Skip to main content

Advertisement

Log in

The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

The presence of moderate to severe bone marrow (BM) fibrosis has been shown to be an adverse feature in patients with primary myelodysplastic syndromes (MDS). However, the clinical importance of BM fibrosis is not clear in therapy-related MDS. We retrieved all therapy-related MDS (t-MDS) cases (n = 266) diagnosed at our hospital over a 10-year period (2003–2012). Reticulin and trichrome stains were performed in cases in which BM fibrosis was suspected on initial evaluation of hematoxylin and eosin-stained slide. BM fibrosis was graded according to European consensus guidelines, and a score of MF2/MF3 was defined as moderate/severe fibrosis. Moderate/severe BM fibrosis was found in 47 (17 %) patients. Compared to 219 patients with no/mild BM fibrosis, the patients with moderate/severe fibrosis presented with severer thrombocytopenia (p = 0.039) and higher numbers of circulating blasts (p = 0.051) but with similar degrees of anemia and neutropenia, transfusion requirements, and similar incidences of hepatosplenomegaly and constitutional symptoms. Histological examination revealed a comparable BM cellularity and BM blast percentage, but markedly increased megakaryocytes (p < 0.001) in the fibrotic group. Although the risk distribution of cytogenetic data was similar according to the New Comprehensive Cytogenetic Scoring criteria, −5 and −17 were more frequently observed in t-MDS with moderate/severe BM fibrosis (p = 0.031 and p = 0.043, respectively). With a median follow-up of 11.5 months, patients with moderate/severe BM fibrosis showed a similar risk of acute myeloid leukemia transformation and a comparable overall survival in univariate and multivariate analyses. Moderate/severe BM fibrosis in patients with t-MDS is associated with certain clinicopathological and genetic features. However, unlike the situation in patients with primary MDS, moderate/severe BM fibrosis does not add additional risk to patients with therapy-related MDS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kvasnicka HM, Thiele J, Schmitt-Graeff A, Diehl V, Zankovich R, Niederle N, Leder LD, Schaefer HE (2001) Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase Ph(1+) chronic myelogenous leukemia: a multicenter trial. J Clin Oncol 19(12):2994–3009

    PubMed  CAS  Google Scholar 

  2. Subramanian R, Basu D, Dutta TK (2007) Significance of bone marrow fibrosis in multiple myeloma. Pathology 39(5):512–515. doi:10.1080/00313020701570038

    Article  PubMed  CAS  Google Scholar 

  3. Thiele J, Kvasnicka HM (2005) Hematopathologic findings in chronic idiopathic myelofibrosis. Semin Oncol 32(4):380–394. doi:10.1053/j.seminoncol.2005.04.010

    Article  PubMed  Google Scholar 

  4. Thiele J, Kvasnicka HM (2006) Grade of bone marrow fibrosis is associated with relevant hematological findings—a clinicopathological study on 865 patients with chronic idiopathic myelofibrosis. Ann Hematol 85(4):226–232. doi:10.1007/s00277-005-0042-8

    Article  PubMed  CAS  Google Scholar 

  5. Vener C, Fracchiolla NS, Gianelli U, Calori R, Radaelli F, Iurlo A, Caberlon S, Gerli G, Boiocchi L, Deliliers GL (2008) Prognostic implications of the European consensus for grading of bone marrow fibrosis in chronic idiopathic myelofibrosis. Blood 111(4):1862–1865. doi:10.1182/blood-2007-09-112953

    Article  PubMed  CAS  Google Scholar 

  6. 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. Modern pathology 25(9):1193–1202. doi:10.1038/modpathol.2012.87

    Article  PubMed  Google Scholar 

  7. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114(5):937–951. doi:10.1182/blood-2009-03-209262

    Article  PubMed  CAS  Google Scholar 

  8. Verhoef GE, De Wolf-Peeters C, Ferrant A, Deprez S, Meeus P, Stul M, Zachee P, Cassiman JJ, Van den Berghe H, Boogaerts MA (1991) Myelodysplastic syndromes with bone marrow fibrosis: a myelodysplastic disorder with proliferative features. Ann Hematol 63(5):235–241

    Article  PubMed  CAS  Google Scholar 

  9. Della Porta MG, Malcovati L (2011) Myelodysplastic syndromes with bone marrow fibrosis. Haematologica 96(2):180–183. doi:10.3324/haematol.2010.039875

    Article  PubMed  Google Scholar 

  10. Buesche G, Teoman H, Wilczak W, Ganser A, Hecker H, Wilkens L, Gohring G, Schlegelberger B, Bock O, Georgii A, Kreipe H (2008) Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia 22(2):313–322. doi:10.1038/sj.leu.2405030

    Article  PubMed  CAS  Google Scholar 

  11. Della Porta MG, Malcovati L, Boveri E, Travaglino E, Pietra D, Pascutto C, Passamonti F, Invernizzi R, Castello A, Magrini U, Lazzarino M, Cazzola M (2009) Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J Clin Oncol 27(5):754–762. doi:10.1200/JCO.2008.18.2246

    Article  PubMed  Google Scholar 

  12. Kroger N, Zabelina T, van Biezen A, Brand R, Niederwieser D, Martino R, Lim ZY, Onida F, Schmid C, Garderet L, Robin M, van Gelder M, Marks R, Symeonidis A, Kobbe G, de Witte T (2011) Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis. Haematologica 96(2):291–297. doi:10.3324/haematol.2010.031229

    Article  PubMed  Google Scholar 

  13. Voso MT, D’Alo F, Greco M, Fabiani E, Criscuolo M, Migliara G, Pagano L, Fianchi L, Guidi F, Hohaus S, Leone G (2010) Epigenetic changes in therapy-related MDS/AML. Chemico-biological interactions 184(1–2):46–49. doi:10.1016/j.cbi.2009.10.013

    Article  PubMed  CAS  Google Scholar 

  14. Greco M, D’Alo F, Scardocci A, Criscuolo M, Fabiani E, Guidi F, Di Ruscio A, Migliara G, Pagano L, Fianchi L, Chiusolo P, Hohaus S, Leone G, Voso MT (2010) Promoter methylation of DAPK1, E-cadherin and thrombospondin-1 in de novo and therapy-related myeloid neoplasms. Blood cells, molecules & diseases 45(3):181–185. doi:10.1016/j.bcmd.2010.05.008

    Article  CAS  Google Scholar 

  15. Li L, Li M, Sun C, Francisco L, Chakraborty S, Sabado M, McDonald T, Gyorffy J, Chang K, Wang S, Fan W, Li J, Zhao LP, Radich J, Forman S, Bhatia S, Bhatia R (2011) Altered hematopoietic cell gene expression precedes development of therapy-related myelodysplasia/acute myeloid leukemia and identifies patients at risk. Cancer cell 20(5):591–605. doi:10.1016/j.ccr.2011.09.011

    Article  PubMed  CAS  Google Scholar 

  16. Christiansen DH, Andersen MK, Desta F, Pedersen-Bjergaard J (2005) Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 19(12):2232–2240. doi:10.1038/sj.leu.2404009

    Article  PubMed  CAS  Google Scholar 

  17. Singh ZN, Huo D, Anastasi J, Smith SM, Karrison T, Le Beau MM, Larson RA, Vardiman JW (2007) Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am J Clin Pathol 127(2):197–205. doi:10.1309/NQ3PMV4U8YV39JWJ

    Article  PubMed  Google Scholar 

  18. Vardiman JW, Arber DA, Brunning RD, Larson RA, Matutes E, Baumann I, Thiele J (eds) (2008) Therapy-related myeloid neoplasms. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer (IARC), vol 184, 4th edn. Elsevier, Lyon, pp 16–20

    Google Scholar 

  19. Klyuchnikov E, Holler E, Bornhauser M, Kobbe G, Nagler A, Shimoni A, Konecke C, Wolschke C, Bacher U, Zander AR, Kroger N (2012) Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced-intensity allografting. Br J Haematol. doi:10.1111/bjh.12013

    PubMed  Google Scholar 

  20. Quintas-Cardama AKH, Shan J, Jabbour E, Faderl S, Wierda WG, RavandiF KT, Wang SA, Pierce S, Kantarjian HM, Garcia-Manero G (2012) A prognostic model of therapy-related myelodysplastic syndrome for predicting survival and transformation to acute myeloid leukemia. Blood 118(suppl 1):967

    Google Scholar 

  21. Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90(8):1128–1132

    PubMed  Google Scholar 

  22. Khoury JD, Sen F, Abruzzo LV, Hayes K, Glassman A, Medeiros LJ (2003) Cytogenetic findings in blastoid mantle cell lymphoma. Hum Pathol 34(10):1022–1029

    Article  PubMed  CAS  Google Scholar 

  23. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstocker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D (2012) Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120(12):2454–2465. doi:10.1182/blood-2012-03-420489

    Article  PubMed  CAS  Google Scholar 

  24. Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J, Granada I, Hildebrandt B, Slovak ML, Ohyashiki K, Steidl C, Fonatsch C, Pfeilstocker M, Nosslinger T, Valent P, Giagounidis A, Aul C, Lubbert M, Stauder R, Krieger O, Garcia-Manero G, Faderl S, Pierce S, Le Beau MM, Bennett JM, Greenberg P, Germing U, Haase D (2012) New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol 30(8):820–829. doi:10.1200/JCO.2011.35.6394

    Article  PubMed  Google Scholar 

  25. Chen W, Konoplev S, Medeiros LJ, Koeppen H, Leventaki V, Vadhan-Raj S, Jones D, Kantarjian HM, Falini B, Bueso-Ramos CE (2009) Cuplike nuclei (prominent nuclear invaginations) in acute myeloid leukemia are highly associated with FLT3 internal tandem duplication and NPM1 mutation. Cancer 115(23):5481–5489. doi:10.1002/cncr.24610

    Article  PubMed  CAS  Google Scholar 

  26. Millecker L, Lennon PA, Verstovsek S, Barkoh B, Galbincea J, Hu P, Chen SS, Jones D (2010) Distinct patterns of cytogenetic and clinical progression in chronic myeloproliferative neoplasms with or without JAK2 or MPL mutations. Cancer genetics and cytogenetics 197(1):1–7. doi:10.1016/j.cancergencyto.2009.10.014

    Article  PubMed  CAS  Google Scholar 

  27. Gustafson SA, Lin P, Chen SS, Chen L, Abruzzo LV, Luthra R, Medeiros LJ, Wang SA (2009) Therapy-related acute myeloid leukemia with t (8;21) (q22;q22) shares many features with de novo acute myeloid leukemia with t (8;21)(q22;q22) but does not have a favorable outcome. Am J Clin Pathol 131(5):647–655. doi:10.1309/AJCP5ETHDXO6NCGZ

    Article  PubMed  CAS  Google Scholar 

  28. Tefferi A (2005) Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol 23(33):8520–8530. doi:10.1200/JCO.2004.00.9316

    Article  PubMed  CAS  Google Scholar 

  29. Kanagal-Shamanna R, Bueso-Ramos CE, Barkoh B, Lu G, Wang S, Garcia-Manero G, Vadhan-Raj S, Hoehn D, Medeiros LJ, Yin CC (2012) Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53. Cancer 118(11):2879–2888. doi:10.1002/cncr.26537

    Article  PubMed  CAS  Google Scholar 

  30. Hussein K, Van Dyke DL, Tefferi A (2009) Conventional cytogenetics in myelofibrosis: literature review and discussion. Eur J Haematol 82(5):329–338. doi:10.1111/j.1600-0609.2009.01224.x

    Article  PubMed  Google Scholar 

  31. Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A (2005) Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood 105(3):973–977. doi:10.1182/blood-2004-07-2864

    Article  PubMed  CAS  Google Scholar 

  32. Barosi G, Bergamaschi G, Marchetti M, Vannucchi AM, Guglielmelli P, Antonioli E, Massa M, Rosti V, Campanelli R, Villani L, Viarengo G, Gattoni E, Gerli G, Specchia G, Tinelli C, Rambaldi A, Barbui T (2007) JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood 110(12):4030–4036. doi:10.1182/blood-2007-07-099184

    Article  PubMed  CAS  Google Scholar 

  33. Klimek VM, Dolezal EK, Tees MT, Devlin SM, Stein K, Romero A, Nimer SD (2012) Efficacy of hypomethylating agents in therapy-related myelodysplastic syndromes. Leuk Res 36(9):1093–1097. doi:10.1016/j.leukres.2012.04.025

    Article  PubMed  CAS  Google Scholar 

  34. Breccia M, Salaroli A, Loglisci G, Martelli M, D’Elia GM, Nanni M, Mauro FR, Alimena G (2011) 5′-Azacitidine for therapy-related myelodysplastic syndromes after non-Hodgkin lymphoma treatment. Leuk Res 35(10):1409–1411. doi:10.1016/j.leukres.2011.05.030

    Article  PubMed  CAS  Google Scholar 

  35. Buhr T, Busche G, Choritz H, Langer F, Kreipe H (2003) Evolution of myelofibrosis in chronic idiopathic myelofibrosis as evidenced in sequential bone marrow biopsy specimens. Am J Clin Pathol 119(1):152–158. doi:10.1309/PTVG-B3DX-B8A8-M7KD

    Article  PubMed  Google Scholar 

  36. Morel F, Le Bris MJ, Herry A, Morice P, De Braekeleer M (2003) Trisomy 15 as the sole abnormality in myelodysplastic syndromes: case report and review of the literature. Leukemia & lymphoma 44(3):549–551. doi:10.1080/1042819021000055084

    Article  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no competing interests.

Authors’ information

BF and WX conducted this study as visiting scholars at The University of Texas M.D. Anderson Cancer Center.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sa A. Wang.

Additional information

Informed consent was obtained from all patients for being included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fu, B., Ok, C.Y., Goswami, M. et al. The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes. Ann Hematol 92, 1335–1343 (2013). https://doi.org/10.1007/s00277-013-1776-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-013-1776-3

Keywords

Navigation