TY - JOUR
T1 - TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML
AU - Vadakekolathu, Jayakumar
AU - Lai, Catherine
AU - Reeder, Stephen
AU - Church, Sarah E.
AU - Hood, Tressa
AU - Lourdusamy, Anbarasu
AU - Rettig, Michael P.
AU - Aldoss, Ibrahim
AU - Advani, Anjali S.
AU - Godwin, John
AU - Wieduwilt, Matthew J.
AU - Arellano, Martha
AU - Muth, John
AU - Yau, Tung On
AU - Ravandi, Farhad
AU - Sweet, Kendra
AU - Altmann, Heidi
AU - Foulds, Gemma A.
AU - Stölzel, Friedrich
AU - Middeke, Jan Moritz
AU - Ciciarello, Marilena
AU - Curti, Antonio
AU - Valk, Peter J.M.
AU - Löwenberg, Bob
AU - Gojo, Ivana
AU - Bornhäuser, Martin
AU - DiPersio, John F.
AU - Davidson-Moncada, Jan K.
AU - Rutella, Sergio
N1 - Funding Information:
This work was supported by grants from the Qatar National Research Fund (NPRP8-2297-3-494) and the John and Lucille van Geest Foundation (S. Rutella) and by the National Institutes of Health, National Cancer Institute (Outstanding Investigator Award R35 CA210084 [J.F.D.] and Research Specialist Award R50 CA211466 [M.P.R.]).
Funding Information:
The authors thank Barbara Shepherd for providing medical writing support. The Study Alliance of Leukemia (www.sal-aml.org) is gratefully acknowledged for providing primary patient material and clinical data. This work was supported by grants from the Qatar National Research Fund (NPRP8-2297-3-494) and the John and Lucille van Geest Foundation (S. Rutella) and by the National Institutes of Health, National Cancer Institute (Outstanding Investigator Award R35 CA210084 [J.F.D.] and Research Specialist Award R50 CA211466 [M.P.R.]).
Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020/10/15
Y1 - 2020/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85096176936&partnerID=8YFLogxK
U2 - 10.1182/BLOODADVANCES.2020002512
DO - 10.1182/BLOODADVANCES.2020002512
M3 - Article
C2 - 33057635
AN - SCOPUS:85096176936
SN - 2473-9529
VL - 4
SP - 5011
EP - 5024
JO - Blood advances
JF - Blood advances
IS - 20
ER -