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A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
Article

Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

1
Department of Regulatory Affairs and Clinical Research, Aptevo Therapeutics, Seattle, WA 98121, USA
2
Immuno-Oncology Program, Ares Pharmaceuticals, St. Paul, MN 55110, USA
3
Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
4
The James Cancer Hospital, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
5
Harold C. Simmons Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
6
Roswell Park Comprehensive Cancer Center, Department of Medicine, Buffalo, NY 14263, USA
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Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT 84112, USA
8
Greenville Health System, Institute for Translational Oncology Research, Greenville, SC 29605, USA
9
Department of Medicine, Division of Hematology & Oncology, University of Florida, Gainesville, FL 32610, USA
10
Division of Hematologic Malignancies and Cellular Therapeutics, The University of Kansas Cancer Center, Westwood, KS 66205, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Pau Montesinos
Cancers 2021, 13(21), 5287; https://doi.org/10.3390/cancers13215287
Received: 16 September 2021 / Accepted: 19 October 2021 / Published: 21 October 2021
(This article belongs to the Special Issue Acute Myeloid Leukemia (AML))
Cytokine release syndrome is a potentially life-threatening complication of therapy with T-cell engaging bispecific antibodies. Here we evaluated the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome who received weekly intravenous infusions of the CD3xCD123 bispecific antibody APVO436. Cytokine release syndrome was encountered in 10 of 46 patients (21.7%) treated with APVO436 with a cumulative Grade 3/4 cytokine release syndrome incidence of 8.7%. Cytokine profiling in patients who developed cytokine release syndrome after APVO436 infusion indicated that the predominant cytokine in this inflammatory cytokine response was IL-6. The findings from this research provide new insights regarding the biology and effective management of cytokine release syndrome in leukemia patients treated with T-cell redirecting bispecific antibodies.
We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions. View Full-Text
Keywords: AML; CD123; bispecific antibody; T-cells; leukemia; clinical study; APVO436 AML; CD123; bispecific antibody; T-cells; leukemia; clinical study; APVO436
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MDPI and ACS Style

Uckun, F.M.; Watts, J.; Mims, A.S.; Patel, P.; Wang, E.; Shami, P.J.; Cull, E.; Lee, C.; Cogle, C.R.; Lin, T.L. Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436. Cancers 2021, 13, 5287. https://doi.org/10.3390/cancers13215287

AMA Style

Uckun FM, Watts J, Mims AS, Patel P, Wang E, Shami PJ, Cull E, Lee C, Cogle CR, Lin TL. Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436. Cancers. 2021; 13(21):5287. https://doi.org/10.3390/cancers13215287

Chicago/Turabian Style

Uckun, Fatih M., Justin Watts, Alice S. Mims, Prapti Patel, Eunice Wang, Paul J. Shami, Elizabeth Cull, Cynthia Lee, Christopher R. Cogle, and Tara L. Lin. 2021. "Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436" Cancers 13, no. 21: 5287. https://doi.org/10.3390/cancers13215287

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