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Wiener klinische Wochenschrift

, Volume 129, Issue 9–10, pp 293–302 | Cite as

Austrian recommendations for the management of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis: an expert statement

  • Thamer SliwaEmail author
  • Christine Beham-Schmid
  • Sonja Burgstaller
  • Veronika Buxhofer-Ausch
  • Günther Gastl
  • Klaus Geissler
  • Maria Krauth
  • Peter Krippl
  • Alois Lang
  • Andreas Petzer
  • Stefan Wöhrer
  • Albert Wölfler
  • Heinz Gisslinger
consensus report

Summary

The entity “myelofibrosis” represents a subgroup of the Philadelphia chromosome-negative myeloproliferative neoplasms. It comprises primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. This heterogeneous disease is characterized by clonal myeloproliferation, dysregulated kinase signalling and the abnormal expression of several proinflammatory cytokines. Clinically, patients present with symptoms related to thrombocytosis/leukocytosis, anemia and/or progressive splenomegaly. Mutations in Janus kinase 2, an enzyme that is essential for the normal development of erythrocytes, granulocytes, and platelets, notably the V617F mutation, have been identified in approximately 60% of patients with primary myelofibrosis. Recent molecular advances have not only elucidated critical pathways in the pathogenesis of the disease, but also contributed to a more precise assessment of a patient’s individual risk. While allogeneic stem cell transplantation remains the only curative treatment, the natural course of the disease and the patient’s survival and quality of life may be improved by new treatments, notably ruxolitinib, the first Janus kinase 1/2 inhibitor approved for the management of myelofibrosis. Additional treatment options are being explored.

Keywords

Primary myelofibrosis Post-polycythemia myelofibrosis Post-essential thrombocythemia myelofibrosis Management recommendations Targeted therapies Janus kinase inhibitors Ruxolitinib 

Notes

Acknowledgements

The development of these recommendations was supported by Novartis Pharma GmbH, Austria including funding of a medical writer. The authors did not receive financial compensation from Novartis Pharma GmbH for authoring the manuscript.

Conflict of interest

The following authors declare that they have served as consultants or received financial support for performing a research project of industrial companies: S. Burgstaller: Novartis, AOP Orphan, Celgene; K. Geissler: Novartis; A. Lang: Novartis; A. Petzer: Novartis; A. Wölfler: Novartis; H. Gisslinger: Novartis, AOP Orphan, Baxalta, Celgene. T. Sliwa, C. Beham-Schmid, V. Buxhofer-Ausch, G. Gastl, M. Krauth, P. Krippl and S. Wöhrer declare that they have no competing interests.

References

  1. 1.
    Hasselbalch HC. The role of cytokines in the initiation and progression of myelofibrosis. Cytokine Growth Factor Rev. 2013;24(2):133–45. doi: 10.1016/j.cytogfr.2013.01.004.CrossRefPubMedGoogle Scholar
  2. 2.
    Gisslinger H, Jeryczynski G, Gisslinger B, Wolfler A, Burgstaller S, Buxhofer-Ausch V, et al. Clinical impact of bone marrow morphology for the diagnosis of essential thrombocythemia: comparison between the BCSH and the WHO criteria. Leukemia. 2016;30(5):1126–32.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Thiele J, Kvasnicka HM, Mullauer L, Buxhofer-Ausch V, Gisslinger B, Gisslinger H. Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification. Blood. 2011;117(21):5710–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Barosi G. Essential thrombocythemia vs. early/prefibrotic myelofibrosis: why does it matter. Best Pract Res Clin Haematol. 2014;27(2):129–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Grießhammer M, Baerlocher G, Gisslinger H, Lengfelder E, Petrides PE. https://www.onkopedia.com/de/onkopedia/guidelines/primaere-myelofibrose-pmf/@@view/html/index.html. Accessed May 11, 2016.
  6. 6.
    Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Cahu X, Constantinescu SN. Oncogenic drivers in myeloproliferative neoplasms: from JAK2 to calreticulin mutations. Curr Hematol Malig Rep. 2015;10(4):335–43.CrossRefPubMedGoogle Scholar
  9. 9.
    Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Plos Med. 2006;3(7):e270.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28(7):1472–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Milosevic Feenstra JD, Nivarthi H, Gisslinger H, Leroy E, Rumi E, Chachoua I, et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016;127(3):325–32.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yonal-Hindilerden I, Daglar-Aday A, Akadam-Teker B, Yilmaz C, Nalcaci M, Yavuz AS, et al. Prognostic significance of ASXL1, JAK2V617F mutations and JAK2V617F allele burden in Philadelphia-negative myeloproliferative neoplasms. J Blood Med. 2015;6(4459634):157–75.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7(3912063):89–101.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F, Mesa RA, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9):1139–45.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kaifie A, Kirschner M, Wolf D, Maintz C, Hanel M, Gattermann N, et al. Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German SAL-MPN-registry. J Hematol Oncol. 2016;9:18.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Emanuel RM, Dueck AC, Geyer HL, Kiladjian JJ, Slot S, Zweegman S, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012;30(33):4098–103.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Barbui T, Thiele J, Vannucchi AM, Tefferi A. Problems and pitfalls regarding WHO-defined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia. Leukemia. 2013;27(10):1953–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Kvasnicka HM, Beham-Schmid C, Bob R, Dirnhofer S, Hussein K, Kreipe H, et al. Problems and pitfalls in grading of bone marrow fibrosis, collagen deposition and osteosclerosis – a consensus-based study. Histopathology. 2016;68(6):905–15.CrossRefPubMedGoogle Scholar
  19. 19.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.CrossRefPubMedGoogle Scholar
  20. 20.
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, 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(5):937–51.CrossRefPubMedGoogle Scholar
  21. 21.
    Barbui T, Thiele J, Vannucchi AM, Tefferi A. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood Cancer J. 2015;5(4558589):e337.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22(2):437–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Hasselbalch HC, Bjorn ME. MPNs as inflammatory diseases: the evidence, consequences, and perspectives. Mediators Inflamm. 2015;2015:102476.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tefferi A. Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88(2):141–50.CrossRefPubMedGoogle Scholar
  25. 25.
    Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, 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):2895–901.CrossRefPubMedGoogle Scholar
  26. 26.
    Tefferi A, Guglielmelli P, Lasho TL, Rotunno G, Finke C, Mannarelli C, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494–500.CrossRefPubMedGoogle Scholar
  27. 27.
    Vannucchi AMGP, Rotunno G. Mutation-Enhanced International Prognostic Scoring System (MIPSS) for primary myelofibrosis: an AGIMM & IWG-MRT project. American Society of Hematology (ASH) Annual Meeting, San Francisco. 2014, p Abstract #405.Google Scholar
  28. 28.
    Kroger NM, Deeg JH, Olavarria E, Niederwieser D, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015;29(11):2126–33.CrossRefPubMedGoogle Scholar
  29. 29.
    Kroger N, Giorgino T, Scott BL, Ditschkowski M, Alchalby H, Cervantes F, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125(21):3347–50, quiz 64.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.CrossRefPubMedGoogle Scholar
  32. 32.
    Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30:1701. doi: 10.1038/leu.2016.148.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Verstovsek SMR, Gotlib J. et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 5‑year final efficacy and safety analysis from COMFORT-I. 2016 American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) annual meeting, Copenhagen, 9.-12. Jun 2016. : ; 2016, p Abstract #S452.Google Scholar
  34. 34.
    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.CrossRefPubMedGoogle Scholar
  35. 35.
    Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29(10):2062–8.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Jaekel N, Behre G, Behning A, Wickenhauser C, Lange T, Niederwieser D, et al. Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib. Bone Marrow Transplant. 2014;49(2):179–84.CrossRefPubMedGoogle Scholar
  37. 37.
    Tabarroki A, Saunthararajah Y, Visconte V, Cinalli T, Colaluca K, Rogers HJ, et al. Ruxolitinib in combination with DNA methyltransferase inhibitors: clinical responses in patients with symptomatic myelofibrosis with cytopenias and elevated blast(s) counts. Leuk Lymphoma. 2015;56(2):497–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Talpaz M, Paquette R, Afrin L, Hamburg SI, Prchal JT, Jamieson K, et al. Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. J Hematol Oncol. 2013;6(1):81.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Bjorn ME, Holmstrom MO, Hasselbalch HC. Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients. Leuk Lymphoma. 2016;57(1):125–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc. 2011;86(12):1188–91.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Mesa RA, Nagorney DS, Schwager S, Allred J, Tefferi A. Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer. 2006;107(2):361–70.CrossRefPubMedGoogle Scholar
  42. 42.
    Martinez-Trillos A, Gaya A, Maffioli M, Arellano-Rodrigo E, Calvo X, Diaz-Beya M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol. 2010;89(12):1233–7.CrossRefPubMedGoogle Scholar
  43. 43.
    McMullin MF, Harrison CN, Niederwieser D, Demuynck H, Jakel N, Gopalakrishna P, et al. The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis. Exp Hematol Oncol. 2015;4:26.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Cervantes F, Isola IM, Alvarez-Larran A, Hernandez-Boluda JC, Correa JG, Pereira A. Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results. Ann Hematol. 2015;94(11):1791–6.CrossRefPubMedGoogle Scholar
  45. 45.
    Hertzberg MS, Wong M. Hypercalcemia and adrenal insufficiency in a patient with myelofibrosis. Am J Hematol. 2000;63(2):105.Google Scholar
  46. 46.
    Tefferi A, Verstovsek S, Barosi G, Passamonti F, Roboz GJ, Gisslinger H, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol. 2009;27(27):4563–9.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Pardanani A, Abdelrahman RA, Finke C, Lasho TT, Begna KH, Al-Kali A, et al. Genetic determinants of response and survival in momelotinib-treated patients with myelofibrosis. Leukemia. 2015;29(3):741–4.CrossRefPubMedGoogle Scholar
  48. 48.
    Verstovsek S, Komrokji RS. A comprehensive review of pacritinib in myelofibrosis. Future Oncol. 2015;11(20):2819–30.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Daver N, G‑MG, Cortes JE. et al. 5‑Azacitidine (AZA) in combination with ruxolitinib (RUX) as therapy for patients with myelodysplastic/myeloproliferative neoplasms (MDS/MPNS). American Society of Hematology (ASH) Annual Meeting, Orlando. 2015, p Abstract # 823.Google Scholar
  50. 50.
    Ianotto JC, Boyer-Perrard F, Gyan E, Laribi K, Cony-Makhoul P, Demory JL, et al. Efficacy and safety of pegylated-interferon alpha-2a in myelofibrosis: a study by the FIM and GEM French cooperative groups. Br J Haematol. 2013;162(6):783–91.CrossRefPubMedGoogle Scholar
  51. 51.
    Bachleitner-Hofmann T, Gisslinger H. The role of interferon-alpha in the treatment of idiopathic myelofibrosis. Ann Hematol. 1999;78(12):533–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Pieri LPC, Arena U. et al. Long term follow up of a phase 2 study of ruxolitinib in patients with splanchnic vein thrombosis associated with myeloproliferative neoplasm. American Society of Hematology (ASH) Annual Meeting, Orlando. 2015, p Abstract # 2803.Google Scholar
  53. 53.
    Caocci G, Murgia F, Podda L, Solinas A, Atzeni S, La Nasa G. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia. 2014;28(1):225–7.CrossRefPubMedGoogle Scholar
  54. 54.
    Hopman RK, Lawrence SJ, Oh ST. Disseminated tuberculosis associated with ruxolitinib. Leukemia. 2014;28(8):1750–1.CrossRefPubMedGoogle Scholar
  55. 55.
    Fenaux P, Haase D, Sanz GF, Santini V, Buske C, Group EGW. Myelodysplastic syndromes: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii57–iii69.CrossRefPubMedGoogle Scholar
  56. 56.
    Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe AS, et al. Use of JAK inhibitors in the management of myelofibrosis: a revision of the British Committee for Standards in Haematology Guidelines for Investigation and Management of Myelofibrosis 2012. Br J Haematol. 2014;167(3):418–20.CrossRefPubMedGoogle Scholar
  57. 57.
    Vannucchi AM, Barbui T, Cervantes F, Harrison C, Kiladjian JJ, Kroger N, et al. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v85–v99.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Thamer Sliwa
    • 1
    Email author
  • Christine Beham-Schmid
    • 2
  • Sonja Burgstaller
    • 3
  • Veronika Buxhofer-Ausch
    • 4
  • Günther Gastl
    • 5
  • Klaus Geissler
    • 6
  • Maria Krauth
    • 7
  • Peter Krippl
    • 8
  • Alois Lang
    • 9
  • Andreas Petzer
    • 10
  • Stefan Wöhrer
    • 11
  • Albert Wölfler
    • 12
  • Heinz Gisslinger
    • 7
  1. 1.3rd Medical DepartmentHanusch HospitalViennaAustria
  2. 2.Institute of PathologyMedical University of GrazGrazAustria
  3. 3.Department of Internal Medicine IVKlinikum Wels-GrieskirchenWelsAustria
  4. 4.Department of Internal Medicine IElisabethinen Hospital LinzLinzAustria
  5. 5.Division of Hematology and OncologyInnsbruck Medical UniversityInnsbruckAustria
  6. 6.5th Medical Department with Hematology, Oncology and Palliative MedicineHospital HietzingViennaAustria
  7. 7.Department of Internal Medicine I, Division of Hematology and Blood CoagulationMedical University of ViennaViennaAustria
  8. 8.Department of Internal Medicine with Hematology and OncologySteiermärkische Krankenanstaltengesellschaft m. b. H. Krankenhausverbund Feldbach-FürstenfeldFürstenfeldAustria
  9. 9.Department of Internal MedicineLKH FeldkirchFeldkirchAustria
  10. 10.Department of Medical Oncology, Hematology and GastroenterologyBarmherzige Schwestern Hospital LinzLinzAustria
  11. 11.Department of OncologyLandesklinikum Wiener NeustadtWiener NeustadtAustria
  12. 12.Division of HematologyMedical University of GrazGrazAustria

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