{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:49:25Z","timestamp":1790660965161,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R\/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this <jats:italic>post-hoc<\/jats:italic> analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R\/R AML\/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R\/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R\/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels &amp;gt;0.08 mcg\/kg that were active in preclinical NOD\/SCID mouse xenograft models of AML. APVO436 activated patients\u2019 T-cells as evidenced by reduced numbers of circulating CD123<jats:sup>+<\/jats:sup>CD34<jats:sup>+<\/jats:sup> and CD33<jats:sup>+<\/jats:sup>CD34<jats:sup>+<\/jats:sup> peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg\/kg to 0.7 mcg\/kg in 4 R\/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg\/kg to 0.8 mcg\/kg. The median survival for the combined group of 14 R\/R AML\/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R\/R AML\/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its <jats:italic>in vivo<\/jats:italic> immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.<\/jats:p>","DOI":"10.3389\/fonc.2021.806243","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T06:57:07Z","timestamp":1642057027000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed\/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA"],"prefix":"10.3389","volume":"11","author":[{"given":"Justin","family":"Watts","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara L.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Mims","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prapti","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anoush","family":"Shahidzadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Shami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Cull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Cogle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunice","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih M.","family":"Uckun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"E224","DOI":"10.3390\/cancers11020224","article-title":"Current Therapeutic Results and Treatment Options for Older Patients With Relapsed Acute Myeloid Leukemia","volume":"11","author":"Ferrara","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1182\/blood.2019001239","article-title":"How I Treat Acute Myeloid Leukemia in the Era of New Drugs","volume":"135","author":"DiNardo","year":"2020","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32904","article-title":"Treating Acute Myeloid Leukemia in the Modern Era: A Primer","volume":"126","author":"Blum","year":"2020","journal-title":"Cancer"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1011","article-title":"Advances in the Treatment of Acute Myeloid Leukemia: New Drugs and New Challenges","volume":"10","author":"Short","year":"2020","journal-title":"Cancer Discov"},{"key":"B5","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/s41408-020-00376-1","article-title":"New Directions for Emerging Therapies in Acute Myeloid Leukemia: The Next Chapter","volume":"10","author":"Daver","year":"2020","journal-title":"Blood Cancer J"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-08-733196","article-title":"Diagnosis and Management of AML in Adults: 2017 ELN Recommendations From an International Expert Panel","volume":"129","author":"D\u00f6hner","year":"2017","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1182\/blood-2018-08-868752","article-title":"Venetoclax Combined With Decitabine or Azacitidine in Treatment-Naive, Elderly Patients With Acute Myeloid Leukemia","volume":"133","author":"DiNardo","year":"2019","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2989","DOI":"10.2217\/fon-2021-0262","article-title":"Venetoclax-Based Combinations for the Treatment of Newly Diagnosed Acute Myeloid Leukemia","volume":"17","author":"Othman","year":"2021","journal-title":"Future Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1097\/MOH.0000000000000490","article-title":"Progress in the Problem of Relapsed or Refractory Acute Myeloid Leukemia","volume":"26","author":"Mims","year":"2019","journal-title":"Curr Opin Hematol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000404","article-title":"Relapsed\/refractory Acute Myeloid Leukemia: Any Progress","volume":"29","author":"Schlenk","year":"2017","journal-title":"Curr Opin Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1038\/s41419-020-03144-y","article-title":"Targeting BCL-2 in B-Cell Malignancies and Overcoming Therapeutic Resistance","volume":"11","author":"Kapoor","year":"2020","journal-title":"Cell Death Dis"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0233-1","article-title":"Venetoclax With Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Acute Myeloid Leukemia Patients","volume":"24","author":"Pollyea","year":"2018","journal-title":"Nat Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.12.013","article-title":"BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells","volume":"12","author":"Lagadinou","year":"2013","journal-title":"Cell Stem Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.ccell.2018.10.005","article-title":"Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells","volume":"34","author":"Jones","year":"2018","journal-title":"Cancer Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-03-0852","article-title":"Elevated Expression of IL-3Ralpha in Acute Myelogenous Leukemia Is Associated With Enhanced Blast Proliferation, Increased Cellularity, and Poor Prognosis","volume":"100","author":"Testa","year":"2002","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-012-1501-7","article-title":"Flow Cytometric Quantification and Immunophenotyping of Leukemic Stem Cells in Acute Myeloid Leukemia","volume":"91","author":"Hwang","year":"2012","journal-title":"Ann Hematol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.stem.2009.04.018","article-title":"Monoclonal-Antibody Mediated Targeting of CD123, IL-3 Receptor Alpha Chain, Eliminates Human Acute Myeloid Leukemia Stem Cells","volume":"5","author":"Jin","year":"2009","journal-title":"Cell Stem Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1159\/000480448","article-title":"CD34+CD38-CD123+ Cells Are Present in Virtually All Acute Myeloid Leukaemia Blasts: A Promising Single Unique Phenotype for Minimal Residual Disease Detection","volume":"138","author":"Al-Mawali","year":"2017","journal-title":"Acta Haematol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2011.047894","article-title":"High Levels of CD34+CD38low\/-CD123+ Blasts Are Predictive of an Adverse Outcome in Acute Myeloid Leukemia: A Groupe Ouest-Est Des Leucemies Aigues Et Maladies Du Sang (GOELAMS) Study","volume":"96","author":"Vergez","year":"2011","journal-title":"Haematologica"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V122.21.360.360","article-title":"Targeting CD123 in Leukemic Stem Cells Using Dual Affinity Re-Targeting Molecules (Darts\u00ae)","volume":"122","author":"Hussaini MH","year":"2013","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020007732","article-title":"Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia","volume":"137","author":"Uy","year":"2021","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-021-01253-x","article-title":"T-Cell-Based Immunotherapy of Acute Myeloid Leukemia: Current Concepts and Future Developments","volume":"35","author":"Daver","year":"2021","journal-title":"Leukemia"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.656218","article-title":"Immunotherapy in Acute Myeloid Leukemia: Where We Stand","volume":"11","author":"Isidori","year":"2021","journal-title":"Front Oncol"},{"key":"B25","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.AM2019-LB-199","article-title":"APVO436, a Bispecific Anti-CD123 X Anti-CD3 ADAPTIR\u2122 Molecule for Redirected T-Cell Cytotoxicity With Limited Cytokine Release, Is Well Tolerated in Repeat Dose Toxicology Studies in Cynomolgus Macaques [Abstract]","author":"Comeau","year":"2019"},{"key":"B26","first-page":"Abstract nr B111","article-title":"Characterization of APVO436, a Bispecific Anti-CD123 X Anti-CD3 ADAPTIR\u2122 Molecule for Redirected T-Cell Cytotoxicity, in Preclinical Models of AML and Nonhuman Primates [Abstract]","author":"Comeau","year":"2018"},{"key":"B27","first-page":"Abstract nr 1786","article-title":"APVO436, a Bispecific Anti-CD123 X Anti-CD3 ADAPTIR\u2122 Molecule for Redirected T-Cell Cytotoxicity, Induces Potent T-Cell Activation, Proliferation and Cytotoxicity With Limited Cytokine Release [Abstract]","author":"Comeau","year":"2018"},{"key":"B28","doi-asserted-by":"publisher","first-page":"4113","DOI":"10.3390\/cancers13164113","article-title":"Clinical Phase 1b Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients With Relapsed\/Refractory Acute Myeloid Leukemia or Myelodysplasia","volume":"13","author":"Uckun","year":"2021","journal-title":"Cancers"},{"key":"B29","doi-asserted-by":"publisher","first-page":"5287","DOI":"10.3390\/cancers13215287","article-title":"Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients With Relapsed\/Refractory AML or MDS Treated With CD3xCD123 Bispecific Antibody Apvo436","volume":"13","author":"Uckun","year":"2021","journal-title":"Cancers"},{"key":"B30","doi-asserted-by":"publisher","first-page":"74","DOI":"10.3390\/cancers12010074","article-title":"A Phase 1b Clinical Study of Combretastatin A1 Diphosphate (OXi4503) and Cytarabine (ARA-C) in Combination (OXA) for Patients With Relapsed or Refractory Acute Myeloid Leukemia","volume":"12","author":"Uckun","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30010-X","article-title":"Safety and Preliminary Efficacy of Venetoclax With Decitabine or Azacitidine in Elderly Patients With Previously Untreated Acute Myeloid Leukaemia: A non-Randomised, Open-Label, Phase 1b Study","volume":"19","author":"DiNardo","year":"2018","journal-title":"Lancet Oncol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e549","DOI":"10.1097\/HS9.0000000000000549","article-title":"Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed\/Refractory Advanced Myeloid Malignancies","volume":"5","author":"Feld","year":"2021","journal-title":"HemaSphere"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25000","article-title":"Clinical Experience With the BCL2-Inhibitor Venetoclax in Combination Therapy for Relapsed and Refractory Acute Myeloid Leukemia and Related Myeloid Malignancies","volume":"93","author":"DiNardo","year":"2018","journal-title":"Am J Hematol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1182\/blood.2019004537","article-title":"Immunogenomic Identification and Characterization of Granulocytic Myeloid-Derived Suppressor Cells in Multiple Myeloma","volume":"136","author":"Perez","year":"2020","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009081","article-title":"Venetoclax Enhances T Cell-Mediated Antileukemic Activity by Increasing ROS\u00a0Production","volume":"138","author":"Lee","year":"2021","journal-title":"Blood"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.806243\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T06:57:10Z","timestamp":1642057030000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.806243\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,13]]},"references-count":35,"alternative-id":["10.3389\/fonc.2021.806243"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.806243","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,13]]},"article-number":"806243"}}