Current Hematologic Malignancy Reports

, Volume 10, Issue 2, pp 112–117 | Cite as

Secondary Acute Myeloid Leukemias Arising From Philadelphia Chromosome Negative Myeloproliferative Neoplasms: Pathogenesis, Risk Factors, and Therapeutic Strategies

  • Michael Tallarico
  • Olatoyosi Odenike
Acute Myeloid Leukemias (R Stone, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Acute Myeloid Leukemias


The classic Philadelphia chromosome negative myeloproliferative neoplasms including primary myelofibrosis, polycythemia vera, and essential thrombocythemia are associated with a variable propensity for transformation into acute myeloid leukemia. Leukemic transformation in these disorders, so called MPN-blast phase, is uniformly associated with a poor prognosis. In recent years, there has been an increasing understanding of the molecular complexity underlying Philadelphia chromosome negative myeloproliferative neoplasms (Ph− MPNs), and this has spurred efforts to investigate the molecular risk factors associated with clinical outcome in these disorders, including the risk of leukemic transformation. At the same time, there is an ongoing and significant need for new approaches which have the potential to change the natural history of these disorders. This review will focus on the risk factors associated with the development of MPN in blast phase (MPN-BP) including clinical and molecular risk factors, current treatment strategies, and emerging investigational approaches.


Secondary AML MPN-blast phase Leukemic transformation Philadelphia chromosome negative MPN Primary myelofibrosis Polycythemia vera 


Compliance with Ethics Guidelines

Conflict of Interest

Dr. Michael Tallarico declares no potential conflict of interest.

Dr. Olatoyosi Odenike reports grants paid to her institution for clinical research from Eisai; Lily, Novartis, NS-Pharma, S*Bio, Incyte, Gilead, MEI-Pharma, Topotarget, Astex, Celgene, Geron, Sunesis, Spectrum, Sanofi; personal fees for advisory board participation from Sunesis, Spectrum, Sanofi, Incyte and Algeta.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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

  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    Cervantes F, Tassies D, Salgado C, et al. Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol. 1991;85:124–7.CrossRefPubMedGoogle Scholar
  3. 3.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27:1874–81.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.CrossRefPubMedGoogle Scholar
  6. 6.••
    Tefferi A, Guglielmelli P, Larson DR, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124:2507–13. quiz 2615. This large study involving more than 1500 patients demonstrates that patients with primary myelofibrosis who are negative for CALR, MPL, and JAK2 have an inferior outcome and an increased risk of leukemic transformation. The study also outlines the natural history of Ph-MPNs, demonstrates a superior survival in ET compared with PV, and underscores the fact that even in the genomic era, clinical phenotype is still relevant with regard to predicting the natural history of these disorders. Google Scholar
  7. 7.
    Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895–901.CrossRefPubMedGoogle Scholar
  8. 8.
    Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115:1703–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Passamonti F, Cervantes F, Vannucchi AM, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood. 2010;116:2857–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Tam CS, Kantarjian H, Cortes J, et al. Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. J Clin Oncol. 2009;27:5587–93.CrossRefPubMedGoogle Scholar
  11. 11.
    Passamonti F, Rumi E, Elena C, et al. Incidence of leukaemia in patients with primary myelofibrosis and RBC-transfusion-dependence. Br J Haematol. 2010;150:719–21.CrossRefPubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined dynamic international prognostic scoring system for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29:392–7.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    Rumi E, Harutyunyan A, Elena C, et al. Identification of genomic aberrations associated with disease transformation by means of high-resolution SNP array analysis in patients with myeloproliferative neoplasm. Am J Hematol. 2011;86:974–9.CrossRefPubMedGoogle Scholar
  17. 17.••
    Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90. This study demonstrates for the first time the occurrence of mutations in CALR in the majority of JAK2 mutation and MPL mutation-negative MPNs. In addition, the favorable prognostic impact conferred by the presence of this mutation was also demonstrated. CrossRefPubMedGoogle Scholar
  18. 18.••
    Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405. This study demonstrates for the first time the occurrence of mutations in CALR in the majority of JAK2 mutation and MPL mutation-negative MPNs. CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.••
    Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27:1861–9. This comprehensive analysis of 10 recurrently mutated candidate genes in two large multi institutional cohorts of patients with PMF demonstrated that mutations in five genes including ASXL1, EZH2, SRSF2, and IDH1/2 were associated with poor clinical outcome, including increased risk of leukemic transformation in primary myelofibrosis. CrossRefPubMedGoogle Scholar
  20. 20.
    Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123:2220–8.CrossRefPubMedGoogle Scholar
  21. 21.
    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;108:3548–55.CrossRefPubMedGoogle Scholar
  22. 22.
    Theocharides A, Boissinot M, Girodon F, et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood. 2007;110:375–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Green A, Beer P. Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med. 2010;362:369–70.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.•
    Rampal R, Ahn J, Abdel-Wahab O, et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2014;111:E5401–10. This study illustrates the important role of TP53 mutations in facilitating leukemic transformation in Ph− MPN. In addition a murine model of JAK2V617F mutant, TP53-deficient AML is developed, providing an in vivo validation of the role of TP53 mutations in the pathogenesis of MPN-BP. This murine model is also a valuable tool for investigating novel therapies and approaches in MPN-BP. Google Scholar
  27. 27.
    Harutyunyan A, Klampfl T, Cazzola M, et al. p53 lesions in leukemic transformation. N Engl J Med. 2011;364:488–90.CrossRefPubMedGoogle Scholar
  28. 28.•
    Kennedy JA, Atenafu EG, Messner HA, et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood. 2013;121:2725–33. This retrospective study highlights the potential role of allogeneic stem cell transplantation in modifying the natural history of MPN-BP in the context of relatively uniform treatment strategy in which patients were offered induction therapy based on their level of fitness. CrossRefPubMedGoogle Scholar
  29. 29.
    Cahu X, Chevallier P, Clavert A, et al. Allo-SCT for Philadelphia-negative myeloproliferative neoplasms in blast phase: a study from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC). Bone Marrow Transplant. 2014;49:756–60.CrossRefPubMedGoogle Scholar
  30. 30.
    Robin M, Giannotti F, Deconinck E, et al. Unrelated cord blood transplantation for patients with primary or secondary myelofibrosis. Biol Blood Marrow Transplant. 2014;20:1841–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Mascarenhas J, Navada S, Malone A, et al. Therapeutic options for patients with myelofibrosis in blast phase. Leuk Res. 2010;34:1246–9.CrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787–98.CrossRefPubMedGoogle Scholar
  34. 34.
    Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807.CrossRefPubMedGoogle Scholar
  35. 35.•
    Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:426–35. This study demonstrates the superiority of ruxolitinib to the best available therapy in the context of second-line therapy for PV. CrossRefPubMedGoogle Scholar
  36. 36.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Odenike O. Beyond JAK inhibitor therapy in myelofibrosis. Hematol Am Soc Hematol Educ Program. 2013;2013:545–52.CrossRefGoogle Scholar
  38. 38.
    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.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Medicine, Section of Hematology/OncologyThe University of ChicagoChicagoUSA
  2. 2.The Comprehensive Cancer CenterThe University of ChicagoChicagoUSA

Personalised recommendations