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AML is the most common adult leukaemia, with a 5-year overall survival rate of only 28%1 – the lowest survival rate of all leukaemias.

AML diagnosis is complex, with a range of possible mutations having a different impact on prognosis. The most common is FMS-like tyrosine kinase-3 (FLT3),2,3 affecting ~30% of your AML patients2 and with reported 5-year overall survival as low as 15%.4

FLT3 has two common mutation locations:

  • Internal tandem duplication (ITD) is the most common, affecting ~25–30%2
  • Tyrosine kinase domain (TKD), affecting ~7%2
Diagram showing the prevalence and prognosis associated with eleven types of mutations in AML.

 

 

Impact of FLT3-ITD mutation

A FLT3-ITD diagnosis is associated with a significant impact on prognosis:26

 

Diagram showing the prevalence and prognosis associated with eleven types of mutations in AML.

 

 

Impact of FLT3-TKD mutation

Currently the impact on prognosis of a TKD mutation is unclear, with both negative and positive effects reported.27,28

 

Current treatments

For newly diagnosed AML patients eligible for high-dose chemotherapy there are only a few options:

  • Chemotherapy:
    • Induction
    • Consolidation
  • NICE-recommended targeted therapies in newly diagnosed AML patients fit for intensive chemotherapy:
    • RYDAPT®▼ (midostaurin):29 indicated in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by RYDAPT single agent maintenance therapy, for adult patients with newly diagnosed AML who are FLT3 mutation-positive
    • VYXEOS®30 (liposomal daunorubicin and cytarabine):9 indicated for the treatment of adults with newly-diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC)
    • MYLOTARG® (gemtuzumab ozogamicin):10 indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive AML, except acute promyelocytic leukaemia (APL)
  • Stem cell transplant
  • Supportive care

 

 

Diagram showing how testing for FLT3 mutations is essential for all AML patients.

 

Guideline recommendations

Choosing the right treatment pathway for each AML patient requires having all relevant information. Guidelines now recognise the need for timely FLT3 testing to form part of the diagnostic process.32

In 2017 the European LeukemiaNet (ELN) revised their guidelines for AML to state that:

  • FLT3 mutational screening should be available within 48 to 72 hours (at least in patients eligible for intensive chemotherapy)32

 

CR, complete remission; NICE, National Institute for Health and Care Excellence.

 

 

References

  1. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2016, National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/csr/1975_2016/. Last accessed May 2020.
  2. Patel JP, Gönen M, Figueroa ME, et al. N Engl J Med. 2012;22;366(12):1079–1089.
  3. Papaemmanuil E, Gerstung M, Bullinger L, et al. N Engl J Med. 2016:374(23):2209–2221.
  4. Gale RE, Green C, Allen C, et al. Blood. 2008;111(5):2776–2784.
  5. Boissel N, Cayuela JM, Preudhomme C, et al. Leukemia. 2002;16(9):1699–1704.
  6. Grafone T, Palmisano M, Nicci C, Storti S. Oncol Rev. 2012;6(1):e8.
  7. Pratcorona M, Abbas S, Sanders MA, et al. Haematologica. 2012;97(3):388–392.
  8. Paschka P, Schlenk RF, Gaidzik VI, et al. Haematologica. 2015;100(3):324–330.
  9. Tang JL, Hou HA, Chen CY, et al. Blood. 2009;114(26):5352–5361.
  10. Greif PA, Konstandin NP, Metzeler KH, et al. Haematologica. 2012;97(12):1909–1915.
  11. Döhner K, Schlenk RF, Habdank M, et al. Blood. 2005;106(12):3740–3746.
  12. Schnittger S, Schoch C, Kern W, et al. Blood. 2005;106(12):3733–3739.
  13. Wouters BJ, Lӧwenberg B, Erpelinck-Verschueren CA, et al. Blood. 2009;113(13):3088–3091.
  14. Dufour A, Schneider F, Metzeler KH, et al. J Clin Oncol. 2010;28(4):570–577.
  15. Marcucci G, Metzeler KH, Schwind S, et al. J Clin Oncol. 2012;30(7):742–750.
  16. Gaidzik VI, Schlenk RF, Paschka P, et al. Blood. 2013;121(23):4769–4777.
  17. DiNardo CD, Ravandi F, Agresta S, et al. Am J Hematol. 2015;90(8):732–736.
  18. Green CL, Evans CM, Zhao L, et al. Blood. 2011;118(2):409–412.
  19. Bowen DT, Frew ME, Hills R, et al. Blood. 2005;106(6):2113–2119.
  20. Illmer T, Thiede C, Fredersdorf A, et al. Clin Cancer Res. 2005;11(9):3217–3224.
  21. Abdel-Wahab O, Mullally A, Hedvat C, et al. Blood. 2009;114(1):144–147.
  22. Nibourel O, Kosmider O, Cheok M, et al. Blood. 2010;116(7):1132–1135.
  23. Grimwade D, Ivey A, Huntly BJP. Blood. 2016;127(1):29–41.
  24. Krauth MT, Alpermann T, Bacher U, et al. Leukemia. 2015;29(3):660–667.
  25. Hou H-A, Chou W-C, Kuo Y-Y, et al. Blood Cancer J. 2015;5:e331.
  26. Kottaridis PD, Gale RE, Frew ME, et al. Blood. 2001;98(6):1752–1759.
  27. Whitman SP, Ruppert AS, Radmacher MD, et al. Blood. 2008;111(3);1552–1559.
  28. Mead AJ, Linch DC, Hills RK, et al. Blood. 2007;110(4):1262–1270.
  29. National Institute for Health and Care Excellence. RYDAPT technology appraisal. Available at: https://www.nice.org.uk/guidance/TA523. Last accessed May 2020.
  30. National Institute for Health and Care Excellence. VYXEOS technology appraisal. Available at https://www.nice.org.uk/guidance/TA552. Last accessed May 2020.
  31. National Institute for Health and Care Excellence. MYLOTARG technology appraisal. Available at: https://www.nice.org.uk/guidance/ta545. Last accessed May 2020.
  32. Döhner H, Estey E, Grimwade D, et al. Blood. 2017;129(4):424–447.

 

 

    HCP20-C027 June 2020.
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