Vol 13, No 1 (2022)
Case report
Published online: 2022-03-31

open access

Page views 4539
Article views/downloads 344
Get Citation

Connect on Social Media

Connect on Social Media

Efficacy of midostaurin combined with intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation in a patient with NPM1 and FLT3-TKD mutated acute myeloid leukaemia with clinical high-risk features

Elżbieta Patkowska1, Monika Prochorec-Sobieszek2, Ewa Lech-Marańda1, Barbara Nasiłowska-Adamska3
Hematology in Clinical Practice 2022;13(1):23-30.


Many genetic disorders occur in patients suffering from acute myeloid leukaemia (AML). The most common mutations found in such patients are in the nucleophosmin (NPM) gene and the FLT3 tyrosine kinase receptor gene. NPM1 mutation is observed in 30–35% of adult AML patients (50–60% of AML with normal karyotype), showing a favourable prognosis. The presence of point FLT3 comutations occur in the tyrosine kinase domain (TKD) are associated with even more favourable prognosis. However FLT3 comutations i.e. internal tandem duplication (ITD) in particular with high allelic ratio (ITDhigh) worsen the course of leukemia and treatment outcomes. Deploying FLT3 tyrosine kinase inhibitors thus offers a prospect for improving treatment and prolonging the survival of patients with AML, burdened with the FLT3 gene mutation. Midostaurin and gilteritinib are type I FLT3 inhibitors which are used to treat patients with AML FLT3-TKD due to their mechanism of action.

This paper presents the case of a 30-year-old AML patient diagnosed with NPM1 and FLT3-TKD mutations, bone marrow reticuline fibrosis and extramedullary sites of AML. Treatment was individualized and induction chemotherapy was combined with midostaurin. After first-line treatment with midostaurin, complete remission was achieved, as confirmed by histopathological examination of the bone marrow. Subsequently, two cycles of consolidation chemotherapy were given, and allogeneic haematopoietic stem cells were transplanted from an unrelated donor after myeloablative conditioning. The patient has remained in complete leukaemia remission, 3 years after diagnosis.

Article available in PDF format

View PDF Download PDF file


  1. Winer ES, Stone RM. Novel therapy in Acute myeloid leukemia (AML): moving toward targeted approaches. Ther Adv Hematol. 2019; 10: 2040620719860645.
  2. Kayser S, Levis MJ. Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol. 2018; 180(4): 484–500.
  3. Bohl SR, Bullinger L, Rücker FG. New targeted agents in acute myeloid leukemia: new hope on the rise. Int J Mol Sci. 2019; 20(8).
  4. Rowe JM. Will new agents impact survival in AML? Best Pract Res Clin Haematol. 2019; 32(4): 101094.
  5. Lee YT, Tan YiJ, Oon CE. Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol. 2018; 834: 188–196.
  6. 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.
  7. 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.
  8. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016; 374(23): 2209–2221.
  9. Lagunas-Rangel FA, Chávez-Valencia V. FLT3-ITD and its current role in acute myeloid leukaemia. Med Oncol. 2017; 34(6): 114.
  10. Daver N, Schlenk RF, Russell NH, et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019; 33(2): 299–312.
  11. Iwai T, Yokota S, Nakao M, et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. Leukemia. 1999; 13(1): 38–43.
  12. 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.
  13. 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.
  14. 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.
  15. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001; 97(8): 2434–2439.
  16. Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005; 19(8): 1345–1349.
  17. Mead AJ, Linch DC, Hills RK, et al. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood. 2007; 110(4): 1262–1270.
  18. 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): 454–464.
  19. Gorcea CM, Burthem J, Tholouli E. ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutation: background and design of the ADMIRAL trial. Future Oncol. 2018; 14(20): 1995–2004.
  20. Boissel N, Renneville A, Biggio V, et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood. 2005; 106(10): 3618–3620.
  21. 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.
  22. Suzuki T, Kiyoi H, Ozeki K, et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood. 2005; 106(8): 2854–2861.
  23. 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.
  24. Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2007; 109(3): 874–885.
  25. Ivey A, Hills R, Simpson M, et al. UK National Cancer Research Institute AML Working Group. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016; 374(5): 422–433.
  26. Krönke J, Schlenk RF, Jensen KO, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011; 29(19): 2709–2716.
  27. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974; 18(4): 295–304.
  28. Falini B, Bolli N, Liso A, et al. Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia. 2009; 23(10): 1731–1743.
  29. Brunetti L, Gundry M, Sorcini D, et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell. 2018; 34(3): 499–512.e9.
  30. Cazzaniga G, Dell'Oro MG, Mecucci C, et al. Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood. 2005; 106(4): 1419–1422.
  31. Nagel G, Weber D, Fromm E, et al. German-Austrian AML Study Group (AMLSG). Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Ann Hematol. 2017; 96(12): 1993–2003.
  32. Falini B, Martelli MP, Pileri SA, et al. Molecular and alternative methods for diagnosis of acute myeloid leukemia with mutated NPM1: flexibility may help. Haematologica. 2010; 95(4): 529–534.
  33. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006; 107(10): 4011–4020.
  34. 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.
  35. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016; 374(23): 2209–2221.
  36. Eisfeld AK, Kohlschmidt J, Mims A, et al. Additional gene mutations may refine the 2017 European LeukemiaNet classification in adult patients with de novo acute myeloid leukemia aged <60 years. Leukemia. 2020; 34(12): 3215–3227.
  37. Vardiman JW. Appendix 2. In: Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. ed. WHO Classification of Tumours of Haemopoietic and Lymphoid Tissues. Revised 4th edition. IARC, Lyon 2017: 1023–1024.
  38. Xu Z. AML with myelodysplasia-related changes masquerades as acute panmyelosis with myelofibrosis. Blood. 2017; 130(15): 1775.
  39. Thiele J, Kvasnicka HM, Schmitt-Graeff A. Acute panmyelosis with myelofibrosis. Leuk Lymphoma. 2004; 45(4): 681–687.
  40. Thiele J, Kvasnicka HM, Zerhusen G, et al. Acute panmyelosis with myelofibrosis: a clinicopathological study on 46 patients including histochemistry of bone marrow biopsies and follow-up. Ann Hematol. 2004; 83(8): 513–521.
  41. Orazi A, O'Malley DP, Jiang J, et al. Acute panmyelosis with myelofibrosis: an entity distinct from acute megakaryoblastic leukemia. Mod Pathol. 2005; 18(5): 603–614.
  42. Koenig KL, Sahasrabudhe KD, Sigmund AM, et al. AML with myelodysplasia-related changes: development, challenges, and treatment advances. Genes (Basel). 2020; 11(8).
  43. Østgård LSG, Nørgaard JM, Sengeløv H, et al. Comorbidity and performance status in acute myeloid leukemia patients: a nation-wide population-based cohort study. Leukemia. 2015; 29(3): 548–555.
  44. Montalban-Bravo G, Kanagal-Shamanna R, Class CA, et al. Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy. Am J Hematol. 2020; 95(6): 612–622.
  45. Falini B, Macijewski K, Weiss T, et al. Multilineage dysplasia has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1). Blood. 2010; 115(18): 3776–3786.
  46. Naous R, Gentile T, Vajpayee N. 201 Evaluation of bone marrow fibrosis in NPM-positive AML: a retrospective study. Am J Clin Pathol. 2018; 149(Suppl_1): S85–S86.
  47. Falini B, Nicoletti I, Bolli N, et al. Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. Haematologica. 2007; 92(4): 519–532.
  48. Bacher U, Haferlach C, Kern W, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters — an analysis of 3082 patients. Blood. 2008; 111(5): 2527–2537.
  49. Boddu P, Kantarjian H, Borthakur G, et al. Co-occurrence of -TKD and mutations defines a highly favorable prognostic AML group. Blood Adv. 2017; 1(19): 1546–1550.
  50. Lachowiez CA, Loghavi S, Kadia TM, et al. Outcomes of older patients with NPM1-mutated AML: current treatments and the promise of venetoclax-based regimens. Blood Adv. 2020; 4(7): 1311–1320.
  51. Kasper S, Breitenbuecher F, Heidel F, et al. Targeting MCL-1 sensitizes FLT3-ITD-positive leukemias to cytotoxic therapies. Blood Cancer J. 2012; 2(3): e60.
  52. Uckelmann HJ, Kim S, Wong E, et al. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science. 2020; 367(6477): 586–590.
  53. Klossowski S, Miao H, Kempinska K, et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J Clin Invest. 2020; 130(2): 981–997.
  54. Fischer MA, Friedlander SY, Arrate MP, et al. Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies. Blood Adv. 2020; 4(3): 586–598.
  55. Cela I, Di Matteo A, Federici L. Nucleophosmin in its interaction with ligands. Int J Mol Sci. 2020; 21(14).
  56. Voso MT, Larson RA, Jones D, et al. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial. Blood Adv. 2020; 4(19): 4945–4954.
  57. Carreras E, Dufour C, Mohty M, Kröger N. ed. The EBMT handbook. Hematopoietic stem cell transplantation and cellular therapies. Springer Open, Cham 2019: 507–521.
  58. Perry M, Bertoli S, Rocher C, et al. FLT3-TKD mutations associated with NPM1 mutations define a favorable-risk group in Patients With Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk. 2018; 18(12): e545–e550.

Hematology in Clinical Practice