Skip to main content

Thank you for visiting 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.

ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients



In a cohort of 466 patients, we sought to clarify the prognostic relevance of ASXL1 and SETBP1 mutations, among others, in World Health Organization-defined chronic myelomonocytic leukemia (CMML) and its added value to the Mayo prognostic model. In univariate analysis, survival was adversely affected by ASXL1 (nonsense and frameshift) but not SETBP1 mutations. In multivariable analysis, ASXL1 mutations, absolute monocyte count >10 × 10(9)/l, hemoglobin <10 g/dl, platelets <100 × 10(9)/l and circulating immature myeloid cells were independently predictive of shortened survival: hazard ratio (95% confidence interval (CI)) values were 1.5 (1.1–2.0), 2.2 (1.6–3.1), 2.0 (1.6–2.6), 1.5 (1.2–1.9) and 2.0 (1.4–2.7), respectively. A regression coefficient-based prognostic model based on these five risk factors delineated high (≥3 risk factors; HR 6.2, 95% CI 3.7–10.4) intermediate-2 (2 risk factors; HR 3.4, 95% CI 2.0–5.6) intermediate-1 (one risk factor; HR 1.9, 95% CI 1.1–3.3) and low (no risk factors) risk categories with median survivals of 16, 31, 59 and 97 months, respectively. Neither ASXL1 nor SETBP1 mutations predicted leukemic transformation. The current study confirms the independent prognostic value of nonsense/frameshift ASXL1 mutations in CMML and signifies its added value to the Mayo prognostic model, as had been shown previously in the French consortium model.

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

Access options

Rent or buy this article

Prices vary by article type



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

Figure 1
Figure 2
Figure 3


  1. Swederlow S, Campo E, Harris NL, Jaffe ES, Stefano PA, Stein H et aleds WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon, 2008.

    Google Scholar 

  2. Patnaik MM, Parikh SA, Hanson CA, Tefferi A . Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review. Br J Haematol 2014; 165: 273–286.

    Article  Google Scholar 

  3. Damm F, Itzykson R, Kosmider O, Droin N, Renneville A, Chesnais V et al. SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias. Leukemia 2013; 27: 1401–1403.

    Article  CAS  Google Scholar 

  4. Gelsi-Boyer V, Trouplin V, Adelaide J, Bonansea J, Cervera N, Carbuccia N et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009; 145: 788–800.

    Article  CAS  Google Scholar 

  5. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013; 31: 2428–2436.

    Article  CAS  Google Scholar 

  6. Laborde R, Patnaik M, Lasho T, Finke C, Hanson C, Knudson R et al. SETBP1 mutations in 415 patients with primary myelofibrosis or chronic myelomonocytic leukemia: independent prognostic impact in CMML. Leukemia 2013; 27: 2100–2102.

    Article  CAS  Google Scholar 

  7. Meggendorfer M, Roller A, Haferlach T, Eder C, Dicker F, Grossmann V et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood 2012; 120: 3080–3088.

    Article  CAS  Google Scholar 

  8. Abdel-Wahab O, Pardanani A, Patel J, Wadleigh M, Lasho T, Heguy A et al. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Leukemia 2011; 25: 1200–1202.

    Article  CAS  Google Scholar 

  9. Piazza R, Valletta S, Winkelmann N, Redaelli S, Spinelli R, Pirola A et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 2013; 45: 18–24.

    Article  CAS  Google Scholar 

  10. Patnaik MM, Padron E, LaBorde RR, Lasho TL, Finke CM, Hanson CA et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 2013; 27: 1504–1510.

    Article  CAS  Google Scholar 

  11. Meggendorfer M, Bacher U, Alpermann T, Haferlach C, Kern W, Gambacorti-Passerini C et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia 2013; 27: 1852–1860.

    Article  CAS  Google Scholar 

  12. Such E, Cervera J, Costa D, Sole F, Vallespi T, Luno E et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 2011; 96: 375–383.

    Article  Google Scholar 

  13. Onida F, Kantarjian HM, Smith TL, Ball G, Keating MJ, Estey EH et al. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 2002; 99: 840–849.

    Article  CAS  Google Scholar 

  14. Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood 2012; 120: 4168–4171.

    Article  CAS  Google Scholar 

  15. Patnaik MM, Lasho TL, Hodnefield JM, Knudson RA, Ketterling RP, Garcia-Manero G et al. SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value. Blood 2012; 119: 569–572.

    Article  CAS  Google Scholar 

  16. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69.

    Article  CAS  Google Scholar 

  17. Tefferi A . Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010; 24: 1128–1138.

    Article  CAS  Google Scholar 

  18. Abdel-Wahab O, Kilpivaara O, Patel J, Busque L, Levine RL . The most commonly reported variant in ASXL1 (c.1934dupG;p.Gly646TrpfsX12) is not a somatic alteration. Leukemia 2010; 24: 1656–1657.

    Article  CAS  Google Scholar 

  19. Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci MJ, Birnbaum D . Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol 2012; 5: 12.

    Article  CAS  Google Scholar 

  20. Thol F, Friesen I, Damm F, Yun H, Weissinger EM, Krauter J et al. Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol 2011; 29: 2499–2506.

    Article  CAS  Google Scholar 

  21. Boultwood J, Perry J, Pellagatti A, Fernandez-Mercado M, Fernandez-Santamaria C, Calasanz MJ et al. Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Leukemia 2010; 24: 1062–1065.

    Article  CAS  Google Scholar 

  22. Carbuccia N, Murati A, Trouplin V, Brecqueville M, Adelaide J, Rey J et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 2009; 23: 2183–2186.

    Article  CAS  Google Scholar 

  23. Carbuccia N, Trouplin V, Gelsi-Boyer V, Murati A, Rocquain J, Adelaide J et al. Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias. Leukemia 2010; 24: 469–473.

    Article  CAS  Google Scholar 

  24. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364: 2496–2506.

    Article  CAS  Google Scholar 

  25. Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27: 1861–1869.

    Article  CAS  Google Scholar 

  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; e-pub ahead of print 5 February 2014 doi:10.1038/leu.2014.57.

    Article  CAS  Google Scholar 

  27. Damaj G, Joris M, Chandesris O, Hanssens K, Soucie E, Canioni D et al. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS One 2014; 9: e85362.

    Article  Google Scholar 

  28. Schwaab J, Schnittger S, Sotlar K, Walz C, Fabarius A, Pfirrmann M et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013; 122: 2460–2466.

    Article  CAS  Google Scholar 

  29. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    Article  CAS  Google Scholar 

  30. Schnittger S, Eder C, Jeromin S, Alpermann T, Fasan A, Grossmann V et al. ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 2013; 27: 82–91.

    Article  CAS  Google Scholar 

  31. Shen Y, Zhu YM, Fan X, Shi JY, Wang QR, Yan XJ et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood 2011; 118: 5593–5603.

    Article  CAS  Google Scholar 

  32. Metzeler KH, Becker H, Maharry K, Radmacher MD, Kohlschmidt J, Mrozek K et al. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood 2011; 118: 6920–6929.

    Article  CAS  Google Scholar 

  33. Tefferi A, Finke CM, Lasho TL, Wassie EA, Knudson R, Ketterling RP et al. U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype. Leukemia 2014; 28: 431–433.

    Article  CAS  Google Scholar 

Download references


This study is supported in part by grants from the ‘Myeloproliferative Disorders Foundation, Chicago, IL, USA’ and ‘The Henry J. Predolin Foundation for Research in Leukemia, Mayo Clinic, Rochester, MN, USA’.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to A Tefferi or E Solary.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Patnaik, M., Itzykson, R., Lasho, T. et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia 28, 2206–2212 (2014).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links