Current Hematologic Malignancy Reports

, Volume 8, Issue 2, pp 116–122

Acute Myeloid Leukemia Following a Myeloproliferative Neoplasm: Clinical Characteristics, Genetic Features and Effects of Therapy

Acute Leukemias (E Feldman, Section Editor)

Abstract

Acute myeloid leukemia (AML) is an uncommon, but often deadly complication of myeloproliferative neoplasms (MPN). Post-MPN AML usually occurs years after the initial MPN diagnosis with an average age of onset between 64 and 68 years. Chromosome abnormalities are common and many patients have cytogenetic changes that are associated with poor risk features. Post-MPN AML is characterized by acquired somatic gene mutations, but, interestingly, mutations thought to have an etiologic role in the MPN, such as JAK2V617F, are sometimes absent in the AML clone. Conventional AML-style treatment appears to have limited efficacy, although when coupled to allogeneic stem cell transplantation, some patients have long-term survival. Less-intensive therapies such as hypomethylating agents and the JAK inhibitor, ruxolitinib, may be effective in some patients. New treatments have prompted efforts to characterize therapeutic responses better.

Keywords

Acute myeloid leukemia Myeloproliferative neoplasm Myeloproliferative disorder Blast phase Cytogenetics Genetics Hypomethylating JAK inhibitor Clonal Classification Response 

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.PubMedGoogle Scholar
  2. 2.
    Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–97.PubMedCrossRefGoogle Scholar
  3. 3.
    Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. 2005;280:22788–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Druker BJ. Perspectives on the development of imatinib and the future of cancer research. Nat Med. 2009;15:1149–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Skversky NJ, Yarrow MW, Lewinn EB. Phenylbutazone in the treatment of deep-vein thrombophlebitis; a preliminary report. J Albert Einstein Med Cent (Phila). 1957;5:268–71.Google Scholar
  6. 6.
    Bank A, Larsen PR, Anderson HM. Di Guglielmo’s syndrome after polycythemia. N Engl J Med. 1966;275:489–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Passamonti F, Rumi E, Arcaini L, et al. Leukemic transformation of polycythemia vera: a single center study of 23 patients. Cancer. 2005;104:1032–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105:973–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Tam CS, Nussenzveig RM, Popat U, et al. The natural history and treatment outcome of blast phase BCR-ABL- myeloproliferative neoplasms. Blood. 2008;112:1628–37.PubMedCrossRefGoogle Scholar
  10. 10.
    Abdulkarim K, Girodon F, Johansson P, et al. AML transformation in 56 patients with Ph-MPD in two well defined populations. Eur J Haematol. 2009;82:106–11.PubMedCrossRefGoogle Scholar
  11. 11.
    Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:14–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Campbell PJ, Baxter EJ, Beer PA, et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood. 2006;108(10):3548–55.PubMedCrossRefGoogle Scholar
  13. 13.
    •• Beer PA, Delhommeau F, LeCouedic JP, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 2010;115:2891–900. This study investigated the evolution of the acute leukemic clone from a cell that was evolutionarily distinct from the MPN clone.Google Scholar
  14. 14.
    •• Abdel-Wahab O, Manshouri T, Patel J, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res. 2010;70:447–52. Genetic analysis of 63 patients with post-MPN AML identifying TET2, AXL1 and IDH1 in addition to JAK2 as common mutations.PubMedCrossRefGoogle Scholar
  15. 15.
    Harutyunyan A, Klampfl T, Cazzola M, Kralovics R. p53 lesions in leukemic transformation. New Engl J Med. 2011;364:488–90.PubMedCrossRefGoogle Scholar
  16. 16.
    Ding Y, Harada Y, Imagawa J, Kimura A, Harada H. AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms. Blood. 2009;114(25):5201–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Puda A, Milosevic JD, Berg T, et al. Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies. Am J Hematol. 2012;87:245–50.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang SJ, Rampal R, Manshouri T, et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood. 2012;119:4480–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Abdel-Wahab O, Pardanani A, Rampal R, et al. DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms. Leukemia. 2011;25:1219–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Tefferi A, Lasho TL, Abdel-Wahab O, et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia. 2010;24:1302–9.PubMedCrossRefGoogle Scholar
  21. 21.
    •• Thoennissen NH, Krug UO, Lee DH, Kawamata N, Iwanski GB, Lasho T, et al. Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms. Blood. 2010;115:2882–90. Analysis of 71 patients with post-MPN-AML identified established targets such as ETV6, p53 and RUNX1 and also identified new candidate genes.PubMedCrossRefGoogle Scholar
  22. 22.
    Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med. 1981;304:441–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Fruchtman SM, Mack K, Kaplan ME, et al. From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol. 1997;34:17–23.PubMedGoogle Scholar
  24. 24.
    Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105:2664–70.PubMedCrossRefGoogle Scholar
  25. 25.
    Bjorkholm M, Derolf AR, Hultcrantz M, et al. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol. 2011;29:2410–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Huang J, Li CY, Mesa RA, et al. Risk factors for leukemic transformation in patients with primary myelofibrosis. Cancer. 2008;112:2726–32.PubMedCrossRefGoogle Scholar
  27. 27.
    Cherington C, Slack JL, Leis J, et al. Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase. Leuk Res. 2012;36:1147–51.PubMedCrossRefGoogle Scholar
  28. 28.
    Mascarenhas J, Roper N, Chaurasia P, Hoffman R. Epigenetic abnormalities in myeloproliferative neoplasms: a target for novel therapeutic strategies. Clin Epigenetics. 2011;2:197–212.PubMedCrossRefGoogle Scholar
  29. 29.
    •• Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood. 2010;116:3735–42. Treatment of patients with post-MPN AML with the hypomethylating agent, azacytidine, resulted in a complete response in 24 % and an overall response rate of 52 %.PubMedCrossRefGoogle Scholar
  30. 30.
    Mascarenhas J, Navada S, Malone A, et al. Therapeutic options for patients with myelofibrosis in blast phase. Leuk Res. 2010;34:1246–9.PubMedCrossRefGoogle Scholar
  31. 31.
    •• Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012;119:4614–8. In this phase 2 study, 3 of 16 patients achieved either a complete response or a complete response with incomplete blood count recovery with the JAK inhibitor, ruxolitinib, and a total of 60 % appeared to have clinical benefit.PubMedCrossRefGoogle Scholar
  32. 32.
    •• Mascarenhas J, Heaney ML, Najfeld V, et al. Proposed criteria for response assessment in patients treated in clinical trials for myeloproliferative neoplasms in blast phase (MPN-BP): formal recommendations from the post-myeloproliferative neoplasm acute myeloid leukemia consortium. Leuk Res. 2012;36:1500–4. Proposal for a new response classification specific for post-MPN AML that encompasses responses of both the blastic component and the underlying MPN.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of MedicineColumbia University Medical CenterNew YorkUSA
  2. 2.Leukemia Service, Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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