title: Measurement of in vivo BCR-ABL kinase inhibition to monitor imatinib-induced target blockade and predict response in chronic myeloid leukemia.
abstract: OBJECTIVE
  Intrinsic sensitivity to imatinib, based on measurement of inhibitory concentration 50% for imatinib, is variable in untreated patients with chronic myeloid leukemia (CML). This suggests that patient-tailored dosing may be more rational than a fixed dose for all. Dose optimization potentially could be based on accurate measurement of the level of BCR-ABL kinase inhibition achieved in vivo.
  
  
  METHODS
  In vivo kinase inhibition was measured by calculating the reduction in protein (p)--Crkl level in mononuclear blood cells taken from 49 CML patients at weekly intervals after imatinib therapy was commenced.
  
  
  RESULTS
  Greater than 50% inhibition (> 50% reduction in p-Crkl from baseline) was achieved by 21% of patients by days 7 to 14 (and maintained in all patients on days 21 to 28) and an additional 24% of patients achieved more than 50% inhibition by days 21 to 28. Thus, overall 45% of patients achieved more than 50% inhibition. All of these patients achieved major molecular responses by 24 months compared with 56% of the patients who failed to achieve 50% kinase inhibition (P < .001). Patients with less than 50% kinase inhibition were also more likely to have suboptimal responses.
  
  
  CONCLUSIONS
  In vivo BCR-ABL kinase inhibition can be assessed in the first month of imatinib therapy and may provide a valuable guide to optimization of dosage. The extent of BCR-ABL kinase inhibition is an excellent predictor of cytogenetic and molecular response. These observations suggest that dose adjustment based on in vivo measurements of drug-induced target inhibition could be applied in settings beyond imatinib and may be a more effective approach than using one dose for all patients in targeted anticancer therapy.
authors: Division of Hematology, Institute of Medical and Veterinary Science, Adelaide, Australia. deb.white@imvs.sa.gov.au
authors: Deborah
authors: D
authors: White
authors: Verity
authors: V
authors: Saunders
authors: Andrew
authors: A
authors: Grigg
authors: Chris
authors: C
authors: Arthur
authors: Robin
authors: R
authors: Filshie
authors: Michael F
authors: MF
authors: Leahy
authors: Kevin
authors: K
authors: Lynch
authors: L Bik
authors: LB
authors: To
authors: Timothy
authors: T
authors: Hughes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors; D000328:Adult; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011237:Predictive Value of Tests; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; C082869:CRKL protein; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl