Novel Therapeutic Targets in Acute Myeloid Leukemia (AML)

Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Cancer stat facts: leukemia, acute myeloid leukemia (AML). National Cancer Institute, DCCPS, Surveillance Research Program. 2023. https://seer.cancer.gov/statfacts/html/amyl.html

Rausch C, Rothenberg-Thurley M, Dufour A, et al. Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia. Leukemia. 2023;37(6):1234–44. https://doi.org/10.1038/s41375-023-01884-2.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sasaki K, Ravandi F, Kadia TM, et al. De novo acute myeloid leukemia: a population-based study of outcome in the United States based on the Surveillance, Epidemiology, and End Results (SEER) database, 1980 to 2017. Cancer. 2021;127(12):2049–61. https://doi.org/10.1002/cncr.33458.

Article  PubMed  Google Scholar 

Kantarjian H, Kadia T, DiNardo C, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021;11(2):41. https://doi.org/10.1038/s41408-021-00425-3.

Article  PubMed  PubMed Central  Google Scholar 

DeWolf S, Tallman MS. How I treat relapsed or refractory AML. Blood. 2020;136(9):1023–32. https://doi.org/10.1182/blood.2019001982.

Article  PubMed  PubMed Central  Google Scholar 

Ganzel C, Sun Z, Cripe LD, et al. Very poor long-term survival in past and more recent studies for relapsed AML patients: the ECOG-ACRIN experience. Am J Hematol. 2018;93(8):1074–81. https://doi.org/10.1002/ajh.25162.

Article  PubMed  PubMed Central  Google Scholar 

Bhola PD, Letai A. Mitochondria-judges and executioners of cell death sentences. Mol Cell. 2016;61(5):695–704. https://doi.org/10.1016/j.molcel.2016.02.019.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Letai A, Sorcinelli MD, Beard C, et al. Antiapoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell. 2004;6(3):241–9. https://doi.org/10.1016/j.ccr.2004.07.011.

Article  CAS  PubMed  Google Scholar 

Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17. https://doi.org/10.1158/2159-8290.cd-16-0313.

Article  CAS  PubMed  PubMed Central  Google Scholar 

DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–29. https://doi.org/10.1056/NEJMoa2012971.

Article  CAS  PubMed  Google Scholar 

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):2137–45. https://doi.org/10.1182/blood.2020004856.

Article  CAS  PubMed  PubMed Central  Google Scholar 

•• Lachowiez CA, Atluri H, DiNardo CD. Advancing the standard: venetoclax combined with intensive induction and consolidation therapy for acute myeloid leukemia. Ther Adv Hematol. 2022;13(20406207221093964. https://doi.org/10.1177/20406207221093964. This article identifies the increasing importance of incorporating Venetoclax to intensive induction chemotherapy to improve outcomes for patients with AML.

Lachowiez CA, Reville PK, Kantarjian H, et al. Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study. Lancet Haematol. 2022;9(5):e350–60. https://doi.org/10.1016/s2352-3026(22)00076-x.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Grafone T, Palmisano M, Nicci C, et al. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol Rev. 2012;6(1): e8. https://doi.org/10.4081/oncol.2012.e8.

Article  PubMed  PubMed Central  Google Scholar 

Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 2010;116(24):5089–102. https://doi.org/10.1182/blood-2010-04-261867.

Article  CAS  PubMed  Google Scholar 

Fröhling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372–80. https://doi.org/10.1182/blood-2002-05-1440.

Article  CAS  PubMed  Google Scholar 

Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9. https://doi.org/10.1182/blood.v98.6.1752.

Article  CAS  PubMed  Google Scholar 

Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood. 2002;100(1):59–66. https://doi.org/10.1182/blood.v100.1.59.

Article  CAS  PubMed  Google Scholar 

Li S, Li N, Chen Y, et al. FLT3-TKD in the prognosis of patients with acute myeloid leukemia: a meta-analysis. Front Oncol. 2023;13:1086846. https://doi.org/10.3389/fonc.2023.1086846.

Alotaibi AS, Yilmaz M, Kanagal-Shamanna R, et al. Patterns of resistance differ in patients with acute myeloid leukemia treated with type I versus type II FLT3 inhibitors. Blood Cancer Discov. 2021;2(2):125–34. https://doi.org/10.1158/2643-3230.bcd-20-0143.

Article  CAS  PubMed  Google Scholar 

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(5):454–64. https://doi.org/10.1056/NEJMoa1614359.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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):1728–40. https://doi.org/10.1056/NEJMoa1902688.

Article  CAS  PubMed  Google Scholar 

Numan Y, Abdel Rahman Z, Grenet J, et al. Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors. Am J Hematol. 2022;97(3):322–8. https://doi.org/10.1002/ajh.26447.

Article  CAS  PubMed  Google Scholar 

Pratz KW, Cherry M, Altman JK, et al. Gilteritinib in combination with induction and consolidation chemotherapy and as maintenance therapy: a phase IB study in patients with newly diagnosed AML. J Clin Oncol. 2023;Jco2202721. https://doi.org/10.1200/jco.22.02721.

Wang ES, Montesinos P, Minden MD, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845–57. https://doi.org/10.1182/blood.2021014586.

Article  CAS  PubMed  PubMed Central  Google Scholar 

•• 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):1571–83. This article identifies the importance of incorporating the FLT-3 inhibitor quizartinib with intensive induction chemotherapy to improve outcomes for patients with FLT-3 mutated AML.

Article  CAS  PubMed  Google Scholar 

Cortes JE, Khaled S, Martinelli G, et al. 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. 2019;20(7):984–97. https://doi.org/10.1016/s1470-2045(19)30150-0.

Article  CAS  PubMed  Google Scholar 

Röllig C, Serve H, Noppeney R, et al. Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial. Leukemia. 2021;35(9):2517–25. https://doi.org/10.1038/s41375-021-01148-x.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wei AH, Kennedy GA, Morris KL, et al. Results of a phase 2, randomized, double-blind study of sorafenib versus placebo in combination with intensive chemotherapy in previously untreated patients with FLT3-ITD acute myeloid leukemia (ALLG AMLM16). Blood. 2020;136(Supplement 1):36–8. https://doi.org/10.1182/blood-2020-137334.

Article  Google Scholar 

Sasaki K, Kantarjian HM, Kadia T, et al. Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. Cancer. 2019;125(21):3755–66. https://doi.org/10.1002/cncr.32387.

Article  CAS  PubMed  Google Scholar 

Yilmaz M, Muftuoglu M, Kantarjian HM, et al. Quizartinib (QUIZ) with decitabine (DAC) and venetoclax (VEN) is active in patients (pts) with FLT3-ITD mutated acute myeloid leukemia (AML): a phase I/II clinical trial. Journal of Clinical Oncology 2022;40(16_suppl):7036–7036. https://doi.org/10.1200/JCO.2022.40.16_suppl.7036.

• Short N, DiNardo CD, Daver N, et al. Updated results from a phase I/II study of the triplet combination of azacitidine, venetoclax and gilteritinib for patients with FLT3-mutated acute myeloid leukemia. Blood. 2022;140(1):2007–9. This trial demonstrates the feasability of FLT-3 inhibition with Gilteritinib along with low intensity Azacitidine venetoclax for patients with FLT-3 mutated AML, who are unfit for intensive induction.

Article  Google Scholar 

Schiller GJ, Tuttle P, Desai P. Allogeneic hematopoietic stem cell transplantation in FLT3-ITD-positive acute myelogenous leukemia: the role for FLT3 tyrosine kinase inhibitors post-transplantation. Biol Blood Marrow Transplant. 2016;22(6):982–90. https://doi.org/10.1016/j.bbmt.2016.01.013.

Article  CAS  PubMed  Google Scholar 

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. https://doi.org/10.1200/jco.19.03345.

Article  PubMed  Google Scholar 

Maziarz RT, Levis M, Patnaik MM, et al. Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. Bone Marrow Transplant. 2021;56(5):1180–9. https://doi.org/10.1038/s41409-020-01153-1.

Article  CAS  PubMed 

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