Molecular-Targeted Therapy of Pediatric Acute Myeloid Leukemia

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 Jun 24

PMID 35745032

Authors

Piotr Obszanski

Anna Kozlowska

Jakub Wancowiat

Julia Twardowska

Monika Lejman

Joanna Zawitkowska

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukemia (AML) accounts for approximately 15-20% of all childhood leukemia cases. The overall survival of children with acute myeloid leukemia does not exceed 82%, and the 5-year event-free survival rates range from 46% to 69%. Such suboptimal outcomes are the result of numerous mutations and epigenetic changes occurring in this disease that adversely affect the susceptibility to treatment and relapse rate. We describe various molecular-targeted therapies that have been developed in recent years to meet these challenges and were or are currently being studied in clinical trials. First introduced in adult AML, novel forms of treatment are slowly beginning to change the therapeutic approach to pediatric AML. Despite promising results of clinical trials investigating new drugs, further clinical studies involving greater numbers of pediatric patients are still needed to improve the outcomes in childhood AML.

Citing Articles

Methylmalonic acidemia with homocystinuria in acute myeloid leukemia: a case report.

Cheng Y, Zhang A BMC Pediatr. 2025; 25(1):107.

PMID: 39939869 PMC: 11817874. DOI: 10.1186/s12887-024-05025-1.

Application of a high-throughput swarm-based deep neural network Algorithm reveals SPAG5 downregulation as a potential therapeutic target in adult AML.

Ajonu C, Grundy R, Ball G, Zafeiris D Funct Integr Genomics. 2025; 25(1):8.

PMID: 39762615 PMC: 11703901. DOI: 10.1007/s10142-024-01514-9.

Glycolysis and chemoresistance in acute myeloid leukemia.

Yang Y, Pu J, Yang Y Heliyon. 2024; 10(15):e35721.

PMID: 39170140 PMC: 11336864. DOI: 10.1016/j.heliyon.2024.e35721.

Case report: Clinical features of pediatric acute myeloid leukemia presenting with cardiac tamponade: a case series study and literature review.

Li T, Tang X, He X, Zhang L, Zhang Y, Wang L Front Oncol. 2024; 14:1391768.

PMID: 38939339 PMC: 11208300. DOI: 10.3389/fonc.2024.1391768.

Exploring the mechanism of fraxetin against acute myeloid leukemia through cell experiments and network pharmacology.

Fang T, Liu L, Liu W BMC Complement Med Ther. 2024; 24(1):226.

PMID: 38858650 PMC: 11163689. DOI: 10.1186/s12906-024-04529-8.

References

Wei A, Montesinos P, Ivanov V, DiNardo C, Novak J, Laribi K . Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020; 135(24):2137-2145. PMC: 7290090. DOI: 10.1182/blood.2020004856. View

Wei A, Strickland Jr S, Hou J, Fiedler W, Lin T, Walter R . 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):1277-1284. PMC: 6524989. DOI: 10.1200/JCO.18.01600. View

Rubnitz J, Inaba H, Dahl G, Ribeiro R, Bowman W, Taub J . Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010; 11(6):543-52. PMC: 3171799. DOI: 10.1016/S1470-2045(10)70090-5. View

Swaminathan M, Wang E . Novel therapies for AML: a round-up for clinicians. Expert Rev Clin Pharmacol. 2021; 13(12):1389-1400. DOI: 10.1080/17512433.2020.1850255. View

Hafeez U, Parakh S, Gan H, Scott A . Antibody-Drug Conjugates for Cancer Therapy. Molecules. 2020; 25(20). PMC: 7587605. DOI: 10.3390/molecules25204764. View

Kiyoi H, Kawashima N, Ishikawa Y . FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development. Cancer Sci. 2019; 111(2):312-322. PMC: 7004512. DOI: 10.1111/cas.14274. View

Pan T, Qi J, You T, Yang L, Wu D, Han Y . Addition of histone deacetylase inhibitors does not improve prognosis in patients with myelodysplastic syndrome and acute myeloid leukemia compared with hypomethylating agents alone: A systematic review and meta-analysis of seven prospective cohort.... Leuk Res. 2018; 71:13-24. DOI: 10.1016/j.leukres.2018.06.007. View

Gamis A, Alonzo T, Meshinchi S, Sung L, Gerbing R, Raimondi S . Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014; 32(27):3021-32. PMC: 4162498. DOI: 10.1200/JCO.2014.55.3628. View

Aung M, Mills M, Bittencourt-Silvestre J, Keeshan K . Insights into the molecular profiles of adult and paediatric acute myeloid leukaemia. Mol Oncol. 2021; 15(9):2253-2272. PMC: 8410545. DOI: 10.1002/1878-0261.12899. View

10.

Figueroa M, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos P . DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010; 17(1):13-27. PMC: 3008568. DOI: 10.1016/j.ccr.2009.11.020. View

11.

Lambert J, Pautas C, Terre C, Raffoux E, Turlure P, Caillot D . Gemtuzumab ozogamicin for acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2018; 104(1):113-119. PMC: 6312010. DOI: 10.3324/haematol.2018.188888. View

12.

Goldberg A, Atallah E, Rizzieri D, Walter R, Chung K, Spira A . Camidanlumab tesirine, an antibody-drug conjugate, in relapsed/refractory CD25-positive acute myeloid leukemia or acute lymphoblastic leukemia: A phase I study. Leuk Res. 2020; 95:106385. DOI: 10.1016/j.leukres.2020.106385. View

13.

Ungerstedt J . Epigenetic Modifiers in Myeloid Malignancies: The Role of Histone Deacetylase Inhibitors. Int J Mol Sci. 2018; 19(10). PMC: 6212943. DOI: 10.3390/ijms19103091. View

14.

Daver N, Venugopal S, Ravandi F . FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. Blood Cancer J. 2021; 11(5):104. PMC: 8159924. DOI: 10.1038/s41408-021-00495-3. View

15.

Augsberger C, Hanel G, Xu W, Pulko V, Hanisch L, Augustin A . Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody. Blood. 2021; 138(25):2655-2669. PMC: 9037755. DOI: 10.1182/blood.2020010477. View

16.

Lange B, Smith F, Feusner J, Barnard D, Dinndorf P, Feig S . Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood. 2007; 111(3):1044-53. PMC: 2214754. DOI: 10.1182/blood-2007-04-084293. View

17.

Hoffmeister L, Orhan E, Walter C, Niktoreh N, Hanenberg H, von Neuhoff N . Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia. Cancers (Basel). 2021; 13(19). PMC: 8508499. DOI: 10.3390/cancers13194817. View

18.

Zwaan C, Soderhall S, Brethon B, Luciani M, Rizzari C, Stam R . A phase 1/2, open-label, dose-escalation study of midostaurin in children with relapsed or refractory acute leukaemia. Br J Haematol. 2018; 185(3):623-627. DOI: 10.1111/bjh.15593. View

19.

Place A, Goldsmith K, Bourquin J, Loh M, Gore L, Morgenstern D . Accelerating drug development in pediatric cancer: a novel Phase I study design of venetoclax in relapsed/refractory malignancies. Future Oncol. 2018; 14(21):2115-2129. DOI: 10.2217/fon-2018-0121. View

20.

Burnett A, Hills R, Milligan D, Goldstone A, Prentice A, McMullin M . Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2009; 28(4):586-95. DOI: 10.1200/JCO.2009.22.9088. View