Skip to main content

Advertisement

SpringerLink
Log in

Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy

  • Case Report
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Tyrosine kinase inhibitors (TKIs) are standard therapies for chronic myeloid leukemia (CML) that can eradicate Ph-positive leukemic cells. However, disease control is not achievable in a minority of cases, most commonly due to evolution of TKI-resistant clones. There have also been rare cases of emergence of Ph-negative clones with other cytogenetic abnormalities, and, less commonly, development of Ph-negative acute myeloid leukemia (AML), whose molecular pathogenesis is largely unknown. Here we report molecular features of a patient with Ph + CML who developed Ph-negative AML after showing a major molecular response to dasatinib. A 55-year-old man was diagnosed with CML. He achieved a complete cytogenetic response three months after dasatinib therapy but developed AML with normal karyotype 1 year later. After receiving induction and consolidation chemotherapy for AML, the patient achieved complete remission with no evidence of CML under maintenance with bosutinib. Targeted sequencing of serial bone marrow samples identified mutations in IDH2 and NPM1 in the Ph-negative AML cells, which had not been detected in CML cells. These results suggest that Ph-negative AML in this patient originated from a preleukemic population, which might have expanded during or after the successful elimination of CML clones with TKI therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

    Article  CAS  Google Scholar 

  2. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70.

    Article  CAS  Google Scholar 

  3. Saglio G, Kim D-W, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–9.

    Article  CAS  Google Scholar 

  4. Kantarjian H, O’Brien S, Jabbour E, Garcia-Manero G, Quintas-Cardama A, Shan J, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood. 2012;119:1981–7.

    Article  CAS  Google Scholar 

  5. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016;34:2333–40.

    Article  CAS  Google Scholar 

  6. Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim D-W, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044–54.

    Article  CAS  Google Scholar 

  7. Bumm T, Müller C, Al-Ali H-K, Krohn K, Shepherd P, Schmidt E, et al. Emergence of clonal cytogenetic abnormalities in Ph−cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood. 2003;101:1941–9.

    Article  CAS  Google Scholar 

  8. Terre C, Eclache V, Rousselot P, Imbert M, Charrin C, Gervais C, et al. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. Leukemia. 2004;18:1340–6.

    Article  CAS  Google Scholar 

  9. Deininger MWN, Cortes J, Paquette R, Park B, Hochhaus A, Baccarani M, et al. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in philadelphia chromosome-negative cells. Cancer. 2007;110:1509–19.

    Article  Google Scholar 

  10. De Melo VAS, Milojkovic D, Khorashad JS, Marin D, Goldman JM, Apperley JF, et al. Philadelphia-negative clonal hematopoiesis is a significant feature of dasatinib therapy for chronic myeloid leukemia. Blood. 2007;110:3086–7.

    Article  Google Scholar 

  11. Wang H, Jin J, Wang Y, Huang X, Huang J. Clonal chromosomal abnormalities in Philadelphia-negative cells in chronic myeloid leukemia patients treated with nilotinib used in first-line therapy. Ann Hematol. 2013;92:1625–32.

    Article  CAS  Google Scholar 

  12. Issa GC, Kantarjian HM, Gonzalez GN, Borthakur G, Tang G, Wierda W, et al. Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment. Blood. 2017;130:2084–91.

    Article  CAS  Google Scholar 

  13. Bidet A, Dulucq S, Smol T, Marceau-Renaut A, Morisset S, Coiteux V, et al. Poor prognosis of chromosome 7 clonal aberrations in philadelphia-negative metaphases and relevance of potential underlying myelodysplastic features in chronic myeloid leukemia. Haematologica. 2019;104:1150–5.

    Article  CAS  Google Scholar 

  14. Kovitz C, Kantarjian H, Garcia-Manero G, Abruzzo LV, Cortes J. Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia. Blood. 2006;108:2811–3.

    Article  CAS  Google Scholar 

  15. Pawarode A, Sait SNJ, Nganga A, Coignet LJ, Barcos M, Baer MR. Acute myeloid leukemia developing during imatinib mesylate therapy for chronic myeloid leukemia in the absence of new cytogenetic abnormalities. Leuk Res. 2007;31:1589–92.

    Article  CAS  Google Scholar 

  16. Ross DM, Jackson SR, Browett PJ. Philadelphia-negative secondary acute myeloid leukaemia during imatinib treatment for chronic phase chronic myeloid leukaemia. Leuk Lymphoma. 2007;48:1231–3.

    Article  CAS  Google Scholar 

  17. Jabbour E, Kantarjian HM, Abruzzo LV, O’Brien S, Garcia-Manero G, Verstovsek S, et al. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood. 2007;110:2991–5.

    Article  CAS  Google Scholar 

  18. Georgiou G, Efthymiou A, Vardounioti I, Boutsikas G, Angelopoulou MK, Vassilakopoulos TP, et al. Development of acute myeloid leukemia with NPM1 mutation, in Ph-negative clone, during treatment of CML with imatinib. Leukemia. 2012;26:824–6.

    Article  CAS  Google Scholar 

  19. Krysiak K, Christopher MJ, Skidmore ZL, Demeter RT, Magrini V, Kunisaki J, et al. A genomic analysis of Philadelphia chromosome-negative AML arising in patients with CML. Blood Cancer J. 2016;6:e413.

    Article  CAS  Google Scholar 

  20. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7.

    Article  CAS  Google Scholar 

  21. Stein MK, Crawley M, Vick E, Martin MG. Concomitant ATM mutations identified by next generation sequencing in a patient with new-onset acute myeloid leukemia following imatinib treatment for chronic myeloid leukemia. World J Oncol. 2018;9:66–7.

    Article  Google Scholar 

  22. Gong Z, Xu ML, Chen M, Cui W, Kantarjian HM, Cortes JE, et al. Philadelphia chromosome-negative acute leukemia in patients with chronic myeloid leukemia. Am J Hematol. 2019;94:E256–9.

    Article  Google Scholar 

  23. Medinger M, Passweg JR. Acute myeloid leukaemia genomics. Br J Haematol Engl. 2017;179:530–42.

    Article  CAS  Google Scholar 

  24. Schmidt M, Rinke J, Schäfer V, Schnittger S, Kohlmann A, Obstfelder E, et al. Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status. Leukemia. 2014;28:2292–9.

    Article  CAS  Google Scholar 

  25. Mitani K, Nagata Y, Sasaki K, Yoshida K, Chiba K, Tanaka H, et al. Somatic mosaicism in chronic myeloid leukemia in remission. Blood. 2016;128:2863–6.

    Article  CAS  Google Scholar 

  26. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.

    Article  Google Scholar 

  27. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472–8.

    Article  CAS  Google Scholar 

  28. Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.

    Article  Google Scholar 

  29. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.

    Article  CAS  Google Scholar 

  30. 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;18:553–67.

    Article  CAS  Google Scholar 

  31. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483:474–8.

    Article  CAS  Google Scholar 

  32. Brunetti L, Gundry MC, Goodell MA. New insights into the biology of acute myeloid leukemia with mutated NPM1. Int J Hematol. 2019;110:150–60.

    Article  CAS  Google Scholar 

  33. Brunetti L, Gundry MC, Sorcini D, Guzman AG, Huang Y-H, Ramabadran R, et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell. 2018;34(499–512):e9.

    Google Scholar 

  34. Grimwade D, Ivey A, Huntly BJP. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127:29–41.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan

    Fumi Nakamura, Honoka Arai, Motoshi Ichikawa, Shiho Furuichi, Fusako Nagasawa, Wataru Takahashi, Tomoyuki Handa, Yuko Nakamura, Yuka Nakamura, Ko Sasaki & Kinuko Mitani

  2. Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan

    Yasuhito Nannya & Seishi Ogawa

  3. Laboratory of DNA Information Analysis, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Hiroko Tanaka & Satoru Miyano

Authors
  1. Fumi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Honoka Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuhito Nannya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Motoshi Ichikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shiho Furuichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fusako Nagasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wataru Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tomoyuki Handa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuko Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroko Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuka Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ko Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Satoru Miyano
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Seishi Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kinuko Mitani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kinuko Mitani.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakamura, F., Arai, H., Nannya, Y. et al. Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy. Int J Hematol 113, 936–940 (2021). https://doi.org/10.1007/s12185-020-03074-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-020-03074-7

Keywords

Search

Navigation