Opinion statement
Myeloid sarcoma, a rare malignant tumor characterized by the invasion of extramedullary tissue by immature myeloid cells, commonly occurs concomitantly with acute myeloid leukemia, myelodysplastic syndromes, or myeloproliferative neoplasms. The rarity of myeloid sarcoma poses challenges for diagnosis and treatment. Currently, treatments for myeloid sarcoma remain controversial and primarily follow protocols for acute myeloid leukemia, such as chemotherapy utilizing multi-agent regimens, in addition to radiation therapy and/or surgery. The advancements in next-generation sequencing technology have led to significant progress in the field of molecular genetics, resulting in the identification of both diagnostic and therapeutic targets. The application of targeted therapeutics, such as FMS-like tyrosine kinase 3(FLT3) inhibitors, isocitrate dehydrogenases(IDH) inhibitors, and the B cell lymphoma 2(BCL2) inhibitors, has facilitated the gradual transformation of traditional chemotherapy into targeted precision therapy for acute myeloid leukemia. However, the field of targeted therapy for myeloid sarcoma is relatively under-investigated and not well-described. In this review, we comprehensively summarize the molecular genetic characteristics of myeloid sarcoma and the current application of targeted therapeutics.
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References and Recommended Reading
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Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703–19. https://doi.org/10.1038/s41375-022-01613-1.
Solh M, Solomon S, Morris L, Holland K, Bashey A. Extramedullary acute myelogenous leukemia. Blood Rev. 2016;30(5):333–9. https://doi.org/10.1016/j.blre.2016.04.001.
Shahin OA, Ravandi F. Myeloid sarcoma. Curr Opin Hematol. 2020;27(2):88–94. https://doi.org/10.1097/MOH.0000000000000571.
Eckardt JN, Stolzel F, Kunadt D, Rollig C, Stasik S, Wagenfuhr L, et al. Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations. J Hematol Oncol. 2022;15(1):60. https://doi.org/10.1186/s13045-022-01267-7.
Claerhout H, Van Aelst S, Melis C, Tousseyn T, Gheysens O, Vandenberghe P, et al. Clinicopathological characteristics of de novo and secondary myeloid sarcoma: a monocentric retrospective study. Eur J Haematol. 2018;100(6):603–12. https://doi.org/10.1111/ejh.13056.
Stolzel F, Luer T, Lock S, Parmentier S, Kuithan F, Kramer M, et al. The prevalence of extramedullary acute myeloid leukemia detected by (18)FDG-PET/CT: final results from the prospective PETAML trial. Haematologica. 2020;105(6):1552–8. https://doi.org/10.3324/haematol.2019.223032.
Shimizu H, Saitoh T, Hatsumi N, Takada S, Handa H, Jimbo T, et al. Prevalence of extramedullary relapses is higher after allogeneic stem cell transplantation than after chemotherapy in adult patients with acute myeloid leukemia. Leuk Res. 2013;37(11):1477–81. https://doi.org/10.1016/j.leukres.2013.08.017.
Dohner H, Wei AH, Lowenberg B. Towards precision medicine for AML. Nat Rev Clin Oncol. 2021;18(9):577–90. https://doi.org/10.1038/s41571-021-00509-w.
Shallis RM, Gale RP, Lazarus HM, Roberts KB, Xu ML, Seropian SE, et al. Myeloid sarcoma, chloroma, or extramedullary acute myeloid leukemia tumor: A tale of misnomers, controversy and the unresolved. Blood Rev. 2021;47:100773. https://doi.org/10.1016/j.blre.2020.100773.
Kaur V, Swami A, Alapat D, Abdallah AO, Motwani P, Hutchins LF, et al. Clinical characteristics, molecular profile and outcomes of myeloid sarcoma: a single institution experience over 13 years. Hematology. 2018;23(1):17–24. https://doi.org/10.1080/10245332.2017.1333275.
Almond LM, Charalampakis M, Ford SJ, Gourevitch D, Desai A. Myeloid sarcoma: presentation, diagnosis, and treatment. Clin Lymphoma Myeloma Leuk. 2017;17(5):263–7. https://doi.org/10.1016/j.clml.2017.02.027.
Pileri SA, Ascani S, Cox MC, Campidelli C, Bacci F, Piccioli M, et al. Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients. Leukemia. 2007;21(2):340–50. https://doi.org/10.1038/sj.leu.2404491.
Bakst RL, Tallman MS, Douer D, Yahalom J. How I treat extramedullary acute myeloid leukemia. Blood. 2011;118(14):3785–93. https://doi.org/10.1182/blood-2011-04-347229.
Pastoret C, Houot R, Llamas-Gutierrez F, Boulland ML, Marchand T, Tas P, et al. Detection of clonal heterogeneity and targetable mutations in myeloid sarcoma by high-throughput sequencing. Leuk Lymphoma. 2017;58(4):1008–12. https://doi.org/10.1080/10428194.2016.1225208. Present potential targetable mutations in myeloid sarcoma.
Kashofer K, Gornicec M, Lind K, Caraffini V, Schauer S, Beham-Schmid C, et al. Detection of prognostically relevant mutations and translocations in myeloid sarcoma by next generation sequencing. Leuk Lymphoma. 2018;59(2):501–4. https://doi.org/10.1080/10428194.2017.1339879.
Fouillet L, Daguenet E, Guyotat D, Campos-Guyotat L, Grange R, Cornillon J, et al. A complex mutational profile and a distinct clonal evolution during NPM1 myeloid sarcoma. Leuk Lymphoma. 2019;60(9):2328–30. https://doi.org/10.1080/10428194.2019.1571199.
Wang J, Ye X, Fan C, Zhou J, Luo S, Jin J, et al. Leukemia cutis with IDH1, DNMT3A and NRAS mutations conferring resistance to venetoclax plus 5-azacytidine in refractory AML. Biomark Res. 2020;8(1):65. https://doi.org/10.1186/s40364-020-00246-9.
Werstein B, Dunlap J, Cascio MJ, Ohgami RS, Fan G, Press R, et al. Molecular discordance between myeloid sarcomas and concurrent bone marrows occurs in actionable genes and is associated with worse overall survival. J Mol Diagn. 2020;22(3):338–45. https://doi.org/10.1016/j.jmoldx.2019.11.004.
Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299–312. https://doi.org/10.1038/s41375-018-0357-9.
Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia. 2003;17(9):1738–52. https://doi.org/10.1038/sj.leu.2403099.
Kennedy VE, Smith CC. FLT3 mutations in acute myeloid leukemia: key concepts and emerging controversies. Front Oncol. 2020;10:612880. https://doi.org/10.3389/fonc.2020.612880.
Klug LR, Kent JD, Heinrich MC. Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases. Pharmacol Ther. 2018;191:123–34. https://doi.org/10.1016/j.pharmthera.2018.06.016.
Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ. 2021;375:n2026. https://doi.org/10.1136/bmj.n2026.
Thol F, Ganser A. Treatment of relapsed acute myeloid leukemia. Curr Treat Options Oncol. 2020;21(8):1–11. https://doi.org/10.1007/s11864-020-00765-5.
Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18(8):1061–75. https://doi.org/10.1016/S1470-2045(17)30416-3.
Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, 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.
Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, et al. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022;139(23):3366–75. https://doi.org/10.1182/blood.2021011583.
Rollig C, Serve H, Huttmann A, Noppeney R, Muller-Tidow C, Krug U, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16(16):1691–9. https://doi.org/10.1016/S1470-2045(15)00362-9.
Chen X, Huang J, Xu N, Fan Z, Nie D, Huang F, et al. A phase 2 study of sorafenib combined with conventional therapies in refractory central nervous system leukemia. Cancer. 2022;128(11):2138–47. https://doi.org/10.1002/cncr.34182. A Phase II clinical study of sorafenib for refractory central nervous system leukemia resulted in an overall CR rate of 80.8% and an ORR of 88.5%.
Arrigo G, D’Ardia S, Audisio E, Cerrano M, Freilone R, Giai V, et al. Gilteritinib in isolated breast relapse of FLT3positive acute myeloid leukemia: a case report and review of literature. Acta Haematol. 2022;145(5):566–70. https://doi.org/10.1159/000524878.
Brodie R, Langabeer SE, Quinn J, McMenamin ME, Hayden PJ. Sorafenib for relapsed FLT3-ITD-positive acute myeloid leukemia postallogeneic stem cell transplantation presenting as leukemia cutis. Clin Case Rep. 2019;7(12):2579–80. https://doi.org/10.1002/ccr3.2487.
Ogawara Y, Katsumoto T, Aikawa Y, Shima Y, Kagiyama Y, Soga T, et al. IDH2 and NPM1 mutations cooperate to activate Hoxa9/Meis1 and hypoxia pathways in acute myeloid leukemia. Cancer Res. 2015;75(10):2005–16. https://doi.org/10.1158/0008-5472.CAN-14-2200.
Kickingereder P, Sahm F, Radbruch A, Wick W, Heiland S, Deimling A, et al. IDH mutation status is associated with a distinct hypoxia/angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging in human glioma. Sci Rep. 2015;5:16238. https://doi.org/10.1038/srep16238.
Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. https://doi.org/10.1056/NEJMoa1301689.
McMurry H, Fletcher L, Traer E. IDH inhibitors in AML-promise and pitfalls. Curr Hematol Malig Rep. 2021;16(2):207–17. https://doi.org/10.1007/s11899-021-00619-3.
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67. https://doi.org/10.1016/j.ccr.2010.11.015.
Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol. 2010;28(14):2348–55. https://doi.org/10.1200/JCO.2009.27.3730.
Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem. 2004;279(32):33946–57. https://doi.org/10.1074/jbc.M404298200.
Martelli MP, Martino G, Cardinali V, Falini B, Martinelli G, Cerchione C. Enasidenib and ivosidenib in AML. Minerva Med. 2020;111(5):411–26. https://doi.org/10.23736/S0026-4806.20.07024-X.
Fan B, Le K, Manyak E, Liu H, Prahl M, Bowden CJ, et al. Longitudinal pharmacokinetic/pharmacodynamic profile of AG-120, a potent inhibitor of the IDH1 mutant protein, in a phase 1 study of IDH1-mutant advanced hematologic malignancies. Blood. 2015;126(23):1310. https://doi.org/10.1182/blood.V126.23.1310.1310.
DiNardo C, de Botton S, Pollyea DA, Stein EM, Fathi AT, Roboz GJ, et al. Molecular profiling and relationship with clinical response in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class potent inhibitor of mutant IDH1, in addition to data from the completed dose escalation portion of the phase 1 study. Blood. 2015;126(23):1306. https://doi.org/10.1182/blood.V126.23.1306.1306.
DiNardo CD, de Botton S, Stein EM, Roboz GJ, Swords RT, Pollyea DA, et al. Determination of IDH1 mutational burden and clearance via next-generation sequencing in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class inhibitor of mutant IDH1. Blood. 2016;128(22):1070. https://doi.org/10.1182/blood.V128.22.1070.1070.
Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463–71. https://doi.org/10.1182/blood.2019002140.
Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–31. https://doi.org/10.1182/blood-2017-04-779405.
Choi M, Jeon YK, Sun CH, Yun HS, Hong J, Shin DY, et al. RTK-RAS pathway mutation is enriched in myeloid sarcoma. Blood Cancer J. 2018;8(5):43. https://doi.org/10.1038/s41408-018-0083-6.
Ball S, Knepper TC, Deutsch YE, Samra W, Watts JM, Bradley TJ, et al. Molecular annotation of extramedullary acute myeloid leukemia identifies high prevalence of targetable mutations. Cancer. 2022;128(21):3880–7. https://doi.org/10.1002/cncr.34459. In this multicenter retrospective study, next-generation sequencing was used to analyze 58 patients with extramedullary acute myeloid leukemia, and at least one targetable or potentially targetable alteration was found in 52% of patients.
Gupta L, Levoska MA, Sharma T, Honda K, Prendes MA. Bilateral periorbital leukemia cutis presenting as suspected cellulitis. Orbit. 2022;41(4):506–8. https://doi.org/10.1080/01676830.2021.1893343.
Lee D, Omofoye OA, Karnati T, Graff JP, Shahlaie K. Intracranial myeloid sarcoma presentation in distant acute myeloid leukemia remission. J Clin Neurosci. 2021;89:158–60. https://doi.org/10.1016/j.jocn.2021.05.001.
Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26(9):1324–37. https://doi.org/10.1038/sj.onc.1210220.
Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8. https://doi.org/10.1038/nm.3048.
Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017;16(4):273–84. https://doi.org/10.1038/nrd.2016.253.
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, 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.
Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, et al. Venetoclax plus LDAC for patients with untreated AML ineligible for intensive chemotherapy: phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137–45. https://doi.org/10.1182/blood.2020004856.
Lou Y, Shao L, Mao L, Lu Y, Ma Y, Fan C, et al. Efficacy and predictive factors of venetoclax combined with azacitidine as salvage therapy in advanced acute myeloid leukemia patients: a multicenter retrospective study. Leuk Res. 2020;91:106317. https://doi.org/10.1016/j.leukres.2020.106317.
Aldoss I, Yang D, Aribi A, Ali H, Sandhu K, Al Malki MM, et al. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica. 2018;103(9):e404–7. https://doi.org/10.3324/haematol.2018.188094.
Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421–8. https://doi.org/10.1158/0008-5472.CAN-07-5836.
Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30(5):488–96. https://doi.org/10.1200/JCO.2011.34.7898.
Otoukesh S, Zhang J, Nakamura R, Stein AS, Forman SJ, Marcucci G, et al. The efficacy of venetoclax and hypomethylating agents in acute myeloid leukemia with extramedullary involvement. Leuk Lymphoma. 2020;61(8):2020–3. https://doi.org/10.1080/10428194.2020.1742908. A cohort study of 18 patients with myeloid sarcoma treated with VEN and hypomethylating agents obtained an ORR of 45%.
Pan W, Zhao X, Shi W, Jiang Z, Xiao H. Venetoclax induced complete remission in extramedullary relapse of AML co-harboring NPM1, TET2, and NRAS mutations after haploidentical hematopoietic stem cell transplantation. Leuk Lymphoma. 2020;61(11):2756–9. https://doi.org/10.1080/10428194.2020.1779255.
Mandhan N, Yassine F, Li K, Badar T. Bladder myeloid sarcoma with TP53 mutated myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome: response to decitabine-venetoclax regimen. Leuk Res Rep. 2022;17:100286. https://doi.org/10.1016/j.lrr.2021.100286.
Kanate AS, Vos J, Chargualaf MJ. Venetoclax for refractory myeloid sarcoma. J Oncol Pract. 2019;15(7):413–5. https://doi.org/10.1200/JOP.18.00753.
Reda G, Cassin R, Dovrtelova G, Matteo C, Giannotta J, D’Incalci M, et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica. 2019;104(5):e222–3. https://doi.org/10.3324/haematol.2018.213157.
Zhang X, Chen J, Wang W, Li X, Tan Y, Zhang X, et al. Treatment of central nervous system relapse in acute promyelocytic leukemia by venetoclax: a case report. Front Oncol. 2021;11:693670. https://doi.org/10.3389/fonc.2021.693670.
Klossowski S, Miao H, Kempinska K, Wu T, Purohit T, Kim E, et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J Clin Invest. 2020;130(2):981–97. https://doi.org/10.1172/JCI129126.
George B, Kantarjian H, Baran N, Krocker JD, Rios A. TP53 in acute myeloid leukemia: molecular aspects and patterns of mutation. Int J Mol Sci. 2021;22(19):10782. https://doi.org/10.3390/ijms221910782.
Barbosa K, Li S, Adams PD, Deshpande AJ. The role of TP53 in acute myeloid leukemia: challenges and opportunities. Genes Chromosom Cancer. 2019;58(12):875–88. https://doi.org/10.1002/gcc.22796.
Zhang Q, Bykov VJN, Wiman KG, Zawacka-Pankau J. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 2018;9(5):439. https://doi.org/10.1038/s41419-018-0463-7.
Sallman DA, DeZern AE, Garcia-Manero G, Steensma DP, Roboz GJ, Sekeres MA, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021;39(14):1584–94. https://doi.org/10.1200/JCO.20.02341.
Cluzeau T, Sebert M, Rahme R, Cuzzubbo S, Lehmann-Che J, Madelaine I, et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myelodysplasies (GFM). J Clin Oncol. 2021;39(14):1575–83. https://doi.org/10.1200/JCO.20.02342.
Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18(3):153–67. https://doi.org/10.1038/nri.2017.108.
Kawamoto K, Miyoshi H, Suzuki T, Kiyasu J, Yokoyama S, Sasaki Y, et al. Expression of programmed death ligand 1 is associated with poor prognosis in myeloid sarcoma patients. Hematol Oncol. 2018;36(3):591–9. https://doi.org/10.1002/hon.2506. Expression of PD-L1 on stromal cells within the tumor microenvironment was found to be associated with poorer overall survival and progression-free survival and was also identified as an independent poor prognostic factor.
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Fu, L., Zhang, Z., Chen, Z. et al. Gene Mutations and Targeted Therapies of Myeloid Sarcoma. Curr. Treat. Options in Oncol. 24, 338–352 (2023). https://doi.org/10.1007/s11864-023-01063-6
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DOI: https://doi.org/10.1007/s11864-023-01063-6