Dataset Information

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

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 × 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.

SUBMITTER: Vadakekolathu J

PROVIDER: S-EPMC7594389 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Vadakekolathu Jayakumar J Lai Catherine C Reeder Stephen S Church Sarah E SE Hood Tressa T Lourdusamy Anbarasu A Rettig Michael P MP Aldoss Ibrahim I Advani Anjali S AS Godwin John J Wieduwilt Matthew J MJ Arellano Martha M Muth John J Yau Tung On TO Ravandi Farhad F Sweet Kendra K Altmann Heidi H Foulds Gemma A GA Stölzel Friedrich F Middeke Jan Moritz JM Ciciarello Marilena M Curti Antonio A Valk Peter J M PJM Löwenberg Bob B Gojo Ivana I Bornhäuser Martin M DiPersio John F JF Davidson-Moncada Jan K JK Rutella Sergio S

Blood advances 20201001 20

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 retarg ...[more]

PMID: 33057635

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Dataset Information

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

Publications

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

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