TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML

Jayakumar Vadakekolathu, Catherine Lai, Stephen Reeder, Sarah E. Church, Tressa Hood, Anbarasu Lourdusamy, Michael P. Rettig, Ibrahim Aldoss, Anjali S. Advani, John Godwin, Matthew J. Wieduwilt, Martha Arellano, John Muth, Tung On Yau, Farhad Ravandi, Kendra Sweet, Heidi Altmann, Gemma A. Foulds, Friedrich Stölzel, Jan Moritz MiddekeMarilena Ciciarello, Antonio Curti, Peter J.M. Valk, Bob Löwenberg, Ivana Gojo, Martin Bornhäuser, John F. DiPersio, Jan K. Davidson-Moncada, Sergio Rutella

Research output: Contribution to journalArticlepeer-review

Abstract

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 3 CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples frompatientswith 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-kB 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.

Original languageEnglish (US)
Pages (from-to)5011-5024
Number of pages14
JournalBlood Advances
Volume4
Issue number20
DOIs
StatePublished - Oct 15 2020

ASJC Scopus subject areas

  • Hematology

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