Consider mutation status in your treatment strategy

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a high degree of recurrent genetic mutations,
several of which have been linked to poor prognosis.1,19 These mutations include FLT3-ITD, ASXL1, RUNX1, TP53,
and KIT.11-14,17,18,20,21,23,24,27

FLT3 is mutated in ≈1/3 of newly diagnosed AML cases, the majority of which are cytogenetically normal AML (CN-AML).1,14,45,48-50 While FLT3 mutations can occur as either internal tandem duplications (ITDs) or point mutations in the tyrosine kinase domain (TKD), ITD mutations are more prevalent.1,45 Additionally, only ITD mutations have been linked definitively to poor prognosis.1,45

Although some studies show an association between
FLT3-TKD mutations and poor prognosis, others show no prognostic impact or favorable outcomes associated with
FLT3 -TKD mutations.1,45


Prevalence: ≈25%11,14
Prognostic impact: Poor1,15,16


Prevalence: ≈7%1,45
Prognostic impact: Undetermined1,45

FLT3-ITD represents a poor prognostic factor compared to FLT3-TKD in AML1,15,16,45

In a recent retrospective analysis of 676 adult patients with de novo AML, survival data showed that FLT3-ITD
mutations were associated with significantly worse prognosis than FLT3-TKD mutations and FLT3 wild type (FLT3 WT).

5-year overall survival

5-year overall survival

FLT3-ITD   22.6%
FLT3-TKD   46.1%
FLT3 WT   42.4%

FLT3-ITD mutations were present in 20% of patients, and FLT3-TKD mutations were present in 4.7% of patients.

Differential analyses of patients stratified according to age and chromosomal abnormalities also showed a worse prognosis in FLT3-ITD–positive cases compared with FLT3-TKD–positive cases.

AML, acute myeloid leukemia; CN-AML, cytogenetically normal AML; FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication; FLT3-TKD, FLT3 tyrosine kinase domain; FLT3 WT, FLT3 wild type; ITD/ITDs, internal tandem duplication/internal tandem duplications; TKD, tyrosine kinase domain.
FLT3-ITD mutation:
One of the worst molecular prognostic factors in AML1,16

The FLT3-ITD mutation constitutively activates FLT3 kinase activity, inhibits cell differentiation, and drives proliferation and survival of leukemic cells.16 Patients with AML harboring a FLT3-ITD mutation typically have a significant disease burden presenting as leukocytosis, with high infiltration of bone marrow.48

Due to the aggressive nature of FLT3-ITD AML,1,2,48 prompt, early collaboration and communication among treating and transplant physicians and pathologists is critical in providing comprehensive patient care.

The FLT3-ITD mutation in AML has been associated with significantly shorter49,50,52-55,a:

  • Overall survival (OS)
  • Remission duration
  • Disease- or event-free survival

a Compared with FLT3 wild type.

In an analysis of 854 adult patients with AML, the presence of FLT3-ITD had a significant adverse effect on relapse rate, disease-free survival, and OS.12

Relapse rate
Disease-free survival

In a UK study of 854 younger adult patients mostly with de novo AML from 2 trials, FLT3-ITD mutations were present in 27% of patients. Median follow-up was 52 months.12

AML, acute myeloid leukemia; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication; OS, overall survival.

Patients with FLT3-ITD mutations may benefit from HSCT56-58

Allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be an important treatment option in carefully selected patients. In patients newly diagnosed with FLT3-ITD–mutated AML, HSCT has been associated with longer OS, compared with patients who either did not complete HSCT or received chemotherapy.56-58

In a retrospective analysis of 122 patients with AML who received intensive chemotherapy with or without allogeneic HSCT, median overall survival significantly improved in patients with FLT3-ITD who had received allogeneic HSCT compared to patients with FLT3-ITD who had not received allogeneic HSCT (P = 0.006).58

Median OS

Median OS

FLT3 WT/no HSCT (n=59) 40.7 mo
FLT3 WT/HSCT (n=29) 53.4 mo
FLT3-ITD/no HSCT (n=24) 9.8 mo
FLT3-ITD/HSCT (n=10) Not reached

A subgroup analysis of patients with CR1 status also showed significantly longer median OS among patients
with FLT3-ITD who received HSCT compared with patients who did not receive HSCT (not reached vs 17.1 months, P = 0.047).

When HSCT is part of a desired treatment strategy, it is important to collaborate early with transplant physicians and initiate a donor search rapidly.48

Dr Pollyea discusses the therapeutic benefits of HSCT in AML patients classified as intermediate or poor risk

,, Helping more
patients achieve and
maintain remission
is important to
improving long-term
survival in this
poor-risk group. ,,

AML, acute myeloid leukemia; CR1, first complete remission; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication; FLT3 WT, FLT3 wild type; HSCT, hematopoietic stem cell transplantation; OS, overall survival.

Dr Pollyea discusses prognostic and therapeutic implications of aggressive mutations in AML

,,FLT3-ITD is one of the worst molecular prognostic factors in AML and is the most common poor prognostic marker.,,

What impact do different mutations have on patient outcomes?

Share your experience
Of your newly diagnosed patients with AML, what
percentage do you believe have a FLT3-ITD mutation?
See responses >
See how others responded:
Reported percentage of patients with AML who
have a FLT-ITD mutation at diagnosis
  1. National Comprehensive Cancer Network, Inc. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Acute Myeloid Leukemia. Version 3.2020. National Comprehensive Cancer Network, Inc, website. Published December 23, 2019. Accessed February 3, 2020.
  2. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
  3. Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93(9):3074-3080.
  4. Bowen DT, Frew ME, Hills R, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood. 2005;106(6):2113-2119.
  5. Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114(1):144-147.
  6. Nibourel O, Kosmider O, Cheok M, et al. Incidence and prognostic value of TET2 alterations in de novo acute myeloid leukemia achieving complete remission. Blood. 2010;116(7):1132-1135.
  7. Rampal R, Figueroa ME. Wilm tumor 1 mutations in the pathogenesis of acute myeloid leukemia. Haematologica. 2016;101(6):672-679.
  8. O’Brien EC, Prideaux S, Chevassut T. The epigenetic landscape of acute myeloid leukemia. Adv Hematol. 2014;2014:103175. Published March 23, 2014. Accessed January 11, 2018.
  9. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152.
  10. Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S. Implications of NRAS mutations in AML: a study of 2502 patients. Blood. 2006;107(10):3847-3853.
  11. Kainz B, Heintel D, Marculescu R, et al. Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16). Hematol J. 2002;3(6):283-289.
  12. Kottaridis PD, Gale RE, Frew ME, et al. The presence of 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):1752-1759.
  13. Santos FPS, Jones D, Qiao W, et al. Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia [published online for public access]. Cancer. 2011;117(10):2145-2155.
  14. Schneider F, Hoster E, Schneider S, et al. Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Ann Hematol. 2012;91(1):9-18.
  15. Boissel N, Cayuela JM, Preudhomme C, et al. Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy. Leukemia. 2002;16(9):1699-1704.
  16. Grafone T, Palmisano M, Nicci C, Storti S. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment [eCollection published March 5, 2012]. Oncol Rev. 2012;6(1):e8. doi:10.4081/oncol.2012.e8
  17. Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci MJ, Birnbaum D. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases [published online March 21, 2012]. J Hematol Oncol. 2012;5:12. doi:10.1186/1756-8722-5-12
  18. Pratcorona M, Abbas S, Sanders MA, et al. Acquired mutations in ASXL1 in acute myeloid leukemia: prevalence and prognostic value. Haematologica. 2012;97(3):388-392.
  19. Paschka P, Schlenk RF, Gaidzik VI, et al. ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group. Haematologica. 2015;100(3):324-330.
  20. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074.
  21. Tang JL, Hou HA, Chen CY, et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood. 2009;114(26):5352-5361.
  22. Greif PA, Konstandin NP, Metzeler KH, et al. RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes. Haematologica. 2012;97(12):1909-1915.
  23. Nahi H, Selivanova G, Lehmann S, et al. Mutated and non-mutated TP53 as targets in the treatment of leukaemia. Br J Haematol. 2008;141(4):445-453.
  24. Hou H-A, Chou W-C, Kuo Y-Y, et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution [published online July 31, 2015]. Blood Cancer J. 2015;5:e331. doi:10.1038/bcj.2015.59
  25. Wattel E, Preudhomme C, Hecquet B, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994;84(9):3148-3157.
  26. Haferlach C, Dicker F, Herholz H, Schnittger S, Kern W, Haferlach T. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia. 2008;22(8):1539-1541.
  27. Medinger M, Passweg JR. Acute myeloid leukaemia genomics. Br J Haematol. 2017;179(4):530-542.
  28. 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.
  29. Falini B, Mecucci C, Tiacci E, et al; GIMEMA Acute Leukemia Working Party. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-266.
  30. Döhner K, Schlenk RF, Habdank M, et al; AML Study Group (AMLSG). Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12):3740-3746.
  31. Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106(12):3733-3739.
  32. Thiede C, Koch S, Creutzig E, et al; Deutsche Studieninitiative Leukämie (DSIL). Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107(10):4011-4020.
  33. Wouters BJ, Lӧwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009;113(13):3088-3091.
  34. Dufour A, Schneider F, Metzeler KH, et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28(4):570-577.
  35. Marcucci G, Metzeler KH, Schwind S, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2012;30(7):742-750.
  36. Gaidzik VI, Schlenk RF, Paschka P, et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood. 2013;121(23):4769-4777.
  37. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2):272-281.
  38. DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML [published online for public access]. Am J Hematol. 2015;90(8):732-736. doi:10.1002/ajh.24072
  39. Green CL, Evans CM, Zhao L, et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011;118(2):409-412.
  40. Boissel N, Nibourel O, Renneville A, Huchette P, Dombret H, Preudhomme C. Differential prognosis impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood. 2011;117(13):3696-3697.
  41. Illmer T, Thiede C, Fredersdorf A, et al. Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts. Clin Cancer Res. 2005;11(9):3217-3224.
  42. Radich JP, Kopecky KJ, Willman CL, et al. N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood. 1990;76(4):801-807.
  43. Gaidzik VI, Paschka P, Späth D, et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML Study Group. J Clin Oncol. 2012;30(12):1350-1357.
  44. Chou W-C, Chou S-C, Liu C-Y, et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood. 2011;118(14):3803-3810.
  45. Grimwade D, Ivey A, Huntly BJP. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127(1):29-41.
  46. Krauth MT, Alpermann T, Bacher U, et al. WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups. Leukemia. 2015;29(3):660-667.
  47. Hou HA, Huang TC, Lin LI, et al.WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood. 2010;115(25):5222-5231.
  48. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? [published online for public access]. Hematology Am Soc Hematol Educ Program. 2013;2013:220-226. doi:10.1182/asheducation-2013.1.220
  49. Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a Cancer and Leukemia Group B study. Cancer Res. 2001;61(19):7233-7239.
  50. 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.
  51. Sakaguchi M, Yamaguchi H, Kuboyama M, et al. Significance of FLT3-tyrosine kinase domain mutation as a prognostic factor for acute myeloid leukemia. Int J Hematol. 2019;110(5):566-574.
  52. 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):4372-4380.
  53. Sheikhha MH, Awan A, Tobal K, Liu Yin JA. Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol J. 2003;4(1):41-46.
  54. Whitman SP, Maharry K, Radmacher MD, et al. FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood. 2010;116(18):3622-3626.
  55. Moreno I, Martín G, Bolufer P, et al. Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica. 2003;88(1):19-24.
  56. 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):982-990.
  57. Ma Y, Wu Y, Shen Z, Zhang X, Zeng D, Kong P. Is allogeneic transplantation really the best treatment for FLT3/ITD-positive acute myeloid leukemia? A systematic review. Clin Transplant. 2015;29(2):149-160.
  58. Lin PH, Lin CC, Yang HI, et al. Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. Leuk Res. 2013;37(3):287-292.
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