Skip to main content
SpringerLink
Log in

Targeted Therapies in Pediatric Acute Myeloid Leukemia - Evolving Therapeutic Landscape

  • Review Article
  • Published:
Indian Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Acute myeloid leukemia (AML) accounts for 25% of all leukemia diagnosis and is characterized by distinct cytogenetic and molecular profile. Advances in the understanding of the causative driver mutations, risk-based therapy and better supportive care have led to an overall improvement in survival with frontline therapy. Despite these improvements, a significant number fail either because of primary refractory disease to the conventional 7+3 combination of anthracyclines and cytosine arabinoside (Cytarabine; Ara-C) or experience relapse post remission. Salvage therapy is complicated by the cardiotoxicity driven limitations on the reuse of anthracyclines and development of resistance to cytarabine. In this chapter authors will review the recent studies with targeted agents for refractory AML including targets for immunotherapeutic strategies.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. 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;12:3225.

    Article  CAS  PubMed  Google Scholar 

  2. Lamble AJ, Tasian SK. Opportunities for immunotherapy in childhood acute myeloid leukemia. Blood Adv. 2019;3:3750–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zarnegar-Lumley S, Caldwell KJ, Rubnitz JE. Relapsed acute myeloid leukemia in children and adolescents: Current treatment options and future strategies. Leukemia. 2022;36:1951–60.

    Article  PubMed  Google Scholar 

  4. Armenian S, Bhatia S. Predicting and Preventing Anthracycline-Related Cardiotoxicity. Am Soc Clin Oncol Educ Book. 2018;38:3–12.

    Article  PubMed  Google Scholar 

  5. Garg A, Ganguly S, Vishnubhatla S, Chopra A, Bakhshi S. Outpatient ADE (cytarabine, daunorubicin, and etoposide) is feasible and effective for the first relapse of pediatric acute myeloid leukemia: A prospective, phase II study. Pediatr Blood Cancer. 2020;67:e28404.

    Article  CAS  PubMed  Google Scholar 

  6. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000;21:485–95.

    Article  CAS  PubMed  Google Scholar 

  7. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617–29.

  8. Karol SE, Alexander TB, Budhraja A, et al. Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: A phase 1, dose-escalation study. Lancet Oncol. 2020;21:551–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lapalombella R, Sun Q, Williams K, et al. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood. 2012;120:4621–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McCall D, Roth M, Mahadeo KM, et al. Gilteritinib combination therapies in pediatric patients with FLT3-mutated acute myeloid leukemia. Blood Adv. 2021;5:5215–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sharawat SK, Bakhshi R, Vishnubhatla S, Gupta R, Bakhshi S. FLT3-ITD mutation in relation to FLT3 expression in pediatric AML: A prospective study from India. Pediatr Hematol Oncol. 2014;31:131–7.

    Article  CAS  PubMed  Google Scholar 

  12. Inaba H, Rubnitz JE, Coustan-Smith E, et al. Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol. 2011;29:3293–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zwaan CM, Söderhäll S, Brethon B, et al. A phase 1/2, open-label, dose-escalation study of midostaurin in children with relapsed or refractory acute leukaemia. Br J Haematol. 2019;185:623–7.

    Article  PubMed  Google Scholar 

  15. Reinhardt D, Zwaan CM, Hoenekopp A, et al. Phase II study of midostaurin + chemotherapy in pediatric patients with untreated, newly diagnosed, FLT3-mutated acute myeloid leukemia (AML). Blood. 2019;134:3835.

    Article  Google Scholar 

  16. Sharawat SK, Gupta R, Raina V, et al. Increased coexpression of c-KIT and FLT3 receptors on myeloblasts: Independent predictor of poor outcome in pediatric acute myeloid leukemia. Cytometry B Clin Cytom. 2013;84:390–7.

    Article  PubMed  Google Scholar 

  17. Tarlock K, Alonzo TA, Wang YC, et al. Functional properties of KIT mutations are associated with differential clinical outcomes and response to targeted therapeutics in CBF acute myeloid leukemia. Clin Cancer Res. 2019;25:5038–48.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Krivtsov AV, Evans K, Gadrey JY, et al. A Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia. Cancer Cell. 2019;36:660-73.e11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Brivio E, Baruchel A, Beishuizen A, et al. Targeted inhibitors and antibody immunotherapies: Novel therapies for paediatric leukaemia and lymphoma. Eur J Cancer. 2022;164:1–17.

    Article  CAS  PubMed  Google Scholar 

  20. Shukla N, Wetmore C, O’Brien MM, et al. Final report of phase 1 study of the DOT1L inhibitor, pinometostat (EPZ-5676), in children with relapsed or refractory MLL-r acute leukemia. Blood. 2016;128:2780.

    Article  Google Scholar 

  21. 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.

    Article  Google Scholar 

  22. Stresemann C, Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008;123:8–13.

    Article  CAS  PubMed  Google Scholar 

  23. Newcombe AA, Gibson BES, Keeshan K. Harnessing the potential of epigenetic therapies for childhood acute myeloid leukemia. Exp Hematol. 2018;63:1–11.

    Article  PubMed  Google Scholar 

  24. Krali O, Palle J, Bäcklin CL, et al. DNA methylation signatures predict cytogenetic subtype and outcome in pediatric acute myeloid leukemia (AML). Genes (Basel). 2021;12:895.

    Article  CAS  PubMed  Google Scholar 

  25. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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;378:2386–98.

    Article  CAS  PubMed  Google Scholar 

  27. Sano H, Shimada A, Taki T, et al. RAS mutations are frequent in FAB type M4 and M5 of acute myeloid leukemia, and related to late relapse: A study of the Japanese Childhood AML Cooperative Study Group. Int J Hematol. 2012;95:509–15.

    Article  PubMed  Google Scholar 

  28. Borthakur G, Popplewell L, Boyiadzis M, et al. Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Cancer. 2016;122:1871–9.

    Article  CAS  PubMed  Google Scholar 

  29. Le Q, Hadland B, Smith JL, et al. CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target. J Clin Invest. 2022;132:e157101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tang T, Le Q, Castro S, et al. Targeting FOLR1 in high-risk CBF2AT3-GLIS2 pediatric AML with STRO-002 FOLR1-antibody-drug conjugate. Blood Adv. 2022;6:5933–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lamba JK, Chauhan L, Shin M, et al. CD33 splicing polymorphism determines gemtuzumab ozogamicin response in de novo acute myeloid leukemia: Report from randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2017;35:2674–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pollard JA, Loken M, Gerbing RB, et al. CD33 expression and its association with gemtuzumab ozogamicin response: Results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2016;34:747–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang QS, Wang Y, Lv HY, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther. 2015;23:184–91.

    Article  CAS  PubMed  Google Scholar 

  34. Jin X, Zhang M, Sun R, et al. First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia. J Hematol Oncol. 2022;15:88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim MY, Yu KR, Kenderian SS, et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell. 2018;173:1439–53.e19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021;137:751–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lamble AJ, Eidenschink Brodersen L, Alonzo TA, et al. CD123 expression is associated with high-risk disease characteristics in childhood acute myeloid leukemia: A report from the Children’s Oncology Group. J Clin Oncol. 2022;40:252–61.

    Article  CAS  PubMed  Google Scholar 

  38. Johnson S, Burke S, Huang L, et al. Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J Mol Biol. 2010;399:436–49.

    Article  CAS  PubMed  Google Scholar 

  39. Barwe SP, Kisielewski A, Bonvini E, et al. Efficacy of flotetuzumab in combination with cytarabine in patient-derived xenograft models of pediatric acute myeloid leukemia. J Clin Med. 2022;11:1333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Angelova E, Audette C, Kovtun Y, et al. CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia. Haematologica. 2019;104:749–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380:1628–37.

    Article  CAS  PubMed  Google Scholar 

  42. Jaiswal S, Jamieson CH, Pang WW, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138:271–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sikic BI, Lakhani N, Patnaik A, et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J Clin Oncol. 2019;37:946–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Haddad F, Daver N. Targeting CD47/SIRPα in acute myeloid leukemia and myelodysplastic syndrome: Preclinical and clinical developments of magrolimab. J Immunother Precis Oncol. 2021;4:67–71.

    Article  PubMed  PubMed Central  Google Scholar 

  46. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Riether C, Schürch CM, Bührer ED, et al. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J Exp Med. 2017;214:359–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sauer T, Parikh K, Sharma S, et al. CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity. Blood. 2021;138:318–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ho PA, Zeng R, Alonzo TA, et al. Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): A report from the Children’s Oncology Group. Blood. 2010;116:702–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Augsberger C, Hänel G, Xu W, et al. Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody. Blood. 2021;138:2655–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rafiq S, Purdon TJ, Daniyan AF, et al. Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms tumor 1 antigen. Leukemia. 2017;31:1788–97.

    Article  CAS  PubMed  Google Scholar 

  52. Chapuis AG, Egan DN, Bar M, et al. T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant. Nat Med. 2019;25:1064–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang H, Bu C, Peng Z, et al. Characteristics of anti-CLL1 based CAR-T therapy for children with relapsed or refractory acute myeloid leukemia: The multi-center efficacy and safety interim analysis. Leukemia. 2022;36:2596–604.

    Article  CAS  PubMed  Google Scholar 

  54. Bolouri H, Farrar JE, Triche T Jr, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018;24:103–12.

    Article  CAS  PubMed  Google Scholar 

  55. Niswander LM, Graff ZT, Chien CD, et al. Potent preclinical activity of FLT3-directed chimeric antigen receptor T cell immunotherapy against FLT3-mutant acute myeloid leukemia and KMT2A-rearranged acute lymphoblastic leukemia. Haematologica. 2023;108. https://doi.org/10.3324/haematol.2022.281456.

  56. Tabata R, Chi S, Yuda J, Minami Y. Emerging immunotherapy for acute myeloid leukemia. Int J Mol Sci. 2021;22:1944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Berger KN, Pu JJ. PD-1 pathway and its clinical application: A 20year journey after discovery of the complete human PD-1 gene. Gene. 2018;638:20–5.

    Article  CAS  PubMed  Google Scholar 

  58. Chen C, Liang C, Wang S, et al. Expression patterns of immune checkpoints in acute myeloid leukemia. J Hematol Oncol. 2020;13:28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Qian CS, Ma X, Wang J, et al. PD1 inhibitor in combination with 5-azacytidine and low-dose DLI for the successful treatment of AML patients who relapsed after transplantation. Bone Marrow Transplant. 2021;56:1003–5.

    Article  CAS  PubMed  Google Scholar 

  60. Broglie L, Gershan J, Burke MJ. Checkpoint inhibition of PD-L1 and CTLA-4 in a child with refractory acute leukemia. Int J Hematol Oncol. 2019;8:IJH10.

Download references

Author information

Author notes

  1. Eman T. Al-Antary and Avanti Gupte are first co-authors.

Authors and Affiliations

  1. Division of Hematology/Oncology, Children’s Hospital of Michigan, Pediatric Blood and Marrow Transplantation Program, Barbara Ann Karmanos Cancer Center, Detroit, MI, USA

    Eman T. Al-Antary, Avanti Gupte & Yaddanapudi Ravindranath

  2. Department of Pediatrics, Central Michigan University College of Medicine, Mt Clemons, MI, USA

    Eman T. Al-Antary & Avanti Gupte

  3. Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI, USA

    Yaddanapudi Ravindranath

Authors
  1. Eman T. Al-Antary
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Avanti Gupte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yaddanapudi Ravindranath
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ET Al-Antary and AG: Contributed equally in writing the manuscript. YR: Editorial revision. YR will act as guarantor for this manuscript.

Corresponding author

Correspondence to Eman T. Al-Antary.

Ethics declarations

Conflict of Interest

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Antary, E.T., Gupte, A. & Ravindranath, Y. Targeted Therapies in Pediatric Acute Myeloid Leukemia - Evolving Therapeutic Landscape. Indian J Pediatr 91, 176–183 (2024). https://doi.org/10.1007/s12098-023-04741-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12098-023-04741-3

Keywords

Search

Navigation