Genomic characterization in triple-negative primary myelofibrosis and other myeloid neoplasms with bone marrow fibrosis
- 71 Downloads
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.
KeywordsPrimary myelofibrosis Myelodysplastic syndromes Diagnosis Prognosis Genomic classification
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.
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.
- 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
- 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
- 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
- 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.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.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
- 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.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
- 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.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
- 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