Abstract
Major route additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukaemia (CML) indicate an increased risk of progression and shorter survival. Since major route ACA are almost always unbalanced, it is unclear whether other unbalanced ACA at diagnosis also confer an unfavourable prognosis. On the basis of 1348 Philadelphia chromosome-positive chronic phase patients of the randomized CML study IV, we examined the impact of unbalanced minor route ACA at diagnosis versus major route ACA on prognosis. At diagnosis, 1175 patients (87.2 %) had a translocation t(9;22)(q34;q11) and 74 (5.5 %) a variant translocation t(v;22) only, while a loss of the Y chromosome (−Y) was present in addition in 44 (3.3 %), balanced or unbalanced minor route ACA each in 17 (1.3 %) and major route ACA in 21 (1.6 %) cases. Patients with unbalanced minor route ACA had no significantly different cumulative incidences of complete cytogenetic remission or major molecular remission and no significantly different progression-free survival (PFS) or overall survival (OS) than patients with t(9;22), t(v;22), −Y and balanced minor route karyotypes. In contrast, patients with major route ACA had a shorter OS and PFS than all other groups (all pairwise comparisons to each of the other groups: p ≤ 0.015). Five-year survival probabilities were for t(9;22) 91.4 % (95 % CI 89.5–93.1), t(v; 22) 87 % (77.2–94.3), −Y 89.0 % (76.7–97.0), balanced 100 %, unbalanced minor route 92.3 % (72.4–100) and major route 52.2 % (28.2–75.5). We conclude that only major route, but not balanced or unbalanced minor route ACA at diagnosis, has a negative impact on prognosis of CML.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Fabarius A, Leitner A, Hochhaus A, Müller MC, Hanfstein B, Haferlach C et al (2011) Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 118(26):6760–6768
Schoch C, Haferlach T, Kern W, Schnittger S, Berger U, Hehlmann R et al (2003) Occurrence of additional chromosome aberrations in chronic myeloid leukemia patients treated with imatinib mesylate. Leukemia 17(2):461–463
Verma D, Kantarjian H, Shan J, O'Brien S, Estrov Z, Garcia-Manero G et al (2010) Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer 116(11):2673–2681
Rowley JD (1973) Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243(5405):290–293
O'Dwyer ME, Mauro MJ, Kurilik G, Mori M, Balleisen S, Olson S et al (2002) The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100(5):1628–1633
O'Dwyer ME, Mauro MJ, Blasdel C, Farnsworth M, Kurilik G, Hsieh YC et al (2004) Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 103(2):451–455
Mitelman F, Levan G, Nilsson PG, Brandt L (1976) Non-random karyotypic evolution in chronic myeloid leukemia. Int J Cancer 18(1):24–30
Johansson B, Fioretos T, Mitelman F (2002) Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 107(2):76–94
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122(6):872–884
Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Muller MC, Pletsch N et al (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29(12):1634–1642
Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J et al (2009) Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 27(35):6041–6051
Schoch C, Schnittger S, Bursch S, Gerstner D, Hochhaus A, Berger U et al (2002) Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases. Leukemia 16(1):53–59
Shaffer L, McGowan-Jordan J, Schmid M eds. (2013) ISCN 2013 An international system for human cytogenetic nomenclature. Basel: Karger
Kalmanti L, Saussele S, Lauseker M, Muller MC, Dietz CT, Heinrich L et al (2015) Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia 29(5):1123–1132
Testoni N, Marzocchi G, Luatti S, Amabile M, Baldazzi C, Stacchini M et al (2009) Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP. Blood 114(24):4939–4943
Emig M, Saussele S, Wittor H, Weisser A, Reiter A, Willer A et al (1999) Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR. Leukemia 13(11):1825–1832
Cross NCP, White HE, Müller MC, Saglio G, Hochhaus A (2012) Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 26(10):2172–2175
Gooley TA, Leisenring W, Crowley J, Storer BE (1999) Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 18(6):695–706
Pfirrmann M, Hochhaus A, Lauseker M, Saussele S, Hehlmann R, Hasford J (2011) Recommendations to meet statistical challenges arising from endpoints beyond overall survival in clinical trials on chronic myeloid leukemia. Leukemia 25(9):1433–1438
Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC et al (1998) A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90(11):850–858
Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G et al (2011) Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 118(3):686–692
Skorski T (2002) Oncogenic tyrosine kinases and the DNA-damage response. Nat Rev Cancer 2(5):351–360
Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M et al (2006) BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 108(1):319–327
Luatti S, Castagnetti F, Marzocchi G, Baldazzi C, Gugliotta G, Iacobucci I et al (2012) Additional chromosomal abnormalities in Philadelphia-positive clone: adverse prognostic influence on frontline imatinib therapy: a GIMEMA Working Party on CML analysis. Blood 120(4):761–767
Mitelman F (1993) The cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma 11(s1):11–15
Fabarius A, Haferlach C, Hochhaus A, Muller MC, Hanfstein B, Gohring G et al (2012) Impact of balanced or unbalanced karyotype at diagnosis on prognosis of CML: long-term observation from 1346 patients of the randomized CML study IV. ASH Ann Meet Abst 120(21):913
Fabarius A, Duesberg P, Giehl M, Seifarth W, Hochhaus A, Hehlmann R (2008) Genomic instability in context of the chromosomal theory. Cell Oncol 30(6):503–504
Schoch C, Kohlmann A, Dugas M, Kern W, Hiddemann W, Schnittger S et al (2005) Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q. Leukemia 19(7):1224–1228
Pavelka N, Rancati G, Zhu J, Bradford WD, Saraf A, Florens L et al (2010) Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468(7321):321–325
Holland AJ, Cleveland DW (2012) Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep 13(6):501–514
Acknowledgments
The contributions of Gabriele Bartsch, Andrea Elett, Elke Matzat, Uwe Böhm, Sabine Dean, Christine Folz, Michaela Hausmann, Elke Matzat, Regina Pleil-Lösch, Inge Stalljann and all CML trial participants are acknowledged.
Authors’ contribution
AF, LK, CD, SS and RH had the primary responsibility for the publication. RH, AH, MP and JH contributed to the design of the study. All others contributed to the collection and assembly of data, cytogenetic, molecular and statistical analysis and the interpretation of results. All authors have checked and approved the final version of the manuscript.
Compliance with ethical standards
ᅟ
Conflict of interest
The CML study IV is supported by the Deutsche Krebshilfe (Nr. 106642), Novartis, Nürnberg, Germany, Kompetenznetz für Akute and Chronische Leukämien (BMBF 01GI0270), José-Carreras Leukämiestiftung (DJCLS H09/01f, H06/04v, H03/01) and the European LeukemiaNet (LSHC-CT-2004-503216).
Ethics approval
The protocol followed the Declaration of Helsinki and was approved by the ethics committee of the Medical Faculty Mannheim at the University Heidelberg, Germany and by local ethics committees of the participating centres.
Consent to participate
Written informed consent was obtained from all patients prior to entering the study.
Author information
Authors and Affiliations
Consortia
Corresponding author
Additional information
Alice Fabarius, Lida Kalmanti and Christian T. Dietz contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(PDF 86 kb)
Rights and permissions
About this article
Cite this article
Fabarius, A., Kalmanti, L., Dietz, C.T. et al. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML. Ann Hematol 94, 2015–2024 (2015). https://doi.org/10.1007/s00277-015-2494-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-015-2494-9