Skip to main content

Advertisement

SpringerLink
Log in

Prognostic importance of additional cytogenetic anomalies in chronic myeloid leukemia

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Additional chromosomal abnormalities (ACAs) in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) are strongly associated with disease progression, but their prognostic impact and effect on treatment response are not clear. While the onset of ACAs in Ph-negative cells during treatment has been described, their origin and clinical significance remain to be clarified. Between January 2008 and January 2011, 105 patients with Ph-positive CML were analyzed. With a median follow-up of 25.5 months, 18 CML patients (17 %) with ACAs in either CP (n = 12) or advanced phases (n = 6) were identified. The median age of the patients was 53.5 years at diagnosis. ACAs were determined in Ph-positive metaphases of 12 patients and in Ph-negative metaphases of 5 patients. One patient showed trisomy 8 both in Ph-positive and in Ph-negative metaphases. The median follow-up after the detection of ACAs was 11.9 months. None of the patients carrying ACAs in their Ph-negative metaphases developed AP or BP; however, 7 out of 12 patients (58 %) having ACAs in their Ph-positive metaphases developed AP/BC at diagnosis or follow-up (p = 0.03). All the patients carrying ACAs in only Ph-negative metaphases achieved optimal response under tyrosine kinase inhibitor (TKI) therapy, whereas only 4 out of 12 patients (25 %) had optimal TKI response in patients with ACAs in Ph-positive metaphases (p = 0.009). The presence of ACAs in Ph-positive cells during TKI therapy may reflect genetic instability and therefore negatively affect OS. Conventional cytogenic analyses remain mandatory during follow-up of patients with CML under TKI therapy.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Pane F, Intrieri M, Quintarelli C, Izzo B, Muccioli GC, Salvatore F. BCR/ABL genes and leukemic phenotype: from molecular mechanisms to clinical correlations. Oncogene. 2002;21:8652–67.

    Article  PubMed  CAS  Google Scholar 

  2. Marktel S, Marin D, Foot N, Szydlo R, Bua M, Karadimitris A, De Melo VA, Kotzampaltiris P, Dazzi F, Rahemtulla A, Olavarria E, Apperley JF, Goldman JM. Chronic myeloid leukemia in chronic phase responding to imatinib: the occurrence of additional cytogenetic abnormalities predicts disease progression. Haematologica. 2003;88:260–7.

    PubMed  CAS  Google Scholar 

  3. Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD, Cervantes F, Rozman C, Carbonell F, Anger B, Heimpel H, et al. Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome positive chronic granulocytic leukemia. Blood. 1988;72:294–8.

    PubMed  CAS  Google Scholar 

  4. Kantarjian HM, Smith TL, McCreddie KB, Keating MJ, Walters RS, Talpaz M, Hester JP, Bligham G, Gehan E, Freireich EJ. Chronic myelogenous leukemia: a multivariate analysis of the associations of patients characteristics and therapy with survival. Blood. 1985;66:1326–35.

    PubMed  CAS  Google Scholar 

  5. Mitelman F. The cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma. 1993;11:11–5.

    Article  PubMed  Google Scholar 

  6. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol. 2002;107:76–94.

    Article  PubMed  CAS  Google Scholar 

  7. Cortes JE, Talpaz M, Giles F, O’Brien S, Rios MB, Shan J, Garcia-Manero G, Faderl S, Thomas DA, Wierda W, Ferrajoli A, Jeha S, Kantarjian HM. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood. 2003;101:3794–800.

    Article  PubMed  CAS  Google Scholar 

  8. O’Dwyer ME, Mauro MJ, Blasdel C, Farnsworth M, Kurilik G, Hsieh YC, Mori M, Druker BJ. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood. 2004;103:451–5.

    Article  PubMed  Google Scholar 

  9. Cortes JE, Talpaz M, O’Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Verstovsek S, Rios MB, Shan J, Kantarjian HM. Staging of chronic myeloid leukemia in the imatinib era. An evaluation of World Health Organisation proposal. Cancer. 2006;106:1306–15.

    Article  PubMed  CAS  Google Scholar 

  10. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, Hochhaus A, Horowitz M, Hughes T, Kantarjian H, Larson R, Radich J, Simonsson B, Silver RT, Goldman J. European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendations of European Leukemianet. J Clin Oncol. 2009;27:6041–51.

    Article  PubMed  CAS  Google Scholar 

  11. Deininger MW, Cortes J, Paquette R, Park B, Hochhaus A, Baccarani M, Stone R, Fischer T, Kantarjian H, Niederwieser D, Gambacorti-Passerini C, So C, Gathmann I, Goldman JM, Smith D, Druker BJ, Guilhot F. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer. 2007;110:1509–19.

    Article  PubMed  Google Scholar 

  12. Jabbour E, Kantarjian HM, Abruzzo LV, O’Brien S, Garcia-Manero G, Verstovsek S, Shan J, Rios MB, Cortes J. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood. 2007;110:2991–5.

    Article  PubMed  CAS  Google Scholar 

  13. Shaffer LG, Slovak ML, Campbell LJ, editors. ISCN: an international system for human cytogenetic nomenclature. Basel: S. Karger; 2009.

    Google Scholar 

  14. Farag SS, Ruppert AS, Mrόzek K, Carroll AJ, Pettenati MJ, Le Beau MM, Peterson BL, Powell BL, Ozer H, Silver RT, Larson RA, Bloomfield CD. Prognostic significance of additional abnormalities in newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukaemia treated with interferon alpha: a Cancer and Leukemia Group B study. Int J Oncol. 2004;25:143–51.

    PubMed  Google Scholar 

  15. Luatti S, Castagnetti F, Marzocchi G, Baldazzi C, Gugliotta G, Iacobucci I, Specchia G, Zanatta L, Rege-Cambrin G, Mancini M, Abruzzese E, Zaccaria A, Grimoldi MG, Gozzetti A, Ameli G, Capucci MA, Palka G, Bernasconi P, Palandri F, Pane F, Saglio G, Martinelli G, Rosti G, Baccarani M. Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) working party on CML. Additional chromosomal abnormalities in Philadelphia-positive clone: adverse prognostic influence on frontline imatinib therapy: a GIMEMA Working Party on CML anaysis. Blood. 2012;120:761–7.

    Article  PubMed  CAS  Google Scholar 

  16. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, Apperley J, Cervantes F, Cortes J, Deininger M, Gratwohl A, Guilhot F, Horowitz M, Hughes T, Kantarjian H, Larson R, Niederwieser D, Silver R. European LeukemiaNet. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–20.

    Article  PubMed  CAS  Google Scholar 

  17. Schoch C, Haferlach T, Kern W, Schnittger S, Berger U, Hehlmann R, Hiddemann W, Hochhaus A. Occurrence of additional chromosome aberrations in chronic myeloid leukemia patients treated with imatinib mesylate. Leukemia. 2003;17:461–3.

    Article  PubMed  CAS  Google Scholar 

  18. Verma D, Kantarjian H, Shan J, O’Brien S, Estrov Z, Garcia-Manero G, Koller C, Borthakur G, Cortes J. Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer. 2010;116:2673–81.

    PubMed  CAS  Google Scholar 

  19. Fabarius A, Leitner A, Hochhaus A, Müller MC, Hanfstein B, Haferlach C, Göhring G, Schlegelberger B, Jotterand M, Reiter A, Jung-Munkwitz S, Proetel U, Schwaab J, Hofmann WK, Schubert J, Einsele H, Ho AD, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Lauseker M, Pfirrmann M, Hasford J, Saussele S. Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) and the German CML Study Group. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118:6760–8.

    Article  PubMed  CAS  Google Scholar 

  20. Marin D, Milojkovic D, Olavarria E, Khorashad JS, de Lavallade H, Reid AG, Foroni L, Rezvani K, Bua M, Dazzi F, Pavlu J, Klammer M, Kaeda JS, Goldman JM, Apperley JF. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. 2008;112:4437–44.

    Article  PubMed  CAS  Google Scholar 

  21. O’Dwyer ME, Mauro MJ, Kurilik G, Mori M, Balleissen S, Olson S, Magenis E, Capdeville R, Druker BJ. The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood. 2002;100:1628–33.

    Article  PubMed  Google Scholar 

  22. Falchi L, Rege-Cambrin G, Fava C, Donti E, Luzi D, Giugliano E, Gubbiotti M, Schippa M, Liberati AM. Sustained molecular remissions are achievable with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia and additional cytogenetic clonal evolution. Cancer Genet Cytogenet. 2010;199:139–42.

    Article  PubMed  CAS  Google Scholar 

  23. Mohamed AN, Pemberton P, Zonder J, Schiffer CA. The effect of imatinib mesylate on patients with Philadelphia chromosome-positive chronic myeloid leukemia with secondary chromosomal aberrations. Clin Cancer Res. 2003;9:1333–7.

    PubMed  CAS  Google Scholar 

  24. Cannella L, Loglisci G, Nanni M, De Cuia MR, Colafigli G, Salaroli A, Serrao A, Alimena G, Breccia M. Trisomy 8 in Philadelphia chromosome negative cell preceding the evolution of a Philadelphia chromosome positive clone with the same additional change during imatinib treatment: revisiting the role of genetic instability in chronic myeloid leukemia. Leuk Lymphoma. 2012;53:497–8.

    Article  PubMed  Google Scholar 

  25. Feldman E, Najfeld V, Schuster M, Roboz G, Chadburn A, Silver RT. The emergence of Ph-, trisomy -8+ cells in patients with chronic myeloid leukemia treated with imatinib mesylate. Exp Hematol. 2003;31:702–7.

    Article  PubMed  CAS  Google Scholar 

  26. Zaccaria A, Valenti AM, Donti E, Gozzetti A, Ronconi S, Spedicato F. Persistence of chromosomal abnormalities additional to the Philadelphia chromosome after Philadelphia chromosome disappearance during imatinib therapy for chronic myeloid leukemia. Haematologica. 2007;92:564–5.

    Article  PubMed  Google Scholar 

  27. Baldazzi C, Luatti S, Marzocchi G, Stacchini M, Gamberini C, Castagnetti F, Palandri F, Rosti G, Baccarani M, Testoni N. Emergence of clonal chromosomal abnormalities in Philadelphia negative hematopoiesis in chronic myeloid leukemia patients treated with nilotinib after failure of imatinib therapy. Leuk Res. 2009;33:e218–20.

    Article  PubMed  CAS  Google Scholar 

  28. De Melo VA, Milojkovic D, Khorashad JS, Marin D, Goldman JM, Apperley JF, Reid AG. Philadelphia-negative clonal hematopoiesis is a significant feature of dasatinib therapy for chronic myeloid leukemia. Blood. 2007;110:3086–7.

    Article  PubMed  Google Scholar 

  29. Quintás-Cardama A, Cortes JE, Kantarjiyan HM. Early cytogenetic and molecular response during first-line treatment of chronic myeloid leukemia in chronic phase: long-term implications. Cancer. 2011;117:5261–70.

    Article  PubMed  Google Scholar 

  30. Lippert E, Etienne G, Mozziconacci MJ, Laibe S, Gervais C, Girault S, Gachard N, Tigaud I, Dastugue N, Huguet F, Fort MP, Legros L, Eclache V, Mahon FX. Loss of Y chromosome in Philadelphia-positive cells predicts a poor prognosis of chronic myeloid leukaemia patients to imatinib mesylate therapy. Haematologica. 2010;95:1604–7.

    Article  PubMed  CAS  Google Scholar 

  31. Haferlach C, Bacher U, Schnittger S, Weiss T, Kern W, Haferlach T. Similar patterns of chromosome abnormalities in CML occur in addition to the Philadelphia chromosome with or without tyrosine kinase inhibitor treatment. Leukemia. 2010;24:638–40.

    Article  PubMed  CAS  Google Scholar 

  32. Deininger MW. Cytogenetic studies in patients on imatinib. Semin Hematol. 2003;40:50–5.

    PubMed  Google Scholar 

  33. Meggyesi N, Kozma A, Halm G, Nahajevszky S, Bátai A, Fekete S, Barta A, Ujj G, Lueff S, Sipos A, Adám E, Bors A, Reményi P, Masszi T, Tordai A, Andrikovics H. Additional chromosome abnormalities, BCR-ABL tyrosine kinase domain mutations and clinical outcome in Hungarian tyrosine kinase inhibitor-resistant chronic myelogenous leukemia patients. Acta Haematol. 2012;127:34–42 (Epub 2011 Oct 14).

    Google Scholar 

  34. Najfeld V. Letter to the editor regarding the article “Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenic and prognostic implications”. Cancer Genet Cytogenet. 2010;203:355–6; author reply 357–8.

    Google Scholar 

  35. Zaccaria A, Testoni N, Valenti AM, Luatti S, Tonelli M, Marzocchi G, Cipriani R, Baldazzi C, Giannini B, Stacchini M, Gamberini C, Castagnetti F, Rosti G, Azzena A, Cavazzini F, Cianciulli AM, Dalsass A, Donti E, Giugliano E, Gozzetti A, Grimoldi MG, Ronconi S, Santoro A, Spedicato F, Zanatta L. GIMEMA working party on CML. Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenetic and prognostic implications. Cancer Genet Cytogenet. 2010;199:76–80.

    Article  PubMed  CAS  Google Scholar 

  36. Fialkow PJ, Jacobson RJ, Papayannopoulou T. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med. 1977;63:125–30.

    Article  PubMed  CAS  Google Scholar 

  37. Fialkow PJ, Martin PJ, Najfeld V, Penfold GK, Jacobson RJ, Hansen JA. Evidence for a multistep pathogenesis of chronic myelogenous leukemia. Blood. 1981;58:158–63.

    PubMed  CAS  Google Scholar 

  38. Martin PJ, Najfeld V, Fialkow PJ. B-lymphoid cell involvement in chronic myelogenous leukemia: implications for the pathogenesis of the disease. Cancer Genet Cytogenet. 1982;6:359–68.

    Article  PubMed  CAS  Google Scholar 

  39. Raskind WH, Ferraris AM, Najfeld V, Jacobson RJ, Moohr JW, Fialkow PJ. Further evidence for the existence of a clonal Ph-negative stage in some cases of Ph-positive chronic myelocytic leukemia. Leukemia. 1993;7:1163–7.

    PubMed  CAS  Google Scholar 

  40. Andersen MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brøndum-Nielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia. 2002;16:1390–3.

    Article  PubMed  CAS  Google Scholar 

  41. Bumm T, Muller C, Al-Ali HK, et al. Emergence of clonal cytogenetic abnormalities in Ph− cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood. 2003;101:1941–9.

    Article  PubMed  CAS  Google Scholar 

  42. Fabarius A, Willer A, Yerganian G, Hehlmann R, Duesberg P. Specific aneusomies in Chinese hamster cells at different stages of neoplastic transformation, initiated by nitrosomethylurea. Proc Natl Acad Sci USA. 2002;99:6778–83.

    Article  PubMed  CAS  Google Scholar 

  43. Fabarius A, Li R, Yerganian G, Hehlmann R, Duesberg P. Specific clones of spontaneously evolving karyotypes generate individuality of cancers. Cancer Genet Cytogenet. 2008;180:89–99.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

We declared that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Basic Oncology, Cancer Institute, Hacettepe University, 06100, Sihhiye, Ankara, Turkey

    Sureyya Bozkurt, Ayten Inanc & Emin Kansu

  2. Department of Internal Medicine, Division of Hematology, Hacettepe University, 06100, Sihhiye, Ankara, Turkey

    Burak Uz, Yahya Buyukasik, Ozlen Bektas & Hakan Goker

Authors
  1. Sureyya Bozkurt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Burak Uz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yahya Buyukasik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ozlen Bektas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ayten Inanc
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hakan Goker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emin Kansu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sureyya Bozkurt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bozkurt, S., Uz, B., Buyukasik, Y. et al. Prognostic importance of additional cytogenetic anomalies in chronic myeloid leukemia. Med Oncol 30, 443 (2013). https://doi.org/10.1007/s12032-012-0443-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-012-0443-1

Keywords

Search

Navigation