Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Myeloproliferative Neoplasias

Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis

Leukemia volume 29, pages 1344–1349 (2015)Cite this article

Subjects

Abstract

We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (⩽40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early-PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P=0.04), longer survival (100% versus 96%, P=0.05) and better combined-EFS (86% versus 71%, P=0.02). However, non-type 1/type 2 CALR mutations (‘minor’ mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53–68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these ‘triple-negative’ patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Palandri F, Polverelli N, Ottaviani E, Castagnetti F, Baccarani M, Vianelli N . Long-term follow-up of essential thrombocythemia in young adults: treatment strategies, major thrombotic complications and pregnancy outcomes. A study of 76 patients. Haematologica 2010; 95: 1038–1040.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Millard FE, Hunter CS, Anderson M, Edelman MJ, Kosty MP, Luiken GA et al. Clinical manifestations of essential thrombocythemia in young adults. Am J Hematol 1990; 33: 27–31.

    Article  CAS  PubMed  Google Scholar 

  3. Giona F, Teofili L, Capodimonti S, Laurino M, Martini M, Marzella D et al. CALR mutations in patients with essential thrombocythemia diagnosed in childhood and adolescence. Blood 2014; 123: 3677–3679.

    Article  CAS  PubMed  Google Scholar 

  4. Randi ML, Bertozzi I, Rumi E, Elena C, Finazzi G, Vianelli N et al. Pregnancy complications predict thrombotic events in young women with essential thrombocythemia. Am J Hematol 2014; 89: 306–309.

    Article  PubMed  Google Scholar 

  5. Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, Drummond M et al. Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 2010; 149: 352–375.

    Article  CAS  PubMed  Google Scholar 

  6. Barbui T, Thiele J, Carobbio A, Passamonti F, Rumi E, Randi ML et al. Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis. Blood 2012; 120: 569–571.

    Article  CAS  PubMed  Google Scholar 

  7. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369: 2391–2405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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: 2379–2390.

    Article  CAS  PubMed  Google Scholar 

  9. Chen CC, Gau JP, Chou HJ, You JY, Huang CE, Chen YY et al. Frequencies, clinical characteristics, and outcome of somatic CALR mutations in JAK2-unmutated essential thrombocythemia. Ann Hematol 2014; 93: 2029–2036.

    Article  CAS  PubMed  Google Scholar 

  10. Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014; 123: 1544–1551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rotunno G, Mannarelli C, Guglielmelli P, Pacilli A, Pancrazzi A, Pieri L et alAssociazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014; 123: 1552–1555.

    Article  CAS  PubMed  Google Scholar 

  12. Andrikovics H, Krahling T, Balassa K, Halm G, Bors A, Koszarska M et al. Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations. Haematologica 2014; 99: 1184–1190.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Qiao C, Sun C, Ouyang Y, Wang JJ, Qian SX, Li JY et al. Clinical importance of different calreticulin gene mutation types in wild-type JAK2 essential thrombocythemia and myelofibrosis patients. Haematologica 2014; 99: e182–e184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tefferi A, Wassie EA, Lasho TL, Finke C, Belachew AA, Ketterling RP et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia 2014; 28: 2300–2303.

    Article  CAS  PubMed  Google Scholar 

  15. 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: 937–951.

    Article  CAS  PubMed  Google Scholar 

  16. Tefferi A, Vardiman JW . Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-ofcare diagnostic algorithms. Leukemia 2008; 22: 14–22.

    Article  CAS  PubMed  Google Scholar 

  17. Kvasnicka HM, Thiele J . Prodromal myeloproliferative neoplasms: the 2008 WHO classification. Am J Hematol 2010; 85: 62–69.

    PubMed  Google Scholar 

  18. Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013; 368: 22–33.

    Article  CAS  PubMed  Google Scholar 

  19. 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: 437–438.

    Article  CAS  PubMed  Google Scholar 

  20. Swerdlow SH, Campo E, Harris L, Jaffe ES, Pileri SA, Stein H et al WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues4th ednIARC: Lyon, 2008, 127–129.

    Google Scholar 

  21. Jovanovic JV, Ivey A, Vannucchi AM, Lippert E, Oppliger Leibundgut E, Cassinat B et al. Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study. Leukemia 2013; 27: 2032–2039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. dos Santos MT, Mitne-Neto M, Miyashiro K, Chauffaille Mde L, Rizzatti EG . Molecular genetic tests for JAK2V617F, Exon12_JAK2 and MPLW515K/L are highly informative in the evaluation of patients suspected to have BCR-ABL1-negative myeloproliferative neoplasms. J Clin Pathol 2014; 67: 176–178.

    Article  PubMed  Google Scholar 

  23. Kohlmann A, Klein HU, Weissmann S, Bresolin S, Chaplin T, Cuppens H et al. The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories. Leukemia 2011; 25: 1840–1848.

    Article  CAS  PubMed  Google Scholar 

  24. Shaffer LG, Slovak ML, Campbell LJ . ISCN 2009: International System of Human Cytogenetic Nomenclature. Karger AG: Basel, Switzerland, 2009.

    Google Scholar 

  25. Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol 2011; 29: 3179–3184.

    Article  PubMed  Google Scholar 

  26. Thiele J, Kvasnicka HM, Müllauer 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: 5710–5718.

    Article  CAS  PubMed  Google Scholar 

  27. Carobbio A, Finazzi G, Thiele J, Kvasnicka HM, Passamonti F, Rumi E et al. Blood tests may predict early primary myelofibrosis in patients presenting with essential thrombocythemia. Am J Hematol 2012; 87: 203–204.

    Article  PubMed  Google Scholar 

  28. Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 2011; 117: 5857–5859.

    Article  CAS  PubMed  Google Scholar 

  29. Palandri F, Polverelli N, Catani L, Ottaviani E, Baccarani M, Vianelli N . Impact of leukocytosis on thrombotic risk and survival in 532 patients with essential thrombocythemia: a retrospective study. Ann Hematol 2011; 90: 933–938.

    Article  PubMed  Google Scholar 

  30. Godfrey AL, Chen E, Pagano F, Ortmann CA, Silber Y, Bellosillo B et al. JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone. Blood 2012; 120: 2704–2707.

    Article  CAS  PubMed  Google Scholar 

  31. Gold LI, Eggleton P, Sweetwyne MT, Van Duyn LB, Greives MR, Naylor SM et al. Calreticulin: non-endoplasmic reticulum functions in physiology and disease. FASEB J 2010; 24: 665–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Caramelo JJ, Parodi AJ . Getting in and out from calnexin/calreticulin cycles. J Biol Chem 2008; 283: 10221–10225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cabagnols X, Defour JP, Ugo V, Ianotto JC, Mossuz P, Mondet J et al. Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocytemia: relevance for disease evolution. Leukemia 2014; 29: 249–252.

    Article  PubMed  Google Scholar 

  34. Tefferi A, Wassie EA, Guglielmelli P, Gangat N, Belachew AA, Lasho TL et al. Type 1 versus type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. Am J Hematol 2014; 89: e121–e124.

    Article  CAS  PubMed  Google Scholar 

  35. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 2012; 120: 5128–5133.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by BolognAIL, ELN, AIRC, progetto Regione-Università 2010-2012, FP7 and NGS-PTL Project.

Author Contributions

FP designed the research, analyzed data and wrote the paper. RL, NP, AT, MC and BM collected the data and gave the final approval. MP and EO performed molecular analysis. NT performed cytogenetic analysis. FM, FA, GA, MC, GM, LC, MB and NV reviewed the paper and gave the final approval.

Author information

Authors and Affiliations

  1. Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology ‘L. and A. Seràgnoli’, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy

    F Palandri, N Polverelli, M Perricone, E Ottaviani, N Testoni, M Cavo, G Martinelli, L Catani, M Baccarani & N Vianelli

  2. Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy

    R Latagliata, M Breccia & G Alimena

  3. Division of Hematology, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Reggio Emilia, Italy

    A Tieghi & F Merli

  4. Department of Clinical and Experimental Medicine, Section of Hematology and BMT Unit, University of Parma, Parma, Italy

    M Crugnola & F Aversa

  5. Division of Hematology, Azienda Ospedaliera 'Bianchi Melacrino Morelli', Reggio Calabria, Italy

    B Martino

Authors
  1. F Palandri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Latagliata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Polverelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Tieghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Crugnola
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Martino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Perricone
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Breccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E Ottaviani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N Testoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F Merli
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. F Aversa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. G Alimena
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Cavo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. G Martinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. L Catani
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M Baccarani
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. N Vianelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Palandri.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Palandri, F., Latagliata, R., Polverelli, N. et al. Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis. Leukemia 29, 1344–1349 (2015). https://doi.org/10.1038/leu.2015.87

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.87

This article is cited by

Search

Advanced search

Quick links