Submitted February 14, 2007
Accepted April 17, 2007
Heterogeneous prognostic impact of derivative chromosome 9 deletions in chronic myelogenous leukemia
Sebastian Kreil, Markus Pfirrmann, Claudia Haferlach, Katherine Waghorn, Andrew Chase, Rudiger Hehlmann, Andreas Reiter, Andreas Hochhaus, and Nicholas C.P. Cross*
Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, United Kingdom
Institut fur Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universitat Munchen, Munich, Germany
MLL Munchner Leukamielabor, Munich, Germany
III. Medizinische Universitatsklinik, Medizinische Fakultat Mannheim der Universitat Heidelberg, Mannheim, Germany
* Corresponding author; email: ncpc{at}soton.ac.uk.
Der(9) deletions are seen in 10-15% of CML patients and have been associated with a poor prognosis, however no studies have been performed in the context of a randomized clinical trial. We developed a DNA-based deletion screen and investigated 339 chronic phase patients treated with interferon-
(IFN) as first line therapy in three controlled German studies with a median observation time of 7 years. Deletions were detected in pretreatment DNA of 59/339 (17%) patients. Of these, 21 spanned the ABL/BCR junction and 38 were centromeric (n=20) or telomeric (n=18) of the breakpoint. There was no significant difference in overall survival between deleted and non-deleted patients. Patients with breakpoint-spanning deletions had poorer survival compared to patients without deletions (4.7 versus 7.8 years; P=0.003) but this was not significant when censored at allogeneic stem cell transplantation (n=129) or imatinib (n=62) treatment in first chronic phase (P=0.078). Unexpectedly, deletions that did not span the breakpoint were associated with improved survival compared to cases without deletions (P=0.001). Multiple Cox regression analysis indicated that deletion status (P=0.007), age (P=0.018) and spleen enlargement (P<0.001) were significant independent indicators of survival and confirmed that only deletions spanning the ABL/BCR breakpoint were associated with an adverse prognosis (P=0.039).
