Skip to main content
SpringerLink
Log in

Future Developments: Novel Agents

  • Chapter
  • First Online:
Acute Myeloid Leukemia

Part of the book series: Hematologic Malignancies ((HEMATOLOGIC))

Abstract

Rapid increases in genomic insights into the molecular sub-structure of acute myeloid leukaemia (AML) have not been followed by similarly rapid improvements in therapeutic options, until recently. A swathe of new drug approvals by the FDA has resulted in a subset of drugs also receiving approval in the European Union (EMA). These drugs have been discussed elsewhere in this book. This chapter will focus on new, non-immune-based therapies which have potential to make a clinical impact for patients with AML in the near future. These agents and their targets include venetoclax (BCL-2), enasidenib (IDH2), ivosidenib (IDH1), glasdegib (Hedgehog), CC-486 (methylation), quizartinib (FLT3), APR-246 (mutant TP53), idasanutlin (MDM2) and pracinostat (HDAC). We aim to briefly summarise key clinical data in relation to these drugs, with a focus on resistance mechanisms and potential future strategies to overcome these evolutionary hurdles.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Abaza YM, Kadia TM, Jabbour EJ, Konopleva MY, Borthakur G, Ferrajoli A, Estrov Z, Wierda WG, Alfonso A, Chong TH, Chuah C, Koh L-P, Goh B-C, Chang JE, Durkes DE, Foudray MC, Kantarjian HM, Dong XQ, Garcia-Manero G (2017) Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies. Cancer 123(24):4851–4859. https://doi.org/10.1002/cncr.30949

    Article  CAS  PubMed  Google Scholar 

  • Aboudalle I, Konopleva MY, Kadia TM, Naqvi K, Vaughan K, Kurt M, Cavazos A, Pierce SA, Takahashi K, Masarova L (2019) A phase Ib/II study of the BCL-2 inhibitor Venetoclax in combination with standard intensive AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed or relapsed/refractory AML. American Society of Hematology, Washington, DC

    Book  Google Scholar 

  • Ali D, Jönsson-Videsäter K, Deneberg S, Bengtzén S, Nahi H, Paul C, Lehmann S (2011) APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells. Eur J Haematol 86(3):206–215

    Article  CAS  PubMed  Google Scholar 

  • Astorgues-Xerri L, Vázquez R, Odore E, Rezai K, Kahatt C, Mackenzie S, Bekradda M, Coudé M-M, Dombret H, Gardin C (2019) Insights into the cellular pharmacological properties of the BET-inhibitor OTX015/MK-8628 (birabresib), alone and in combination, in leukemia models. Leuk Lymphoma 60(12):3067–3070

    Article  PubMed  Google Scholar 

  • Baker SD, Zimmerman EI, Wang Y-D, Orwick S, Zatechka DS, Buaboonnam J, Neale GA, Olsen SR, Enemark EJ, Shurtleff S (2013) Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD–positive acute myeloid leukemia. Clin Cancer Res 19(20):5758–5768

    Article  CAS  PubMed  Google Scholar 

  • Bartaula-Brevik S, Lindstad Brattås MK, Tvedt THA, Reikvam H, Bruserud Ø (2018) Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia. Expert Opin Investig Drugs 27(4):377–387. https://doi.org/10.1080/13543784.2018.1459562

    Article  CAS  PubMed  Google Scholar 

  • Blombery P, Anderson MA, Gong J-N, Thijssen R, Birkinshaw RW, Thompson ER, Teh CE, Nguyen T, Xu Z, Flensburg C (2019) Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov 9(3):342–353

    Article  CAS  PubMed  Google Scholar 

  • Burchert A, Bug G, Finke J, Stelljes M, Rollig C, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G (2018) Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicentre sormain trial. Blood 132(Suppl 1):661

    Article  Google Scholar 

  • Burrows F, Wu T, Kessler L, Li S, Zhang J, Zarrinkar P, Li L, Cierpicki T, Grembecka J, Ren P (2018) Abstract LB-A27: a novel small molecule menin-MLL inhibitor for potential treatment of MLL-rearranged leukemias and NPM1/DNMT3A-mutant AML. AACR

    Google Scholar 

  • Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG, Selivanova G (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8(3):282–288

    Article  CAS  PubMed  Google Scholar 

  • Cancer Genome Atlas Research Network, Ley TJ, Miller C et al (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368(22):2059–2074. https://doi.org/10.1056/NEJMoa1301689

    Article  CAS  Google Scholar 

  • Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie J-N, Legrand O, Thomas X, Turlure P, Reman O (2012) 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 379(9825):1508–1516

    Article  CAS  PubMed  Google Scholar 

  • Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong W-J, Zhao F, Medeiros BC, Tyvoll DA, Majeti R (2015) Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 21(2):178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaturvedi A, Cruz MMA, Jyotsana N, Sharma A, Yun H, Görlich K, Wichmann M, Schwarzer A, Preller M, Thol F (2013) Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 122(16):2877–2887

    Article  CAS  PubMed  Google Scholar 

  • Chen S-L, Qin Z-Y, Hu F, Wang Y, Dai Y-J, Liang Y (2019) The role of the HOXA gene family in acute myeloid leukemia. Genes 10(8):621

    Article  CAS  PubMed Central  Google Scholar 

  • Chua CC, Reynolds J, Salmon JM, Fong C, Ting SB, Tiong IS, Fleming S, MacRaild S, Moujalled DM, Pomilio G (2019) Anti-leukemic activity of single agent Venetoclax in newly diagnosed acute myeloid leukemia: a sub-set analysis of the Caveat study. American Society of Hematology, Washington, DC

    Google Scholar 

  • Chua CC, Roberts AW, Reynolds J, Fong CY, Ting SB, Salmon JM, MacRaild S, Ivey A, Tiong IS, Fleming S, Brown FC, Loo S, Majewski IJ, Bohlander SK, Wei AH (2020) Chemotherapy and Venetoclax in elderly acute myeloid leukemia trial (CAVEAT): a phase Ib dose-escalation study of Venetoclax combined with modified intensive chemotherapy. J Clin Oncol 38(30):3506–3517. https://doi.org/10.1200/jco.20.00572

    Article  CAS  PubMed  Google Scholar 

  • Cluzeau T, Sebert M, Rahmé R, Cuzzubbo S, Walter-Petrich A, Lehmann-che J, Peterlin P, Beve B, Attalah H, Chermat F (2019) APR-246 combined with Azacitidine (AZA) in TP53 mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). A phase 2 study by the Groupe Francophone Des Myélodysplasies (GFM). American Society of Hematology, Washington, DC

    Book  Google Scholar 

  • Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J (2013) Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3–internal tandem duplication status. J Clin Oncol 31(29):3681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E (2018) Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 19(7):889–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cortes JE, Ganguly S, Krämer A, Levis MJ, Martinelli G, Perl AE, Russell NH, Choi Y, Mendell J, Namuyinga R (2019a) Pooled safety analysis of Quizartinib monotherapy in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). American Society of Hematology, Washington, DC

    Book  Google Scholar 

  • Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O (2019b) Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 33(2):379

    Article  CAS  PubMed  Google Scholar 

  • Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA (2019c) Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol 20(7):984–997

    Article  CAS  PubMed  Google Scholar 

  • Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15(1):49–63. https://doi.org/10.1038/nrm3722

    Article  CAS  PubMed  Google Scholar 

  • Daver NG, Garcia JS, Jonas BA, Kelly KR, Assouline S, Brandwein JM, Fenaux P, Olin RL, Martinelli G, Paolini S, Pigneux A, Pollyea DA, Powell BL, Roboz GJ, Tafuri A, Vey N, Visani G, Yee KWL, Dail M, Green C, Kirschbrown WP, Hong W-J, Ott MG, Onishi M, Wang J, Konopleva MY, Andreeff M (2019) 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 134(Suppl_1):229. https://doi.org/10.1182/blood-2019-123711

    Article  Google Scholar 

  • DiNardo C (2019) Enasidenib plus azacitidine significantly improves complete remission and overall response compared with azacitidine alone in patients with newly diagnosed acute myeloid leukemia (AML) with isocitrate dehydrogenase 2 (IDH2) mutations: interim phase II results from an ongoing, randomized study. In: 61st Annual Meeting and Exposition (December 7–10, 2019), 2019. ASH

    Google Scholar 

  • DiNardo CD, Wei AH (2020) How I treat acute myeloid leukemia in the era of new drugs. Blood 135(2):85–96

    Article  PubMed  Google Scholar 

  • DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA (2018a) 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 19(2):216–228. https://doi.org/10.1016/S1470-2045(18)30010-X

    Article  CAS  PubMed  Google Scholar 

  • DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA (2018b) Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 378(25):2386–2398

    Article  CAS  PubMed  Google Scholar 

  • DiNardo C, Takahashi K, Kadia T, Loghavi S, Naqvi K, Bose P, Daver N, Tippett GD, Borthakur G, Cortes J, Chan S, Quek L, Vyas P, Kantarjian H, Konopleva M (2019a) A phase 1b/2 clinical study of targeted IDH1 inhibition with ivosidenib, in combination with the BCL-2 inhibitor venetoclax, for patients with IDH1-mutated (mIDH1) myeloid malignancies: PF291. HemaSphere 3:97. https://doi.org/10.1097/01.Hs9.0000559376.17429.23

    Article  Google Scholar 

  • DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM (2019b) Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133(1):7–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, Thijssen R, Pomilio G, Ivey A, Salmon J (2020a) Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood 135(11):791–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, Thijssen R, Pomilio G, Ivey A, Salmon J, Glytsou C, Fleming SA, Zhang Q, Ma H, Patel KP, Kornblau SM, Xu Z, Chua CC, Chen X, Blombery P, Flensburg C, Cummings N, Aifantis I, Kantarjian H, Huang DCS, Roberts AW, Majewski IJ, Konopleva M, Wei AH (2020b) Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood 135(11):791–803. https://doi.org/10.1182/blood.2019003988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fathi AT, DiNardo CD, Kline I, Kenvin L, Gupta I, Attar EC, Stein EM, de Botton S, AG221-C-001 Study Investigators (2018) Differentiation syndrome associated with Enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol 4(8):1106–1110. https://doi.org/10.1001/jamaoncol.2017.4695

    Article  PubMed  PubMed Central  Google Scholar 

  • Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, Jamieson C, Kiyoi H, Naoe T (2016) Small-molecule hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci 107(10):1422–1429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia Manero G, Atallah E, Khaled SK, Arellano M, Patnaik MM, Odenike O, Sayar H, Tummala M, Patel PA, Ghalie RG, Medeiros BC (2016) A phase 2 study of Pracinostat and Azacitidine in elderly patients with acute myeloid leukemia (AML) not eligible for induction chemotherapy: response and long-term survival benefit. Blood 128(22):100

    Article  Google Scholar 

  • Garcia-Manero G, McCloskey J, Griffiths EA, Yee KW, Zeidan AM, Al-Kali A, Dao K-H, Deeg HJ, Patel PA, Sabloff M (2019) Pharmacokinetic exposure equivalence and preliminary efficacy and safety from a randomized cross over phase 3 study (ASCERTAIN study) of an oral hypomethylating agent ASTX727 (cedazuridine/decitabine) compared to IV decitabine. American Society of Hematology, Washington, DC

    Book  Google Scholar 

  • Glaser SP, Lee EF, Trounson E, Bouillet P, Wei A, Fairlie WD, Izon DJ, Zuber J, Rappaport AR, Herold MJ (2012) Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev 26(2):120–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grundy M, Balakrishnan S, Fox M, Seedhouse CH, Russell NH (2018) Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells. Oncotarget 9(102):37777–37789. https://doi.org/10.18632/oncotarget.26540

    Article  PubMed  PubMed Central  Google Scholar 

  • Harding JJ, Lowery MA, Shih AH, Schvartzman JM, Hou S, Famulare C, Patel M, Roshal M, Do RK, Zehir A, You D, Selcuklu SD, Viale A, Tallman MS, Hyman DM, Reznik E, Finley LWS, Papaemmanuil E, Tosolini A, Frattini MG, MacBeth KJ, Liu G, Fan B, Choe S, Wu B, Janjigian YY, Mellinghoff IK, Diaz LA, Levine RL, Abou-Alfa GK, Stein EM, Intlekofer AM (2018) Isoform switching as a mechanism of acquired resistance to mutant Isocitrate dehydrogenase inhibition. Cancer Discov 8(12):1540. https://doi.org/10.1158/2159-8290.CD-18-0877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Intlekofer AM, Shih AH, Wang B, Nazir A, Rustenburg AS, Albanese SK, Patel M, Famulare C, Correa FM, Takemoto N (2018) Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 559(7712):125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jonas BA, Pollyea DA (2019) How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia 33(12):2795–2804. https://doi.org/10.1038/s41375-019-0612-8

    Article  CAS  PubMed  Google Scholar 

  • Kasper S, Breitenbuecher F, Heidel F, Hoffarth S, Markova B, Schuler M, Fischer T (2012) Targeting MCL-1 sensitizes FLT3-ITD-positive leukemias to cytotoxic therapies. Blood Cancer J 2(3):e60–e60. https://doi.org/10.1038/bcj.2012.5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konopleva M, Letai A (2018) BCL-2 inhibition in AML: an unexpected bonus? Blood 132(10):1007–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi Y-X, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10(5):375–388. https://doi.org/10.1016/j.ccr.2006.10.006

    Article  CAS  PubMed  Google Scholar 

  • Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, McKeegan E, Salem AH, Zhu M, Ricker JL (2016) Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 6(10):1106–1117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konopleva MY, Rollig C, Cavenagh J, Deeren D, Girshova L, Krauter J, Martinelli G, Montesinos P, Neubauer A, Petrini M, Pigneux A, Rambaldi A, Recher C, Rodriguez-Veiga R, Taussig D, Vey N, Yoon S-S, Ott MG, Gamel K, Monnet A, Beckermann BM, Muehlbauer S, Catalani O, Genevray M, Fenaux P, Wei AH (2020) A randomized double-blind phase 3 trial of cytarabine with MDM2 inhibitor idasanutlin or placebo in relapsed/refractory acute myeloid leukemia (R/R AML): primary analysis results of the MIRROS study. In: Paper presented at the 25th EHA annual congress, virtual edition, June 12 2020

    Google Scholar 

  • Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC (2018) 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 36(26):2684–2692. https://doi.org/10.1200/jco.2017.77.6112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levis MJ, Perl AE, Altman JK, Gocke CD, Bahceci E, Hill J, Liu C, Xie Z, Carson AR, McClain V, Stenzel TT, Miller JE (2018) A next-generation sequencing–based assay for minimal residual disease assessment in AML patients with FLT3-ITD mutations. Blood Adv 2(8):825–831. https://doi.org/10.1182/bloodadvances.2018015925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma J, Zhao S, Qiao X, Knight T, Edwards H, Polin L, Kushner J, Dzinic SH, White K, Wang G, Zhao L, Lin H, Wang Y, Taub JW, Ge Y (2019) Inhibition of Bcl-2 synergistically enhances the Antileukemic activity of Midostaurin and Gilteritinib in preclinical models of FLT3-mutated acute myeloid leukemia. Clin Cancer Res 25(22):6815. https://doi.org/10.1158/1078-0432.CCR-19-0832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maiti A, DiNardo CD, Rausch CR, Cortes JE, Pemmaraju N, Daver NG, Ravandi F, Garcia-Manero G, Borthakur GM, Naqvi K (2019a) Ten-day Decitabine with Venetoclax (DEC10-VEN) in acute myeloid leukemia: updated results of a phase II trial. American Society of Hematology, Washington, DC

    Google Scholar 

  • Maiti A, Naqvi K, Kadia TM, Borthakur G, Takahashi K, Bose P, Daver NG, Patel A, Alvarado Y, Ohanian M, DiNardo CD, Cortes JE, Jabbour EJ, Garcia-Manero G, Kantarjian HM, Ravandi F (2019b) Phase II trial of MEK inhibitor Binimetinib (MEK162) in <em>RAS</em>−mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 19(3):142–148.e141. https://doi.org/10.1016/j.clml.2018.12.009

    Article  PubMed  Google Scholar 

  • Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361(11):1058–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McMahon CM, Canaani J, Rea B, Sargent RL, Qualtieri JN, Watt CD, Morrissette JJD, Carroll M, Perl AE (2019a) Gilteritinib induces differentiation in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood Adv 3(10):1581–1585. https://doi.org/10.1182/bloodadvances.2018029496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McMahon CM, Ferng T, Canaani J, Wang ES, Morrissette JJ, Eastburn DJ, Pellegrino M, Durruthy-Durruthy R, Watt CD, Asthana S (2019b) Clonal selection with Ras pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov 9(8):1050–1063

    Article  CAS  PubMed  Google Scholar 

  • Montesinos P, Esteve J, Konopleva M, Martinelli G, Ottmann O, Rodriguez-Veiga R, Röllig C, Wei A, Vey N, Chiu I (2019) MIRROS: an ongoing randomized phase 3 trial of idasanutlin + ARA-C in patients with relapsed or refractory acute myeloid leukemia. Am Soc Clin Oncol

    Google Scholar 

  • Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, Shimada I, Mori K, Kuromitsu S (2017) Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs 35(5):556–565. https://doi.org/10.1007/s10637-017-0470-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moujalled DM, Pomilio G, Ghiurau C, Ivey A, Salmon J, Rijal S, Macraild S, Zhang L, Teh T-C, Tiong I-S, Lan P, Chanrion M, Claperon A, Rocchetti F, Zichi A, Kraus-Berthier L, Wang Y, Halilovic E, Morris E, Colland F, Segal D, Huang D, Roberts AW, Maragno AL, Lessene G, Geneste O, Wei AH (2019) Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. Leukemia 33(4):905–917. https://doi.org/10.1038/s41375-018-0261-3

    Article  CAS  PubMed  Google Scholar 

  • Nechiporuk T, Kurtz SE, Nikolova O, Liu T, Jones CL, D'Alessandro A, Culp-Hill R, d'Almeida A, Joshi SK, Rosenberg M (2019) The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov 9(7):910–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan R, Ruvolo V, Mu H, Leverson JD, Nichols G, Reed JC, Konopleva M, Andreeff M (2017) Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell 32(6):748–760.e746. https://doi.org/10.1016/j.ccell.2017.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pei S, Pollyea DA, Gustafson A, Stevens BM, Minhajuddin M, Fu R, Riemondy KA, Gillen AE, Sheridan RM, Kim J (2020) Monocytic subclones confer resistance to Venetoclax-based therapy in acute myeloid leukemia patients. Cancer Discov 10(4):536–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perl AE, Daver NG, Pratz KW, Maly J, Hong W-J, Bahceci E, Tong B, Tian T, Dilley K (2019a) Venetoclax in combination with Gilteritinib in patients with relapsed/refractory acute myeloid leukemia: a phase 1b study. American Society of Hematology, Washington, DC

    Google Scholar 

  • Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C (2019b) Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 381(18):1728–1740

    Article  CAS  PubMed  Google Scholar 

  • Quek L, David MD, Kennedy A, Metzner M, Amatangelo M, Shih A, Stoilova B, Quivoron C, Heiblig M, Willekens C (2018) Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat Med 24(8):1167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, Altman JK, Arellano ML, Donnellan W, Erba HP, Mannis GN, Pollyea DA, Stein AS, Uy GL, Watts JM, Fathi AT, Kantarjian HM, Tallman MS, Choe S, Dai D, Fan B, Wang H, Zhang V, Yen KE, Kapsalis SM, Hickman D, Liu H, Agresta SV, Wu B, Attar EC, Stone RM (2019) Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 135(7):463–471. https://doi.org/10.1182/blood.2019002140

    Article  CAS  Google Scholar 

  • Sallman D (2019) Phase 2 results of APR-246 and Azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). In: 61st Annual Meeting and Exposition (December 7–10, 2019), 2019. ASH

    Google Scholar 

  • Salmon J, Pomilio G, Moujalled D, MacRaild S, Teh C, Rijal S, Ivey A, Teh T-C, Ekert P, Schoumacher M (2018) Combined BCL-2 and HDAC targeting has potent and TP53 independent activity in AML. Exp Hematol 64:S99–S100

    Article  Google Scholar 

  • Shih AH, Meydan C, Shank K, Garrett-Bakelman FE, Ward PS, Intlekofer AM, Nazir A, Stein EM, Knapp K, Glass J (2017) Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2-and TET2-mutant acute myeloid leukemia. Cancer Discov 7(5):494–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith CC, Lasater EA, Lin KC, Wang Q, McCreery MQ, Stewart WK, Damon LE, Perl AE, Jeschke GR, Sugita M (2014) Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci 111(14):5319–5324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith CC, Lin K, Stecula A, Sali A, Shah NP (2015a) FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors. Leukemia 29(12):2390–2392. https://doi.org/10.1038/leu.2015.165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith CC, Zhang C, Lin KC, Lasater EA, Zhang Y, Massi E, Damon LE, Pendleton M, Bashir A, Sebra R (2015b) Characterizing and overriding the structural mechanism of the quizartinib-resistant FLT3 “gatekeeper” F691L mutation with PLX3397. Cancer Discov 5(6):668–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith CC, Levis MJ, Perl AE, Martinelli G, Neubauer A, Berman E, Montesinos P, Baer MR, Larson RA, Chou W-C (2019) Emerging mutations at relapse in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia who received Gilteritinib therapy in the phase 3 admiral trial. Blood 134(Suppl_1):14

    Article  Google Scholar 

  • Stein EM (2016) Molecular pathways: IDH2 mutations-co-opting cellular metabolism for malignant transformation. Clin Cancer Res 22(1):16–19. https://doi.org/10.1158/1078-0432.CCR-15-0362

    Article  CAS  PubMed  Google Scholar 

  • Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW (2017) Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130(6):722–731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Savona MR, Jongen-Lavrenic M, Altman JK, Thomson B, Blakemore SJ, Daigle SR, Waters NJ, Suttle AB, Clawson A, Pollock R, Krivtsov A, Armstrong SA, DiMartino J, Hedrick E, Löwenberg B, Tallman MS (2018) The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood 131(24):2661–2669. https://doi.org/10.1182/blood-2017-12-818948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stein EM, DiNardo CD, Fathi AT, Pollyea DA, Stone RM, Altman JK, Roboz GJ, Patel MR, Collins R, Flinn IW, Sekeres MA, Stein AS, Kantarjian HM, Levine RL, Vyas P, MacBeth KJ, Tosolini A, VanOostendorp J, Xu Q, Gupta I, Lila T, Risueno A, Yen KE, Wu B, Attar EC, Tallman MS, de Botton S (2019) Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood 133(7):676–687. https://doi.org/10.1182/blood-2018-08-869008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stone RM, Mandrekar S, Sanford BL, Geyer S, Bloomfield CD, Dohner K, Thiede C, Marcucci G, Lo-Coco F, Klisovic RB (2015) The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). American Society of Hematology, Washington, DC

    Google Scholar 

  • Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377(5):454–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang H, Choe S, DiNardo CD, Stein EM, de Botton S, Fathi AT, Tallman MS, Kantarjian HM, Stone RM, Quek L (2019) Complex polyclonal resistance mechanisms to Ivosidenib monotherapy in IDH1-mutant relapsed or refractory acute myeloid leukemia revealed by single cell sequencing analyses. American Society of Hematology, Washington, DC

    Book  Google Scholar 

  • Watts JM, Baer MR, Yang J, Prebet T, Lee S, Schiller GJ, Dinner S, Pigneux A, Montesinos P, Wang ES (2019) Olutasidenib (FT-2102), an IDH1m inhibitor as a single agent or in combination with Azacitidine, induces deep clinical responses with mutation clearance in patients with acute myeloid leukemia treated in a phase 1 dose escalation and expansion study. American Society of Hematology, Washington, DC

    Book  Google Scholar 

  • Wei A, Strickland SA, Roboz GJ, Hou J-Z, Fiedler W, Lin TL, Walter RB, Enjeti A, Chyla B, Popovic R (2017) Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naïve, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes. American Society of Hematology, Washington, DC

    Google Scholar 

  • Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, Ravandi F, Sayar H, Jang JH, Porkka K (2019a) 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. American Society of Hematology, Washington, DC

    Google Scholar 

  • Wei AH, Strickland SA Jr, Hou J-Z, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S (2019b) Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol 37(15):1277–1284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei AH, Strickland SA, Hou J-Z, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S, Chyla B, Popovic R, Salem AH, Agarwal S, Xu T, Fakouhi KM, Humerickhouse R, Hong W-J, Hayslip J, Roboz GJ (2019c) Venetoclax combined with low-dose Cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol 37(15):1277–1284. https://doi.org/10.1200/JCO.18.01600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens DA, Fiedler W, Pagoni M, Samoilova O, Hu Y, Anagnostopoulos A, Bergeron J, Hou J-Z, Murthy V, Yamauchi T, McDonald A, Chyla B, Gopalakrishnan S, Jiang Q, Mendes W, Hayslip J, Panayiotidis P (2020a) Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood 135(24):2137–2145. https://doi.org/10.1182/blood.2020004856

  • Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, Ravandi F, Sayar H, Jang J-H, Porkka K, Selleslag D, Sandhu I, Turgut M, Giai V, Ofran Y, Kizil Çakar M, Botelho de Sousa A, Rybka J, Frairia C, Borin L, Beltrami G, Čermák J, Ossenkoppele GJ, La Torre I, Skikne B, Kumar K, Dong Q, Beach CL, Roboz GJ (2020b) Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med 383(26):2526–2537. https://doi.org/10.1056/NEJMoa200444

  • Williams AB, Nguyen B, Li L, Brown P, Levis M, Leahy D, Small D (2013) Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors. Leukemia 27(1):48–55. https://doi.org/10.1038/leu.2012.191

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Bayle JH, Olson D, Levine AJ (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7(7a):1126–1132

    Article  CAS  PubMed  Google Scholar 

  • Yee K, Martinelli G, Vey N, Dickinson MJ, Seiter K, Assouline S, Drummond M, Yoon S-S, Kasner M, Lee J-H (2014) Phase 1/1b study of RG7388, a potent MDM2 antagonist, in acute myelogenous leukemia (AML) patients (Pts). American Society of Hematology, Washington, DC

    Book  Google Scholar 

  • Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, Choe S, Jin L, Konteatis Z, Cianchetta G, Saunders JO, Salituro FG, Quivoron C, Opolon P, Bawa O, Saada V, Paci A, Broutin S, Bernard OA, de Botton S, Marteyn BS, Pilichowska M, Xu Y, Fang C, Jiang F, Wei W, Jin S, Silverman L, Liu W, Yang H, Dang L, Dorsch M, Penard-Lacronique V, Biller SA, Su S-SM (2017) AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov 7(5):478. https://doi.org/10.1158/2159-8290.CD-16-1034

    Article  CAS  PubMed  Google Scholar 

  • Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q (2009) AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 114(14):2984–2992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Savage S, Schultz AR, Bottomly D, White L, Segerdell E, Wilmot B, McWeeney SK, Eide CA, Nechiporuk T, Carlos A, Henson R, Lin C, Searles R, Ho H, Lam YL, Sweat R, Follit C, Jain V, Lind E, Borthakur G, Garcia-Manero G, Ravandi F, Kantarjian HM, Cortes J, Collins R, Buelow DR, Baker SD, Druker BJ, Tyner JW (2019) Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nat Commun 10(1):244. https://doi.org/10.1038/s41467-018-08263-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia

    Chong Chyn Chua & Andrew H. Wei

  2. Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia

    Chong Chyn Chua & Andrew H. Wei

Authors
  1. Chong Chyn Chua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew H. Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus, Dresden, Germany

    Christoph Röllig

  2. Department of Haematology, Amsterdam University Medical Center location VUMC, Amsterdam, Noord-Holland, The Netherlands

    Gert J. Ossenkoppele

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Chua, C.C., Wei, A.H. (2021). Future Developments: Novel Agents. In: Röllig, C., Ossenkoppele, G.J. (eds) Acute Myeloid Leukemia . Hematologic Malignancies. Springer, Cham. https://doi.org/10.1007/978-3-030-72676-8_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-72676-8_17

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-72675-1

  • Online ISBN: 978-3-030-72676-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation