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Review

An overview of novel therapies in advanced clinical testing for acute myeloid leukemia

ORCID Icon, &
Pages 109-119 | Received 20 Oct 2022, Accepted 26 Jan 2023, Published online: 08 Feb 2023

References

  • Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 2018;392(10147):593–606.
  • Shallis RM, Wang R, Davidoff A, et al. Epidemiology of acute myeloid leukemia: recent progress and enduring challenges. Blood Rev. 2019;36:70–87.
  • Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–1152.
  • Kantarjian H, Kadia T, DiNardo C, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021;11(2):1–25.
  • DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–629.
  • Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137–2145.
  • Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345–1377.
  • Venugopal S, Bar-Natan M, Mascarenhas JO. JAKs to STATs: a tantalizing therapeutic target in acute myeloid leukemia. Blood Rev. 2020 Mar;40:100634.
  • Bloomfield CD, Estey E, Pleyer L, et al. Time to repeal and replace response criteria for acute myeloid leukemia? Blood Rev. 2018 Sep;32(5):416–425.
  • Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10;130(6):722–731.
  • Hourigan CS, Karp JE. Minimal residual disease in acute myeloid leukaemia. Nat Rev Clin Oncol. 2013;10(8):460–471.
  • Short NJ, Ravandi F. How close are we to incorporating measurable residual disease into clinical practice for acute myeloid leukemia? Haematologica. 2019;104(8):1532.
  • Short NJ, Zhou S, Fu C, et al. Association of measurable residual disease with survival outcomes in patients with acute myeloid leukemia: a systematic review and meta-analysis. JAMA Oncol. 2020 Dec 1;6(12):1890–1899.
  • Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood J Am Soc Hematol. 2017;129(4):424–447.
  • DeWolf S, Tallman MS. How I treat relapsed or refractory AML. Blood. 2020;136(9):1023–1032.
  • Ramos NR, Mo CC, Karp JE, et al. Current approaches in the treatment of relapsed and refractory acute myeloid leukemia. J Clin Med. 2015;4(4):665–695.
  • Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254–266.
  • Grisendi S, Mecucci C, Falini B, et al. Nucleophosmin and cancer [Review Article]. Nat Rev Cancer. 2006Jan07; 6:493. online
  • Falini B, Brunetti L, Sportoletti P, et al. NPM1-mutated acute myeloid leukemia: from bench to bedside. Blood. 2020;136(15):1707–1721.
  • Brunetti L, Gundry MC, Sorcini D, et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell. 2018;34(3):499–512. e9.
  • Day MA, Sergeev P, Heckman CA, et al. Preclinical activity of selective syk inhibitors, entospletinib and lanraplenib, alone or combined with targeted agents in ex vivo aml models with diverse mutational backgrounds. Blood. 2021;138:3356.
  • Tyner JW, Tognon CE, Bottomly D, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562(7728):526–531.
  • Uckelmann HJ, Kim SM, Antonissen NJ, et al. MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1 mutations and prevents AML development. Blood. 2018;132:546.
  • Swaminathan M, Bourgeois W, Armstrong SA, et al. Menin inhibitors in acute myeloid leukemia—what does the future hold? Cancer J. 2022;28(1):62–66.
  • Walker AR, Byrd JC, Blachly JS, et al. Entospletinib in combination with induction chemotherapy in previously untreated acute myeloid leukemia: response and predictive significance of HOXA9 and MEIS1 expressionentospletinib+ induction chemotherapy in untreated AML. Clin Cancer Res. 2020;26(22):5852–5859.
  • Byrd JC, Cortes JE, Minden MD, et al. A phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of entospletinib in combination with intensive induction and consolidation chemotherapy in adults with newly diagnosed nucleophosmin 1-mutated acute myeloid leukemia. Blood. 2021 Nov 23;138:1282.
  • Issa GC, Ravandi F, DiNardo CD, et al. Therapeutic implications of menin inhibition in acute leukemias. Leukemia. 2021;35(9):2482–2495.
  • Krivtsov AV, Figueroa ME, Sinha AU, et al. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia. 2013;27(4):852–860.
  • Faber J, Krivtsov AV, Stubbs MC, et al. HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood J Am Soc Hematol. 2009;113(11):2375–2385.
  • Kühn MW, Armstrong SA. Designed to kill: novel menin-MLL inhibitors target MLL-rearranged leukemia. Cancer Cell. 2015;27(4):431–433.
  • Uckelmann HJ, Kim SM, Wong EM, et al. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science. 2020;367(6477):586–590.
  • Wang ES, Altman JK, Pettit K, et al. Preliminary data on a phase 1/2A first in human study of the menin-KMT2A (MLL) inhibitor KO-539 in patients with relapsed or refractory acute myeloid leukemia. Blood. 2020;136:7–8.
  • Kura oncology receives FDA authorization to proceed with phase 1b study of KO-539 in acute myeloid leukemia [internet]. GLOBE NEWSWIRE; 2022. [cited 2022 Jan 20]. Available from: https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-receives-fda-authorization-proceed-phase-1b-study
  • Stein EM, Aldoss I, DiPersio JF, et al. Safety and efficacy of menin inhibition in patients (Pts) with MLL-rearranged and NPM1 mutant acute leukemia: a phase (Ph) 1, first-in-human study of SNDX-5613 (AUGMENT 101). Blood. 2021;138:699.
  • Kadia TM, Jain P, Ravandi F, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016;122(22):3484–3491.
  • Shallis RM, Bewersdorf JP, Stahl MF, et al. Are we moving the needle for patients with TP53-mutated acute myeloid leukemia? Cancers (Basel). 2022;14(10):2434.
  • Short NJ, Montalban-Bravo G, Hwang H, et al. Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia. Blood Adv. 2020;4(22):5681–5689.
  • Venugopal S, Shoukier M, Konopleva M, et al. Outcomes in patients with newly diagnosed TP53‐mutated acute myeloid leukemia with or without venetoclax‐based therapy. Cancer. 2021;127(19):3541–3551.
  • Kim K, Maiti A, Loghavi S, et al. Outcomes of TP53‐mutant acute myeloid leukemia with decitabine and venetoclax. Cancer. 2021;127(20):3772–3781.
  • Saha MN, Qiu L, Chang H. Targeting p53 by small molecules in hematological malignancies. J Hematol Oncol. 2013;6(1):1–9.
  • Maslah N, Salomao N, Drevon L, et al. Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2020;105(6):1539.
  • Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J clin oncol. 2021;39(14):1584.
  • Sallman DA, Komrokji RS, DeZern AE, et al. Long term follow-up and combined phase 2 results of eprenetapopt (APR-246) and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2021 Nov 23;138:246.
  • Aprea therapeutics announces results of primary endpoint from phase 3 trial of eprenetapopt in TP53 mutant myelodysplastic syndromes (MDS) [Internet]. WWW: GLOBE NEWSWIRE; December 28, 2020 Available from: https://ir.aprea.com/news-releases/news-release-details/aprea-therapeutics-announces-results-primary-endpoint-phase-3
  • Mishra A, Tamari R, DeZern AE, et al. Eprenetapopt plus azacitidine after allogeneic hematopoietic stem-cell transplantation for TP53-mutant acute myeloid leukemia and myelodysplastic syndromes. J clin oncol. 2022;JCO:22.00181.
  • Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity. 2018;48(4):812–830.
  • Schwartz S, Patel N, Longmire T, et al. Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor. Adv Immunol. 2022;2. 10.1093/immadv/ltac019.
  • Kikushige Y, Shima T, S-i T, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell. 2010;7(6):708–717.
  • Brunner AM, Esteve J, Porkka K, et al. Efficacy and safety of sabatolimab (mbg453) in combination with hypomethylating agents (hmas) in patients (pts) with very high/high-risk myelodysplastic syndrome (vhr/hr-mds) and acute myeloid leukemia (aml): final analysis from a phase ib study. Blood. 2021;138:244.
  • Zeidan AM, Esteve J, Giagounidis A, et al. The STIMULUS program: clinical trials evaluating sabatolimab (MBG453) combination therapy in patients (Pts) with higher-risk myelodysplastic syndromes (HR-MDS) or acute myeloid leukemia (AML). Blood. 2020;136(Supplement 1):45–46.
  • Mitchell K, Steidl U. Targeting immunophenotypic markers on leukemic stem cells: how lessons from current approaches and advances in the leukemia stem cell (LSC) model can inform better strategies for treating acute myeloid leukemia (AML). Cold Spring Harb Perspect Med. 2020;10(1):a036251.
  • Chao MP, Weissman IL, Majeti R. The CD47–SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol. 2012;24(2):225–232.
  • Sallman DA, Asch AS, Al Malki MM, 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(Supplement_1):569.
  • Garcia-Manero G, Daver NG, Xu J, et al. Magrolimab + azacitidine versus azacitidine + placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): the phase 3, randomized, ENHANCE study. J clin oncol. 2021 May 20;39(15_suppl): TPS7055–TPS7055.
  • Daver N, Konopleva M, Maiti A, et al. Phase I/II study of azacitidine (AZA) with venetoclax (VEN) and magrolimab (Magro) in patients (pts) with newly diagnosed older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML. Blood. 2021 Nov 23;138:371.
  • Daver N, Venugopal S, Ravandi F. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. Blood Cancer J. 2021 May 27;11(5):104.
  • Quizartinib prolonged survival vs placebo plus intensive induction and consolidation therapy followed by single-agent continuation in patients aged 18-75 years with newly diagnosed Flt3-Itd+ AML. In: Erba H, Montesinos P, Vrhovac R, et al., editor. Abstract Book for the 27th Congress of the European Hematology Association HemaSphere2022, Vienna,Austria. p. 1–4130.
  • Stone RM, Manley PW, Larson RA, et al. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018 Feb 27;2(4):444–453.
  • DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–2398.
  • Watts JM, Baer MR, Yang J, et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol. 2023;10(1):e46–58.
  • Stein EM, DiNardo CD, Fathi AT, et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood. 2021 Apr 1;137(13):1792–1803.
  • Venugopal S, Maiti A, DiNardo CD, et al. Decitabine and venetoclax for IDH1/2-mutated acute myeloid leukemia. Am J Hematol. 2021;96(5):E154–E157.
  • Pollyea DA, DiNardo CD, Arellano ML, et al. Impact of venetoclax and azacitidine in treatment-naïve patients with acute myeloid leukemia and IDH1/2 mutations. Clin Cancer Res. 2022;28(13):2753–2761.
  • Desikan SP, Daver N, DiNardo C, et al. Resistance to targeted therapies: delving into FLT3 and IDH. Blood Cancer J. 2022 Jun 09;12(6):91.
  • Lachowiez CA, Garcia JS, Borthakur G, et al. A phase Ib/II study of ivosidenib with venetoclax ± azacitidine in IDH1-mutated hematologic malignancies. J clin oncol. 2022;40(16_suppl):7018.
  • Mesbahi Y, Trahair TN, Lock RB, et al. Exploring the metabolic landscape of AML: from haematopoietic stem cells to myeloblasts and leukaemic stem cells. Front Oncol. 2022;12:807266.
  • Erbani J, Tay J, Barbier V, et al. Acute myeloid leukemia chemo-resistance is mediated by E-selectin receptor CD162 in bone marrow niches. Front Cell Dev Biol. 2020;8:668.
  • Muz B, Abdelghafer A, Markovic M, et al. Targeting E-selectin to tackle cancer using uproleselan. Cancers (Basel). 2021 Jan 18;13(2):335.
  • DeAngelo DJ, Jonas BA, Liesveld JL, et al. Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia. Blood. 2022;139(8):1135–1146.
  • Konopleva M, Letai A. BCL-2 inhibition in AML: an unexpected bonus? Blood. 2018 Sep 6;132(10):1007–1012.
  • DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020 Mar 12;135(11):791–803.
  • Nechiporuk T, Kurtz SE, Nikolova O, et al. The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 2019 Jul;9(7):910–925.
  • Wei AH, Roberts AW, Spencer A, et al. Targeting MCL-1 in hematologic malignancies: rationale and progress. Blood Rev. 2020 Nov;44:100672.
  • Perciavalle RM, Stewart DP, Koss B, et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol. 2012 Apr 29;14(6):575–583.
  • Valentin R, Grabow S, Davids MS. The rise of apoptosis: targeting apoptosis in hematologic malignancies. Blood. 2018;132(12):1248–1264.
  • Zeidner JF, Lee DJ, Frattini M, et al. Phase I study of ALVOCIDIB FOLLOWED by 7+3 (cytarabine + daunorubicin) in newly diagnosed acute myeloid leukemia. Clin Cancer Res. 2021;27(1):60–69.
  • Sekeres MA, Watts J, Radinoff A, et al. Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML. Leukemia. 2021 Jul;35(7):2119–2124.
  • Adès L, Girshova L, Doronin VA, et al. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast percentage AML. Blood Adv. 2022;6:5132–5145.
  • Short NJ, Montalban-Bravo G, Alvarado Y, et al. Azacitidine, venetoclax and pevonedistat as frontline therapy for patients with secondary acute myeloid leukemia who are unfit for intensive chemotherapy: results from a phase i/ii study. Blood. 2021 Nov 23;138:2349.
  • Kojima K, Konopleva M, Samudio IJ, et al. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood. 2005;106(9):3150–3159.
  • Konopleva M, Martinelli G, Daver N, et al. MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020 Nov 01;34(11):2858–2874.
  • 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;12:2903–2910.
  • Konopleva MY, Röllig C, Cavenagh J, et al. Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial. Blood Adv. 2022 Jul 26;6(14):4147–4156.
  • Senapati J, Ishizawa J, Abbas HA, et al. P576: a Phase I/Ii study of milademetan (Ds3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia. HemaSphere. 2022;357439:P576.
  • Venugopal S, Daver N, Ravandi F. An update on the clinical evaluation of antibody-based therapeutics in acute myeloid leukemia. Curr Hematol Malig Rep. 2021 Feb;16(1):89–96.
  • Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628–1637.
  • Togami K, Pastika T, Stephansky J, et al. DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance. J Clin Invest. 2019 Nov 1;129(11):5005–5019.
  • Lane AA, Stein AS, Garcia JS, et al. Safety and efficacy of combining tagraxofusp (sl-401) with azacitidine or azacitidine and venetoclax in a phase 1b study for cd123 positive AML, MDS, or BPDCN. Blood. 2021;138(Supplement 1):2346.
  • Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021;137(6):751–762.
  • Vadakekolathu J, Minden MD, Hood T, et al. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Transl Med. 2020 Jun 3;12:546.
  • MacroGenics provides update on corporate progress and 2021 financial results [internet]. https://www.globenewswire.com/en/news-release/2022/02/24/2391879/0/en/MacroGenics-Provides-Update-on-Corporate-Progress-and-2021-Financial-Results.html Feb/24/2022[cited 2023 Aug 01]
  • Daver N, Aribi A, Montesinos P, et al. Safety and efficacy from a phase 1b/2 study of IMGN632 in combination with azacitidine and venetoclax for patients with CD123-positive acute myeloid leukemia. Blood. 2021;138(Supplement 1):372.

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