Dynamics of BCR-ABL mutated clones prior to hematologic or cytogenetic resistance to imatinib

被引:89
作者
Ernst, Thomas [1 ]
Erben, Philipp [1 ]
Mueller, Martin C. [1 ]
Paschka, Peter [1 ]
Schenk, Thomas [1 ]
Hoffmann, Jana [1 ]
Kreil, Sebastian [1 ]
La Rosee, Paul [1 ]
Hehlmann, Rudiger [1 ]
Hochhaus, Andreas [1 ]
机构
[1] Heidelberg Univ, Med Fak Mannheim, Med Klin 3, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany
关键词
chronic myeloid leukemia; imatinib resistance; BCR-ABL mutation; D-HPLC;
D O I
10.3324/haematol.11993
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:186 / 192
页数:7
相关论文
共 29 条
[1]   Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet [J].
Baccarani, Michele ;
Saglio, Giuseppe ;
Goldman, John ;
Hochhaus, Andreas ;
Simonsson, Bengt ;
Appelbaum, Frederick ;
Apperley, Jane ;
Cervantes, Francisco ;
Cortes, Jorge ;
Deininger, Michael ;
Gratwohl, Alois ;
Guilhot, Frangois ;
Horowitz, Mary ;
Hughes, Timothy ;
Kantarjian, Hagop ;
Larson, Richard ;
Niederwieser, Dielger ;
Silver, Richard ;
Hehlmann, Rudiger .
BLOOD, 2006, 108 (06) :1809-1820
[2]   High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance [J].
Branford, S ;
Rudzki, Z ;
Walsh, S ;
Grigg, A ;
Arthur, C ;
Taylor, K ;
Herrmann, R ;
Lynch, KP ;
Hughes, TP .
BLOOD, 2002, 99 (09) :3472-3475
[3]   Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations [J].
Branford, S ;
Rudzki, Z ;
Parkinson, I ;
Grigg, A ;
Taylor, K ;
Seymour, JF ;
Durrant, S ;
Browett, P ;
Schwarer, AP ;
Arthur, C ;
Catalano, J ;
Leahy, MF ;
Filshie, R ;
Bradstock, K ;
Herrmann, R ;
Joske, D ;
Lynch, K ;
Hughes, T .
BLOOD, 2004, 104 (09) :2926-2932
[4]   Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment [J].
Chu, S ;
Xu, H ;
Shah, NP ;
Snyder, DS ;
Forman, SJ ;
Sawyers, CL ;
Bhatia, R .
BLOOD, 2005, 105 (05) :2093-2098
[5]   Several Bcr-Ab1 kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib [J].
Corbin, AS ;
La Rosée, P ;
Stoffregen, EP ;
Druker, BJ ;
Deininger, MW .
BLOOD, 2003, 101 (11) :4611-4614
[6]   MINIMAL RESIDUAL DISEASE AFTER BONE-MARROW TRANSPLANT FOR CHRONIC MYELOID-LEUKEMIA DETECTED BY THE POLYMERASE CHAIN-REACTION [J].
CROSS, NCP ;
LIN, F ;
BUNGEY, J ;
GOLDMAN, JM .
LEUKEMIA & LYMPHOMA, 1993, 11 :39-43
[7]   Detection of ABL kinase domain mutations with denaturing high-performance liquid chromatography [J].
Deininger, MWN ;
McGreevey, L ;
Willis, S ;
Bainbridge, TM ;
Druker, BJ ;
Heinrich, MC .
LEUKEMIA, 2004, 18 (04) :864-871
[8]  
Ernst T, 2007, HAEMATOL-HEMATOL J, V92, P199
[9]   Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification [J].
Gorre, ME ;
Mohammed, M ;
Ellwood, K ;
Hsu, N ;
Paquette, R ;
Rao, PN ;
Sawyers, CL .
SCIENCE, 2001, 293 (5531) :876-880
[10]   A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib [J].
Gruber, F. X. ;
Hjorth-Hansen, H. ;
Mikkola, I. ;
Stenke, L. ;
Johansen, T. .
LEUKEMIA, 2006, 20 (11) :2057-2060