Monitoring disease response to tyrosine kinase inhibitor therapy in CML.
The remarkable progress made in the treatment of chronic myeloid leukemia (CML) over the past decade has been accompanied by steady improvements in our capacity to accurately and sensitively monitor response to therapy. After the initial target of therapy, complete cytogenetic response (CCR), is achieved, peripheral blood BCR-ABL transcript levels measured by real-time quantitative reverse transcriptase PCR (RQ-PCR) define the subsequent response targets, major and complete molecular response (MMR and CMR). The majority of patients on first-line imatinib therapy achieve a "safe haven" defined as a confirmed MMR, but 20% to 30% stop imatinib due to intolerance and/or resistance. Many imatinib-resistant patients can be effectively treated with second generation tyrosine kinase inhibitors (TKIs), but the actual drug selected should be based on the resistance profile of each inhibitor, in addition to issues of tolerance and disease phase. The main purpose of monitoring response with cytogenetics and RQ-PCR is to identify patients likely to achieve better long-term outcome if they are switched early to second-line therapy, either another TKI or an allograft. Mutation screening is most valuable in cases of loss of response to imatinib or a second-line TKI, but there are other settings where a high yield of mutations may justify regular mutation screening.
Hughes
Timothy P
TP
Centre for Cancer Biology, Departments of Molecular Pathology and Haematology, SA Pathology, Adelaide, Australia. timothy.hughes@health.sa.gov.au
Branford
Susan
S
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001856:Bone Marrow Examination; D003199:Computer Systems; D004252:DNA Mutational Analysis; D016903:Drug Monitoring / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D007958:Leukocyte Count; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D010349:Patient Compliance; D010879:Piperazines / Q000627:therapeutic use; D016133:Polymerase Chain Reaction / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000097:blood; D012334:RNA, Neoplasm / Q000097:blood; D012074:Remission Induction
D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl