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Annals of Hematology

, Volume 98, Issue 10, pp 2319–2328 | Cite as

Genomic characterization in triple-negative primary myelofibrosis and other myeloid neoplasms with bone marrow fibrosis

  • Alberto Alvarez-LarránEmail author
  • Mónica López-Guerra
  • María Rozman
  • Juan-Gonzalo Correa
  • Juan Carlos Hernández-Boluda
  • Mar Tormo
  • Daniel Martínez
  • Iván Martín
  • Dolors Colomer
  • Jordi Esteve
  • Francisco Cervantes
Original Article
  • 179 Downloads

Abstract

Triple-negative primary myelofibrosis (TN-PMF) and other myeloid neoplasms with associated bone marrow fibrosis such as the myelodysplastic syndromes (MDS-F) or the myelodysplastic/myeloproliferative neoplasms (MDS/MPN-F) are rare entities, often difficult to distinguish from each other. Thirty-four patients previously diagnosed with TN-PMF (n = 14), MDS-F (n = 18), or MDS/MPN-F (n = 2) were included in the present study. After central revision of the bone marrow histology, diagnoses according to the 2016-WHO classification were TN-PMF (n = 6), MDS-F (n = 19), and MDS/MPN-F (n = 9), with TN-PMF genotype representing only 4% of a cohort of 141 molecularly annotated PMF. Genomic classification according to next-generation sequencing and cytogenetic study was performed in 28 cases. Median number of mutations was 4 (range 1–7) in cases with TP53 disruption/aneuploidy or with chromatin-spliceosome mutations versus 1 mutation (range 0–2) in other molecular subgroups (p < 0.0001). The number of mutations and the molecular classification were better than PMF and MDS conventional scoring systems to predict survival and progression to acute leukemia. In conclusion, TN-PMF is an uncommon entity when the 2016 WHO criteria are strictly applied. Genomic classification may help in the prognostic assessment of patients with myeloid neoplasms with bone marrow fibrosis.

Keywords

Primary myelofibrosis Myelodysplastic syndromes Diagnosis Prognosis Genomic classification 

Notes

Acknowledgements

This work was supported by the grant PI18/00205 from the Instituto de Salud Carlos III (ISCIII), through the Plan Estatal de Investigación Científica y Técnica y de Innovación and 2017 SGR 1655. This work was co-funded by the European Regional Development Fund (ERDF). We are indebted to the genomics Core facility of the IDIBAPS for the technical help.

Author contributions

AAL designed the study, collected the data, performed the statistical analysis, analyzed and interpreted the results, and wrote the paper. MLG and DC performed the molecular studies, interpreted the results, and wrote the paper. DM and MR reviewed the bone marrow biopsies, interpreted the results, and wrote the paper. JGC, IM, and MT collected the data and approved the final version. JCHB, JE, and FC collected the data, interpreted the results, and wrote the paper.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

277_2019_3766_MOESM1_ESM.xlsx (18 kb)
ESM 1 (XLSX 17 kb)

References

  1. 1.
    Arber D, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405CrossRefGoogle Scholar
  2. 2.
    Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, Gangat N, Fjerza R, Belachew AA, Lasho TL, Ketterling RP, Hanson CA, Rambaldi A, Finazzi G, Thiele J, Barbui T, Pardanani A, Vannucchi AM (2014) Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 124:2507–2513CrossRefGoogle Scholar
  3. 3.
    Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, Maffioli M, Caramazza D, Passamonti F, Pardanani A (2014) CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 28:1472–1477CrossRefGoogle Scholar
  4. 4.
    Tefferi A, Nicolosi M, Mudireddy M, Szuber N, Finke CM, Lasho TL, Hanson CA, Ketterling RP, Pardanani A, Gangat N, Mannarelli C, Fanelli T, Guglielmelli P, Vannucchi AM (2018) Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1,095 patients. Am J Hematol 93:348–355CrossRefGoogle Scholar
  5. 5.
    Maschek H, Georgii A, Kaloutsi V, Werner M, Bandecar K, Kressel MG, Choritz H, Freund M, Hufnagl D (1992) Myelofibrosis in primary myelodysplastic syndromes: a retrospective study of 352 patients. Eur J Haematol 48:208–214CrossRefGoogle Scholar
  6. 6.
    Buesche G, Teoman H, Wilczak W, Ganser A, Hecker H, Wilkens L, Göhring G, Schlegelberger B, Bock O, Georgii A, Kreipe H (2008) Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia 22:313–322CrossRefGoogle Scholar
  7. 7.
    Fu B, Ok CY, Goswami M, Xei W, Jaso JM, Muzzafar T, Bueso-Ramos C, Verstovsek S, Garcia-Manero G, Medeiros LJ, Wang SA (2013) The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic síndromes. Ann Hematol 92:1335–1343CrossRefGoogle Scholar
  8. 8.
    Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P et al (2013) Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122:3616–3627CrossRefGoogle Scholar
  9. 9.
    Grinfeld J, Nangalia J, Baxter EJ, Wedge DC, Angelopoulos N, Cantrill R, Godfrey AL, Papaemmanuil E, Gundem G, MacLean C, Cook J, O’Neil L, O’Meara S, Teague JW, Butler AP, Massie CE, Williams N, Nice FL, Andersen CL, Hasselbalch HC, Guglielmelli P, McMullin MF, Vannucchi AM, Harrison CN, Gerstung M, Green AR, Campbell PJ (2018) Classification and personalized prognosis in myeloproliferative neoplasms. N Engl J Med 379:1416–1430CrossRefGoogle Scholar
  10. 10.
    Thol F, Kade S, Schlarmann C, Löffeld P, Morgan M, Krauter J et al (2012) Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 119:3578–3584CrossRefGoogle Scholar
  11. 11.
    Lundberg P, Karow A, Nienhold R, Looser R, Hao-Shen H, Nissen I, Girsberger S, Lehmann T, Passweg J, Stern M, Beisel C, Kralovics R, Skoda RC (2014) Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood 123:2220–2228CrossRefGoogle Scholar
  12. 12.
    Senín A, Fernández-Rodríguez C, Bellosillo B, Camacho L, Longarón R, Angona A, Besses C, Álvarez-Larrán A (2018) Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up. Ann Hematol 97:443–451CrossRefGoogle Scholar
  13. 13.
    Lasho TL, Mudireddy M, Finke CM, Hanson CA, Ketterling RP, Szuber N, Begna KH, Patnaik MM, Gangat N, Pardanani A, Tefferi A (2018) Targeted next-generation sequencing in blast phase myeloproliferative neoplasms. Blood Advances 2:370–380CrossRefGoogle Scholar
  14. 14.
    Gianelli U, Vener C, Bossi A, Cortinovis I, Iurlo A, Fracchiolla NS, Savi F, Moro A, Grifoni F, de Philippis C, Radice T, Bosari S, Lambertenghi Deliliers G, Cortelezzi A (2012) The European consensus on grading of bone marrow fibrosis allows a better prognostication of patients with primary myelofibrosis. Mod Pathol 25:1193–1202CrossRefGoogle Scholar
  15. 15.
    Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, Vannucchi AM, Mesa RA, Demory JL, Barosi G, Rumi E, Tefferi A (2009) New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 113:2895–2901CrossRefGoogle Scholar
  16. 16.
    Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088Google Scholar
  17. 17.
    Guglielmelli P, Pacilli A, Rotunno G, Rumi E, Rosti V, Delaini F et al (2016) Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. Blood 129:3227–3236CrossRefGoogle Scholar
  18. 18.
    Kröger NM, Deeg JH, Olavarria E, Niederwieser D, Bacigalupo A, Barbui T, Rambaldi A, Mesa R, Tefferi A, Griesshammer M, Gupta V, Harrison C, Alchalby H, Vannucchi AM, Cervantes F, Robin M, Ditschkowski M, Fauble V, McLornan D, Ballen K, Popat UR, Passamonti F, Rondelli D, Barosi G (2015) Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia 29:2126–2133CrossRefGoogle Scholar
  19. 19.
    Barbui T, Tefferi A, Vannucchi AM, Passamonti F, Silver RT, Hoffman R, Verstovsek S, Mesa R, Kiladjian JJ, Hehlmann R, Reiter A, Cervantes F, Harrison C, Mc Mullin MF, Hasselbalch HC, Koschmieder S, Marchetti M, Bacigalupo A, Finazzi G, Kroeger N, Griesshammer M, Birgegard G, Barosi G (2018) Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. Leukemia 32:1057–1069CrossRefGoogle Scholar
  20. 20.
    Salit RB, Deeg HJ (2018) Transplant decisions in patients with myelofibrosis: should mutations be the judge? Biol Blood Marrow Transpl 24:649–658CrossRefGoogle Scholar
  21. 21.
    Ramos F, Robledo C, Izquierdo-García FM, Suárez-Vilela D, Benito R, Fuertes M et al (2016) Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis. Oncotarget 24:30492–30503Google Scholar
  22. 22.
    Wu SJ, Tang JL, Lin CT, Kuo YY, Li LY, Tseng MH, Huang CF, Lai YJ, Lee FY, Liu MC, Liu CW, Hou HA, Chen CY, Chou WC, Yao M, Huang SY, Ko BS, Tsay W, Tien HF (2013) Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression. Am J Hematol 88:E277–E282CrossRefGoogle Scholar
  23. 23.
    Tefferi A, Finke CM, Lasho TL, Hanson CA, Ketterling RP, Gangat N, Pardanani A (2018b) U2AF1 mutation types in primary myelofibrosis: phenotypic and prognostic distinctions. Leukemia 32:2274–2278CrossRefGoogle Scholar
  24. 24.
    Li B, Liu J, Jia Y, Wang J, Xu Z, Qin T, Shi Z, Song Z, Peng S, Huang H, Fang L, Zhang H, Pan L, Hu N, Qu S, Zhang Y, Wu J, Liu N, Ru K, Huang G, Xiao Z (2018) Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes. Genes Chromosom Cancer 57:80–88CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Alberto Alvarez-Larrán
    • 1
    Email author
  • Mónica López-Guerra
    • 2
    • 3
  • María Rozman
    • 2
  • Juan-Gonzalo Correa
    • 1
  • Juan Carlos Hernández-Boluda
    • 4
  • Mar Tormo
    • 4
  • Daniel Martínez
    • 2
  • Iván Martín
    • 4
  • Dolors Colomer
    • 2
    • 3
  • Jordi Esteve
    • 1
  • Francisco Cervantes
    • 1
  1. 1.Hematology DepartmentHospital Clínic, IDIBAPSBarcelonaSpain
  2. 2.Hematopathology Section, Pathology DepartmentHospital Clínic, IDIBAPSBarcelonaSpain
  3. 3.CIBERONCSalamancaSpain
  4. 4.Hematology DepartmentHospital Clínico-INCLIVAValenciaSpain

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