Review Articles
Vol. 18 No. 1 (2026): Mediterranean Journal of Hematology and Infectious Diseases
MOLECULAR MARKERS IN AML: PROGNOSTC IMPLICATIONS AND IMPACT ON TREATMENT DECISION-MAKING
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: October 31, 2026
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Acute myeloid leukemia (AML) is a biologically heterogeneous hematologic malignancy in which recurrent cytogenetic and molecular abnormalities critically influence diagnostic classification, prognosis, therapeutic allocation, measurable residual disease (MRD) assessment, and relapse biology. Over the last decade, next-generation sequencing (NGS) has profoundly expanded the molecular characterization of AML, complementing morphology, immunophenotyping, and cytogenetics and enabling increasingly personalized therapeutic strategies. The European LeukemiaNet (ELN) 2022 recommendations established an integrated cytogenetic-molecular backbone for risk stratification. In contrast, subsequent refinements in the era of hypomethylating agents plus venetoclax demonstrated that molecular risk is increasingly treatment-dependent rather than universally fixed across therapeutic platforms. In parallel, targeted therapies against FLT3, IDH1/2, BCL2, CD33, and menin-dependent transcriptional programs have profoundly reshaped AML management in both fit and unfit patients. Emerging data further indicate that co-mutational architecture, clonal hierarchy, variant allele frequency, and MRD kinetics may refine prognostic assessment beyond traditional single-gene models. Consequently, modern AML management increasingly relies on dynamic molecular interpretation integrating baseline genomics with treatment response and longitudinal disease monitoring. This review discusses the current prognostic and predictive role of major molecular markers in AML, focusing on FLT3-mutated AML, IDH1/2-mutated AML, NPM1-mutated AML, TP53-mutated disease, KIT-mutated core-binding factor AML, and KMT2A/NUP98-driven leukemias, together with treatment-dependent risk stratification, co-mutational refinement, menin inhibitors, germline predisposition syndromes, and MRD-guided therapeutic adaptation. The central concept is that molecular abnormalities should no longer be considered static prognostic labels, but rather operational biomarkers capable of guiding time-sensitive clinical decisions from diagnosis through post-transplant surveillance and relapse management
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1. Döhner H, Estey E, Grimwade D, 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. doi:10.1182/blood.2022016867.
2. Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 2023;401(10374):872-890. doi:10.1016/S0140-6736(22)02043-5.
3. Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074. doi:10.1056/NEJMoa1301689.
4. Ley TJ, Mardis ER, Ding L, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008;456(7218):66-72. doi:10.1038/nature07485.
5. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424-2433. doi:10.1056/NEJMoa1005143.
6. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221. doi:10.1056/NEJMoa1516192.
7. 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;135(11):791-803. doi:10.1182/blood.2019003988.
8. Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia. 2014;28(9):1774-1783. doi:10.1038/leu.2014.124.
9. Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy. Blood. 2020;135(24):2137-2145. doi:10.1182/blood.2020004856.
10. Pollyea DA, Stevens BM, Jones CL, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in AML patients. Nat Med. 2018;24(12):1859-1866. doi:10.1038/s41591-018-0233-1.
11. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089. doi:10.1056/NEJMoa1112304.
12. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated AML. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971.
13. Wei AH, Strickland SA Jr, Hou JZ, 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):1277-1284. doi:10.1200/JCO.18.01600.
14. Perl AE. The role of targeted therapy in the management of patients with AML. Hematology Am Soc Hematol Educ Program. 2021;2021(1):54-65. doi:10.1182/hematology.2021000228.
15. Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125(9):1367-1376. doi:10.1182/blood-2014-11-610543.
16. Medeiros BC, Isidori A, Pollyea DA. AML ontogeny and molecular classification. Leukemia. 2021;35(1):18-30. doi:10.1038/s41375-020-01047-z.
17. McCormick SR, McCormick MJ, Grutkoski PS, et al. Clonal evolution in acute myeloid leukemia. Leukemia. 2010;24(10):1773-1780. doi:10.1038/leu.2010.124.
18. Bataller A, Bazinet A, DiNardo CD, et al. Prognostic risk signature in AML treated with hypomethylating agents and venetoclax. Blood Adv. 2024;8(4):927-935. doi:10.1182/bloodadvances.2023011757.
19. Döhner H, Pratz KW, DiNardo CD, et al. Genetic risk stratification in AML treated with venetoclax and azacitidine. Blood. 2024;144(21):2211-2222. doi:10.1182/blood.2024024944.
20. Döhner H, DiNardo CD, Appelbaum FR, et al. Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations. Blood. 2024;144(21):2169-2173. doi:10.1182/blood.2024025409.
21. Lachowiez CA, Zeidner JF, Othman J, et al.; PRISM-AML Investigators. Risk Prognostication After Hypomethylating Agents Combined With Venetoclax in Acute Myeloid Leukemia: The PRISM Risk Model. J Clin Oncol. 2026;44(25):2422-2434. doi:10.1200/JCO-26-00347.
22. Issa GC, DiNardo CD. Therapeutic implications of molecular profiling in AML. J Clin Oncol. 2023;41(8):1605-1617. doi:10.1200/JCO.22.02118.
23. Heuser M, Freeman SD, Ossenkoppele GJ, et al. 2021 update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021;138(26):2753-2767. doi:10.1182/blood.2021013626.
24. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374(5):422-433. doi:10.1056/NEJMoa1507471.
25. Balsat M, Renneville A, Thomas X, et al. Postinduction minimal residual disease predicts outcome in NPM1-mutated AML. Blood. 2017;129(11):1315-1323. doi:10.1182/blood-2016-08-735928.
26. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225-234. doi:10.1016/j.ccr.2010.01.020.
27. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH mutations result in epigenetic dysregulation. Cancer Cell. 2010;18(6):553-567. doi:10.1016/j.ccr.2010.11.015.
28. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-KG-dependent dioxygenases. Cancer Cell. 2011;19(1):17-30. doi:10.1016/j.ccr.2010.12.014.
29. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations in AML. J Clin Oncol. 2010;28(22):3636-3643. doi:10.1200/JCO.2010.28.3762.
30. Marcucci G, Maharry K, Wu YZ, et al. IDH mutations identify novel prognostic subgroups in AML. J Clin Oncol. 2010;28(14):2348-2355. doi:10.1200/JCO.2009.27.3730.
31. Chou WC, Lei WC, Ko BS, et al. Prognostic implication of IDH mutations in AML. Leukemia. 2011;25(2):246-253. doi:10.1038/leu.2010.274.
32. Green CL, Evans CM, Zhao L, et al. The prognostic significance of CEBPA, NPM1 and FLT3 mutations in AML. Blood. 2010;116(21):354-362. doi:10.1182/blood.V116.21.354.354.
33. Ravandi F, Patel K, Luthra R, et al. Clinical relevance of IDH mutations in AML. Cancer. 2012;118(6):1591-1599. doi:10.1002/cncr.26412.
34. Boissel N, Nibourel O, Renneville A, et al. Prognostic impact of IDH mutations in AML. J Clin Oncol. 2015;33(15):1721-1728. doi:10.1200/JCO.2014.59.8764.
35. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated AML. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344.
36. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984.
37. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory AML. Blood. 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405.
38. Pollyea DA, Tallman MS, de Botton S, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019;33(11):2575-2584. doi:10.1038/s41375-019-0472-2.
39. Daver N, Schlenk RF, Russell NH, et al. Targeting FLT3 mutations in AML. Blood Cancer J. 2019;9(7):60. doi:10.1038/s41408-019-0218-8.
40. Levis M. FLT3 tyrosine kinase domain mutations in AML. Hematology Am Soc Hematol Educ Program. 2013;2013:220-226. doi:10.1182/asheducation-2013.1.220.
41. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for AML with FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359.
42. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688.
43. Schmalbrock LK, Dolnik A, Cocciardi S, et al. Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin. Blood. 2021;137(22):3093-3104. doi:10.1182/blood.2020007626.
44. Cloos J, Goemans BF, Hess CJ, et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006;20(7):1217-1220. doi:10.1038/sj.leu.2404246.
45. Erba HP, Montesinos P, Kim HJ, et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10388):1571-1583. doi:10.1016/S0140-6736(23)00464-6.
46. Burchert A, Bug G, Fritz LV, et al. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN). J Clin Oncol. 2020;38(26):2993-3002. doi:10.1200/JCO.19.03345.
47. Cairoli R, Del Castello L, Imbergamo S, et al. Gilteritinib in FLT3-mutated acute myeloid leukemia: A real-world Italian experience. Cancer. 2025;131(17):e70055. doi:10.1002/cncr.70055.
48. Levis MJ, Hamadani M, Logan B, et al. Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3. J Clin Oncol. 2024;42(15):1766-1775. doi:10.1200/JCO.23.02474.
49. Alotaibi AS, Yilmaz M, Kanagal-Shamanna R, et al. Resistance patterns in AML treated with type I versus type II FLT3 inhibitors. Blood Cancer Discov. 2021;2(2):125-134. doi:10.1158/2643-3230.BCD-20-0143.
50. Alotaibi AS, Yilmaz M, Loghavi S, et al. Emergence of BCR-ABL1 fusion in AML post-FLT3 inhibitor therapy. Front Oncol. 2020;10:588876. doi:10.3389/fonc.2020.588876.
51. Montesinos P, Cheong JW, Daver N, et al. Trial in progress: the phase 3, randomized, double-blind, placebo-controlled QuANTUM-Wild study of quizartinib in combination with chemotherapy and as single-agent maintenance in newly diagnosed, FLT3-ITD-negative acute myeloid leukemia. Blood. 2024;144(Suppl 1):1504.3-1504.5. doi:10.1182/blood-2024-205101.
52. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in AML with normal karyotype. N Engl J Med. 2005;352(3):254-266. doi:10.1056/NEJMoa041974.
53. Loghavi S, Zuo Z, Ravandi F, et al. Clinical features of triple-mutated AML. Blood Adv. 2021;5(7):1837-1847. doi:10.1182/bloodadvances.2020004021.
54. Ostronoff F, Othus M, Gerbing RB, et al. NPM1 combined with FLT3-ITD and DNMT3A in AML prognosis. Leukemia. 2015;29(4):897-904. doi:10.1038/leu.2014.273.
55. Hernández-Sánchez A, Villaverde Ramiro Á, Sträng E, et al. Unravelling co-mutational patterns with prognostic implications in NPM1-mutated adult acute myeloid leukemia: a HARMONY study. Leukemia. 2026;40:418-428. doi:10.1038/s41375-025-02851-9.
56. Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B study. J Clin Oncol. 2006;24(24):3904-3911. doi:10.1200/JCO.2006.06.9500.
57. Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107(9):3463-3468. doi:10.1182/blood-2005-09-3532.
58. Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de novo acute myeloid leukemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508-1516. doi:10.1016/S0140-6736(12)60485-1.
59. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996. doi:10.1016/S1470-2045(14)70281-5.
60. 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(6):660-673. doi:10.1016/j.ccell.2019.11.001.
61. Zeidner JF, Lin TL, Welkie RL, et al. Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML. J Clin Oncol. 2025;43(23):2606-2615. doi:10.1200/JCO-25-00914.
62. Issa GC, Aldoss I, Thirman MJ, et al. Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101). J Clin Oncol. 2025;43(1):75-84. doi:10.1200/JCO.24.00826.
63. De Botton S, Grove CS, Mannis GN, et al. Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study. Blood. 2025;146(9):1065-1077. doi:10.1182/blood.2025028357.
64. Wang ES, Montesinos P, Foran J, et al.; KOMET-001. Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. J Clin Oncol. 2025;43(31):3381-3390. doi:10.1200/JCO-25-01694.
65. Watts J, Madarang E, Cierpicki T, Grembecka J. Menin inhibitors as a treatment for acute leukemia: from bench to the clinic. Blood Neoplasia. 2026;3(3):100253. doi:10.1016/j.bneo.2026.100253.
66. Issa GC, et al. All-Oral Combination of Revumenib, Decitabine, and Venetoclax for Relapsed or Refractory AML (SAVE). J Clin Oncol. 2026;44(22):2110-2120. doi:10.1200/JCO-26-01159.
67. Perner F, Armstrong SA. Menin inhibition in acute myeloid leukemia: emerging mechanisms of resistance and therapeutic strategies. Cancer Discovery. 2024;14(2):214-228. doi:10.1158/2159-8290.CD-23-0674.
68. Chin KK, Abdul-Hay M, Shukla M, et al. Overcoming MEN1-mediated resistance with menin inhibitor switching in KMT2A-rearranged acute myeloid leukemia. Leukemia. 2026;40(6):1331-1334. doi:10.1038/s41375-026-02959-6.
69. Shukla N, Charalambous K, Li S, et al. Detection of MEN1 resistance mutations in cell-free DNA from acute leukemia patients treated with menin inhibitors. Blood Cancer J. 2026;16(1):94. doi:10.1038/s41408-026-01545-4.
70. Shahzad M, Tariq E, Chaudhary SG, et al. Outcomes with allogeneic hematopoietic stem cell transplantation in TP53-mutated acute myeloid leukemia: a systematic review and meta-analysis. Leuk Lymphoma. 2022;63(14):3409-3417. doi:10.1080/10428194.2022.2123228.
71. Badar T, Foran J, Jamy O, et al. Choice of hypomethylating agent for newly diagnosed TP53-mutant acute myeloid leukemia: a COMMAND registry study. Leukemia. 2026. doi:10.1038/s41375-026-03119-6.
72. Zeidner JF, Sallman DA, Récher C, et al. Magrolimab plus azacitidine vs physician's choice for untreated TP53-mutated acute myeloid leukemia: the ENHANCE-2 study. Blood. 2025;146(5):590-600. doi:10.1182/blood.2024027408.
73. Zhao Y, Cao W, Shi J, et al. Peri-transplant TP53 molecular MRD as a prognostic biomarker of relapse in TP53-mutated AML/MDS undergoing allogeneic HCT. Blood Cancer J. 2026;16:103. doi:10.1038/s41408-026-01561-4.
74. Churpek JE, Godley LA. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood. 2019;133(14):1422-1432. doi:10.1182/blood-2018-09-844662. 75. Godley LA, Shimamura A. Genetic predisposition to hematologic malignancies: management and surveillance. Blood. 2017;130(4):424-432. doi:10.1182/blood-2017-02-735563.
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“MOLECULAR MARKERS IN AML: PROGNOSTC IMPLICATIONS AND IMPACT ON TREATMENT DECISION-MAKING” (2026) Mediterranean Journal of Hematology and Infectious Diseases, 18(1), p. e2026087. doi:10.4084/MJHID.2026.087.
Copyright (c) 2026 Patrizia Chiusolo, Roberto Maggi, Angela Alessi, Simona Sica
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