Vol 52, No 4 (2021)
Review article
Published online: 2021-08-31

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Therapy of Philadelphia-negative myeloproliferative neoplasms in the blast phase

Joanna Góra-Tybor1
DOI: 10.5603/AHP.2021.0054
Acta Haematol Pol 2021;52(4):278-283.

Abstract

All four Philadelphia negative myeloproliferative neoplasms: essential thrombocythemia, polycythemia vera, pre-fibrotic myelofibrosis, and myelofibrosis, are at risk of transforming to blast phase disease. The risk is highest in the case of myelofibrosis and amounts to c.20%. In the case of essential thrombocythemia, the transformation rate is 1%, and in polycythemia vera it is 5–10%. The prognosis of patients during the blast crisis is poor, with a median survival time of a few months. For patients who qualify for intensive therapy, the basis of treatment are cycles analogous to those in acute myeloid leukemia and allotransplantation of hematopoietic stem cells. In the remaining patients, hypomethylating drugs such as azacitidine and decitabine can be used. Some hope has been raised by new drugs approved for the treatment of patients with acute myeloid leukemia such as venetoclax, IDH1 and IDH2 inhibitors ivosidenib and enasidenib. It is very important that patients with myeloproliferative neoplasms, especially those with myelofibrosis, properly assess the risk of blast transformation and qualify them early enough for allotransplantation of hematopoietic stem cells. New prognostic scales taking into account molecular factors can be very helpful in the assessment. This article discusses the risk factors of blast transformation, and prognostic scales as well as therapies that can be used during the blast crisis, including new drugs.

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References

  1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20): 2391–2405.
  2. Mesa RA, Verstovsek S, Cervantes F, et al. International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res. 2007; 31(6): 737–740.
  3. Masarova L, Bose P, Zahr A, et al. Do we need to re-define accelerated phase of myelofibrosis? Correlation between blast percentage in myelofibrosis and outcomes. Clin Lymphoma Myeloma Leuk. 2017; 17(Suppl 2): S352.
  4. Yogarajah M, Tefferi A. Leukemic transformation in myeloproliferative neoplasms: a literature review on risk, characteristics, and outcome. Mayo Clin Proc. 2017; 92(7): 1118–1128.
  5. Gangat N, Wolanskyj AP, McClure RF, et al. Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients. Leukemia. 2007; 21(2): 270–276.
  6. Finazzi G, Caruso V, Marchioli R, et al. ECLAP Investigators. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005; 105(7): 2664–2670.
  7. Scherber RM, Mesa RA. Managing myelofibrosis (MF) that "blasts" through: advancements in the treatment of relapsed/refractory and blast-phase MF. Hematology Am Soc Hematol Educ Program. 2018; 2018(1): 118–126.
  8. Tefferi A, Mudireddy M, Mannelli F, et al. Blast phase myeloproliferative neoplasm: Mayo-AGIMM study of 410 patients from two separate cohorts. Leukemia. 2018; 32(5): 1200–1210.
  9. Mudireddy M, Shah S, Lasho T, et al. Prefibrotic versus overtly fibrotic primary myelofibrosis: clinical, cytogenetic, molecular and prognostic comparisons. Br J Haematol. 2018; 182(4): 594–597.
  10. Passamonti F, Rumi E, Arcaini L, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008; 93(11): 1645–1651.
  11. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013; 27(9): 1874–1881.
  12. Bonicelli G, Abdulkarim K, Mounier M, et al. Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera: a population-based study of 327 patients. Br J Haematol. 2013; 160(2): 251–254.
  13. Luque Paz D, Jouanneau-Courville R, Riou J, et al. Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation. Blood Adv. 2020; 4(19): 4887–4897.
  14. Tefferi A, Guglielmelli P, Lasho TL, et al. Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera. Br J Haematol. 2020; 189(2): 291–302.
  15. Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014; 28(9): 1804–1810.
  16. Tefferi A, Finke CM, Lasho TL, et al. U2AF1 mutation types in primary myelofibrosis: phenotypic and prognostic distinctions. Leukemia. 2018; 32(10): 2274–2278.
  17. Loscocco GG, Guglielmelli P, Vannucchi AM. Impact of mutational profile on the management of myeloproliferative neoplasms: a short review of the emerging data. Onco Targets Ther. 2020; 13: 12367–12382.
  18. Tefferi A, Lasho TL, Finke C, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014; 28(7): 1472–1477.
  19. Andrikovics H, Krahling T, Balassa K, et al. Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations. Haematologica. 2014; 99(7): 1184–1190.
  20. Tefferi A, Nicolosi M, Mudireddy M, et al. Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients. Leukemia. 2018; 32(5): 1189–1199.
  21. 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(13): 2895–2901.
  22. 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(9): 1703–1708.
  23. 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(4): 392–397.
  24. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: mutation-enhanced international prognostic score system for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018; 36(4): 310–318.
  25. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ version 2.0: mutation and karyotype-enhanced international prognostic scoring system for primary myelofibrosis. J Clin Oncol. 2018; 36(17): 1769–1770.
  26. Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia. 2018; 32(7): 1631–1642.
  27. Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017; 31(12): 2726–2731.
  28. Kennedy JA, Atenafu EG, Messner HA, et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood. 2013; 121(14): 2725–2733.
  29. Alchalby H, Zabelina T, Stübig T, et al. Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation: a study from the Myeloproliferative Neoplasm Subcommittee of the CMWP of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2014; 20(2): 279–281.
  30. Lancet J, Uy G, Cortes J, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 2016; 34(Suppl 15).
  31. Thepot S, Itzykson R, Seegers V, et al. Groupe Francophone des Myelodysplasies (GFM). 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): 3735–3742.
  32. Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase. Leuk Res. 2015; 39(9): 950–956.
  33. Pemmaraju N, Kantarjian HM, Kadia TM, et al. A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015; 15(3): 171–176.
  34. Mwirigi A, Galli S, Keohane C, 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): 714–716.
  35. Guerra VA, DiNardo C, Konopleva M. Venetoclax-based therapies for acute myeloid leukemia. Best Pract Res Clin Haematol. 2019; 32(2): 145–153.
  36. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant relapsed or refractory acute myeloid leukemia. Blood. 2017; 130(6): 722–731.
  37. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in idh1-mutated relapsed or refractory AML. N Engl J Med. 2018; 378(25): 2386–2398.
  38. Parikh SA, Kantarjian H, Schimmer A, et al. Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. Clin Lymphoma Myeloma Leuk. 2010; 10(4): 285–289.
  39. Rampal R, Ahn J, Abdel-Wahab O, et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci USA. 2014; 111(50): E5401–E5410.
  40. 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(7): 1302–1309.
  41. Morsia E, Gangat N, Foran J, et al. Efficacy of venetoclax plus hypomethylating agent in blast phase myeloproliferative neoplasm. Blood. 2020; 136(Suppl 1): 21.
  42. Cahill K, Patel A, Liu H, et al. Outcomes of IDH-mutated advanced phase ph-negative myeloproliferative neoplasms treated with IDH inhibitors. Blood. 2019; 134(Suppl 1): 4176.