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Leukemic Transformation of Myeloproliferative Neoplasms: Therapeutic and Genomic Considerations

  • Myeloproliferative Neoplasms (B Stein, Section Editor)
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Abstract

Purpose of Review

Although BCR-ABL1-negative myeloproliferative neoplasms (MPN) are chronic, clonal hematopoietic stem cell (HSC) disorders marked by proliferation of one or more myeloid lineages, a substantial proportion of patients transform to acute myeloid leukemia. Leukemic transformation (LT) from a pre-existing MPN carries a dismal prognosis. Here, we review recent genetic, biological, and clinical data regarding LT.

Recent Findings

In the last decade, DNA sequencing has revolutionized our understanding of the genomic landscape of LT. Mutations in TP53, ASXL1, EZH2, IDH1/2, and SRSF2 are significantly associated with increased risk of LT of MPNs. Preclinical modeling of these mutations is underway and has yielded important biological insights, some of which have therapeutic implications.

Summary

Recent progress has led to the identification of recurrent genomic alterations in patients with LT. This has allowed mechanistic and therapeutic insight into the process of LT. In turn, this may lead to more mechanism-based therapeutic strategies that may improve patient outcomes.

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References

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

  1. Chihara D, Kantarjian HM, Newberry KJ, et al. Survival outcome of patients with acute myeloid leukemia transformed from myeloproliferative neoplasms. Blood. 2016;128(22).

  2. •• Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105(3):973–7. This study demonstrates that patients with LT appear to have a poor overall survival regardless of treatment type.

    Article  CAS  PubMed  Google Scholar 

  3. Passamonti F, Rumi E, Arcaini L, Castagnola C, Lunghi M, Bernasconi P, et al. Leukemic transformation of polycythemia vera - a single center study of 23 patients. Cancer. 2005;104(5):1032–6.

    Article  PubMed  Google Scholar 

  4. Thepot S, Itzykson R, Seegers V, Raffoux E, Quesnel B, Chait Y, 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(19):3735–42.

    Article  CAS  PubMed  Google Scholar 

  5. Shanavas M, Popat U, Michaelis LC, Fauble V, McLornan D, Klisovic R, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to Janus kinase 1/2 inhibitors. Biol Blood Marrow Transplant. 2016;22(3):432–40.

    Article  CAS  PubMed  Google Scholar 

  6. Mascarenhas J, Navada S, Malone A, Rodriguez A, Najfeld V, Hoffman R. Therapeutic options for patients with myelofibrosis in blast phase. Leuk Res. 2010;34(9):1246–9.

    Article  PubMed  Google Scholar 

  7. Polliack A, Prokocimer M, Matzner Y. Lymphoblastic leukemic transformation (lymphoblastic crisis) in myelofibrosis and myeloid metaplasia. Am J Hematol. 1980;9(2):211–20.

    Article  CAS  PubMed  Google Scholar 

  8. Cervantes F, Tassies D, Salgado C, Rovira M, Pereira A, Rozman C. Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol. 1991;85(3):124–7.

    Article  CAS  PubMed  Google Scholar 

  9. Huang J, Li CY, Mesa RA, Wu W, Hanson CA, Pardanani A, et al. Risk factors for leukemic transformation in patients with primary myelofibrosis. Cancer. 2008;112(12):2726–32.

    Article  PubMed  Google Scholar 

  10. 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(17):2410–5.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Finazzi G, Caruso V, Marchioli R, Capnist G, Chisesi T, Finelli C, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105(7):2664–70.

    Article  CAS  PubMed  Google Scholar 

  12. Barosi G, Ambrosetti A, Centra A, Falcone A, Finelli C, Foa P, et al. Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia. Blood. 1998;91(10):3630–6.

    CAS  PubMed  Google Scholar 

  13. Barosi G, Ambrosetti A, Buratti A, Finelli C, Liberato NL, Quaglini S, et al. Splenectomy for patients with myelofibrosis with myeloid metaplasia: pretreatment variables and outcome prediction. Leukemia. 1993;7(2):200–6.

    CAS  PubMed  Google Scholar 

  14. Lafaye F, Rain JD, Clot P, Najean Y. Risks and benefits of splenectomy in myelofibrosis: an analysis of 39 cases. Nouv Rev Fr Hematol. 1994;36(5):359–62.

    CAS  PubMed  Google Scholar 

  15. Tam CS, Nussenzveig RM, Popat U, Bueso-Ramos CE, Thomas DA, Cortes JA, et al. The natural history and treatment outcome of blast phase BCR-ABL-myeloproliferative neoplasms. Blood. 2008;112(5):1628–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tefferi A, Mesa RA, Nagorney DM, Schroeder G, Silverstein MN. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood. 2000;95(7):2226–33.

    CAS  PubMed  Google Scholar 

  17. Tam CS, Kantarjian H, Cortes J, Lynn A, Pierce S, Zhou L, 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(33):5587–93.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Fruchtman SM, Mack K, Kaplan ME, Peterson P, Berk PD, Wasserman LR. From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol. 1997;34(1):17–23.

    CAS  PubMed  Google Scholar 

  19. Barbui T. The leukemia controversy in myeloproliferative disorders: is it a natural progression of disease, a secondary sequela of therapy, or a combination of both? Semin Hematol. 2004;41(2 Suppl 3):15–7.

    Article  PubMed  Google Scholar 

  20. Barbui T, Carobbio A, Finazzi G, Vannucchi AM, Barosi G, Antonioli E, et al. Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3. Haematologica. 2011;96(2):315–8.

    Article  CAS  PubMed  Google Scholar 

  21. Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16):2507–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kent DG, Li J, Tanna H, et al. Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion. Plos Biology. 2013;11(6).

  23. Li J, Spensberger D, Ahn JS, Anand S, Beer PA, Ghevaert C, et al. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood. 2010;116(9):1528–38.

    Article  CAS  PubMed  Google Scholar 

  24. Mullally A, Lane SW, Ball B, Megerdichian C, Okabe R, al-Shahrour F, et al. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell. 2010;17(6):584–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ishii T, Zhao Y, Sozer S, Shi J, Zhang W, Hoffman R, et al. Behavior of CD34+ cells isolated from patients with polycythemia vera in NOD/SCID mice. Exp Hematol. 2007;35(11):1633–40.

    Article  CAS  PubMed  Google Scholar 

  26. James C, Mazurier F, Dupont S, Chaligne R, Lamrissi-Garcia I, Tulliez M, et al. The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity. Blood. 2008;112(6):2429–38.

    Article  CAS  PubMed  Google Scholar 

  27. •• Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861–9. This study describes the specific mutations associated with the highest risk of LT.

    Article  CAS  PubMed  Google Scholar 

  28. Lundberg P, Karow A, Nienhold R, Looser R, Hao-Shen H, Nissen I, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123(14):2220–8.

    Article  CAS  PubMed  Google Scholar 

  29. Wang L, Swierczek SI, Drummond J, Hickman K, Kim SJ, Walker K, et al. Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes. Leukemia. 2014;28(4):935–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Delic S, Rose D, Kern W, Nadarajah N, Haferlach C, Haferlach T, et al. Application of an NGS-based 28-gene panel in myeloproliferative neoplasms reveals distinct mutation patterns in essential thrombocythaemia, primary myelofibrosis and polycythaemia vera. Br J Haematol. 2016;175(3):419–26.

    Article  CAS  PubMed  Google Scholar 

  31. Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP, et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood. 2012;120(20):4168–71.

    Article  CAS  PubMed  Google Scholar 

  32. Courtier F, Carbuccia N, Garnier S, Guille A, Adélaïde J, Cervera N, et al. Genomic analysis of myeloproliferative neoplasms in chronic and acute phases. Haematologica. 2017;102(1):e11–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li B, Gale RP, Xu Z, Qin T, Song Z, Zhang P, et al. Non-driver mutations in myeloproliferative neoplasm-associated myelofibrosis. J Hematol Oncol. 2017;10(1):99.

    Article  PubMed  PubMed Central  Google Scholar 

  34. •• Rampal R, Ahn J, Abdel-Wahab O, et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(50):E5401-E5410. This was the description of a JAK2V617F driven murine leukemia model. The study also contains sequencing information from paired MPN and LT samples.

  35. Harutyunyan A, Klampfl T, Cazzola M, Kralovics R. p53 lesions in leukemic transformation. N Engl J Med. 2011;364(5):488–90.

    Article  CAS  PubMed  Google Scholar 

  36. Zoi K, Cross NC. Genomics of myeloproliferative neoplasms. J Clin Oncol. 2017;35(9):947–54.

    Article  CAS  PubMed  Google Scholar 

  37. Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018;15(1):13–30.

    Article  CAS  PubMed  Google Scholar 

  38. Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res. 2010;70(2):447–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SCW, Ramakrishnan A, et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell. 2015;27(5):617–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ortmann CA, Kent DG, Nangalia J, Silber Y, Wedge DC, Grinfeld J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372(7):601–12.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chen E, Schneider RK, Breyfogle LJ, Rosen EA, Poveromo L, Elf S, et al. Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms. Blood. 2015;125(2):327–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Taniguchi Y, et al. Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator. Blood. 2015;125(2):304–15.

    Article  CAS  PubMed  Google Scholar 

  43. Tefferi A, Jimma T, Sulai NH, Lasho TL, Finke CM, Knudson RA, et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia. 2012;26(3):475–80.

    Article  CAS  PubMed  Google Scholar 

  44. Pardanani A, Lasho TL, Finke CM, Mai M, McClure RF, Tefferi A. IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia. 2010;24(6):1146–51.

    Article  CAS  PubMed  Google Scholar 

  45. Sasaki M, Knobbe CB, Munger JC, et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012;488(7413):656−+.

  46. Chen C, Liu Y, Lu C, Cross JR, Morris JP, Shroff AS, et al. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev. 2013;27(18):1974–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chaturvedi A, Cruz MMA, Jyotsana N, et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood. 2013;122(16):2877–87.

    Article  CAS  PubMed  Google Scholar 

  48. McKenney AS, Allison N, Somasundara AVH, et al. JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Investig. 2018;128(2):789–804.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lasho TL, Mudireddy M, Finke CM, Hanson CA, Ketterling RP, Szuber N, et al. Targeted next-generation sequencing in blast phase myeloproliferative neoplasms. Blood Adv. 2018;2(4):370–80.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med. 2013;210(12):2641–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang J, Li Z, He Y, Pan F, Chen S, Rhodes S, et al. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice. Blood. 2014;123(4):541–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22(2):180–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang Y, Akada H, Nath D, Hutchison RE, Mohi G. Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm. Blood. 2016;127(26):3410–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shimizu T, Kubovcakova L, Nienhold R, Zmajkovic J, Meyer SC, Hao-Shen H, et al. Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis. J Exp Med. 2016;213(8):1479–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang SJ, Rampal R, Manshouri T, Patel J, Mensah N, Kayserian A, 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(19):4480–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Granfeldt Ostgard LS, Medeiros BC, Sengelov H, et al. Epidemiology and clinical significance of secondary and therapy-related acute myeloid leukemia: a National Population-Based Cohort Study. J Clin Oncol. 2015;33(31):3641–9.

    Article  PubMed  Google Scholar 

  57. •• Kennedy JA, Atenafu EG, Messner HA, et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood. 2013;121(14):2725–33. This study demonstrates that patients with LT treated with induction chemotherapy may derive benefit if they receive allogeneic stem cell transplant. However, patients who achieve a remission and don't receive transplant may not derive benefit from induction chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  58. Cherington C, Slack JL, Leis J, Adams RH, Reeder CB, Mikhael JR, et al. Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase. Leuk Res. 2012;36(9):1147–51.

    Article  PubMed  Google Scholar 

  59. Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C, 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(20):4614–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mwirigi A, Galli S, Keohane C, Raj K, Radia DH, Harrison CN, et al. Combination therapy with ruxolitinib plus 5-azacytidine or continuous infusion of low dose cytarabine is feasible in patients with blast-phase myeloproliferative neoplasms. Br J Haematol. 2014;167(5):714–6.

    Article  CAS  PubMed  Google Scholar 

  61. Devillier R, Raffoux E, Rey J, Lengline E, Ronchetti AM, Sebert M, et al. Combination therapy with ruxolitinib plus intensive treatment strategy is feasible in patients with blast-phase myeloproliferative neoplasms. Br J Haematol. 2016;172(4):628–30.

    Article  PubMed  Google Scholar 

  62. Rampal Rea. Safety and efficacy of combined ruxolitinib and decitabine in patients with blast-phase MPN and post-MPN AML: results of a phase I study (myeloproliferative disorders research consortium 109 trial). American Society of Hematology annual meeting abstract 2016.

  63. al. Be. Phase I/II study of ruxolitinib (RUX) with decitabine (DAC) in patients with post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML): phase I results. American Society of Hematology annual meeting. 2016.

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Authors and Affiliations

  1. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 443, New York, NY, 10022, USA

    Bing Li & Raajit K. Rampal

  2. MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China

    Bing Li

  3. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    John O. Mascarenhas

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  1. Bing Li
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Correspondence to Raajit K. Rampal.

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Conflict of Interest

Bing Li declares no conflict of interest.

John O. Mascarenhas reports grants from Incyte, Novartis, Janssen, Roche, CTI Biopharma, Pharmaessentia, Celgen, Merck, and Promedior.

Raajit K. Rampal reports personal fees from Incyte, Celgene, Jazz, Apexx, and Agios and grants from Constellation and Stemline.

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

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This article is part of the Topical Collection on Myeloproliferative Neoplasms

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Li, B., Mascarenhas, J.O. & Rampal, R.K. Leukemic Transformation of Myeloproliferative Neoplasms: Therapeutic and Genomic Considerations. Curr Hematol Malig Rep 13, 588–595 (2018). https://doi.org/10.1007/s11899-018-0491-5

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