Abstract
Acute myeloid leukaemia (AML) is an aggressive, heterogenous, and age-related haematological malignancy with dismal prognosis. Conventional therapy for AML consists of frontline induction therapy with cytarabine infusion for 7 days and administration of anthracyclines, most commonly daunorubicin, for 3 days (7 + 3), followed by subsequent consolidation with chemotherapy or allogeneic haematopoietic stem cell transplant (HSCT) for high-risk disease. However, the age-related nature of AML implies that a significant portion of patients are unfit for such intensive regimens and can only be put on palliative treatment. Increasing emphasis is being put on maximizing specificities and potencies of novel agents while minimizing treatment-related toxicities, entailing a future of personalized-therapy in AML. This chapter reviews recently approved agents and agents still in the pipeline for the treatment of AML both in the frontline and the relapsed/refractory setting.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alfayez M, Kantarjian H, Kadia T, Ravandi-Kashani F, Daver N. CPX-351 (vyxeos) in AML. Leuk Lymphoma. 2020;61(2):288–97.
Feldman EJ, Lancet JE, Kolitz JE, Ritchie EK, Roboz GJ, List AF, et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol. 2011;29(8):979–85.
Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs. cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239–46.
Cortes JE, Goldberg SL, Feldman EJ, Rizzeri DA, Hogge DE, Larson M, et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer. 2015;121(2):234–42.
Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684–92.
Guolo F, Fianchi L, Minetto P, Clavio M, Gottardi M, Galimberti S, et al. CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program. Blood Cancer J. 2020;10(10):96.
Chiche E, Rahmé R, Bertoli S, Dumas P-Y, Micol J-B, Hicheri Y, et al. Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort. Blood Adv. 2021;5(1):176–84.
Ramos Perez JM, Kadia TM, Montalban-Bravo G, Benton CB, Faderl S, Sasaki K, et al. Liposomal cytarabine and daunorubicin (CPX-351) in combination with gemtuzumab ozogamicin (GO) in relapsed refractory (R/R) patients with acute myeloid leukemia (AML) and post-hypomethylating agent (post-HMA) failure high-risk myelodysplastic syndrome (HR-MDS). Blood. 2019;134(Suppl_1):2642.
Edwards DKV, Javidi-Sharifi N, Rofelty A, Rosenfeld C, Roth-Carter R, Tardi P, et al. Effective combination of CPX-351 with FLT3 inhibitors in AML blasts harboring the FLT3-ITD mutation. Blood. 2016;128(22):5124.
Weis TM, Marini BL, Bixby DL, Perissinotti AJ. Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia. Crit Rev Oncol Hematol. 2019;141:125–38.
Scholl S, Fleischmann M, Schnetzke U, Heidel FH. Molecular mechanisms of resistance to FLT3 inhibitors in acute myeloid leukemia: ongoing challenges and future treatments. Cells. 2020;9(11):2493.
Liang J, Wu YL, Chen BJ, Zhang W, Tanaka Y, Sugiyama H. The C-kit receptor-mediated signal transduction and tumor-related diseases. Int J Biol Sci. 2013;9(5):435–43.
Linnekin D. Early signaling pathways activated by c-kit in hematopoietic cells. Int J Biochem Cell Biol. 1999;31(10):1053–74.
Malaise M, Steinbach D, Corbacioglu S. Clinical implications of c-kit mutations in acute myelogenous leukemia. Curr Hematol Malig Rep. 2009;4(2):77–82.
Heo S-K, Noh E-K, Kim JY, Jeong YK, Jo J-C, Choi Y, et al. Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death. Sci Rep. 2017;7(1):15278.
Kivioja JL, Thanasopoulou A, Kumar A, Kontro M, Yadav B, Majumder MM, et al. Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia. Leukemia. 2019;33(6):1360–72.
Nicolas B, Aline R, Thibaut L, Pascale Cornillet L, Christian R, Thibaud L, et al. Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French acute myeloid leukemia intergroup trial. Haematologica. 2015;100(6):780–5.
Paschka P, Schlenk RF, Weber D, Benner A, Bullinger L, Heuser M, et al. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial. Leukemia. 2018;32(7):1621–30.
Marcucci G, Geyer S, Laumann K, Zhao W, Bucci D, Uy GL, et al. Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801. Blood Adv. 2020;4(4):696–705.
Kindler T, Breitenbuecher F, Marx A, Beck J, Hess G, Weinkauf B, et al. Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood. 2004;103(10):3644–54.
Smolich BD, Yuen HA, West KA, Giles FJ, Albitar M, Cherrington JM. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood. 2001;97(5):1413–21.
Zhu C, Wei Y, Wei X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019;18(1):153.
Park IK, Mundy-Bosse B, Whitman SP, Zhang X, Warner SL, Bearss DJ, et al. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia. 2015;29(12):2382–9.
Ben-Batalla I, Schultze A, Wroblewski M, Erdmann R, Heuser M, Waizenegger JS, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 2013;122(14):2443–52.
Loges S, Heuser M, Chromik J, Vigil CE, Paschka P, Re F, et al. Durable responses observed in elderly AML patients unfit for intensive chemotherapy with first-in class selective AXL inhibitor bemcentinib (BGB324) in combination with LDAC: phase II open-label study. Blood. 2019;134(Suppl_1):3943.
BerGenBio. BerGenBio presents preliminary phase II clinical data at EHA 24: bemcentinib in combination with low dose chemotherapy yields durable responses in AML patients unfit for intensive chemotherapy. 2019. https://www.bergenbio.com/bergenbio-to-present-preliminary-phase-ii-clinical-data-showing-bemcentinib-in-combination-with-low-dose-chemotherapy-yields-durable-responses-in-aml-patients-unfit-for-intensive-chemotherapy-at-the-2/.
BerGenBio. BerGenBio receives FDA approval of fast track designation for bemcentiniB. 2019.
Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, et al. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Investig New Drugs. 2013;31(4):833–44.
Kosciuczuk EM, Saleiro D, Kroczynska B, Beauchamp EM, Eckerdt F, Blyth GT, et al. Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo. Blood. 2016;128(3):410–4.
Garcia JS, Gandler HI, Fell G, Fiore AJ, Neuberg DS, Anderson A, et al. Targeting MET and FGFR in relapsed or refractory acute myeloid leukemia: preclinical, clinical, and correlative studies. Blood. 2019;134(Suppl_1):2549.
Yasuhiro T, Yoshizawa T, Fujikawa R, Tanaka K, Koike T, Kawabata K. Development of an Axl/Mer dual inhibitor, ONO-9330547: promising single agent activity in an acute myeloid leukemia (AML) model. Blood. 2014;124(21):999.
Gilmour M, Scholtz A, Ottmann OG, Hills RK, Knapper S, Zabkiewicz J. Axl/Mer inhibitor ONO-9330547 as a novel therapeutic agent in a stromal co-culture model of primary acute myeloid Leukaemia (AML). Blood. 2016;128(22):2754.
Ruvolo PP, Ma H, Ruvolo VR, Zhang X, Mu H, Schober W, et al. Anexelekto/MER tyrosine kinase inhibitor ONO-7475 arrests growth and kills FMS-like tyrosine kinase 3-internal tandem duplication mutant acute myeloid leukemia cells by diverse mechanisms. Haematologica. 2017;102(12):2048–57.
Fialin C, Larrue C, Vergez F, Sarry JE, Bertoli S, Mansat-De Mas V, et al. The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors. Leukemia. 2013;27(2):325–35.
Kentsis A, Reed C, Rice KL, Sanda T, Rodig SJ, Tholouli E, et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat Med. 2012;18(7):1118–22.
Mulgrew NM, Kettyle LMJ, Ramsey JM, Cull S, Smyth LJ, Mervyn DM, et al. C-met inhibition in a HOXA9/Meis1 model of CN-AML. Dev Dyn. 2014;243(1):172–81.
Mócsai A, Ruland J, Tybulewicz VLJ. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol. 2010;10(6):387–402.
Boros K, Puissant A, Back M, Alexe G, Bassil CF, Sinha P, et al. Increased SYK activity is associated with unfavorable outcome among patients with acute myeloid leukemia. Oncotarget. 2015;6(28):25575–87.
Polak A, Bialopiotrowicz E, Krzymieniewska B, Wozniak J, Stojak M, Cybulska M, et al. SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism. Cell Death Dis. 2020;11(11):956.
Walker AR, Bhatnagar B, Marcondes AMQ, DiPaolo J, Vasu S, Mims AS, et al. Interim results of a Phase 1b/2 study of entospletinib (GS-9973) monotherapy and in combination with chemotherapy in patients with acute myeloid leukemia. Blood. 2016;128(22):2831.
Walker AR, Byrd JC, Blum W, Lin T, Crosswell HE, Zhang D, et al. Abstract 819: high response rates with entospletinib in patients with t(v;11q23.3);KMT2A rearranged acute myeloid leukemia and acute lymphoblastic leukemia. Cancer Res. 2018;78(13 Suppl):819.
Yu J, Huck J, Theisen M, He H, Tirrell S, Zhang M, et al. Anti-tumor activity of TAK-659, a dual inhibitor of SYK and FLT-3 kinases, in AML models. J Clin Oncol. 2016;(34, 15_suppl):e14091.
Pratz K, Levis MJ, Morris JC, Wise-Draper T, Levy M, Bixby DL, et al. A phase (ph) 1b/2 study of TAK-659, an investigational dual FLT-3 and SYK inhibitor, in patients (Pts) with relapsed or refractory acute myelogenous leukemia (R/R AML). Blood. 2017;130(Suppl 1):2622.
Mohamed AJ, Yu L, Bäckesjö C-M, Vargas L, Faryal R, Aints A, et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009;228(1):58–73.
Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57.
Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol. 2012;31(2):119–32.
Pillinger G, Abdul-Aziz A, Zaitseva L, Lawes M, MacEwan DJ, Bowles KM, et al. Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia. Sci Rep. 2015;5:12949.
Rushworth SA, Murray MY, Zaitseva L, Bowles KM, MacEwan DJ. Identification of Bruton’s tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood. 2014;123(8):1229–38.
Zaitseva L, Murray MY, Shafat MS, Lawes MJ, MacEwan DJ, Bowles KM, et al. Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML. Oncotarget. 2014;5(20):9930–8.
Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562(7728):526–31.
Rushworth SA, Pillinger G, Abdul-Aziz A, Piddock R, Shafat MS, Murray MY, et al. Activity of Bruton’s tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells. Lancet Haematol. 2015;2(5):e204–11.
Wu H, Hu C, Wang A, Weisberg EL, Wang W, Chen C, et al. Ibrutinib selectively targets FLT3-ITD in mutant FLT3-positive AML. Leukemia. 2016;30(3):754–7.
Eide CA, Kurtz SE, Kaempf A, Long N, Agarwal A, Tognon CE, et al. Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia. Leukemia. 2020;34(9):2342–53.
Cortes JE, Jonas BA, Graef T, Luan Y, Stein AS. Clinical experience with ibrutinib alone or in combination with either cytarabine or azacitidine in patients with acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2019;19(8):509–15.e1.
Goldberg AD, Ohanian M, Koller P, Altman JK, Cherry M, Tomlinson B, Chandhok N, Zhang H, Rastgoo N, Benbatoul K, Jin Y. A phase 1a/b dose escalation study of the mutation agnostic FLT3/BTK inhibitor luxeptinib (CG-806) in patients with relapsed or refractory acute myeloid leukemia. Blood. 2021;138:1272.
Debora S, Stefania O, Samantha R, Paola M, Claudia M, Luca A, et al. The new small tyrosine kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs. Haematologica. 2019;105(10):2420–31.
Elgamal OA, Mehmood A, Jeon JY, Carmichael B, Lehman A, Orwick SJ, et al. Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia. J Hematol Oncol. 2020;13(1):8.
Huang S, Pan J, Jin J, Li C, Li X, Huang J, et al. Abivertinib, a novel BTK inhibitor: anti-leukemia effects and synergistic efficacy with homoharringtonine in acute myeloid leukemia. Cancer Lett. 2019;461:132–43.
Voisset E, Brenet F, Lopez S, de Sepulveda P. SRC-family kinases in acute myeloid leukaemia and mastocytosis. Cancers (Basel). 2020;12(7):1996.
MacDonald RJ, Bunaciu RP, Ip V, Dai D, Tran D, Varner JD, et al. Src family kinase inhibitor bosutinib enhances retinoic acid-induced differentiation of HL-60 leukemia cells. Leuk Lymphoma. 2018;59(12):2941–51.
Saito Y, Yuki H, Kuratani M, Hashizume Y, Takagi S, Honma T, et al. A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo. Sci Transl Med. 2013;5(181):181ra52.
Weir MC, Shu ST, Patel RK, Hellwig S, Chen L, Tan L, et al. Selective inhibition of the myeloid Src-family kinase Fgr potently suppresses AML cell growth in vitro and in vivo. ACS Chem Biol. 2018;13(6):1551–9.
Ozawa Y, Williams AH, Estes ML, Matsushita N, Boschelli F, Jove R, et al. Src family kinases promote AML cell survival through activation of signal transducers and activators of transcription (STAT). Leuk Res. 2008;32(6):893–903.
Bourrié B, Brassard DL, Cosnier-Pucheu S, Zilberstein A, Yu K, Levit M, et al. SAR103168: a tyrosine kinase inhibitor with therapeutic potential in myeloid leukemias. Leuk Lymphoma. 2013;54(7):1488–99.
Roboz GJ, Khoury HJ, Jabbour E, Session W, Ritchie EK, Miao H, et al. Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome. Leuk Lymphoma. 2015;56(2):395–400.
Terao T, Minami Y. Targeting hedgehog (Hh) pathway for the acute myeloid leukemia treatment. Cells. 2019;8(4):312.
Aberger F, Hutterer E, Sternberg C, Del Burgo PJ, Hartmann TN. Acute myeloid leukemia—strategies and challenges for targeting oncogenic hedgehog/GLI signaling. Cell Commun Signal. 2017;15(1):8.
Wellbrock J, Latuske E, Köhler J, Wagner K, Stamm H, Vettorazzi E, et al. Expression of hedgehog pathway mediator GLI represents a negative prognostic marker in human acute myeloid leukemia and its inhibition exerts antileukemic effects. Clin Cancer Res. 2015;21(10):2388–98.
Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, Gendron P, Romeo AA, Morris SJ, et al. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature. 2014;511(7507):90–3.
Li X, Chen F, Zhu Q, Ding B, Zhong Q, Huang K, et al. Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells. Oncotarget. 2016;7(22):33004–15.
Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, Jamieson C, et al. Small-molecule hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci. 2016;107(10):1422–9.
Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, et al. Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci. 2017;108(8):1628–33.
Martinelli G, Oehler VG, Papayannidis C, Courtney R, Shaik MN, Zhang X, et al. Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study. Lancet Haematol. 2015;2(8):e339–46.
Savona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, et al. Phase Ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. Clin Cancer Res. 2018;24(10):2294–303.
Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, et al. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018;93(11):1301–10.
Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, 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):379–89.
Heuser M, Robak T, Montesinos P, Leber B, Fiedler WM, Pollyea DA, et al. Glasdegib (GLAS) plus low-dose cytarabine (LDAC) in AML or MDS: BRIGHT AML 1003 final report and four-year overall survival (OS) follow-up. J Clin Oncol. 2020;38(15_suppl):7509.
Huang K, Ding B, Zhong Q, Jiang X, Li X, Wang Z, et al. Hh/IGF-1R/PI3K/Akt/MRP1 pathway induce refractory acute myeloid leukemia and its targeting therapy. Blood. 2014;124(21):3612.
Tibes R, Kosiorek HE, Dueck A, Palmer J, Slack JL, Knight EA, et al. Phase I/IB study of azacitidine and hedgehog pathway inhibition with sonidegib (LDE225) in myeloid malignancies. Blood. 2017;130(Suppl 1):2629.
Shallis RM, Bewersdorf JP, Boddu PC, Zeidan AM. Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia. Expert Rev Anticancer Ther. 2019;19(8):717–29.
Bixby D, Noppeney R, Lin TL, Cortes J, Krauter J, Yee K, et al. Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial. Br J Haematol. 2019;185(3):595–8.
Masetti R, Bertuccio SN, Astolfi A, Chiarini F, Lonetti A, Indio V, et al. Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene. J Hematol Oncol. 2017;10(1):26.
Latuske EM, Stamm H, Klokow M, Vohwinkel G, Muschhammer J, Bokemeyer C, et al. Combined inhibition of GLI and FLT3 signaling leads to effective anti-leukemic effects in human acute myeloid leukemia. Oncotarget. 2017;8(17):29187–201.
Wei AH, Roberts AW, Spencer A, Rosenberg AS, Siegel D, Walter RB, et al. Targeting MCL-1 in hematologic malignancies: rationale and progress. Blood Rev. 2020;44:100672.
Wei Y, Cao Y, Sun R, Cheng L, Xiong X, Jin X, et al. Targeting Bcl-2 proteins in acute myeloid leukemia. Front Oncol. 2020;10(2137):584974.
Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–75.
Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17.
Bogenberger JM, Kornblau SM, Pierceall WE, Lena R, Chow D, Shi CX, et al. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia. 2014;28(8):1657–65.
Bogenberger JM, Delman D, Hansen N, Valdez R, Fauble V, Mesa RA, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56(1):226–9.
DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, et al. 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. Lancet Oncol. 2018;19(2):216–28.
DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17.
Winters AC, Gutman JA, Purev E, Nakic M, Tobin J, Chase S, et al. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Blood Adv. 2019;3(20):2911–9.
Aldoss I, Yang D, Aribi A, Ali H, Sandhu K, Al Malki MM, et al. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica. 2018;103(9):e404–e7.
Wei AH, Strickland SA Jr, Hou JZ, Fiedler W, Lin TL, Walter RB, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a Phase Ib/II study. J Clin Oncol. 2019;37(15):1277–84.
DiNardo CD, Rausch CR, Benton C, Kadia T, Jain N, Pemmaraju N, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93(3):401–7.
Aldoss I, Yang D, Pillai R, Sanchez JF, Mei M, Aribi A, et al. Association of leukemia genetics with response to venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Am J Hematol. 2019;94(10):E253–e5.
Pollyea DA, Stevens BM, Jones CL, Winters A, Pei S, Minhajuddin M, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018;24(12):1859–66.
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–29.
Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137–45.
Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375–88.
Tron AE, Belmonte MA, Adam A, Aquila BM, Boise LH, Chiarparin E, et al. Discovery of mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018;9(1):5341.
Caenepeel S, Brown SP, Belmontes B, Moody G, Keegan KS, Chui D, et al. AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discov. 2018;8(12):1582–97.
Caenepeel SR, Belmontes B, Sun J, Coxon A, Moody G, Hughes PE. Abstract 2027: preclinical evaluation of AMG 176, a novel, potent and selective mcl-1 inhibitor with robust anti-tumor activity in mcl-1 dependent cancer models. Cancer Res. 2017;77(13 Suppl):2027.
Caenepeel S, Karen R, Belmontes B, Verlinsky A, Tan H, Yang Y, et al. Abstract 6218: discovery and preclinical evaluation of AMG 397, a potent, selective and orally bioavailable MCL1 inhibitor. Cancer Res. 2020;80(16 Suppl):6218.
Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538(7626):477–82.
Moujalled DM, Pomilio G, Ghiurau C, Ivey A, Salmon J, Rijal S, et al. Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. Leukemia. 2019;33(4):905–17.
Anstee NS, Bilardi RA, Ng AP, Xu Z, Robati M, Vandenberg CJ, et al. Impact of elevated anti-apoptotic MCL-1 and BCL-2 on the development and treatment of MLL-AF9 AML in mice. Cell Death Differ. 2019;26(7):1316–31.
Lee T, Christov PP, Shaw S, Tarr JC, Zhao B, Veerasamy N, et al. Discovery of potent myeloid cell Leukemia-1 (mcl-1) inhibitors that demonstrate in vivo activity in mouse xenograft models of human cancer. J Med Chem. 2019;62(8):3971–88.
Ramsey HE, Fischer MA, Lee T, Gorska AE, Arrate MP, Fuller L, et al. A novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia. Cancer Discov. 2018;8(12):1566–81.
Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Bruekner SR, Koss B, et al. A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol. 2012;19(9):1175–86.
Richard DJ, Lena R, Bannister T, Blake N, Pierceall WE, Carlson NE, et al. Hydroxyquinoline-derived compounds and analoguing of selective mcl-1 inhibitors using a functional biomarker. Bioorg Med Chem. 2013;21(21):6642–9.
Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003;22(53):8628–33.
Prabhu VV, Talekar MK, Lulla AR, Kline CLB, Zhou L, Hall J, et al. Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies. Cell Cycle. 2018;17(4):468–78.
Edwards H, Ge Y. ONC201 shows promise in AML treatment. Cell Cycle. 2018;17(3):277.
Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, et al. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci Signal. 2016;9(415):ra17.
Wagner J, Kline CL, Ralff MD, Lev A, Lulla A, Zhou L, et al. Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212. Cell Cycle. 2017;16(19):1790–9.
Nii T, Prabhu VV, Ruvolo V, Madhukar N, Zhao R, Mu H, et al. Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia. Leukemia. 2019;33(12):2805–16.
Konopleva M, Martinelli G, Daver N, Papayannidis C, Wei A, Higgins B, et al. MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020;34(11):2858–74.
Loizou E, Banito A, Livshits G, Ho Y-J, Koche RP, Sánchez-Rivera FJ, et al. A gain-of-function p53-mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor FOXH1. Cancer Discov. 2019;9(7):962.
Barbosa K, Li S, Adams PD, Deshpande AJ. The role of TP53 in acute myeloid leukemia: challenges and opportunities. Genes Chromosom Cancer. 2019;58(12):875–88.
Tiong IS, Wei AH. New drugs creating new challenges in acute myeloid leukemia. Genes Chromosom Cancer. 2019;58(12):903–14.
Sallman DA. To target the untargetable: elucidation of synergy of APR-246 and azacitidine in TP53 mutant myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2020;105(6):1470–2.
Maslah N, Salomao N, Drevon L, Verger E, Partouche N, Ly P, et al. Synergistic effects of PRIMA-1(met) (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2020;105(6):1539–51.
Sallman DA, DeZern AE, Steensma DP, Sweet KL, Cluzeau T, Sekeres MA, et al. Phase 1b/2 combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Blood. 2018;132(Suppl 1):3091.
Yan W, Jung YS, Zhang Y, Chen X. Arsenic trioxide reactivates proteasome-dependent degradation of mutant p53 protein in cancer cells in part via enhanced expression of Pirh2 E3 ligase. PLoS One. 2014;9(8):e103497.
Yan W, Zhang Y, Zhang J, Liu S, Cho SJ, Chen X. Mutant p53 protein is targeted by arsenic for degradation and plays a role in arsenic-mediated growth suppression. J Biol Chem. 2011;286(20):17478–86.
Noguera NI, Pelosi E, Angelini DF, Piredda ML, Guerrera G, Piras E, et al. High-dose ascorbate and arsenic trioxide selectively kill acute myeloid leukemia and acute promyelocytic leukemia blasts in vitro. Oncotarget. 2017;8(20):32550–65.
Schlenk RF, Döhner K, Kneba M, Götze K, Hartmann F, Del Valle F, et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG trial AML HD98B. Haematologica. 2009;94(1):54–60.
Martelli MP, Gionfriddo I, Mezzasoma F, Milano F, Pierangeli S, Mulas F, et al. Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells. Blood. 2015;125(22):3455–65.
El Hajj H, Dassouki Z, Berthier C, Raffoux E, Ades L, Legrand O, et al. Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells. Blood. 2015;125(22):3447–54.
Khurana A, Shafer DA. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco Targets Ther. 2019;12:2903–10.
Yee K, Martinelli G, Assouline S, Kasner M, Vey N, Kelly KR, et al. Phase 1b study of the MDM2 antagonist RG7112 in combination with 2 doses/schedules of cytarabine. Blood. 2013;122(21):498.
Andreeff M, Kelly KR, Yee K, Assouline S, Strair R, Popplewell L, et al. Results of the Phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22(4):868–76.
Yee K, Martinelli G, Vey N, Dickinson MJ, Seiter K, Assouline S, et al. Phase 1/1b study of RG7388, a potent MDM2 antagonist, in acute Myelogenous leukemia (AML) patients (Pts). Blood. 2014;124(21):116.
Dangl M, Chien Y, Lehmann C, Friess T. Abstract 5505: synergistic anticancer activity of clinical stage, non-genotoxic apoptosis inducing agents RG7388 (MDM2 antagonist) and ABT-199 (GDC-0199, BCL2 inhibitor) in p53 wild-type AML tumor models. Cancer Res. 2014;74(19 Suppl):5505.
Daver NG, Garcia JS, Jonas BA, Kelly KR, Assouline S, Brandwein JM, et al. Updated results from the venetoclax (Ven) in combination with idasanutlin (Idasa) arm of a phase 1b trial in elderly patients (Pts) with relapsed or refractory (R/R) AML ineligible for cytotoxic chemotherapy. Blood. 2019;134(Suppl_1):229.
Nishida Y, Ishizawa J, Ruvolo V, Kojima K, Montoya RH, Daver NG, et al. Dual inhibition of MDM2 and XPO1 synergizes to induce apoptosis in acute myeloid leukemia progenitor cells with wild-type TP53 through nuclear accumulation of p53 and suppression of c-Myc. Blood. 2019;134(Suppl_1):2556.
Abdul Razak AR, Miller WH Jr, Uy GL, Blotner S, Young AM, Higgins B, et al. A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors. Investig New Drugs. 2020;38(4):1156–65.
Erba HP, Becker PS, Shami PJ, Grunwald MR, Flesher DL, Zhu M, et al. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv. 2019;3(13):1939–49.
ASH Clinical News. Early-phase trials of HDM201 show promise in leukemias. 2017. https://www.ashclinicalnews.org/meeting-news/early-phase-trials-hdm201-show-promise-leukemias/.
Nepstad I, Hatfield KJ, Grønningsæter IS, Reikvam H. The PI3K-Akt-mTOR signaling pathway in human acute myeloid leukemia (AML) cells. Int J Mol Sci. 2020;21(8):2907.
Perl AE, Kasner MT, Tsai DE, Vogl DT, Loren AW, Schuster SJ, et al. A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res. 2009;15(21):6732–9.
Park S, Chapuis N, Saint Marcoux F, Recher C, Prebet T, Chevallier P, et al. A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia. 2013;27(7):1479–86.
Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2006;12(17):5165–73.
Alan KB, Emma Das G, Steve K, Asim K, Marion S, Lars K, et al. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica. 2018;103(10):1654–61.
Amadori S, Stasi R, Martelli AM, Venditti A, Meloni G, Pane F, et al. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107). Br J Haematol. 2012;156(2):205–12.
Rizzieri DA, Feldman E, Dipersio JF, Gabrail N, Stock W, Strair R, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2008;14(9):2756–62.
Herschbein L, Liesveld JL. Dueling for dual inhibition: means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML. Blood Rev. 2018;32(3):235–48.
Vargaftig J, Farhat H, Ades L, Briaux A, Benoist C, Turbiez I, et al. Phase 2 trial of single agent Gedatolisib (PF-05212384), a dual PI3K/mTOR inhibitor, for adverse prognosis and relapse/refractory AML: clinical and Transcriptomic results. Blood. 2018;132(Suppl 1):5233.
Lang F, Wunderle L, Badura S, Schleyer E, Brüggemann M, Serve H, et al. A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia. BMC Pharmacol Toxicol. 2020;21(1):70.
Abou Zahr A, Borthakur G. Emerging cell cycle inhibitors for acute myeloid leukemia. Expert Opin Emerg Drugs. 2017;22(2):137–48.
Carter JL, Hege K, Yang J, Kalpage HA, Su Y, Edwards H, et al. Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Target Ther. 2020;5(1):288.
Molina JR, Sun Y, Protopopova M, Gera S, Bandi M, Bristow C, et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018;24(7):1036–46.
Liu F, Kalpage HA, Wang D, Edwards H, Hüttemann M, Ma J, et al. Cotargeting of mitochondrial complex I and Bcl-2 shows antileukemic activity against acute myeloid leukemia cells reliant on oxidative phosphorylation. Cancers (Basel). 2020;12(9):2400.
Panina SB, Pei J, Baran N, Konopleva M, Kirienko NV. Utilizing synergistic potential of mitochondria-targeting drugs for leukemia therapy. Front Oncol. 2020;10:435.
Baccelli I, Gareau Y, Lehnertz B, Gingras S, Spinella J-F, Corneau S, et al. Mubritinib targets the electron transport chain complex i and reveals the landscape of OXPHOS Dependency in acute myeloid leukemia. Cancer Cell. 2019;36(1):84–99.e8.
Ricciardi MR, Mirabilii S, Allegretti M, Licchetta R, Calarco A, Torrisi MR, et al. Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. Blood. 2015;126(16):1925–9.
Cloos J, Roeten MS, Franke NE, van Meerloo J, Zweegman S, Kaspers GJ, et al. (Immuno)proteasomes as therapeutic target in acute leukemia. Cancer Metastasis Rev. 2017;36(4):599–615.
Enrique C, Stela Á-F, Patricia M, Jesús M-S, Maria Belén V, Mercedes G, et al. The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype. Haematologica. 2008;93(1):57–66.
Tomlinson BK, Tuscano JM, Abedi M, Welborn J, Arora M, O’Donnell RT, et al. A phase II study of bortezomib in combination with pegylated liposomal doxorubicin for acute myeloid leukemia. Am J Hematol. 2019;94(11):E291–E4.
Swords RT, Kelly KR, Smith PG, Garnsey JJ, Mahalingam D, Medina E, et al. Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood. 2010;115(18):3796–800.
Sen S, De Leon JP, Smith PG, Roboz GJ, Guzman ML. Investigational NEDD8-activating enzyme (NAE) inhibitor, MLN4924, demonstrates activity against primary AML blast, progenitor and stem cell populations. Blood. 2011;118(21):1414.
Zhou L, Chen S, Zhang Y, Kmieciak M, Leng Y, Li L, et al. The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR. Blood. 2016;127(18):2219–30.
Knorr KL, Schneider PA, Meng XW, Dai H, Smith BD, Hess AD, et al. MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors. Cell Death Differ. 2015;22(12):2133–42.
Short NPB, Dinardo C, Garcia-Manero G, Muftuoglu M, Alaniz Z, Patel K, Montalban-Bravo G, Jain N, Alvarado Y, Jabbour E, Andreeff M, Delumpa R, Kantarjian H, Cortes J. Preliminary results of a phase I/II study of azacitidine, venetoclax and pevonedistat in patients with secondary acute myeloid leukemia who are unfit for intensive chemotherapy. 2020. https://library.ehaweb.org/eha/2020/eha25th/294475/nicholas.short.preliminary.results.of.a.phase.i.ii.study.of.azacitidine.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D2%2Asearch%3Dblast.
Ishikawa Y, Nakayama K, Morimoto M, Mizutani A, Nakayama A, Toyoshima K, et al. Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication. Oncogenesis. 2017;6(9):e377.
Swords RT, Coutre S, Maris MB, Zeidner JF, Foran JM, Cruz J, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018;131(13):1415–24.
Sekeres MA, Watts J, Radinoff A, Sangerman MA, Cerrano M, Lopez PF, et al. Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML. Leukemia. 2021;
Talati C, Sweet KL. Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives. Int J Hematol Oncol. 2018;7(3):Ijh04.
Ranganathan P, Yu X, Na C, Santhanam R, Shacham S, Kauffman M, et al. Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood. 2012;120(9):1765–73.
Ranganathan P, Kashyap T, Yu X, Meng X, Lai T-H, McNeil B, et al. XPO1 inhibition using selinexor synergizes with chemotherapy in acute myeloid leukemia by targeting DNA repair and restoring topoisomerase IIα to the nucleus. Clin Cancer Res. 2016;22(24):6142–52.
Ramzi A, Ezhilarasi C, Michael PR, Kathryn MT, Peter AR, Camille NA, et al. Selinexor combined with cladribine, cytarabine, and filgrastim in relapsed or refractory acute myeloid leukemia. Haematologica. 2020;105(8):e404–e7.
Zhang W, Ly C, Ishizawa J, Mu H, Ruvolo V, Shacham S, et al. Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial. Haematologica. 2018;103(10):1642–53.
Garzon R, Savona M, Baz R, Andreeff M, Gabrail N, Gutierrez M, et al. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Blood. 2017;129(24):3165–74.
Karyopharm Press Release. Karyopharm annouces results from interim analysis of phase II OPRA study evaluating selinexor in relapsed/refractory acute myeloid leukemia. 2017. https://www.globenewswire.com/news-release/2017/03/02/930523/0/en/Karyopharm-Announces-Results-from-Interim-Analysis-of-Phase-2-SOPRA-Study-Evaluating-Selinexor-in-Relapsed-Refractory-Acute-Myeloid-Leukemia.html.
Pardee TS, Pladna KM, Lyerly S, Dralle S, Manuel M, Ellis LR, Howard DS, Bhave R, Powell BL. Frontline selinexor and chemotherapy is highly active in older adults with acute myeloid leukemia (AML). Blood. 2020;136(Suppl 1):24–5.
Sweet K, Komrokji R, Padron E, Cubitt CL, Turner JG, Zhou J, et al. Phase I clinical trial of selinexor in combination with daunorubicin and cytarabine in previously untreated poor-risk acute myeloid leukemia. Clin Cancer Res. 2020;26(1):54–60.
Fiedler W, Heuser M, Chromik J, Thol F, Bokemeyer C, Theile S, et al. Phase II results of Ara-C and Idarubicin in combination with the selective inhibitor of nuclear export (SINE) compound Selinexor (KPT-330) in patients with relapsed or refractory AML. Blood. 2016;128(22):341.
Fiedler W, Chromik J, Amberg S, Kebenko M, Thol F, Schlipfenbacher V, et al. A Phase II study of selinexor plus cytarabine and idarubicin in patients with relapsed/refractory acute myeloid leukaemia. Br J Haematol. 2020;190(3):e169–e73.
Alexander TB, Lacayo NJ, Choi JK, Ribeiro RC, Pui CH, Rubnitz JE. Phase I study of selinexor, a selective inhibitor of nuclear export, in combination with fludarabine and cytarabine, in pediatric relapsed or refractory acute leukemia. J Clin Oncol. 2016;34(34):4094–101.
Uy GL, Rettig MP, Fletcher T, Riedell PA, Stockerl-Goldstein KE, Ghobadi A, et al. Selinexor in combination with cladribine, cytarabine and G-CSF for relapsed or refractory AML. Blood. 2017;130(Suppl 1):816.
Wang AY, Weiner HL, Green M, Larson RA, Odenike O, Artz A, et al. Combination of selinexor with high-dose cytarabine (HiDAC) and mitoxantrone (Mito) for remission induction in acute myeloid leukemia (AML) is feasible and tolerable. Blood. 2016;128(22):212.
Wang AY, Weiner H, Green M, Chang H, Fulton N, Larson RA, et al. A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia. J Hematol Oncol. 2018;11(1):4.
Bhatnagar B, Zhao Q, Mims AS, Vasu S, Behbehani GK, Larkin K, et al. Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study. Leuk Lymphoma. 2020;61(2):387–96.
Daver NG, Assi R, Kantarjian HM, Cortes JE, Ravandi F, Konopleva MY, et al. Final results of Phase I/II study of selinexor (SEL) with sorafenib in patients (pts) with relapsed and/or refractory (R/R) FLT3 mutated acute myeloid leukemia (AML). Blood. 2018;132(Suppl 1):1441.
Cooperrider JH, Fulton N, Artz AS, Larson RA, Stock W, Kosuri S, et al. Phase I trial of maintenance selinexor after allogeneic hematopoietic stem cell transplantation for patients with acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2020;55(11):2204–6.
Hing ZA, Fung HY, Ranganathan P, Mitchell S, El-Gamal D, Woyach JA, et al. Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia. 2016;30(12):2364–72.
Etchin J, Berezovskaya A, Conway AS, Galinsky IA, Stone RM, Baloglu E, et al. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells. Leukemia. 2017;31(1):143–50.
Fischer MA, Arrate PM, Chang H, Gorska AE, Fuller LS, Ramsey HE, et al. Abstract 1877: selective inhibitor of nuclear export (SINE) compound, eltanexor (KPT-8602), synergizes with venetoclax (ABT-199) to eliminate leukemia cells and extend survival in an in vivo model of acute myeloid leukemia. Cancer Res. 2018;78(13 Suppl):1877.
Fischer MA, Friedlander SY, Arrate MP, Chang H, Gorska AE, Fuller LD, et al. Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies. Blood Adv. 2020;4(3):586–98.
Fennell KA, Bell CC, Dawson MA. Epigenetic therapies in acute myeloid leukemia: where to from here? Blood. 2019;134(22):1891–901.
Duchmann M, Itzykson R. Clinical update on hypomethylating agents. Int J Hematol. 2019;110(2):161–9.
Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, Macbeth KJ, et al. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011;29(18):2521–7.
Savona MR, Kolibaba K, Conkling P, Kingsley EC, Becerra C, Morris JC, et al. Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies. Am J Hematol. 2018;93(10):1199–206.
Roboz GJ, Montesinos P, Selleslag D, Wei A, Jang JH, Falantes J, et al. Design of the randomized, phase III, QUAZAR AML maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia. Future Oncol. 2016;12(3):293–302.
Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, et al. The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. Blood. 2019;134(Suppl_2):LBA-3.
Kantarjian HM, Roboz GJ, Kropf PL, Yee KWL, O’Connell CL, Tibes R, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 2017;18(10):1317–26.
Issa GC, Kantarjian HM, Xiao L, Ning J, Alvarado Y, Borthakur G, et al. Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality. Leukemia. 2020;34(11):2914–24.
Roboz GJ, Kantarjian HM, Yee KWL, Kropf PL, O’Connell CL, Griffiths EA, et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer. 2018;124(2):325–34.
Astex Pharmaceuticals. Astex and Otsuka announce results of phase 3 ASTRAL-2 and ASTRAL-3 studies of guadecitabine (SGI-110) in patients with previously treated acute myeloid leukemia (AML) and myelodysplastic syndromes or chronic myelomonocytic leukemia (MDS/CMML). Pleasanton, CA: Astex Pharmaceuticals; 2020.
San José-Enériz E, Gimenez-Camino N, Agirre X, Prosper F. HDAC inhibitors in acute myeloid leukemia. Cancers (Basel). 2019;11(11):1794.
Fiskus W, Wang Y, Joshi R, Rao R, Yang Y, Chen J, et al. Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells. Clin Cancer Res. 2008;14(19):6106–15.
Miller CP, Rudra S, Keating MJ, Wierda WG, Palladino M, Chandra J. Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells. Blood. 2009;113(18):4289–99.
Shiozawa K, Nakanishi T, Tan M, Fang HB, Wang WC, Edelman MJ, et al. Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. Clin Cancer Res. 2009;15(5):1698–707.
Wei Y, Kadia T, Tong W, Zhang M, Jia Y, Yang H, et al. The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Autophagy. 2010;6(7):976–8.
Zhou L, Zhang Y, Chen S, Kmieciak M, Leng Y, Lin H, et al. A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations. Leukemia. 2015;29(4):807–18.
Lin WH, Yeh TK, Jiaang WT, Yen KJ, Chen CH, Huang CT, et al. Evaluation of the antitumor effects of BPR1J-340, a potent and selective FLT3 inhibitor, alone or in combination with an HDAC inhibitor, vorinostat, in AML cancer. PLoS One. 2014;9(1):e83160.
Schaefer EW, Loaiza-Bonilla A, Juckett M, DiPersio JF, Roy V, Slack J, et al. A phase 2 study of vorinostat in acute myeloid leukemia. Haematologica. 2009;94(10):1375–82.
Kadia TM, Yang H, Ferrajoli A, Maddipotti S, Schroeder C, Madden TL, et al. A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia. Br J Haematol. 2010;150(1):72–82.
Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012;30(18):2204–10.
Walter RB, Medeiros BC, Gardner KM, Orlowski KF, Gallegos L, Scott BL, et al. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study. Haematologica. 2014;99(1):54–9.
Walter RB, Medeiros BC, Powell BL, Schiffer CA, Appelbaum FR, Estey EH. Phase II trial of vorinostat and gemtuzumab ozogamicin as induction and post-remission therapy in older adults with previously untreated acute myeloid leukemia. Haematologica. 2012;97(5):739–42.
Kirschbaum M, Gojo I, Goldberg SL, Bredeson C, Kujawski LA, Yang A, et al. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Br J Haematol. 2014;167(2):185–93.
How J, Minden MD, Brian L, Chen EX, Brandwein J, Schuh AC, et al. A phase I trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia. Leuk Lymphoma. 2015;56(10):2793–802.
Mims AS, Mishra A, Orwick S, Blachly J, Klisovic RB, Garzon R, et al. A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485. Haematologica. 2018;103(6):982–7.
Sayar H, Cripe LD, Saliba AN, Abu Zaid M, Konig H, Boswell HS. Combination of sorafenib, vorinostat and bortezomib for the treatment of poor-risk AML: report of two consecutive clinical trials. Leuk Res. 2019;77:30–3.
Craddock CF, Houlton AE, Quek LS, Ferguson P, Gbandi E, Roberts C, et al. Outcome of azacitidine therapy in acute myeloid leukemia is not improved by concurrent vorinostat therapy but is predicted by a diagnostic molecular signature. Clin Cancer Res. 2017;23(21):6430–40.
Holkova B, Supko JG, Ames MM, Reid JM, Shapiro GI, Perkins EB, et al. A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Clin Cancer Res. 2013;19(7):1873–83.
Anne M, Sammartino D, Barginear MF, Budman D. Profile of panobinostat and its potential for treatment in solid tumors: an update. Onco Targets Ther. 2013;6:1613–24.
Blagitko-Dorfs N, Schlosser P, Greve G, Pfeifer D, Meier R, Baude A, et al. Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation. Leukemia. 2019;33(4):945–56.
Fiskus W, Buckley K, Rao R, Mandawat A, Yang Y, Joshi R, et al. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther. 2009;8(10):939–50.
Gopalakrishnapillai A, Kolb EA, McCahan SM, Barwe SP. Epigenetic drug combination induces remission in mouse xenograft models of pediatric acute myeloid leukemia. Leuk Res. 2017;58:91–7.
Schwartz J, Niu X, Walton E, Hurley L, Lin H, Edwards H, et al. Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia ex vivo. Am J Transl Res. 2016;8(9):3893–902.
Qi W, Zhang W, Edwards H, Chu R, Madlambayan GJ, Taub JW, et al. Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo. Cancer Biol Ther. 2015;16(12):1784–93.
Fiskus W, Sharma S, Saha S, Shah B, Devaraj SG, Sun B, et al. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia. 2015;29(6):1267–78.
Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SG, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2014;28(11):2155–64.
Fiskus W, Sharma S, Qi J, Valenta JA, Schaub LJ, Shah B, et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014;13(5):1142–54.
Pietschmann K, Bolck HA, Buchwald M, Spielberg S, Polzer H, Spiekermann K, et al. Breakdown of the FLT3-ITD/STAT5 axis and synergistic apoptosis induction by the histone deacetylase inhibitor panobinostat and FLT3-specific inhibitors. Mol Cancer Ther. 2012;11(11):2373–83.
Jiang XJ, Huang KK, Yang M, Qiao L, Wang Q, Ye JY, et al. Synergistic effect of panobinostat and bortezomib on chemoresistant acute myelogenous leukemia cells via AKT and NF-κB pathways. Cancer Lett. 2012;326(2):135–42.
Mandawat A, Fiskus W, Buckley KM, Robbins K, Rao R, Balusu R, et al. Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists. Blood. 2010;116(24):5306–15.
Maiso P, Colado E, Ocio EM, Garayoa M, Martín J, Atadja P, et al. The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia. 2009;23(12):2265–74.
Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin a and the histone deacetylase inhibitor panobinostat against human AML cells. Blood. 2009;114(13):2733–43.
Ocio EM, Herrera P, Olave MT, Castro N, Pérez-Simón JA, Brunet S, et al. Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib/II panobidara study. Haematologica. 2015;100(10):1294–300.
Wieduwilt MJ, Pawlowska N, Thomas S, Olin R, Logan AC, Damon LE, et al. Histone deacetylase inhibition with panobinostat combined with intensive induction chemotherapy in older patients with acute myeloid leukemia: Phase I study results. Clin Cancer Res. 2019;25(16):4917–23.
Garcia-Manero G, Sekeres MA, Egyed M, Breccia M, Graux C, Cavenagh JD, et al. A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. Leukemia. 2017;31(12):2799–806.
Schlenk RF, Krauter J, Raffoux E, Kreuzer KA, Schaich M, Noens L, et al. Panobinostat monotherapy and combination therapy in patients with acute myeloid leukemia: results from two clinical trials. Haematologica. 2018;103(1):e25–e8.
Dai Y, Chen S, Wang L, Pei XY, Kramer LB, Dent P, et al. Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbations in NF-κB and Bim. Br J Haematol. 2011;153(2):222–35.
Kirschbaum MH, Foon KA, Frankel P, Ruel C, Pulone B, Tuscano JM, et al. A phase 2 study of belinostat (PXD101) in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia: a California cancer consortium study. Leuk Lymphoma. 2014;55(10):2301–4.
Holkova B, Tombes MB, Shrader E, Cooke SS, Wan W, Sankala H, et al. Phase I trial of belinostat and bortezomib in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia in blast crisis. Blood. 2011;118(21):2598.
Holkova B, Bose P, Tombes MB, Shrader E, Wan W, Weir-Wiggins C, et al. Phase I trial of belinostat and bortezomib in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia in blast crisis—one year update. Blood. 2012;120(21):3588.
Abaza YM, Kadia TM, Jabbour EJ, Konopleva MY, Borthakur G, Ferrajoli A, et al. Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies. Cancer. 2017;123(24):4851–9.
ClinicalTrials.gov. An efficacy and safety study of pracinostat in combination with azacitidine in adults with acute myeloid leukemia. 2020. https://clinicaltrials.gov/ct2/show/NCT03151408.
Barbetti V, Gozzini A, Rovida E, Morandi A, Spinelli E, Fossati G, et al. Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells. Oncogene. 2008;27(12):1767–78.
Golay J, Cuppini L, Leoni F, Micò C, Barbui V, Domenghini M, et al. The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells. Leukemia. 2007;21(9):1892–900.
Zabkiewicz J, Gilmour M, Hills R, Vyas P, Bone E, Davidson A, et al. The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias. Oncotarget. 2016;7(13):16650–62.
Vey N, Prebet T, Thalamas C, Charbonnier A, Rey J, Kloos I, et al. Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia. Leuk Lymphoma. 2017;58(8):1880–6.
Li Y, Chen K, Zhou Y, Xiao Y, Deng M, Jiang Z, et al. A new strategy to target acute myeloid leukemia stem and progenitor cells using Chidamide, a histone Deacetylase inhibitor. Curr Cancer Drug Targets. 2015;15(6):493–503.
Lin L, Que Y, Lu P, Li H, Xiao M, Zhu X, et al. Chidamide inhibits acute myeloid leukemia cell proliferation by lncRNA VPS9D1-AS1 Downregulation via MEK/ERK signaling pathway. Front Pharmacol. 2020;11:569651.
Mao J, Li S, Zhao H, Zhu Y, Hong M, Zhu H, et al. Effects of chidamide and its combination with decitabine on proliferation and apoptosis of leukemia cell lines. Am J Transl Res. 2018;10(8):2567–78.
Li Q, Huang JC, Liao DY, Wu Y. Chidamide plus decitabine synergistically induces apoptosis of acute myeloid leukemia cells by upregulating PERP. Am J Transl Res. 2020;12(7):3461–75.
Li X, Yan X, Guo W, Huang X, Huang J, Yu M, et al. Chidamide in FLT3-ITD positive acute myeloid leukemia and the synergistic effect in combination with cytarabine. Biomed Pharmacother. 2017;90:699–704.
Huang H, Wenbing Y, Dong A, He Z, Yao R, Guo W. Chidamide enhances the cytotoxicity of cytarabine and sorafenib in acute myeloid leukemia cells by modulating H3K9me3 and autophagy levels. Front Oncol. 2019;9:1276.
Wang H, Liu YC, Zhu CY, Yan F, Wang MZ, Chen XS, et al. Chidamide increases the sensitivity of refractory or relapsed acute myeloid leukemia cells to anthracyclines via regulation of the HDAC3 -AKT-P21-CDK2 signaling pathway. J Exp Clin Cancer Res. 2020;39(1):278.
Li Y, Wang Y, Zhou Y, Li J, Chen K, Zhang L, et al. Cooperative effect of chidamide and chemotherapeutic drugs induce apoptosis by DNA damage accumulation and repair defects in acute myeloid leukemia stem and progenitor cells. Clin Epigenetics. 2017;9:83.
Chen K, Yang Q, Zha J, Deng M, Zhou Y, Fu G, et al. Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia. Cell Death Dis. 2020;11(9):778.
Ye J, Zha J, Shi Y, Li Y, Yuan D, Chen Q, et al. Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair. Clin Epigenetics. 2019;11(1):137.
Zhang H, Li L, Li M, Huang X, Xie W, Xiang W, et al. Combination of betulinic acid and chidamide inhibits acute myeloid leukemia by suppression of the HIF1α pathway and generation of reactive oxygen species. Oncotarget. 2017;8(55):94743–58.
Wang L, Luo J, Chen G, Fang M, Wei X, Li Y, et al. Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study. Clin Epigenetics. 2020;12(1):132.
Ramsey JM, Kettyle LM, Sharpe DJ, Mulgrew NM, Dickson GJ, Bijl JJ, et al. Entinostat prevents leukemia maintenance in a collaborating oncogene-dependent model of cytogenetically normal acute myeloid leukemia. Stem Cells. 2013;31(7):1434–45.
Nishioka C, Ikezoe T, Yang J, Takeuchi S, Koeffler HP, Yokoyama A. MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. Leuk Res. 2008;32(9):1382–92.
Nishioka C, Ikezoe T, Yang J, Koeffler HP, Yokoyama A. Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell. Leukemia. 2008;22(7):1449–52.
Nishioka C, Ikezoe T, Yang J, Koeffler HP, Yokoyama A. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia. 2008;22(12):2159–68.
Nishioka C, Ikezoe T, Yang J, Udaka K, Yokoyama A. Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of mcl-1 in acute myelogenous leukemia cells. Leuk Res. 2011;35(7):932–9.
Gojo I, Jiemjit A, Trepel JB, Sparreboom A, Figg WD, Rollins S, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood. 2007;109(7):2781–90.
Fandy TE, Herman JG, Kerns P, Jiemjit A, Sugar EA, Choi SH, et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood. 2009;114(13):2764–73.
Prebet T, Sun Z, Figueroa ME, Ketterling R, Melnick A, Greenberg PL, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US leukemia intergroup trial E1905. J Clin Oncol. 2014;32(12):1242–8.
Lillico R, Lawrence CK, Lakowski TM. Selective DOT1L, LSD1, and HDAC class I inhibitors reduce HOXA9 expression in MLL-AF9 rearranged leukemia cells, but dysregulate the expression of many histone-modifying enzymes. J Proteome Res. 2018;17(8):2657–67.
Garcia-Manero G, Assouline S, Cortes J, Estrov Z, Kantarjian H, Yang H, et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood. 2008;112(4):981–9.
Yan B, Chen Q, Shimada K, Tang M, Li H, Gurumurthy A, et al. Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia. Leukemia. 2019;33(4):931–44.
Shaker S, Bernstein M, Momparler LF, Momparler RL. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2′-deoxycytidine) and histone deacetylation (trichostatin a, depsipeptide) in combination against myeloid leukemic cells. Leuk Res. 2003;27(5):437–44.
Byrd JC, Marcucci G, Parthun MR, Xiao JJ, Klisovic RB, Moran M, et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood. 2005;105(3):959–67.
Klimek VM, Fircanis S, Maslak P, Guernah I, Baum M, Wu N, et al. Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res. 2008;14(3):826–32.
Craddock C, Tholouli E, Munoz Vicente S, Gbandi E, Houlton AE, Drummond MW, et al. Safety and clinical activity of combined romidepsin and azacitidine therapy in high risk acute myeloid leukemia: preliminary results of the romaza trial. Blood. 2017;130(Suppl 1):2581.
Kosugi H, Towatari M, Hatano S, Kitamura K, Kiyoi H, Kinoshita T, et al. Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy. Leukemia. 1999;13(9):1316–24.
Maeda T, Towatari M, Kosugi H, Saito H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood. 2000;96(12):3847–56.
Fredly H, Gjertsen BT, Bruserud O. Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents. Clin Epigenetics. 2013;5(1):12.
Trus MR, Yang L, Suarez Saiz F, Bordeleau L, Jurisica I, Minden MD. The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells. Leukemia. 2005;19(7):1161–8.
Liu N, Wang C, Wang L, Gao L, Cheng H, Tang G, et al. Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis. Int J Mol Med. 2016;37(6):1686–96.
ten Cate B, Samplonius DF, Bijma T, de Leij LF, Helfrich W, Bremer E. The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells. Leukemia. 2007;21(2):248–52.
Nie D, Huang K, Yin S, Li Y, Xie S, Ma L, et al. Synergistic/additive interaction of valproic acid with bortezomib on proliferation and apoptosis of acute myeloid leukemia cells. Leuk Lymphoma. 2012;53(12):2487–95.
Wang AH, Wei L, Chen L, Zhao SQ, Wu WL, Shen ZX, et al. Synergistic effect of bortezomib and valproic acid treatment on the proliferation and apoptosis of acute myeloid leukemia and myelodysplastic syndrome cells. Ann Hematol. 2011;90(8):917–31.
Heo SK, Noh EK, Yoon DJ, Jo JC, Park JH, Kim H. Dasatinib accelerates valproic acid-induced acute myeloid leukemia cell death by regulation of differentiation capacity. PLoS One. 2014;9(2):e98859.
McCormack E, Haaland I, Venås G, Forthun RB, Huseby S, Gausdal G, et al. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia. 2012;26(5):910–7.
Fuchs O, Provaznikova D, Marinov I, Kuzelova K, Spicka I. Antiproliferative and proapoptotic effects of proteasome inhibitors and their combination with histone deacetylase inhibitors on leukemia cells. Cardiovasc Hematol Disord Drug Targets. 2009;9(1):62–77.
Chen J, Wang G, Wang L, Kang J, Wang J. Curcumin p38-dependently enhances the anticancer activity of valproic acid in human leukemia cells. Eur J Pharm Sci. 2010;41(2):210–8.
Guo SQ, Zhang YZ. Histone deacetylase inhibition: an important mechanism in the treatment of lymphoma. Cancer Biol Med. 2012;9(2):85–9.
Fredly H, Stapnes Bjørnsen C, Gjertsen BT, Bruserud Ø. Combination of the histone deacetylase inhibitor valproic acid with oral hydroxyurea or 6-mercaptopurin can be safe and effective in patients with advanced acute myeloid leukaemia—a report of five cases. Hematology. 2010;15(5):338–43.
Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110(7):2302–8.
Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, et al. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015;121(4):556–61.
Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007;25(25):3884–91.
Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108(10):3271–9.
Corsetti MT, Salvi F, Perticone S, Baraldi A, De Paoli L, Gatto S, et al. Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C. Leuk Res. 2011;35(8):991–7.
Lane S, Gill D, McMillan NA, Saunders N, Murphy R, Spurr T, et al. Valproic acid combined with cytosine arabinoside in elderly patients with acute myeloid leukemia has in vitro but limited clinical activity. Leuk Lymphoma. 2012;53(6):1077–83.
Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C, et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer. 2006;106(1):112–9.
Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B, Steidl C, et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005;84(Suppl 1):61–6.
Raffoux E, Chaibi P, Dombret H, Degos L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica. 2005;90(7):986–8.
Bug G, Ritter M, Wassmann B, Schoch C, Heinzel T, Schwarz K, et al. Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer. 2005;104(12):2717–25.
Tassara M, Döhner K, Brossart P, Held G, Götze K, Horst HA, et al. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood. 2014;123(26):4027–36.
Gambacorta V, Gnani D, Vago L, Di Micco R. Epigenetic therapies for acute myeloid leukemia and their immune-related effects. Front Cell Dev Biol. 2019;7:207.
Schenk T, Chen WC, Göllner S, Howell L, Jin L, Hebestreit K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18(4):605–11.
Wass M, Göllner S, Besenbeck B, Schlenk RF, Mundmann P, Göthert JR, et al. A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy. Leukemia. 2021;35(3):701–11.
Sharma SK, Wu Y, Steinbergs N, Crowley ML, Hanson AS, Casero RA, et al. (Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. J Med Chem. 2010;53(14):5197–212.
Schmitt ML, Hauser A-T, Carlino L, Pippel M, Schulz-Fincke J, Metzger E, et al. Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity. J Med Chem. 2013;56(18):7334–42.
Zheng Y-C, Duan Y-C, Ma J-L, Xu R-M, Zi X, Lv W-L, et al. Triazole–dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration. J Med Chem. 2013;56(21):8543–60.
Ma L-Y, Zheng Y-C, Wang S-Q, Wang B, Wang Z-R, Pang L-P, et al. Design, synthesis, and structure–activity relationship of novel LSD1 inhibitors based on pyrimidine–thiourea hybrids as potent, orally active antitumor agents. J Med Chem. 2015;58(4):1705–16.
Itoh Y, Aihara K, Mellini P, Tojo T, Ota Y, Tsumoto H, et al. Identification of SNAIL1 peptide-based irreversible lysine-specific demethylase 1-selective inactivators. J Med Chem. 2016;59(4):1531–44.
Wu F, Zhou C, Yao Y, Wei L, Feng Z, Deng L, et al. 3-(Piperidin-4-ylmethoxy)pyridine containing compounds are potent inhibitors of lysine specific demethylase 1. J Med Chem. 2016;59(1):253–63.
Borrello MT, Schinor B, Bartels K, Benelkebir H, Pereira S, Al-Jamal WT, et al. Fluorinated tranylcypromine analogues as inhibitors of lysine-specific demethylase 1 (LSD1, KDM1A). Bioorg Med Chem Lett. 2017;27(10):2099–101.
Sartori L, Mercurio C, Amigoni F, Cappa A, Fagá G, Fattori R, et al. Thieno[3,2-b]pyrrole-5-carboxamides as new reversible inhibitors of histone lysine demethylase KDM1A/LSD1. Part 1: high-throughput screening and preliminary exploration. J Med Chem. 2017;60(5):1673–92.
Sugino N, Kawahara M, Tatsumi G, Kanai A, Matsui H, Yamamoto R, et al. A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers. Leukemia. 2017;31(11):2303–14.
Yang C, Wang W, Liang J-X, Li G, Vellaisamy K, Wong C-Y, et al. A rhodium(III)-based inhibitor of lysine-specific histone demethylase 1 as an epigenetic modulator in prostate cancer cells. J Med Chem. 2017;60(6):2597–603.
Liu HM, Suo FZ, Li XB, You YH, Lv CT, Zheng CX, et al. Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors. Eur J Med Chem. 2019;175:357–72.
Liang L, Wang H, Du Y, Luo B, Meng N, Cen M, et al. New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: design, synthesis and biological evaluation. Bioorg Chem. 2020;99:103808.
Maes T, Mascaró C, Tirapu I, Estiarte A, Ciceri F, Lunardi S, et al. ORY-1001, a potent and selective covalent KDM1A inhibitor, for the treatment of acute leukemia. Cancer Cell. 2018;33(3):495–511.e12.
Salamero O, Montesinos P, Willekens C, Pérez-Simón JA, Pigneux A, Récher C, et al. First-in-human phase I study of Iadademstat (ORY-1001): a first-in-class lysine-specific histone demethylase 1A inhibitor, in relapsed or refractory acute myeloid leukemia. J Clin Oncol. 2020;38(36):4260–73.
Smitheman KN, Severson TM, Rajapurkar SR, McCabe MT, Karpinich N, Foley J, et al. Lysine specific demethylase 1 inactivation enhances differentiation and promotes cytotoxic response when combined with all-trans retinoic acid in acute myeloid leukemia across subtypes. Haematologica. 2019;104(6):1156–67.
Reyes-Garau D, Ribeiro ML, Roué G. Pharmacological targeting of BET bromodomain proteins in acute myeloid leukemia and malignant lymphomas: from molecular characterization to clinical applications. Cancers (Basel). 2019;11(10):1483.
Herrmann H, Blatt K, Shi J, Gleixner KV, Cerny-Reiterer S, Müllauer L, et al. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML. Oncotarget. 2012;3(12):1588–99.
Kang C, Kim CY, Kim HS, Park SP, Chung HM. The bromodomain inhibitor JQ1 enhances the responses to all-trans retinoic acid in HL-60 and MV4-11 leukemia cells. Int J Stem Cells. 2018;11(1):131–40.
Pericole FV, Lazarini M, de Paiva LB, Duarte ADSS, Vieira Ferro KP, Niemann FS, et al. BRD4 inhibition enhances azacitidine efficacy in acute myeloid leukemia and myelodysplastic syndromes. Front Oncol. 2019;9:16.
Fiskus W, Sharma S, Qi J, Shah B, Devaraj SG, Leveque C, et al. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Mol Cancer Ther. 2014;13(10):2315–27.
Gerlach D, Tontsch-Grunt U, Baum A, Popow J, Scharn D, Hofmann MH, et al. The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML. Oncogene. 2018;37(20):2687–701.
Coudé MM, Braun T, Berrou J, Dupont M, Bertrand S, Masse A, et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015;6(19):17698–712.
Gillberg L, Ørskov AD, Nasif A, Ohtani H, Madaj Z, Hansen JW, et al. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: normalization of plasma vitamin C induces epigenetic changes. Clin Epigenetics. 2019;11(1):143.
Mastrangelo D, Massai L, Fioritoni G, Coco FL, Noguera N, Testa U. High doses of vitamin c and leukemia: in vitro update. In: Myeloid leukemia. London: InTech; 2018.
Zhao H, Huayuan Z, Yu Z, Li J, Qian S. The synergy of vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia. Blood. 2017;130(Suppl 1):1339.
Cao F, Townsend EC, Karatas H, Xu J, Li L, Lee S, et al. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol Cell. 2014;53(2):247–61.
Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, et al. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell. 2015;27(4):589–602.
He S, Senter TJ, Pollock J, Han C, Upadhyay SK, Purohit T, et al. High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction. J Med Chem. 2014;57(4):1543–56.
Grembecka J, He S, Shi A, Purohit T, Muntean AG, Sorenson RJ, et al. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat Chem Biol. 2012;8(3):277–84.
Dzama MM, Steiner M, Rausch J, Sasca D, Schönfeld J, Kunz K, et al. Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition. Blood. 2020;136(21):2442–56.
Klossowski S, Miao H, Kempinska K, Wu T, Purohit T, Kim E, et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J Clin Invest. 2020;130(2):981–97.
Rau RE, Rodriguez BA, Luo M, Jeong M, Rosen A, Rogers JH, et al. DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia. Blood. 2016;128(7):971–81.
Kühn MW, Hadler MJ, Daigle SR, Koche RP, Krivtsov AV, Olhava EJ, et al. MLL partial tandem duplication leukemia cells are sensitive to small molecule DOT1L inhibition. Haematologica. 2015;100(5):e190–3.
Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Savona MR, et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018;131(24):2661–9.
Liu W, Deng L, Song Y, Redell M. DOT1L inhibition sensitizes MLL-rearranged AML to chemotherapy. PLoS One. 2014;9(5):e98270.
Ueda K, Yoshimi A, Kagoya Y, Nishikawa S, Marquez VE, Nakagawa M, et al. Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16. Cancer Sci. 2014;105(5):512–9.
Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, Tay KG, et al. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood. 2011;118(10):2830–9.
Jiang X, Lim CZ, Li Z, Lee PL, Yatim SM, Guan P, et al. Functional characterization of D9, a novel Deazaneplanocin a (DZNep) analog, in targeting acute myeloid leukemia (AML). PLoS One. 2015;10(4):e0122983.
Xu B, On DM, Ma A, Parton T, Konze KD, Pattenden SG, et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood. 2015;125(2):346–57.
Cheung N, Fung TK, Zeisig BB, Holmes K, Rane JK, Mowen KA, et al. Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia. Cancer Cell. 2016;29(1):32–48.
Kaushik S, Liu F, Veazey KJ, Gao G, Das P, Neves LF, et al. Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia. 2018;32(2):499–509.
Lin AB, McNeely SC, Beckmann RP. Achieving precision death with cell-cycle inhibitors that target DNA replication and repair. Clin Cancer Res. 2017;23(13):3232–40.
Esposito MT, So CW. DNA damage accumulation and repair defects in acute myeloid leukemia: implications for pathogenesis, disease progression, and chemotherapy resistance. Chromosoma. 2014;123(6):545–61.
Fritz C, Portwood SM, Przespolewski A, Wang ES. PARP goes the weasel! Emerging role of PARP inhibitors in acute leukemias. Blood Rev. 2021;45:100696.
Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99.
Faraoni I, Compagnone M, Lavorgna S, Angelini DF, Cencioni MT, Piras E, et al. BRCA1, PARP1 and γH2AX in acute myeloid leukemia: role as biomarkers of response to the PARP inhibitor olaparib. Biochim Biophys Acta. 2015;1852(3):462–72.
Yamauchi T, Uzui K, Nishi R, Shigemi H, Ueda T. Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in CD33-positive HL-60 myeloid leukemia cells. Anticancer Res. 2014;34(10):5487–94.
Wang L, Cai W, Zhang W, Chen X, Dong W, Tang D, et al. Inhibition of poly(ADP-ribose) polymerase 1 protects against acute myeloid leukemia by suppressing the myeloproliferative leukemia virus oncogene. Oncotarget. 2015;6(29):27490–504.
Portwood S, Puchalski RA, Walker RM, Wang ES. 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.
Robert C, Nagaria PK, Pawar N, Adewuyi A, Gojo I, Meyers DJ, et al. Histone deacetylase inhibitors decrease NHEJ both by acetylation of repair factors and trapping of PARP1 at DNA double-strand breaks in chromatin. Leuk Res. 2016;45:14–23.
Muvarak NE, Chowdhury K, Xia L, Robert C, Choi EY, Cai Y, et al. Enhancing the cytotoxic effects of PARP inhibitors with DNA demethylating agents—a potential therapy for cancer. Cancer Cell. 2016;30(4):637–50.
Gaymes TJ, Shall S, MacPherson LJ, Twine NA, Lea NC, Farzaneh F, et al. Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes. Haematologica. 2009;94(5):638–46.
Garcia TB, Snedeker JC, Baturin D, Gardner L, Fosmire SP, Zhou C, et al. A small-molecule inhibitor of WEE1, AZD1775, synergizes with olaparib by impairing homologous recombination and enhancing DNA damage and apoptosis in acute leukemia. Mol Cancer Ther. 2017;16(10):2058–68.
Gojo I, Beumer JH, Pratz KW, McDevitt MA, Baer MR, Blackford AL, et al. A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia. Clin Cancer Res. 2017;23(3):697–706.
Pratz KW, Rudek MA, Gojo I, Litzow MR, McDevitt MA, Ji J, et al. A phase I study of topotecan, carboplatin and the PARP inhibitor veliparib in acute leukemias, aggressive myeloproliferative neoplasms, and chronic myelomonocytic leukemia. Clin Cancer Res. 2017;23(4):899–907.
Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. 2017;9(375):eaal2463.
Fordham SE, Blair HJ, Elstob CJ, Plummer R, Drew Y, Curtin NJ, et al. Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase. Blood Adv. 2018;2(10):1157–69.
Morgado-Palacin I, Day A, Murga M, Lafarga V, Anton ME, Tubbs A, et al. Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML. Sci Signal. 2016;9(445):ra91.
Ma J, Li X, Su Y, Zhao J, Luedtke DA, Epshteyn V, et al. Mechanisms responsible for the synergistic antileukemic interactions between ATR inhibition and cytarabine in acute myeloid leukemia cells. Sci Rep. 2017;7(1):41950.
Grosjean-Raillard J, Tailler M, Adès L, Perfettini JL, Fabre C, Braun T, et al. ATM mediates constitutive NF-kappaB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene. 2009;28(8):1099–109.
David L, Fernandez-Vidal A, Bertoli S, Grgurevic S, Lepage B, Deshaies D, et al. CHK1 as a therapeutic target to bypass chemoresistance in AML. Sci Signal. 2016;9(445):ra90.
Vincelette ND, Ding H, Huehls AM, Flatten KS, Kelly RL, Kohorst MA, et al. Effect of CHK1 inhibition on CPX-351 cytotoxicity in vitro and ex vivo. Sci Rep. 2019;9(1):3617.
Zhao J, Niu X, Li X, Edwards H, Wang G, Wang Y, et al. Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Oncotarget. 2016;7(23):34785–99.
David L, Manenti S, Récher C, Hoffmann JS, Didier C. Targeting ATR/CHK1 pathway in acute myeloid leukemia to overcome chemoresistance. Mol Cell Oncol. 2017;4(5):e1289293.
Dai Y, Chen S, Kmieciak M, Zhou L, Lin H, Pei XY, et al. The novel Chk1 inhibitor MK-8776 sensitizes human leukemia cells to HDAC inhibitors by targeting the intra-S checkpoint and DNA replication and repair. Mol Cancer Ther. 2013;12(6):878–89.
Webster JA, Tibes R, Morris L, Blackford AL, Litzow M, Patnaik M, et al. Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia. Leuk Res. 2017;61:108–16.
Porter CC, Kim J, Fosmire S, Gearheart CM, van Linden A, Baturin D, et al. Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia. Leukemia. 2012;26(6):1266–76.
Tibes R, McDonagh KT, Lekakis L, Bogenberger JM, Kim S, Frazer N, et al. Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias. Investig New Drugs. 2015;33(2):389–96.
Yang C, Boyson CA, Di Liberto M, Huang X, Hannah J, Dorn DC, et al. CDK4/6 inhibitor PD 0332991 sensitizes acute myeloid leukemia to cytarabine-mediated cytotoxicity. Cancer Res. 2015;75(9):1838–45.
Uras IZ, Walter GJ, Scheicher R, Bellutti F, Prchal-Murphy M, Tigan AS, et al. Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood. 2016;127(23):2890–902.
Uras IZ, Maurer B, Nebenfuehr S, Zojer M, Valent P, Sexl V. Therapeutic vulnerabilities in FLT3-mutant AML unmasked by palbociclib. Int J Mol Sci. 2018;19(12):3987.
Li C, Liu L, Liang L, Xia Z, Li Z, Wang X, et al. AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia. Mol Cancer Ther. 2015;14(2):375–83.
Fröhling S, Agrawal M, Jahn N, Fransecky LR, Baldus CD, Wäsch R, et al. CDK4/6 inhibitor palbociclib for treatment of KMT2A-rearranged acute myeloid leukemia: interim analysis of the AMLSG 23-14 trial. Blood. 2016;128(22):1608.
Kadia TM, Konopleva MY, Garcia-Manero G, Benton CB, Wierda WG, Bose P, et al. Phase I study of palbociclib alone and in combination in patients with relapsed and refractory (R/R) leukemias. Blood. 2018;132(Suppl 1):4057.
Sorf A, Sucha S, Morell A, Novotna E, Staud F, Zavrelova A, et al. Targeting pharmacokinetic drug resistance in acute myeloid leukemia cells with CDK4/6 inhibitors. Cancers (Basel). 2020;12(6):1596.
Borthakur GM, Donnellan WB, Solomon SR, Abboud C, Nazha A, Mazan M, et al. SEL120—a first-in-class CDK8/19 inhibitor as a novel option for the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome—data from preclinical studies and introduction to a phase Ib clinical trial. Blood. 2019;134(Suppl_1):2651.
Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature. 2015;526(7572):273–6.
Chantkran W, Zheleva D, Frame S, Hsieh Y-C, Copland M. Combination of CYC065, a second generation CDK2/9 inhibitor, with venetoclax or standard chemotherapies—a novel therapeutic approach for acute myeloid leukaemia (AML). Blood. 2019;134(Suppl_1):3938.
Cidado J, Boiko S, Proia T, Ferguson D, Criscione SW, San Martin M, et al. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin Cancer Res. 2020;26(4):922–34.
Luedtke DA, Su Y, Ma J, Li X, Buck SA, Edwards H, et al. Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia. Signal Transduct Target Ther. 2020;5(1):17.
Li KL, Bray SC, Iarossi D, Adams J, Zhong L, Noll B, et al. Investigation of a novel cyclin-dependent-kinase (CDK) inhibitor Cdki-73 as an effective treatment option for MLL-AML. Blood. 2015;126(23):1365.
Phillips DC, Jin S, Gregory GP, Zhang Q, Xue J, Zhao X, et al. A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies. Leukemia. 2020;34(6):1646–57.
Nishi R, Shigemi H, Negoro E, Okura M, Hosono N, Yamauchi T. Venetoclax and alvocidib are both cytotoxic to acute myeloid leukemia cells resistant to cytarabine and clofarabine. BMC Cancer. 2020;20(1):984.
Karp JE, Ross DD, Yang W, Tidwell ML, Wei Y, Greer J, et al. Timed sequential therapy of acute leukemia with flavopiridol: in vitro model for a phase I clinical trial. Clin Cancer Res. 2003;9(1):307–15.
Bogenberger J, Whatcott C, Hansen N, Delman D, Shi CX, Kim W, et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017;8(63):107206–22.
Karp JE, Passaniti A, Gojo I, Kaufmann S, Bible K, Garimella TS, et al. Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin Cancer Res. 2005;11(23):8403–12.
Zeidner JF, Karp JE. Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia. Leuk Res. 2015;39(12):1312–8.
Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100(9):1172–9.
Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, et al. Final results of a randomized multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus cytarabine and daunorubicin (7 + 3) in newly diagnosed high-risk acute myeloid leukemia (AML). Leuk Res. 2018;72:92–5.
Baker A, Gregory GP, Verbrugge I, Kats L, Hilton JJ, Vidacs E, et al. The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia. Cancer Res. 2016;76(5):1158–69.
Gojo I, Sadowska M, Walker A, Feldman EJ, Iyer SP, Baer MR, et al. Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias. Cancer Chemother Pharmacol. 2013;72(4):897–908.
Willems E, Dedobbeleer M, Digregorio M, Lombard A, Lumapat PN, Rogister B. The functional diversity of aurora kinases: a comprehensive review. Cell Div. 2018;13(1):7.
Brunner AM, Blonquist TM, DeAngelo DJ, McMasters M, Winer ES, Hobbs GS, et al. Phase II clinical trial of alisertib, an Aurora a kinase inhibitor, in combination with induction chemotherapy in high-risk, untreated patients with acute myeloid leukemia. Blood. 2018;132(Suppl 1):766.
Löwenberg B, Muus P, Ossenkoppele G, Rousselot P, Cahn JY, Ifrah N, et al. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia. Blood. 2011;118(23):6030–6.
Kantarjian HM, Sekeres MA, Ribrag V, Rousselot P, Garcia-Manero G, Jabbour EJ, et al. Phase I study assessing the safety and tolerability of barasertib (AZD1152) with low-dose cytosine arabinoside in elderly patients with AML. Clin Lymphoma Myeloma Leuk. 2013;13(5):559–67.
Ghelli Luserna di Rora’ A, Iacobucci I, Martinelli G. The cell cycle checkpoint inhibitors in the treatment of leukemias. J Hematol Oncol. 2017;10(1):77.
Brandwein JM. Targeting polo-like kinase 1 in acute myeloid leukemia. Ther Adv Hematol. 2015;6(2):80–7.
Gjertsen BT, Schöffski P. Discovery and development of the polo-like kinase inhibitor volasertib in cancer therapy. Leukemia. 2015;29(1):11–9.
Gumireddy K, Reddy MV, Cosenza SC, Boominathan R, Baker SJ, Papathi N, et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell. 2005;7(3):275–86.
Navada SC, Fruchtman SM, Odchimar-Reissig R, Demakos EP, Petrone ME, Zbyszewski PS, et al. A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia. Leuk Res. 2018;64:10–6.
Navada SC, Garcia-Manero G, OdchimarReissig R, Pemmaraju N, Alvarado Y, Ohanian MN, et al. Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: results of a phase 1 study. Leuk Res. 2020;94:106369.
Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, et al. BI 6727, a polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009;15(9):3094–102.
Bug G, Schlenk RF, Müller-Tidow C, Lübbert M, Krämer A, Fleischer F, et al. Phase I/II study of BI 6727 (volasertib), an intravenous polo-like kinase-1 (Plk1) inhibitor, in patients with acute myeloid leukemia (AML): results of the dose finding for BI 6727 in combination with low-dose cytarabine. Blood. 2010;116(21):3316.
Bug G, Müller-Tidow C, Schlenk RF, Krämer A, Lübbert M, Krug U, et al. Phase I/II study of volasertib (BI 6727), an intravenous polo-like kinase (Plk) inhibitor, in patients with acute myeloid leukemia (AML): updated results of the dose finding phase I part for volasertib in combination with low-dose cytarabine (LD-Ara-C) and as monotherapy in relapsed/refractory AML. Blood. 2011;118(21):1549.
Döhner H, Lübbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood. 2014;124(9):1426–33.
Cortes J, Podoltsev N, Kantarjian H, Borthakur G, Zeidan AM, Stahl M, et al. Phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia. Int J Hematol. 2021;113(1):92–9.
Ridgefield C. Results of phase III study of volasertib for the treatment of acute myeloid leukemia presented at European Hematology Association Annual Meeting Boehringer Ingelheim. 2016. https://www.boehringer-ingelheim.us/press-release/results-phase-iii-study-volasertib-treatment-acute-myeloid-leukemia-presented-european.
Zeidan AM, Ridinger M, Lin TL, Becker PS, Schiller GJ, Patel PA, et al. A phase Ib study of onvansertib, a novel oral PLK1 inhibitor, in combination therapy for patients with relapsed or refractory acute myeloid leukemia. Clin Cancer Res. 2020;26(23):6132–40.
Lee K-H, Schlenk RF, Bug G, Müller-Tidow C, Waesch RM, Nachbaur D, et al. Polo-like kinase-1 (Plk-1) inhibitor BI 2536 induces mitotic arrest and apoptosis in vivo: first demonstration of target inhibition in the bone marrow of AML patients. Blood. 2008;112(11):2641.
Müller-Tidow C, Bug G, Schlenk R, Lübbert M, Krämer A, Krauter J, et al. Phase I/II study of BI 2536, an intravenous polo-like Kinase-1 (Plk-1) inhibitor, in elderly patients with relapsed or refractory acute myeloid leukemia (AML): first results of a multi-center trial. Blood. 2008;112(11):2973.
Müller-Tidow C, Bug G, Lübbert M, Krämer A, Krauter J, Valent P, et al. A randomized, open-label, phase I/II trial to investigate the maximum tolerated dose of the polo-like kinase inhibitor BI 2536 in elderly patients with refractory/relapsed acute myeloid leukaemia. Br J Haematol. 2013;163(2):214–22.
Hikichi Y, Honda K, Hikami K, Miyashita H, Kaieda I, Murai S, et al. TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens. Mol Cancer Ther. 2012;11(3):700–9.
Casolaro A, Golay J, Albanese C, Ceruti R, Patton V, Cribioli S, et al. The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia. PLoS One. 2013;8(3):e58424.
Brenner AK, Reikvam H, Rye KP, Hagen KM, Lavecchia A, Bruserud Ø. CDC25 inhibition in acute myeloid leukemia-a study of patient heterogeneity and the effects of different inhibitors. Molecules. 2017;22(3):446.
Chae H-D, Dutta R, Tiu B, Hoff FW, Accordi B, Serafin V, et al. RSK inhibitor BI-D1870 inhibits acute myeloid leukemia cell proliferation by targeting mitotic exit. Oncotarget. 2020;11(25):2387–403.
Dutta R, Castellanos M, Tiu B, Chae H-D, Davis KL, Sakamoto KM. RSK inhibition suppresses AML proliferation through activation of DNA damage pathways and S phase arrest. Blood. 2016;128(22):2894.
Rashidi A, Uy GL. Targeting the microenvironment in acute myeloid leukemia. Curr Hematol Malig Rep. 2015;10(2):126–31.
Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood. 2012;119(17):3917–24.
Uy GL, Avigan D, Cortes JE, Becker PS, Chen RW, Liesveld JL, et al. Safety and tolerability of plerixafor in combination with cytarabine and daunorubicin in patients with newly diagnosed acute myeloid leukemia- preliminary results from a phase I study. Blood. 2011;118(21):82.
Roboz GJ, Scandura JM, Ritchie E, Dault Y, Lam L, Xie W, et al. Combining decitabine with plerixafor yields a high response rate in newly diagnosed older patients with AML. Blood. 2013;122(21):621.
Andreeff M, Borthakur G, Zeng Z, Kelly MA, Wang R-Y, McQueen TJ, et al. Mobilization and elimination of FLT3-ITD+ acute myelogenous leukemia (AML) stem/progenitor cells by plerixafor, G-CSF, and sorafenib: phase I trial results in relapsed/refractory AML patients. J Clin Oncol. 2014;32(15_suppl):7033.
Barbier V, Erbani J, Fiveash C, Davies JM, Tay J, Tallack MR, et al. Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance. Nat Commun. 2020;11(1):2042.
DeAngelo DJ, Liesveld JL, Jonas BA, O’Dwyer ME, Bixby DL, Magnani JL, et al. A phase I/II study of GMI-1271, a novel E-selectin antagonist, in combination with induction chemotherapy in relapsed/refractory and elderly previously untreated acute myeloid leukemia; results to date. Blood. 2016;128(22):4049.
DeAngelo DJ, Jonas BA, Liesveld JL, Bixby DL, Advani AS, Marlton P, et al. GMI-1271 improves efficacy and safety of chemotherapy in R/R and newly diagnosed older patients with AML: results of a Phase 1/2 study. Blood. 2017;130(Suppl 1):894.
DeAngelo DJ, Jonas BA, Becker PS, O’Dwyer M, Advani AS, Marlton P, et al. GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML. J Clin Oncol. 2017;35(15_suppl):2560.
Stanchina M, Soong D, Zheng-Lin B, Watts JM, Taylor J. Advances in acute myeloid leukemia: recently approved therapies and drugs in development. Cancers (Basel). 2020;12(11):3225.
Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie J-N, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508–16.
Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, 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. 2019;104(1):113–9.
Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, 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):972–9.
Schlenk RF, Paschka P, Krzykalla J, Weber D, Kapp-Schwoerer S, Gaidzik VI, et al. Gemtuzumab ozogamicin in NPM1-mutated acute myeloid leukemia: early results from the prospective randomized AMLSG 09-09 Phase III study. J Clin Oncol. 2020;38(6):623–32.
Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, 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):1455–63.
Bixby DL, Stein AS, Fathi AT, Kovacsovics TJ, Levy MY, Erba HP, et al. Vadastuximab talirine monotherapy in older patients with treatment naive CD33-positive acute myeloid leukemia (AML). Blood. 2016;128(22):590.
Stein EM, Walter RB, Erba HP, Fathi AT, Advani AS, Lancet JE, et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood. 2018;131(4):387–96.
Fathi AT, Erba HP, Lancet JE, Stein EM, Ravandi F, Faderl S, et al. Vadastuximab talirine plus hypomethylating agents: a well-tolerated regimen with high remission rate in frontline older patients with acute myeloid leukemia (AML). Blood. 2016;128(22):591.
Fathi AT, Erba HP, Lancet JE, Stein EM, Ravandi F, Faderl S, et al. A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML. Blood. 2018;132(11):1125–33.
Hofland P. Phase III CASCADE clinical trial of vadastuximab talirine in frontline acute myeloid leukemia discontinued ADC review. Journal of Antibody-Drug Conjugates. 2017. https://www.adcreview.com/news/phase-iii-cascade-clinical-trial-vadastuximab-talirine-frontline-acute-myeloid-leukemia-discontinued/.
Whiteman KR, Noordhuis P, Walker R, Watkins K, Kovtun Y, Harvey L, et al. The antibody-drug conjugate (ADC) IMGN779 is highly active in vitro and in vivo against acute myeloid leukemia (AML) with FLT3-ITD mutations. Blood. 2014;124(21):2321.
Kovtun Y, Noordhuis P, Whiteman KR, Watkins K, Jones GE, Harvey L, et al. IMGN779, a novel CD33-targeting antibody-drug conjugate with DNA-alkylating activity, exhibits potent antitumor activity in models of AML. Mol Cancer Ther. 2018;17(6):1271–9.
Cortes JE, DeAngelo DJ, Erba HP, Traer E, Papadantonakis N, Arana-Yi C, 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(Suppl 1):26.
Daver NG, Erba HP, Papadantonakis N, DeAngelo DJ, Wang ES, Konopleva MY, et al. A phase I, first-in-human study evaluating the safety and preliminary Antileukemia activity of IMGN632, a novel CD123-targeting antibody-drug conjugate, in patients with relapsed/refractory acute myeloid leukemia and other CD123-positive hematologic malignancies. Blood. 2018;132(Suppl 1):27.
Kuruvilla VM, Zhang Q, Daver N, Watkins K, Sloss CM, Zweidler-McKay PA, et al. Combining IMGN632, a novel CD123-targeting antibody drug conjugate with azacitidine and venetoclax facilitates apoptosis in vitro and prolongs survival in vivo in AML models. Blood. 2020;136(Suppl 1):32–3.
Williams BA, Law A, Hunyadkurti J, Desilets S, Leyton JV, Keating A. Antibody therapies for acute myeloid leukemia: unconjugated, toxin-conjugated, radio-conjugated and multivalent formats. J Clin Med. 2019;8(8):1261.
Matthews DC, Appelbaum FR, Eary JF, Fisher DR, Durack LD, Hui TE, et al. Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood. 1999;94(4):1237–47.
Pagel JM, Appelbaum FR, Eary JF, Rajendran J, Fisher DR, Gooley T, et al. 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood. 2006;107(5):2184–91.
Pagel JM, Gooley TA, Rajendran J, Fisher DR, Wilson WA, Sandmaier BM, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-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):5444–53.
Mawad R, Gooley TA, Rajendran JG, Fisher DR, Gopal AK, Shields AT, et al. Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome. Biol Blood Marrow Transplant. 2014;20(9):1363–8.
Orozco JJ, Kenoyer A, Balkin ER, Gooley TA, Hamlin DK, Wilbur DS, et al. Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment. Blood. 2016;127(3):352–9.
Orozco JJ, Zeller J, Pagel JM. Radiolabeled antibodies directed at CD45 for conditioning prior to allogeneic transplantation in acute myeloid leukemia and myelodysplastic syndrome. Ther Adv Hematol. 2012;3(1):5–16.
Jurcic JG, Ravandi F, Pagel JM, Park JH, Smith BD, Douer D, et al. Phase I trial of α-particle therapy with actinium-225 (225Ac)-lintuzumab (anti-CD33) and low-dose cytarabine (LDAC) in older patients with untreated acute myeloid leukemia (AML). J Clin Oncol. 2015;33(15_suppl):7050.
Ravandi F, Assi R, Daver N, Benton CB, Kadia T, Thompson PA, 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):e480–8.
Guy DG, Uy GL. Bispecific antibodies for the treatment of acute myeloid leukemia. Curr Hematol Malig Rep. 2018;13(6):417–25.
Taghiloo S, Asgarian-Omran H. Immune evasion mechanisms in acute myeloid leukemia: a focus on immune checkpoint pathways. Crit Rev Oncol Hematol. 2021;157:103164.
Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE, et al. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, phase II study. Cancer Discov. 2019;9(3):370–83.
Daver NG, Garcia-Manero G, Konopleva MY, Alfayez M, Pemmaraju N, Kadia TM, et al. Azacitidine (AZA) with nivolumab (Nivo), and AZA with Nivo + ipilimumab (Ipi) in relapsed/refractory acute myeloid leukemia: a non-randomized, prospective, phase 2 study. Blood. 2019;134(Suppl_1):830.
Liao D, Wang M, Liao Y, Li J, Niu T. A review of efficacy and safety of checkpoint inhibitor for the treatment of acute myeloid leukemia. Front Pharmacol. 2019;10:609.
Gojo I, Stuart RK, Webster J, Blackford A, Varela JC, Morrow J, et al. Multi-center 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(Suppl_1):832.
Lindblad KE, Thompson J, Gui G, Valdez J, Worthy T, Tekleab H, et al. Pembrolizumab and Decitabine for refractory or relapsed acute myeloid leukemia. Blood. 2018;132(Suppl 1):1437.
Zeidner JF, Vincent BG, Esparza S, Ivanova A, Moore DT, Foster MC, et al. Final clinical results of a phase II study of high dose cytarabine followed by pembrolizumab in relapsed/refractory AML. Blood. 2019;134(Suppl_1):831.
Zheng H, Mineishi S, Claxton DF, Zhu J, Zhao C, Jia B, et al. Effect of avelumab to immune response in AML: a phase I study of avelumab in combination with decitabine as first line treatment of unfit patients. Blood. 2019;134(Suppl_1):3939.
Zeidan AM, Cavenagh J, Voso MT, Taussig D, Tormo M, Boss I, et al. Efficacy and safety of azacitidine (AZA) in combination with the anti-PD-L1 durvalumab (durva) for the front-line treatment of older patients (pts) with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy (IC) and Pts with higher-risk myelodysplastic syndromes (HR-MDS): results from a large, international, randomized phase 2 study. Blood. 2019;134(Suppl_1):829.
Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143–53.
Borate U, Esteve J, Porkka K, Knapper S, Vey N, Scholl S, et al. Phase Ib study of the anti-TIM-3 antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood. 2019;134(Suppl_1):570.
Chao MP, Takimoto CH, Feng DD, McKenna K, Gip P, Liu J, et al. Therapeutic targeting of the macrophage immune checkpoint CD47 in myeloid malignancies. Front Oncol. 2019;9:1380.
Sallman DA, Asch AS, Al Malki MM, Lee DJ, Donnellan WB, Marcucci G, et al. The first-in-class anti-CD47 antibody magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: ongoing phase 1b results. Blood. 2019;134(Suppl_1):569.
Deng J, Zhao S, Zhang X, Jia K, Wang H, Zhou C, He Y. OX40 (CD134) and OX40 ligand, important immune checkpoints in cancer. OncoTargets and therapy. 2019;12:7347.
Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol. 2015;8:130.
Krupka C, Kufer P, Kischel R, Zugmaier G, Bögeholz J, Köhnke T, et al. CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood. 2014;123(3):356–65.
Laszlo GS, Gudgeon CJ, Harrington KH, Dell’Aringa J, Newhall KJ, Means GD, 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):554–61.
Subklewe M, Stein A, Walter RB, Bhatia R, Wei AH, Ritchie D, 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(Suppl_1):833.
Reusch U, Harrington KH, Gudgeon CJ, Fucek I, Ellwanger K, Weichel M, et al. Characterization of CD33/CD3 tetravalent bispecific tandem diabodies (TandAbs) for the treatment of acute myeloid leukemia. Clin Cancer Res. 2016;22(23):5829–38.
Westervelt P, Cortes JE, Altman JK, Long M, Oehler VG, Gojo I, 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(Suppl_1):834.
Uy GL, Godwin J, Rettig MP, Vey N, Foster M, Arellano ML, et al. Preliminary results of a phase 1 study of flotetuzumab, a CD123 x CD3 bispecific Dart® protein, in patients with relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. Blood. 2017;130(Suppl 1):637.
Xencor. Xencor announces partial clinical hold on phase 1 study of XmAb14045. 2019. https://investors.xencor.com/news-releases/news-release-details/xencor-announces-partial-clinical-hold-phase-1-study-xmab14045.
Wire B. Xencor announces partial clinical hold lifted on phase 1 study of XmAb®14045. 2019. https://www.businesswire.com/news/home/20190430005312/en/Xencor-Announces-Partial-Clinical-Hold-Lifted-on-Phase-1-Study-of-XmAb®14045.
Ravandi F, Bashey A, Foran JM, Stock W, Mawad R, Blum W, et al. Complete responses in relapsed/refractory acute myeloid leukemia (AML) patients on a weekly dosing schedule of XmAb14045, a CD123 x CD3 T cell-engaging bispecific antibody: initial results of a phase 1 study. Blood. 2018;132(Suppl 1):763.
Przespolewski AC, Griffiths EA. BITES and CARS and checkpoints, oh my! Updates regarding immunotherapy for myeloid malignancies from the 2018 annual ASH meeting. Blood Rev. 2020;43:100654.
Sallman DA, Brayer J, Sagatys EM, Lonez C, Breman E, Agaugué S, et al. NKG2D-based chimeric antigen receptor therapy induced remission in a relapsed/refractory acute myeloid leukemia patient. Haematologica. 2018;103(9):e424–e6.
Sallman DA, Kerre T, Poire X, Havelange V, Lewalle P, Davila ML, et al. Remissions in relapse/refractory acute myeloid leukemia patients following treatment with NKG2D CAR-T therapy without a prior preconditioning chemotherapy. Blood. 2018;132(Suppl 1):902.
Liu F, Cao Y, Pinz K, Ma Y, Wada M, Chen K, et al. First-in-human CLL1-CD33 compound CAR T cell therapy induces complete remission in patients with refractory acute myeloid leukemia: update on Phase 1 clinical trial. Blood. 2018;132(Suppl 1):901.
Fang Liu HZ, Lihua Sun, Yecheng Li, Shan Zhang, Guangcui He, Hai Yi, Masayuki Wada, Kevin G Pinz, Kevin H Chen, Yu Ma, Yisong Xiong, Yi Su, Yupo Ma. First-in-human CLL1-CD33 compound car (CCAR) T cell therapy in relapsed and refractory acute myeloid leukemia. 2020. https://library.ehaweb.org/eha/2020/eha25th/294969/fang.liu.first-in-human.cll1-cd33.compound.car.28ccar29.t.cell.therapy.in.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Ds149.
Myburgh R, Kiefer JD, Russkamp NF, Magnani CF, Nuñez N, Simonis A, et al. Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. Leukemia. 2020;34(10):2688–703.
Sommer C, Cheng H-Y, Yeung YA, Nguyen D, Sutton J, Melton Z, et al. Preclinical evaluation of ALLO-819, an allogeneic CAR T cell therapy targeting FLT3 for the treatment of acute myeloid leukemia. Blood. 2019;134(Suppl_1):3921.
Dos Santos C, Xiaochuan S, Chenghui Z, Habineza Ndikuyeze G, Glover J, Secreto T, et al. Anti-leukemic activity of daratumumab in acute myeloid leukemia cells and patient-derived Xenografts. Blood. 2014;124(21):2312.
Mistry JJ, Hellmich C, Moore JA, Marlein CR, Pillinger G, Collins A, et al. Daratumumab inhibits AML metabolic capacity and tumor growth through inhibition of CD38 mediated mitochondrial transfer from bone marrow stromal cells to blasts in the leukemic microenvironment. Blood. 2019;134(Suppl_1):1385.
Jelinek T, Zabaleta A, Perez C, Ajona D, Alignani D, Rodriguez I, et al. Pre-clinical efficacy of the anti-CD38 monoclonal antibody (mAb) Isatuximab in acute myeloid leukemia (AML). Blood. 2017;130(Suppl 1):2655.
Busfield SJ, Biondo M, Wong M, Ramshaw HS, Lee EM, Ghosh S, et al. Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC. Leukemia. 2014;28(11):2213–21.
Kubasch AS, Schulze F, Giagounidis A, Götze KS, Krönke J, Sockel K, et al. Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents. Leukemia. 2020;34(4):1182–6.
Montesinos P, Roboz GJ, Bulabois CE, Subklewe M, Platzbecker U, Ofran Y, 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.
Bjordahl R, Gaidarova S, Woan K, Cichocki F, Bonello G, Robinson M, et al. FT538: preclinical development of an off-the-shelf adoptive NK cell immunotherapy with targeted disruption of CD38 to prevent anti-CD38 antibody-mediated fratricide and enhance ADCC in multiple myeloma when combined with daratumumab. Blood. 2019;134(Suppl_1):133.
Janakiram M, Vij R, Siegel DS, Shih T, Weymer S, Valamehr B, et al. A phase I study of FT538, a first-of-kind, off-the-shelf, multiplexed engineered, iPSC-derived NK cell therapy as monotherapy in relapsed/refractory acute myelogenous leukemia and in combination with daratumumab or elotuzumab in relapsed/refractory multiple myeloma. Blood. 2020;136(Suppl 1):3.
Maslak PG, Dao T, Bernal Y, Chanel SM, Zhang R, Frattini M, et al. Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia. Blood Adv. 2018;2(3):224–34.
SELLAS. SELLAS announces positive follow-up phase 1/2 clinical data for galinpepimut-S (GPS) in acute myeloid leukemia (AML). 2020. https://www.globenewswire.com/news-release/2020/02/26/1990972/0/en/SELLAS-Announces-Positive-Follow-Up-Phase-1-2-Clinical-Data-for-Galinpepimut-S-GPS-in-Acute-Myeloid-Leukemia-AML.html.
Kobayashi Y, Sakura T, Miyawaki S, Toga K, Sogo S, Heike Y. A new peptide vaccine OCV-501: in vitro pharmacology and phase 1 study in patients with acute myeloid leukemia. Cancer Immunol Immunother. 2017;66(7):851–63.
van de Loosdrecht AA, van Wetering S, Santegoets S, Singh SK, Eeltink CM, den Hartog Y, et al. A novel allogeneic off-the-shelf dendritic cell vaccine for post-remission treatment of elderly patients with acute myeloid leukemia. Cancer Immunol Immunother. 2018;67(10):1505–18.
Dhodapkar MV, Sznol M, Zhao B, Wang D, Carvajal RD, Keohan ML, et al. Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205. Sci Transl Med. 2014;6(232):232ra51.
Saxena M, Sabado RL, La Mar M, Mohri H, Salazar AM, Dong H, et al. Poly-ICLC, a TLR3 agonist, induces transient innate immune responses in patients with treated HIV-infection: a randomized double-blinded placebo controlled trial. Front Immunol. 2019;10:725.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Gill, H., Yip, A. (2023). In the Pipeline: Emerging Therapy for Acute Myeloid Leukaemia. In: Gill, H., Kwong, YL. (eds) Pathogenesis and Treatment of Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-99-3810-0_16
Download citation
DOI: https://doi.org/10.1007/978-981-99-3810-0_16
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-99-3809-4
Online ISBN: 978-981-99-3810-0
eBook Packages: MedicineMedicine (R0)