PanCancer IO360™ assay was used to assess the expression of 770 genes, including the levels of 14 immune cell types and of 32 immuno-oncology signatures, and their correlation with response to flotetuzumab. Data are presented as score means per group±SEM and analyzed by unpaired t-test. Results. Gene expression analysis of BM samples at baseline stratifies flotetuzumab-treated pts into 3 clusters within an immunological continuum: immune-depleted, immune-exhausted and immune-enriched (Fig. 1A). Pts with primary-refractory disease (refractory to ≥2 induction attempts, first CR of