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Impact of Additional Cytogenetic Alterations At Diagnosis on Prognosis of CML: Long-Term Observation From 1151 Patients of the Randomized CML Study IV
Journal article

Impact of Additional Cytogenetic Alterations At Diagnosis on Prognosis of CML: Long-Term Observation From 1151 Patients of the Randomized CML Study IV

  • Fabarius, Alice III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Leitner, Armin Medizinischen Klinik I, Klinikum Weiden, Weiden, Germany,
  • Hochhaus, Andreas Hematology/Oncology, Universitätsklinikum Jena, Jena, Germany,
  • Müller, Martin C III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Haferlach, Claudia MLL Munich Leukemia Laboratory, Munich, Germany,
  • Göhring, Gudrun Hannover Medical School, Inst. of Cell & Molecular Pathology, Hannover Medical School, Hannover, Germany,
  • Schlegelberger, Brigitte Hannover Medical School, Hannover, Germany,
  • Jotterand, Martine Unité de cytogénétique du cancer, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland,
  • Reiter, Andreas III.Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Jung-Munkwitz, Susanne III. Med. Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Proetel, Ulrike III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Schwaab, Juliana III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany,
  • Hofmann, Wolf-Karsten III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim,
  • Schubert, Joerg E. A. Abteilung für Hämatologie-Onkologie, Evangelisches Krankenhaus Hamm, Hamm, Germany,
  • Einsele, Hermann Department of Internal Medicine II, Division of Hematology and Medical Oncology, Wuerzburg University Medical Center, Wuerzburg, Germany,
  • Ho, Anthony D. Internal Medicine V, University of Heidelberg, Heidelberg, Germany,
  • Falge, Christiane Medizinische Klinik 5, Klinikum Nürnberg Nord, Nürnberg, Germany,
  • Kanz, Lothar Medical Department, Hematology & Oncology, Tuebingen, Germany,
  • Neubauer, Andreas Department of Hematology, Oncology and Immunology, University Hospital of Marburg, Marburg, Germany,
  • Kneba, Michael Campus Kiel, 2nd Dept. of Medicine, University Hospital of Schleswig-Holstein, Kiel, Germany,
  • Stegelmann, Frank Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany,
  • Pfreundschuh, Michael Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg, Germany,
  • Waller, Cornelius F. Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany,
  • Hiddemann, Wolfgang Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Campus Gro ßhadern, Munich, Germany,
  • Baerlocher, Gabriela M. Hematology, University Hospital and University of Bern, Bern, Switzerland,
  • Lauseker, Michael Institute for Medical Informatics and Biometry, Ludwig-Maximilians-Universität München, München, Germany,
  • Pfirrmann, Markus Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, München, Germany
  • Saussele, Susanne III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Hehlmann, Rüdiger III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Hasford, Joerg Institute for Medical Informatics and Biometry, Ludwig-Maximilians-Universität München, München, Germany,
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Published in:
  • Blood. - American Society of Hematology. - 2011, vol. 118, no. 21, p. 782-782
Immunology
Cell Biology
Biochemistry
Hematology
English Abstract
Abstract 782

Introduction:
Current evidence indicates that acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the t(9;22)(q34;q11) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations (ACA) and mutations and thereby progression to accelerated phase and blast crisis (BC). Around 10 –12% of patients in chronic phase (CP) CML have ACA already at diagnosis. During the course of the disease this number rises to 80% in BC. Acquisition of ACA during treatment is considered as a poor prognostic indicator, whereas the impact of ACA at diagnosis is controversial.
Patients and methods: Clinical and cytogenetic data of 1151 out of 1311 patients with Philadelphia and BCR-ABL positive CP CML randomized until 2009 to the German CML-Study IV were investigated in a prospective study. There were 459 females (40%) and 692 males (60%). Median age was 53 years (range, 16–88). All patients were treated with imatinib alone or in combination with interferon alpha or araC. The impact of ACA at diagnosis on time to complete cytogenetic and major molecular remission (CCR, MMR) and progression-free and overall survival (PFS, OS) was investigated. Written informed consent was obtained from all patients prior to entering the study.


Results:
At diagnosis 1003/1151 patients (87%) had the standard t(9;22)(q34;q11) only and 69 patients (6.0%) had a variant t(v;22). In 60 of 69 patients with t(v;22), only one further chromosome was involved in the translocation, in 7 patients two, and in 2 patients three further chromosomes were involved. Seventy-nine patients (6.9%) had ACA. Of these, 38 patients (3.3%) lacked the Y chromosome (-Y) and 41 patients (3.6%) had ACA except -Y. Sixteen of the 41 patients had major-route ACA (+8, i(17)(q10), +der(22)t(9;22)(q34;q11), ider(22)(q10)t(9;22)(q34;q11)) and 25 minor-route ACA [e.g. t(3;12), t(4;6), t(2;16), t(1;21)]. In patients with major-route ACA, trisomy 8 was the most frequent additional alteration (n=9). +der(22)t(9;22)(q34;q11) was observed in six patients, isochromosome (17)(q10) in five patients and ider(22)(q10)t(9;22)(q34;11) in three patients.
After a median observation time of 5.3 years for patients with t(9;22), t(v;22), -Y, minor- and major-route ACA median times to CCR were 1.01, 0.95, 0.98, 1.49 and 1.51 years, to MMR 1.40, 1.58, 1.65, 2.49 and > 7 years, 5-year PFS 90%, 81%, 88%, 96% and 50% and 5-year OS 92%, 87%, 91%, 96% and 53%, respectively. In patients with major-route ACA times to CCR and MMR were longer. PFS and OS were shorter (p<0.001) than with standard t(9;22)(q34;q11). Loss of Y chromosome had no influence on time to CCR or MMR, PFS and OS.


Conclusion:
We conclude that the prognostic impact of additional cytogenetic findings at diagnosis of CML is heterogeneous and consideration of their types may be important. Major-route ACA identify a small group of patients with significantly poorer prognosis as compared to all other patients requiring early and more intensive intervention such as stem cell transplantation.


Disclosures:
Hochhaus: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kneba:Hoffmann La Roche: Honoraria.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/132382
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