title: Factors influencing a second myeloid malignancy in patients with Philadelphia-negative -7 or del(7q) clones during tyrosine kinase inhibitor therapy for chronic myeloid leukemia.
abstract: The detection of Philadelphia-negative (Ph(neg)) cells with non-random karyotypic abnormalities after tyrosine kinase inhibitor (TKI) therapy of chronic myeloid leukaemia (CML) can be associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). To our knowledge, however, there have been no studies on variables influencing the risk of MDS/AML in patients with specific Ph(neg) karyotypes. We systematically examined studies reporting -7 or del(7q) within Ph(neg) cells in TKI-treated CML patients, and abstracted clinical and cytogenetic data from individual reports into a standardized format for further analysis. Of 53 patients, 43 had Ph(neg) -7 clones [as the sole abnormality (-7(sole)) in 29, or with other clones (-7(dual)) in 14], and del(7q) was present in 10. A total of 16/51 evaluable patients, all with -7, transformed to MDS/AML. Transformation was more frequent (15/16 patients) within 6 months of Ph(neg) -7 detection rather than subsequently (P < 0.0001). At first detection after TKI therapy, Ph(neg) abnormal clones comprised ≥50% of Ph(neg) cells in a greater proportion of patients with -7 than del(7q) (P = 0.035). Upon comparing -7(sole) and -7(dual), the latter was likely to be transient (P = 0.004), and AML was frequently observed with persistent -7 clones (P = 0.03). By logistic regression analysis (n = 36), clone size (P = 0.017), time-to-detection longer than 15 months (P = 0.02), and CML response (P = 0.085) were associated with MDS/AML. Validation of these novel associations in registry-based studies will help develop predictive criteria that define the MDS/AML risk in individual patients.
authors.affiliation: Centre for Oncology & Molecular Medicine, Division of Medical Sciences, University of Dundee, Ninewells Hospital & Medical School, Dundee, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Groves
authors.forename: Mark
authors.initials: M
authors.lastname: Sales
authors.forename: Lee
authors.initials: L
authors.lastname: Baker
authors.forename: Michael
authors.initials: M
authors.lastname: Griffiths
authors.forename: Norman
authors.initials: N
authors.lastname: Pratt
authors.forename: Sudhir
authors.initials: S
authors.lastname: Tauro
mesh_terms: D000328:Adult; D000368:Aged; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D003582:Cytogenetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000188:drug therapy / Q000235:genetics*; D010677:Philadelphia Chromosome; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012044:Regression Analysis; D015203:Reproducibility of Results; D012306:Risk
chemical_list: D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases