In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML.

Most patients with de novo chronic myeloid leukemia (CML) achieve good responses to imatinib, but the rate and degree of molecular response is variable. We assessed the inhibitory concentration 50% for imatinib (IC50imatinib) in 62 patients with de novo chronic-phase CML as a predictor of molecular response. IC50imatinib was determined in pretherapy blood samples by measuring the in vitro imatinib-induced reduction of the phosphorylated form of the adaptor protein Crkl (CT10 regulator of kinase like). There was marked variability between patients, with IC50imatinib ranging from 0.375 to 1.8 microM (median, 0.6 microM). Patients with low IC50imatinib (IC50 < or = 0.6 microM; n = 36) had a 36% probability of achieving 2-log reduction in BCR-ABL (breakpoint cluster region-abelson) by 3 months compared with 8% in patients with high IC50imatinib (n = 26) (P = .01). The IC50imatinib was also predictive of molecular response at 12 months, with 47% of patients in the low IC50imatinib group achieving 3-log reduction and 23% in the high IC50imatinib group (P = .03). The predictive power of IC50imatinib was particularly strong in patients with low Sokal scores. These data provide strong evidence that intrinsic sensitivity to imatinib is variable in previously untreated patients with CML, and the actual level of BCR-ABL kinase inhibition achieved is critical to imatinib response. The IC50imatinib potentially provides a new prognostic indicator for molecular response in patients treated with imatinib.

[1]  A. B. Lyons,et al.  Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. , 2005, Blood.

[2]  Munir Pirmohamed,et al.  Active transport of imatinib into and out of cells: implications for drug resistance. , 2004, Blood.

[3]  F. Guilhot.  Sustained Durability of Responses Plus High Rates of Cytogenetic Responses Result in Long-Term Benefit for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Treated with Imatinib (IM) Therapy: Update from the IRIS Study. , 2004 .

[4]  R. Herrmann,et al.  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. , 2004, Blood.

[5]  Ping Chen,et al.  Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor , 2004, Science.

[6]  M. Rocchi,et al.  Derivative Chromosome 9 Deletions in Chronic Myeloid Leukemia are Associated with Loss of Tumor Suppressor Genes , 2004, Leukemia & lymphoma.

[7]  G. Ehninger,et al.  P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate , 2004, Leukemia.

[8]  J. Mestan,et al.  Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. , 2004, Mini reviews in medicinal chemistry.

[9]  A. Heimberger,et al.  Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not affect tumorigenicity in vivo. , 2004, The Journal of investigative dermatology.

[10]  Hiroshi Watanabe,et al.  Interaction of Imatinib Mesilate with Human P-Glycoprotein , 2003, Journal of Pharmacology and Experimental Therapeutics.

[11]  Susan Branford,et al.  Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. , 2003, The New England journal of medicine.

[12]  J. Melo,et al.  MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. , 2003, Blood.

[13]  Francisco Cervantes,et al.  Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. , 2003, The New England journal of medicine.

[14]  S. Silberman,et al.  Imatinib: the first 3 years. , 2002, European journal of cancer.

[15]  P. Paschka,et al.  Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon α , 2002, Leukemia.

[16]  L. Campbell,et al.  Derivative chromosome 9 deletions in chronic myeloid leukemia: poor prognosis is not associated with loss of ABL-BCR expression, elevated BCR-ABL levels, or karyotypic instability. , 2002, Blood.

[17]  AC Eaves,et al.  Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia , 2002, Leukemia.

[18]  C. Barthe,et al.  Roots of clinical resistance to STI-571 cancer therapy. , 2001, Science.

[19]  B. Druker,et al.  Roots of Clinical Resistance to STI-571 Cancer Therapy , 2001, Science.

[20]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[21]  J. Griffin,et al.  ARG tyrosine kinase activity is inhibited by STI571. , 2001, Blood.

[22]  C. Sawyers,et al.  Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. , 2001, The New England journal of medicine.

[23]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[24]  E. Hudson,et al.  The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). , 2000, Journal of cell science.

[25]  M. Varella‐Garcia,et al.  Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. , 2000, Blood.

[26]  M. Leversha,et al.  Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia. , 2000, Blood.

[27]  Branford,et al.  Monitoring chronic myeloid leukaemia therapy by real‐time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics , 1999, British journal of haematology.

[28]  R. Arceci,et al.  Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  C. Sawyers,et al.  Structural Requirements for Function of the Crkl Adapter Protein in Fibroblasts and Hematopoietic Cells , 1998, Molecular and Cellular Biology.

[30]  W. Dalton.  Mechanisms of drug resistance in hematologic malignancies. , 1997, Seminars in hematology.

[31]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[32]  P. Tempst,et al.  Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells. , 1994, Blood.

[33]  B. Druker,et al.  Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. , 1994, The Journal of biological chemistry.

[34]  N. Heisterkamp,et al.  Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. , 1994, Blood.

[35]  N. Heisterkamp,et al.  Isolation and chromosomal localization of CRKL, a human crk-like gene. , 1993, Oncogene.

[36]  O. Witte,et al.  Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. , 1990, Science.

[37]  G. Daley,et al.  Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. , 1990, Science.

[38]  G. Daley,et al.  Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[39]  B. Mayer,et al.  A novel viral oncogene with structural similarity to phospholipase C , 1988, Nature.

[40]  J. Stephenson,et al.  Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22 , 1984, Cell.

[41]  J. Stephenson,et al.  A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia , 1982, Nature.

[42]  P. Goodfellow,et al.  Chromosomal localization of human cellular homologues of two viral oncogenes , 1982, Nature.

[43]  G. Canellos,et al.  Chronic granulocytic leukemia. , 1976, The Medical clinics of North America.

[44]  P. Browett,et al.  Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase , 2003, Leukemia.

[45]  M. Baccarani,et al.  Risk and early cytogenetic response to imatinib and interferon in chronic myeloid leukemia. , 2003, Haematologica.

[46]  T. Meyer,et al.  Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. , 1996, Cancer research.

[47]  M. Baccarani,et al.  Prognostic discrimination in "good-risk" chronic granulocytic leukemia. , 1984, Blood.