Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1 gene expression scores at baseline compared with nonresponders. Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.
Earle A. Chiles Research Institute
Vadakekolathu, Jayakumar; Lai, Catherine; Reeder, Stephen; Church, Sarah E; Hood, Tressa; Lourdusamy, Anbarasu; Rettig, Michael P; Aldoss, Ibrahim; Advani, Anjali S; Godwin, John E; Wieduwilt, Matthew J; Arellano, Martha; Muth, John; Yau, Tung On; Ravandi, Farhad; Sweet, Kendra; Altmann, Heidi; Foulds, Gemma A; Stölzel, Friedrich; Middeke, Jan Moritz; Ciciarello, Marilena; Curti, Antonio; Valk, Peter J M; Löwenberg, Bob; Gojo, Ivana; Bornhäuser, Martin; DiPersio, John F; Davidson-Moncada, Jan K; and Rutella, Sergio, "TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML." (2020). Articles, Abstracts, and Reports. 3757.