Vol 11, No 4 (2020)
Case report
Published online: 2021-03-30

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Difficulties in the management of a patient with acute myeloid leukaemia and high mutant allelic ratio FLT3-ITD — refractoriness to the standard induction therapy along with midostaurin

Elżbieta Patkowska1, Joanna Sawczuk-Chabin1, Iwona Solarska2, Katarzyna Borg3, Ewa Lech-Marańda1
Hematologia 2020;11(4):253-258.


The development of targeted therapies in AML patients enabling treatment individualization, such as new FLT3 tyrosine kinase inhibitors, is a promising option for improving treatment outcomes and prolonging patient survival. However, the treatment of patients with a high FLT3-ITD allelic ratio (FLT3-ITDhigh) associated with an extremely unfavourable prognosis remains a major clinical problem. The study presents a case of a 20-year-old patient with FLT3-ITDhigh extramedullary AML at diagnosis. Individualized chemotherapy according to the DA ‘3 + 7’ regimen combined with midostaurin was administered. After the induction treatment, complete remission (CR) was not achieved. After second induction chemotherapy, CR1 was achieved with the presence of residua disease. One cycle of consolidation chemotherapy was then administered, and after myeloablative conditioning allogeneic hematopoietic stem cell transplantation from an unrelated donor was performed. The patient has remained in CR with no residual disease for 18 months.


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  1. Ley TJ, Miller C, Ding Li, et al. 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.
  2. Papaemmanuil E, Döhner H, Campbell PJ, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016; 374(23): 2209–2221.
  3. Bolouri H, Farrar JE, Triche T, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018; 24(1): 103–112.
  4. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012; 366(12): 1079–1089.
  5. Christen F, Hoyer K, Yoshida K, et al. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood. 2019; 133(10): 1140–1151.
  6. Iwai T, Yokota S, Nakao M, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996; 10(12): 1911–1918.
  7. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002; 99(12): 4326–4335.
  8. 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.
  9. Hannum C, Culpepper J, Campbell D, et al. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature. 1994; 368(6472): 643–648.
  10. Kayser S, Schlenk RF, Londono MC, et al. German-Austrian AML Study Group (AMLSG). Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009; 114(12): 2386–2392.
  11. Breitenbuecher F, Markova B, Kasper S, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood. 2009; 113(17): 4063–4073.
  12. Schlenk RF, Kayser S, Bullinger L, et al. German-Austrian AML Study Group. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014; 124(23): 3441–3449.
  13. Döhner K, Thiede C, Jahn N, et al. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood. 2020; 135(5): 371–380.
  14. Rombouts WJ, Blokland I, Löwenberg B, et al. Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia. 2000; 14(4): 675–683.
  15. Abu-Duhier FM, Goodeve AC, Wilson GA, et al. FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol. 2000; 111(1): 190–195.
  16. 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): 1752–1759.
  17. Wagner K, Damm F, Thol F, et al. FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype. Haematologica. 2011; 96(5): 681–686.
  18. Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011; 117(12): 3294–3301.
  19. Schnittger S, Bacher U, Haferlach C, et al. Diversity of the juxtamembrane and TKD1 mutations (exons 13-15) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data. Genes Chromosomes Cancer. 2012; 51(10): 910–924.
  20. 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.
  21. Gale RE, Green C, Allen C, et al. Medical Research Council Adult Leukaemia Working Party. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008; 111(5): 2776–2784.
  22. Pratcorona M, Brunet S, Nomdedéu J, et al. Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas Mieloblásticas. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood. 2013; 121(14): 2734–2738.
  23. Brown P, Meshinchi S, Levis M, et al. Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Blood. 2004; 104(6): 1841–1849.
  24. Pratz KW, Sato T, Murphy KM, et al. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010; 115(7): 1425–1432.
  25. Cucchi DGJ, Denys B, Kaspers GJL, et al. RNA-based -ITD allelic ratio is associated with outcome and ex vivo response to FLT3 inhibitors in pediatric AML. Blood. 2018; 131(22): 2485–2489.
  26. Paschka P, Schlenk RF, Gaidzik VI, et al. German-Austrian AML Study Group, German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008; 358(18): 1909–1918.
  27. Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. 2005; 106(10): 3658–3665.
  28. Bornhäuser M, Illmer T, Schaich M, et al. AML SHG 96 study group. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. 2007; 109(5): 2264–5; author reply 2265.
  29. Labouré G, Dulucq S, Labopin M, et al. Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD. Biol Blood Marrow Transplant. 2012; 18(12): 1845–1850.
  30. Doubek M, Muzík J, Szotkowski T, et al. Is FLT3 internal tandem duplication significant indicator for allogeneic transplantation in acute myeloid leukemia? An analysis of patients from the Czech Acute Leukemia Clinical Register (ALERT). Neoplasma. 2007; 54(1): 89–94.
  31. Sengsayadeth SM, Jagasia M, Engelhardt BG, et al. Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers. Bone Marrow Transplant. 2012; 47(12): 1535–1537.
  32. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012; 30(7): 735–741.
  33. DeZern AE, Sung A, Kim S, et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant. 2011; 17(9): 1404–1409.
  34. Taylor E, Morris K, Ellis M, et al. FLT3-ITD positive acute myeloid leukemia: A retrospective analysis of the role of allogeneic transplant and allelic ratio in patient management. Asia Pac J Clin Oncol. 2018; 14(6): 426–430.
  35. Schlenk RF, Weber D, Fiedler W, et al. German-Austrian AML Study Group. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with -ITD. Blood. 2019; 133(8): 840–851.

Hematology in Clinical Practice