Blood Res.  2024;59:39. 10.1007/s44313-024-00041-7.

How to improve AML outcomes?

• Tan T
• Bozdag S

• KMID: 2562541
• DOI: http://doi.org/10.1007/s44313-024-00041-7

Abstract

Understanding the intricacies of the pathophysiology and genomic landscape has enhanced the long-term outcomes for patients with acute myeloid leukemia (AML). The identification of novel molecular targets has introduced new therapeutic strategies that attempt to surpass the dominance of the "7 + 3 regimen" established in the 1970s. In 2022, the World Health Organization and International Consensus Classification revised their definitions and approaches to AML, reflecting the current and evolving changes at the molecular level. The guidelines are now grounded in a definition of the disease that emphasizes genetic characteristics. Today, we recognize AML as a genetically diverse disease; a retrospective study identified 5234 driver mutations across 76 genes or genomic regions, with two or more drivers observed in 86% of patients (Papaemmanuil et al., N Engl J Med 374:2209–21, 2016).

Keyword

AML; Treatment; Relapsed; Targeted; Mutations; Outcome

Figure

• 

  Fig. 1 Hierarchical classification of the International Consensus Classification of AML. AML—Acute Myeloid Leukemia, ASXL1—Additional Sex Combs Like 1, BCOR—BCL6 Corepressor, EZH2—Enhancer of Zeste Homolog 2, MDS—Myelodysplastic Syndrome, MPN—Myeloproliferative Neoplasm, RUNX1—Runt-Related Transcription Factor 1, SF3B1—Splicing Factor 3b Subunit 1, SRSF2—Serine/Arginine-Rich Splicing Factor 2, STAG2—Stromal Antigen 2, TP53—Tumor Protein 53, U2AF1—U2 Small Nuclear RNA Auxiliary Factor 1, VAF—Variant Allele Frequency, ZRSR2—Zinc Finger CCCH-Type, RNA-Binding Motif and Serine/Arginine-Rich 2

• 

  Fig. 2 2022 ELN risk classification by genetics at initial diagnosis. AML—Acute Myeloid Leukemia, ASXL1—Additional Sex Combs Like 1, BCOR—BCL6 Corepressor, CEBPA—CCAAT Enhancer Binding Protein Alpha, CREBBP—CREB Binding Protein, EZH2—Enhancer of Zeste Homolog 2, FLT3-ITD—FMS-like Tyrosine Kinase 3-Internal Tandem Duplication, GATA2—GATA Binding Protein 2, KMT2A—Lysine Methyltransferase 2A, MEF2C—Myocyte Enhancer Factor 2C, MLLT3—Myeloid/Lymphoid or Mixed-Lineage Leukemia Translocated to 3, MYH11—Myosin Heavy Chain 11, NPM1—Nucleophosmin 1, NUP214—Nucleoporin 214, RUNX1—Runt-Related Transcription Factor 1, SF3B1—Splicing Factor 3b Subunit 1, SRSF2—Serine/Arginine-Rich Splicing Factor 2, STAG2—Stromal Antigen 2, TP53—Tumor Protein 53, U2AF1—U2 Small Nuclear RNA Auxiliary Factor 1, ZRSR2—Zinc Finger CCCH-Type, RNA-Binding Motif and Serine/Arginine-Rich 2

• 

  Fig. 3 a b Treatment Algorithm for Newly diagnosed patients with AML fit for intensive therapy. AML—Acute Myeloid Leukemia, CBF—Core Binding Factor, CK—Complex Karyotype, CPX351—Liposomal Daunorubicin and Cytarabine, FLT3—FMS-like Tyrosine Kinase 3, GO—Gemtuzumab Ozogamicin, HMA—Hypomethylating Agents, tAML—Therapy-Related Acute Myeloid Leukemia, AML-MR—Acute Myeloid Leukemia with Myelodysplasia-Related Changes, TP53—Tumor Protein 53, Ven—Venetoclax

Reference

1. DiNardo CD, et al. 2016; Interactions and relevance of blast percentage and treatment strategy among younger and older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Am J Hematol. 91(2):227–32. DOI: 10.1002/ajh.24252. PMID: 26799610. PMCID: PMC5486407.

2. Estey E, et al. 1997; Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy, The Journal of the American Society of Hematology. Blood. 90(8):2969–77. DOI: 10.1182/blood.V90.8.2969. PMID: 9376577.

3. DiNardo CD, Garcia-Manero G, Kantarjian HM. 2022; Time to blur the blast boundaries. Cancer, Wiley Online Library. 128(8):1568–70. DOI: 10.1002/cncr.34119. PMID: 35133004.

4. Döhner H, et al. 2022; Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN, The Journal of the American Society of Hematology. Blood. 140(12):1345–77. DOI: 10.1182/blood.2022016867. PMID: 35797463.

5. Fernandez HF, et al. 2009; Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 361(13):1249–59. DOI: 10.1056/NEJMoa0904544. PMID: 19776406. PMCID: PMC4480917.

6. Burnett AK, et al. 2015; A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients, The Journal of the American Society of Hematology. Blood. 125(25):3878–85. DOI: 10.1182/blood-2015-01-623447. PMID: 25833957. PMCID: PMC4505010.

7. Mathilde H-B, et al. 2023; Current results of intensive therapy in younger adults with acute myeloid leukemia (AML): the large randomized French backbone intergroup (BIG)-1 study on behalf of the filo, ALFA, and SFGM-TC study groups. Blood. 142(Supplement 1):967. DOI: 10.1182/blood-2023-179376.

8. Weick JK, et al. 1996; A randomized investigation of high-dose versus standarddose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 88(8):2841–51. DOI: 10.1182/blood.V88.8.2841.bloodjournal8882841. PMID: 8874180.

9. Lancet JE, et al. 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):2684–92. DOI: 10.1200/JCO.2017.77.6112. PMID: 30024784. PMCID: PMC6127025.

10. Daver N, et al. 2022; Phase I/II study of azacitidine (AZA) with venetoclax (VEN) and magrolimab (Magro) IN Patients (pts) with newly diagnosed (ND) older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML. Blood. 140(Supplement 1):141–4. DOI: 10.1182/blood-2022-170188.

11. Castaigne S, et al. 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. The Lancet. 379(9825):1508–16. DOI: 10.1016/S0140-6736(12)60485-1. PMID: 22482940.

12. Döhner H, et al. 2023; Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09-09): a randomised, open-label, multicentre, phase 3 trial. The Lancet Haematology. 10(7):e495–509. DOI: 10.1016/S2352-3026(23)00092-3. PMID: 37187197.

13. Stone RM, et al. 2017; Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 377(5):454–64. DOI: 10.1056/NEJMoa1614359. PMID: 28644114. PMCID: PMC5754190.

14. Döhner H, et al. 2022; Midostaurin plus intensive chemotherapy for younger and older patients with AML and FLT3 internal tandem duplications. Blood Adv. 6(18):5345–55. DOI: 10.1182/bloodadvances.2022007223. PMID: 35486475. PMCID: PMC9631686.

15. Erba H, et al. 2022; S100: 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. HemaSphere. 6:1–2. DOI: 10.1097/01.HS9.0000843296.73803.85. PMID: 14cfe89f08fe40e09ed1e992c0372c53.

16. Lachowiez CA, et al. 2022; Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study. The Lancet Haematology. 9(5):e350–60. DOI: 10.1016/S2352-3026(22)00076-X. PMID: 35483396.

17. DiNardo CD, et al. 2022; Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed acute myeloid leukemia. Am J Hematol. 97(8):1035–43. DOI: 10.1002/ajh.26601. PMID: 35583199.

18. Chua CC, et al. 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):3506–17. DOI: 10.1200/JCO.20.00572. PMID: 32687450.

19. Walter RB, et al. 2021; Measurable residual disease as a biomarker in acute myeloid leukemia: theoretical and practical considerations. Leukemia. 35(6):1529–38. DOI: 10.1038/s41375-021-01230-4. PMID: 33758317.

20. Heuser M, et al. 2021; 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 138(26):2753–67. DOI: 10.1182/blood.2021013626. PMID: 34724563. PMCID: PMC8718623.

21. Shimony S, Stahl M, Stone RM. 2023; Acute myeloid leukemia: 2023 update on diagnosis, risk‑stratification, and management. Am J Hematol. 98(3):502–26. DOI: 10.1002/ajh.26822. PMID: 36594187.

22. Zhao H, Deininger MW. 2022; CSF3R and SETBP1 getting high on LSD1. Blood. 140(6):529–30. DOI: 10.1182/blood.2022016740. PMID: 35951346. PMCID: PMC9373019.

23. DiNardo CD, et al. 2020; 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. The Lancet Haematology. 7(10):e724–36. DOI: 10.1016/S2352-3026(20)30210-6. PMID: 32896301.

24. Cherry EM, et al. 2021; Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia. Blood Adv. 5(24):5565–73. DOI: 10.1182/bloodadvances.2021005538. PMID: 34610123. PMCID: PMC8714726.

25. DiNardo CD, et al. 2020; Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 135(11):791–803. DOI: 10.1182/blood.2019003988. PMID: 31932844. PMCID: PMC7068032.

26. Maiti A, et al. 2021; Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: a propensity score matched analysis stratified by risk of treatment-related mortality. Am J Hematol. 96(3):282–91. DOI: 10.1002/ajh.26061. PMID: 33264443. PMCID: PMC8128145.

27. Aiba M, et al. 2023; Shorter duration of venetoclax administration to 14 days has same efficacy and better safety profile in treatment of acute myeloid leukemia. Ann Hematol. 102(3):541–6. DOI: 10.1007/s00277-023-05102-y. PMID: 36646889. PMCID: PMC9977697.

28. Wang ES, et al. 2021; Impact of FLT3 mutation clearance after Front-Line treatment with gilteritinib plus azacitidine, or gilteritinib or azacitidine alone in patients with newly diagnosed AML: results from the Phase 2/3 lacewing trial. Blood. 138(Supplement 1):3445. DOI: 10.1182/blood-2021-145362.

29. Montesinos P, et al. 2022; Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 386(16):1519–31. DOI: 10.1056/NEJMoa2117344. PMID: 35443108.

30. DiNardo CD, et al. 2018; Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 378(25):2386–98. DOI: 10.1056/NEJMoa1716984. PMID: 29860938.

31. Courtois L, et al. 2023; IL-7 receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK inhibition. Blood. 142(2):158–71. DOI: 10.1182/blood.2022017948. PMID: 37023368.

32. Koenig K, Mims A. 2020; Relapsed or primary refractory AML: moving past MEC and FLAG-ida. Curr Opin Hematol. 27(2):108–14. DOI: 10.1097/MOH.0000000000000561. PMID: 31904664. PMCID: PMC7015186.

33. DiNardo KW, LeBlanc TW, Chen H. 2023; Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH annual meeting. J Hematol Oncol. 16(1):17. DOI: 10.1186/s13045-023-01411-x. PMID: 36869366. PMCID: PMC9983204. PMID: 27e1115377e84fc48bd4d7947d9a3ada.

34. Perl AE, et al. 2019; Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 381(18):1728–40. DOI: 10.1056/NEJMoa1902688. PMID: 31665578.

35. Perl AE, et al. 2022; Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 139(23):3366–75. DOI: 10.1182/blood.2021011583. PMID: 35081255. PMCID: PMC9197557.

36. Short NJ, et al. 2021; A Triplet Combination of Azacitidine, Venetoclax and Gilteritinib for Patients with FLT3 -Mutated Acute Myeloid Leukemia: Results from a Phase I/II Study. Blood. 138(Supplement 1):696. DOI: 10.1182/blood-2021-153571.

37. Cortes JE, et al. 2019; 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):984–97. DOI: 10.1016/S1470-2045(19)30150-0. PMID: 31175001.

38. Lachowiez CA, et al. 2023; A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1 -Mutated Myeloid Malignancies. Blood Cancer Discovery. 4(4):276–93. DOI: 10.1158/2643-3230.BCD-22-0205. PMID: 37102976. PMCID: PMC10320628.

39. Venugopal S, et al. 2022; Efficacy and safety of enasidenib and azacitidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy. Blood Cancer J. 12(1):10. DOI: 10.1038/s41408-021-00604-2. PMID: 35078972. PMCID: PMC8789767. PMID: 0328e19fe8684483adbcc2c3f6e73416.