UNLABELLED: background: Mutations of the BCR-ABL tyrosine kinase domain constitute a major cause of resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia. We sought to improve the diagnostic armamentarium by screening and to analyze the dynamics of mutated clones in chronic myeloid leukemia patients who experienced hematologic or cytogenetic relapse. DESIGN AND METHODS: Ninety-five patients who relapsed during imatinib therapy were screened for BCR-ABL kinase domain mutations using sensitive denaturing high-performance liquid chromatography (D-HPLC) and direct sequencing. To investigate the dynamics of mutated clones D-HPLC was applied to 453 cDNA samples tracking back from relapse towards the start of imatinib therapy. RESULTS: Twenty-two different point mutations affecting 18 amino acids were detectable in 46/79 (58%) and in 7/16 patients (44%) with hematologic or cytogenetic relapse, respectively. A deletion of 81 nucleotides (del248-274) of ABL exon 4 was observed in two patients. Three patients had exclusively single nucleotide polymorphisms (K247R, T315T, E499E, n=1 each) within the BCR-ABL kinase domain. In patients harboring mutations, hematologic relapse occurred after a median of 12.9 months (range, 0.9-44.2), and BCR-ABL mutations first became detectable at a median of 5.8 months (range, 0-30.5) after starting imatinib therapy (p<0.0001). Nine patients showed evidence of BCR-ABL mutations prior to imatinib therapy (T315I, n=4; M351T, n=3; M244V and Y253H, n=1 each). CONCLUSIONS: We conclude that: (i) D-HPLC is a sensitive method for screening for BCR-ABL mutations before and during therapy with tyrosine kinase inhibitors; (ii) the occurrence of BCR-ABL mutations during imatinib therapy is predictive of relapse; (iii) mutations may be detectable several months before relapse, and (iv) the sensitive detection of small numbers of mutated clones could provide clinical benefit by triggering early therapeutic interventions.
UNLABELLED: background: Mutations of the BCR-ABL tyrosine kinase domain constitute a major cause of resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia. We sought to improve the diagnostic armamentarium by screening and to analyze the dynamics of mutated clones in chronic myeloid leukemiapatients who experienced hematologic or cytogenetic relapse. DESIGN AND METHODS: Ninety-five patients who relapsed during imatinib therapy were screened for BCR-ABL kinase domain mutations using sensitive denaturing high-performance liquid chromatography (D-HPLC) and direct sequencing. To investigate the dynamics of mutated clones D-HPLC was applied to 453 cDNA samples tracking back from relapse towards the start of imatinib therapy. RESULTS: Twenty-two different point mutations affecting 18 amino acids were detectable in 46/79 (58%) and in 7/16 patients (44%) with hematologic or cytogenetic relapse, respectively. A deletion of 81 nucleotides (del248-274) of ABL exon 4 was observed in two patients. Three patients had exclusively single nucleotide polymorphisms (K247R, T315T, E499E, n=1 each) within the BCR-ABL kinase domain. In patients harboring mutations, hematologic relapse occurred after a median of 12.9 months (range, 0.9-44.2), and BCR-ABL mutations first became detectable at a median of 5.8 months (range, 0-30.5) after starting imatinib therapy (p<0.0001). Nine patients showed evidence of BCR-ABL mutations prior to imatinib therapy (T315I, n=4; M351T, n=3; M244V and Y253H, n=1 each). CONCLUSIONS: We conclude that: (i) D-HPLC is a sensitive method for screening for BCR-ABL mutations before and during therapy with tyrosine kinase inhibitors; (ii) the occurrence of BCR-ABL mutations during imatinib therapy is predictive of relapse; (iii) mutations may be detectable several months before relapse, and (iv) the sensitive detection of small numbers of mutated clones could provide clinical benefit by triggering early therapeutic interventions.
Authors: Franck E Nicolini; Amr R Ibrahim; Simona Soverini; Giovanni Martinelli; Martin C Müller; Andreas Hochhaus; Inge H Dufva; Dong-Wook Kim; Jorge Cortes; Michael J Mauro; Charles Chuah; Hélène Labussière; Stéphane Morisset; Catherine Roche-Lestienne; Eric Lippert; Sandrine Hayette; Senaka Peter; Wei Zhou; Véronique Maguer-Satta; Mauricette Michallet; John Goldman; Jane F Apperley; François-Xavier Mahon; David Marin; Gabriel Etienne Journal: Haematologica Date: 2013-05-28 Impact factor: 9.941
Authors: Martin C Müller; Jorge E Cortes; Dong-Wook Kim; Brian J Druker; Philipp Erben; Ricardo Pasquini; Susan Branford; Timothy P Hughes; Jerald P Radich; Lynn Ploughman; Jaydip Mukhopadhyay; Andreas Hochhaus Journal: Blood Date: 2009-09-24 Impact factor: 22.113
Authors: Alfonso Quintás-Cardama; Jorge E Cortes; Susan O'Brien; Farhad Ravandi; Gautam Borthakur; David Liu; Eric Bleickardt; Tai-Tsang Chen; Hagop M Kantarjian Journal: Cancer Date: 2009-07-01 Impact factor: 6.860