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Review

Antibody-based therapy for acute myeloid leukemia: a review of phase 2 and 3 trials

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Pages 169-185 | Received 13 Mar 2022, Accepted 22 Jun 2022, Published online: 04 Jul 2022

References

  • Visser O, Trama A, Maynadié M, et al. RARECARE Working Group. Incidence, survival and prevalence of myeloid malignancies in Europe. Eur J Cancer. 2012;48(17):3257–3266.
  • SEER. Howlader N, et al. eds. SEER cancer statistics review, 1975-2013. 2016; National Cancer Institute: Bethesda (MD). http://seer.cancer.gov/csr/1975_2013. Cited June 26, 2022. based on November 2015 SEER data submission, April 2016
  • Luger SM. Treating the elderly patient with acute myelogenous leukemia. In: Hematology am sochematolEduc program. 2010. p. 62–69.
  • Estey E. Treatment of acute myelogenous leukemia. Oncology. 2002;16(3):343–352.
  • Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–464.
  • Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicenter, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18(8):1061–1075.
  • Stein EM, DiNardo CD, Fathi AT, et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood. 2019;133(7):676–687.
  • DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1 -mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–2398.
  • Wei AH, Strickland SA Jr, Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase 1b/2 study. J Clin Oncol. 2019;37(15):1277–1284.
  • DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naïve, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17.
  • Cortes JE, Heidel FH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33(2):379–389.
  • Castaigne S, Pautas C, Terré C, et al. Effects of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukemia (ALFA-0701): a randomized, open-label, phase 3 study. Lancet. 2012;379(9825):1508–1516.
  • Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–497.
  • Walter RB, Appelbaum FR, Estey EH, et al. Acute myeloid leukemia stem cells and CD33 targeted immunotherapy. Blood. 2012;119(26):6198–6208.
  • Haubner S, Perna F, Köhnke T, et al. Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML. Leukemia. 2019;33(1):64–74.
  • Taussig DC, Miraki-Moud F, Anjos-Afonso F, et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood. 2008;112:568–575.
  • Boursilian TE, McEarchern JA, Law CL, et al. Targeting CD70 for human therapeutic use. Adv Exp Med Biol. 2009;647:108–119.
  • Borst J, Hendriks J, Xiao Y. CD27 and CD70 in T cell and B cell activation. Curr Opin Immunol. 2005;17(3):275–281.
  • Claus C, Riether C, Schürch C, et al. CD27 signaling increases the frequency of regulatory T cells and promotes tumor growth. Cancer Res. 2012;72(14):3664–3676.
  • Brown EJ, Frazier WA. Integrin associated protein (CD47) and its ligands. Trends Cell Biol. 2001;11(3):130–135.
  • Saint-Paul L, Nguyen CH, Buffière A, et al. CD45 phosphatase is crucial for human and murine acute myeloid leukemia maintenance through its localization in lipid rafts. Oncotarget. 2016;7(40):64785–64797.
  • Bakker ABH, van den Oudenrijn S, Bakker AQ, et al. C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. Cancer Res. 2004;64(22):8443–8450.
  • Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100(5):1532–1542.
  • Saito Y, Kitamura H, Hijikata A, et al. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med. 2010;2(17):17ra9.
  • Zhou L, Guo X, Jing BA, et al. CD44 is involved in CXCL-12 induced acute myeloid leukemia HL-60 cell polarity. Biocell. 2010;34(2):91–94.
  • Quarona V, Zaccarello G, Chillemi A, et al. CD38 and CD157: a long journey from activation markers to multifunctional molecules. Cytometry B Clin Cytom. 2013;84(4):207–217.
  • Kucia M, Reca R, Mickus K, et al. Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells Dayt Ohio. 2005;23(7):879–894.
  • Menssen HD, Renki HJ, Rodeck U, et al. Presence of Wilm’s tumor gene (wt1) transcripts and the WT1 nuclear protein in the majority of human acute leukemias. Leukemia. 1995;9:1079–1096.
  • Appelbaum FR, Bernstein ID. Gemtuzumab ozogamicin for acute myeloid leukemia. Blood. 2017;130(22):2373–2376.
  • Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29(4):369–377.
  • Delaunay J, Recher C, Pigneux A, et al. Addition of gemtuzumab ozogamicin to chemotherapy improves event-free survival but not overall survival of AML patients with intermediate cytogenetics not eligible for allogeneic transplantation Results of the GOELAMS AML 2006 IR study. Blood. 2011;118(21):79.
  • Burnett AK, Russell NH, Hills RK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012;30(32):3924–3931.
  • Amadori S, Suciu S, Stasi R, et al. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013;31(35):4424–4430.
  • Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34(9):972–979.
  • Petersdorf SH, Kopecky KJ, Slovak M, et al. Phase III study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121(24):4854–4860.
  • Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014;32(27):3021–3022.
  • Lambert J, Pautas C, Terré C, et al., Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 104(1): 113–119. 2019.
  • Candoni A, Papayannidis C, Martinelli G, et al. Flai (fludarabine, cytarabine, idarubicin) plus low-dose gemtuzumab ozogamicin as induction therapy in CD33-positive AML: final results and long term outcome of a phase II multicenter clinical trial. Am J Hematol. 2018;93(5):655–663.
  • Hasle H, Abrahamsson J, Forestier E, et al. Gemtuzumab ozogamicin as postconsolidation therapy does not present relapse in children with AML: results from NOPHO-AML 2004. Blood. 2021;120(5):978–984.
  • Lambert J, Lambert J, Lemasle E, et al. Replacing the anthracycline by gemtuzumab ozogamicin in older patients with de novo standard-risk acute myeloid leukemia treated intensively - results of the randomized ALFA1401-mylofrance 4 study. Blood. 2021;138(Supplement 1):31.
  • Amadori S, Suciu S, Selleslag D, et al. Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19). Br J Haematol. 2010;149(3):376–382.
  • Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the ALFA group. Leukemia. 2006;21(1):66.
  • Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomized controlled trials. Lancet Oncol. 2014;15(9):986–996.
  • Freeman SD, Virgo P, Couzens S, et al. Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013;31(32):4123–4131.
  • Borthakur G, Cortes JE, Estey E, et al. Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia. Am J Hematol. 2014;89(10):964–968.
  • Lambert J, Lambert J, Nibourel O, et al. MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin. Oncotarget. 2014;5(15):6280–6288.
  • Battipaglia G, Labopin M, Candoni A, et al. Risk of sinusoidal obstruction syndrome in allogeneic stem cell transplantation after prior gemtuzumab ozogamicin treatment: a retrospective study from the acute leukemia working party of the EBMT. Bone Marrow Transplant. 2017;52(4):592–599.
  • Larson RA, Sievers EL, Stadtmauer EA, et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005;104(7):1442–1452.
  • Pollard JA, Loken M, Gerbing RB, et al. CD33 expression and its association with gemtuzumab ozogamicin response: results from the randomized phase III children’s oncology group trial AAML0531. J Clin Oncol. 2016;34(7):747–755.
  • Fenwarth L, Fournier E, Cheok M, et al. Biomarkers of gemtuzumab ozogamicin response for acute myeloid leukemia treatment. Int J Mol Sci. 2020;21(16):5626.
  • Burnett AK, Hills RK, Hunter AE, et al. The addition of gemtuzumab ozogamicin to low-dose AraC improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia. 2013;27(1):75–81.
  • Nand S, Othus M, Godwin JE, et al. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013;122(20):3432–3439.
  • Kung Sutherland MS, Walter RB, Jeffrey SC, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 2013;122(8):1455–1463.
  • Fathi AT, Erba HP, Lancet JE, et al. Vadastuximabtalirine plus hypomethylating agents: a well-tolerated regimen with high remission rate in frontline older patients with acute myeloid leukemia (AML). Blood. 2016;128(Suppl.1):591.
  • Stein EM, Walter RB, Erba HP, et al. A phase 1 trial of vadastuximabtalirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood. 2018;131(4):387–396.
  • Erba HP, Levy MY, Vasu S, et al. A phase Ib study of vadastiximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Blood. 2016;128(22):211.
  • Sutherland MSK, Walter RB, Jeffrey SC, et al. SNG-CD33A: a novel CD33-directed antibody-drug conjugate, utilizing pyrrolobenzodiazepine dimmers, demonstrates preclinical antitumor activity against multi-drug resistant human AML. Blood. 2012;120(21):3589.
  • Fathi AT, Erba HP, Lancet JE, et al. A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML. Blood. 2018;132(11):1125–1133.
  • Krystal WM, Walker R, Fishkin N, et al. IMGN779, a CD33-tqrgeted antibody-drug conjugate (ADC) with a novel DNA-alkylating effector molecule, induces DNA damage, cell cycle arrest, and apoptosis in AML cells. Blood. 2015;126(23):1366.
  • Whiteman KR, Noordhuis P, Walker R, et al. The antibody-drug conjugate (ADC) IMGN779 is highly effective in vitro and in vivo against acute myeloid leukemia (AML) with FLT3-ITD mutations. Blood. 2014;124(21):2321.
  • Portwood S, Puchalski RA, Walker RM, et al. Combining IMGN779, a novel anti-CD33 antibody-drug conjugate (ADC), with the PARP inhibitor, olaparib, results in enhanced anti-tumor activity in preclinical acute myeloid leukemia (AML) models. Blood. 2016;128(22):1645.
  • Cortes JE, DeAngelo DJ, Erba HP, et al. Maturing clinical profile of IMGN779, a next-generation CD33-targeting antibody-drug conjugate, in patients with relapsed or refractory acute myeloid leukemia. Blood. 2018;132(Supplement 1):26.
  • Lapusan S, Vidriales MB, Thomas X, et al. Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia. Investig New Drugs. 2012;30(3):1121–1131.
  • Li F, Sutherland MK, Yu C, et al. Characterization of SGN-CD123A, a potent CD123-directed antibody-drug conjugate for acute myeloid leukemia. Mol Cancer Ther. 2018;17(2):554–564.
  • Kovtun Y, Jones GE, Adams S, et al. A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. Blood Adv. 2018;2(8):848–858.
  • Daver NG, Montesinos P, DeAngelo DJ, et al. Clinical profile of IMGN632, a novel CD123-targeting antibody-drug conjugate (ADC) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm (BPDCN). Blood. 2019;134(Supplement_1):734.
  • Daver NG, Montesinos P, DeAngelo DJ, et al. A phase I/II study of IMGN632, a novel CD123-targeting antibody-drug conjugate, in patients with relapsed/refractory acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm and other CD123-positive hematologic malignancies. J Clin Oncol. 2020;38(15_suppl):7563.
  • Mani R, Goswami S, Gopalakrishnan B, et al. The interleukin-3 receptor CD123 targeted SL-401 mediates potent cytotoxic activity against CD34 + CD123 + cells from acute myeloid leukemia/myelodysplastic syndrome patients and healthy donors. Haematologica. 2018;103(8):1288–1297.
  • Frankel AE, Konopleva M, Hogge D, et al. Activity and tolerability of SL-401, a targeted therapy directed to the interleukin-3 receptor on cancer stem cells and tumor bulk, as a single agent in patients with advanced hematologic malignancies. J Clin Oncol. 2013;31(15_suppl):7029.
  • Lane AA, Sweet KI, Wang ES, et al. Results from ongoing phase 2 trial of SL-401 as consolidation therapy in patients with acute myeloid leukemia (AML) in remission with high relapse risk including minimal residual disease (MRD). Blood. 2016;128(22):215.
  • Huang S, Chen Z, Yu JF, et al. Correlation between IL-3 receptor expression and growth potential of human CD34 + Hematopoietic Cells from different tissues. Stem Cells. 1999;17(5):265–272.
  • Lee EM, Yee D, Busfield SI, et al. Efficacy of an Fc-modified anti-CD123 antibody (Csl362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice. Haematologica. 2015;100(7):914–926.
  • Xie LH, Biondo M, Busfield SJ, et al. CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission. Blood Cancer J. 2017;7(6):e567.
  • Smith BD, Robez GJ, Walter RB, et al. Phase I study of CSL362 (anti-IL3rα/anti-CD123 monoclonal antibody) in patients with CD123+ acute myeloid leukemia (AML) in CR at high risk for early relapse. Blood. 2014;124(21):120.
  • Kubasch AS, Schulze F, Götze KS, et al. Anti-CD123 targeted therapy with talacotuzumab in advanced MDS and AML after failing hypomethylating agents – final results of the Samba trial. Blood. 2018;132(Suppl. Supplement 1):4045.
  • Montesinos P, Roboz GJ, Bulabois CE, et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia. 2021;35(1):62–74.
  • Jurcic JG, Deblasio T, Dumont L, et al. Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin Cancer Res. 2000;6(2):372–380.
  • Sekeres MA, Lancet JE, Wood BL, et al. Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica. 2013;98(1):119–128.
  • Feldman EJ, Brandwein J, Stone R, et al. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol. 2005;23(18):4110–4116.
  • Vasu S, He S, Cheney C, et al. Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts. Blood. 2016;127(23):2879–2889.
  • Dos Santos C, Xiaochuan S, Chenghui Z, et al. Anti-leukemic activity of daratumumab in acute myeloid leukemia cells and patient-derived xenografts. Blood. 2014;124(21):2312.
  • Naik J, Themeli M, de Jong Korlaar R, et al. CD38 as a therapeutic target for adult acute myeloid leukemia and T-cell acute lymphoblastic leukemia. Haematologica. 2019;104(3):e100–e103.
  • Mistry JJ, Moore JA, Kumar P, et al. Daratumumab inhibits acute myeloid leukemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells. Haematologica. 2021;106(2):589–592.
  • Strickland SA, Glenn M, Zheng W, et al. SAR650984, a CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies – data from a dose-escalation phase I study. Blood. 2013;122(21):284.
  • Becker PS, Foran JM, Altman JK, et al. Targeting the CXCR4 pathway: safety, tolerability and clinical activity of ulocuplumab (BMS-936564), an anti-CXCR4 antibody, in relapsed/refractory acute myeloid leukemia. Blood. 2014;124(21):386.
  • Guy DG, Uy GL. Bispecific antibodies for the treatment of acute myeloid leukemia. Curr Hematol Malig Rep. 2018;13(6):417–425.
  • Topp MS, Gokbuguet N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66.
  • Friedrich M, Henn A, Raum T, et al. Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia. Mol Cancer Ther. 2014;13(6):1549–1557.
  • Laszlo GS, Gudgeon CJ, Harrington KH, et al. Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML. Blood. 2014;123(4):554–561.
  • Krupka C, Kufer P, Kischel R, et al. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. Leukemia. 2015;30(2):484.
  • Ravandi F, Stein AS, Kantarjian HM, et al., A phase 1 first-in-human study of AMG 330, an anti-CD33 bispecific T-cell engager (BiTE) antibody construct, in relapsed/refractory acute myeloid leukemia (R/R AML). Blood. 132(Suppl.1): 25. 2018.
  • Harrington KH, Gudgeon CJ, Laszlo GS, et al. The broad anti-AML activity of the CD33/CD3 BiTE antibody construct, AML 330, is impacted by disease stage and risk. PLoS One. 2015;10(8):e0135945.
  • Subklewe M, Stein A, Walter RB, et al. Preliminary results from a phase 1 first-in-human study of AMG 673, a novel half-life extended (HLE) anti-CD33/CD3 BiTE® (bispecific T-cell engager) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Blood. 2019;134(Supplement_1):833.
  • Velasquez MP, Bonifant CL, Gottschalk S. Redirecting T cells to hematological malignancies with bispecific antibodies. Blood. 2018;131(1):30–38.
  • Westervelt P, Cortes JE, Altman JK, et al. Phase 1 first-in-human trial of AMV564, a bivalent bispecific (2:2) CD33/CD3 T-cell engager, in patients with relapsed/refractory acute myeloid leukemia (AML). Blood. 2019;134(Supplement_1):834.
  • Ravandi F, Bashey A, Stock W, et al. Complete responses in relapsed/refractory acute myeloid leukemia (AML) patients on a weekly dosing schedule of vibecotamab (XmAb14045), a CD123 x CD3 T cell-engaging bispecific antibody; initial results of a phase 1 study. Blood. 2020;136(Supplement 1):4–5.
  • Stamova S, Cartellieri M, Feldmann A, et al. Unexpected recombinations in single chain bispecific anti-CD3-anti-CD33 antibodies can be avoided by a novel linker module. Mol Immunol. 2011;49(3):474–482.
  • Brauchle B, Goldstein RL, Karbowski CM, et al. Characterization of a novel FLT3 BiTE molecule for the treatment of acute myeloid leukemia. Mol Cancer Ther. 2020;19(9):1875–1888.
  • Gleason MK, Ross JA, Warlick ED, et al. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood. 2014;123(19):3016–3026.
  • Kaneko T, Fusauchi Y, Kakui Y, et al. A bispecific antibody enhances cytokine-induced killer-mediated cytolysis of autologous acute myeloid leukemia cells. Blood. 1993;81(5):1333–1341.
  • Warlick ED, Weisdorf DJ, Vallera DA, et al. GTB-3550 TriKE™ for the treatment of high-risk myelodysplastic syndromes (MDS) and refractory/relapsed acute myeloid leukemia (AML) safety drives natural killer (NK) cell proliferation at initial dose cohorts. Blood. 2020;136(Supplement 1):7–8.
  • Reusch U, Harrington K, Gudgeon C, et al. Characterization of CD33/CD3 tetravalent bispecific tandem diabodies (TandAbs) for the treatment of acute myeloid leukemia. Clin Cancer Res. 2016;22(23):5829–5838.
  • Rossi DI, Rossi EA, Cardillo TM, et al. A new class of bispecific antibodies to redirect T cells for cancer immunotherapy. MAbs. 2014;6(2):381–391.
  • Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021;137(6):751–762.
  • Vadakekolathu J, Lai C, Reeder S, et al. Tp53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood Adv. 2020;4(20):5011–5024.
  • Aldoss I, Uy GL, Vey N, et al. Flotetuzumab as salvage therapy for primary induction failure and early relapse acute myeloid leukemia. Blood. 2020;136(Supplement 1):16–18.
  • Braciak TA, Roskopf CC, Wildenhain S, et al. Dual-targeting triplebody 33-16-123 (Spm-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells. Oncoimmunology. 2018;7(9):e1472195.
  • Van Loo PF, Doornbos R, Dolstra H, et al. Preclinical evaluation of MCLA117, a CLEC12AxCD3 bispecific antibody efficiently targeting a novel leukemic stem cell associated antigen in AML. Blood. 2015;126(23):325.
  • Burke JM, Caron PC, Papadopoulos EB, et al. Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias. Bone Marrow Transplant. 2003;32(6):549–556.
  • Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood. 2002;100(4):1233–1239.
  • Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131 </sup>I–anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009;114(27):5444–5453.
  • Glatting G, Müller M, Koop B, et al. Anti-CD45 monoclonal antibody YAML568: a promising radioimmunoconjugate for targeted therapy of acute leukemia. J Nucl Med. 2006;47(8):1335–1341.
  • Scheinberg DA, Lovett D, Divgi CR, et al. Phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide. J Clin Oncol. 1991;9(3):478–490.
  • Rosenblat TL, McDevitt MR, Mulford DA, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16(21):5303–5311.
  • Jurcic JG, Rosenblat TL, McDevitt MR, et al. Phase I trial of the targeted alpha-particle nano-generator actinium-225 (225Ac)-lintuzumab (anti-CD33; HuM195) in acute myeloid leukemia (AML). Blood. 2011;118(21):768.
  • Ravandi F, Pagel JM, Park JH, et al. Phase I trial of the targeted alpha-particle nano-generator actinium-225 (225Ac)-lintuzumab (anti-CD33) in combination with low-dose cytarabine (LDAC) for older patients with untreated acute myeloid leukemia (AML). Blood. 2013;122(21):1460.
  • Wang QS, Wang Y, Lu HY, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther. 2015;23(1):184–191.
  • Borot F, Wang H, Ma Y, et al. Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies. Proc Natl Acad Sci USA. 2019;116(24):11978–11987.
  • Budde L, Song JY, Kim Y, et al. Remissions of acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm following treatment with CD123-specific CAR T cells: a first-in-human clinical trial. Blood. 2017;130(Suppl_1):811.
  • Jetani H, Garcia-Cadenas I, Nerreter T, et al. CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia. 2018;32(5):1168–1179.
  • Sommer C, Cheng HY, Nguyen D, et al. Allogeneic FLT3 CAR T cells with an off-switch exhibit potent activity against AML and can be depleted to expedite bone marrow recovery. Mol Ther. 2020;28(10):2237–2251.
  • Zhang H, Fang L, Sun L, et al. First-in-human CLL1-CD33 compound CAR (CCAR) T cell therapy in relapsed and refractory acute myeloid leukemia. EHA Proc 2020:S149.
  • Sauer T, Parikh K, Sharma S, et al. CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity. Blood. 2021;138(4):318–330.
  • Pietsch EC, Dong J, Zhang X, et al. Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies. Blood Cancer J. 2017;7(2):e536.
  • Sallman D, Al Malki MM, Asch A, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacytidine is well-tolerated and effective in MDS patients: phase 1b study results. Blood. 2020;136:330.
  • Brierley C, Staves J, Roberts C, et al. The effects of monoclonal anti-CD47 on RBCs, compatibility testing, and transfusion requirements in refractory acute myeloid leukemia. Transfusion. 2019;59(7):2248–2254.
  • Daver N, Konopleva M, Maiti A, et al., Phase I/II study of azacitidine (AZA) with venetoclax (VEN) and magrolimab (Magro) in patients (pts) with newly diagnosed older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML. Blood. 138(abstract): 371. 2021.
  • Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143–153.
  • Zeidan AM, Knaus HA, Robinson TM, et al. A multi-center phase I trial of ipilimumab in patients with myelodysplastic syndromes following hypomethylating agent failure. Clin Cancer Res. 2018;24(15):3519–3527.
  • Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044–3051.
  • Zeidner JF, Vincent BG, Esparza S, et al. Final clinical results of a phase II study of high-dose cytarabine followed by pembrolizumab in relapsed/refractory AML. Blood. 2019;134(Supplement_1):831.
  • Gojo I, Stuart RK, Webster J, et al. Multicenter phase 2 study of pembroluzimab (pembro) and azacitidine (aza) in patients with relapsed/refractory acute myeloid leukemia (AML) and in newly diagnosed (≥ 65 years) AML patients. Blood. 2019;134(Supplement_1):832.
  • Kadia TM, Cortes JE, Ghorab A, et al. Nivolumab maintenance in high-risk acute myeloid leukemia patients. J Clin Oncol. 2018;36(15_suppl):7014.
  • Daver N, Garcia-Manero G, Basu S, et al. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid: a nonrandomized, open-label, phase II study. Cancer Discov. 2019;9(3):370–383.
  • Ravandi F, Assi R, Daver N, et al. Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a single-arm, phase 2 study. Lancet Haematol. 2019;6(9):e480–e488.
  • Brunner AM, Esteve J, Porkka K, et al. Efficacy and safety of sabatolimab (MBG453) in combination with hypomethylating agents (HMAs) in patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS): updated results from a phase 1b study. Blood. 2020;136(Supplement 1):1–2.
  • Silence K, Dreier T, Moshir M, et al. ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade. MAbs. 2014;6(2):523–532.
  • Hinterbrandner M, Kallen NM, Lüthi U, et al. Blocking CD70/CD27 signaling in combination with hypomethylating agents eradicates human CD34+ AML stem/progenitor cells. Blood. 2017;130(Suppl.1):2652.
  • Ochsenbein AF, Riether C, Bacher U, et al. Argx-110 targeting CD70, in combination with azacitidine, shows favorable safety profile and promising anti-leukemia activity in newly diagnosed AML patients in an ongoing phase 1/2 clinical trial. Blood. 2018;132(Suppl. Supplement 1):2680.
  • Ochsenbein AF, Pabst T, Höpner S, et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in humans. Blood. 2019;134(Suppl. Supplement_1):234.
  • Kaeding AJ, Barwe SP, Gopalakrishnapillai A, et al. Mesothelin is a novel cell surface disease marker and potential target in acute myeloid leukemia. Blood Adv. 2021;5(9):2350–2361.
  • Le Q, Castro S, Tang T, et al. Therapeutic targeting of mesothelin with chimeric antigen receptor T cells in acute myeloid leukemia. Clin Cancer Res. 2021;27(20):5718–5730.
  • Plesa A, Roumier C, Gutrin J, et al. Measurable residual disease including AML leukemia stem cell flow evaluation of CPX-351 therapy by multi-parameter flow cytometry. Leuk Res. 2021;111:106673.

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