PT  - JOURNAL ARTICLE
AU  - Randolph, Tim R
TI  - Chronic Myelocytic Leukemia – Part II: Approaches to and Molecular Monitoring of Therapy
AID  - 10.29074/ascls.18.1.49
DP  - 2005 Jan 01
TA  - American Society for Clinical Laboratory Science
PG  - 49--56
VI  - 18
IP  - 1
4099  - http://hwmaint.clsjournal.ascls.org/content/18/1/49.short
4100  - http://hwmaint.clsjournal.ascls.org/content/18/1/49.full
SO  - Clin Lab Sci2005 Jan 01; 18
AB  - Following careful study of this review, the reader will be able to: Describe the first documented therapy for CML.Discuss the chemotherapeutic approach to CML treatment.Discuss one advantage and one disadvantage of alpha interferon and bone marrow/stem cell transplants in the treatment of CML.Discuss the therapeutic approach to CML involving tyrosine kinase inhibitors to include:molecular target of tyrosine kinase inhibitors.function of the tyrosine kinase inhibitors.effectiveness of therapy.drug resistance and adverse events.alternative therapeutic approaches in patients with drug resistance. DATA SOURCES: Current literature.DATA SYNTHESIS: Chronic myelocytic leukemia (CML) was initially described in 1845 and is considered one of the first leukemias discovered. Effective approaches to therapy were not instituted until arsenic was first administered in 1865. Since then, four major therapeutic milestones have been achieved; the development of alkylating agents like busulphan and 6-thioguanine in 1953, alpha interferon in 1983, bone marrow transplantation in 1986, and tyrosine kinase inhibitors in 1998. The discovery that the protein product of this fusion gene expresses constitutive tyrosine kinase activity prompted the synthesis of a designer drug, imatinib mesylate, which binds the fusion protein and neutralizes the tyrosine kinase activity. Molecular methods of detecting BCR-ABL transcripts are showing promise in confirming drug resistance and predicting patient outcomes in response to imatinib mesylate therapy. Evidence of drug resistance can guide physicians in selecting alternative therapeutic approaches early in the course of the disease to potentially rescue non responders. Although the success of clinical trials has been dramatic, drug resistance and disease relapse are issues to be considered.CONCLUSION: The discovery that the BCR/ABL fusion protein exhibits increased and constitutive tyrosine kinase activity led investigators to develop an inhibitor to this activity. The synthesis of imatinib mesylate, currently marketed as Gleevec™ or GlivecR, is in stage III clinical trials and has proven to be the most successful antileukemic drug to date. As in CML, an understanding of the leukemogenic mechanisms involved in other leukemias will provide the groundwork for the development of therapeutic interventions tailored to the specific molecular defects identified, eventually rendering obsolete the shotgun approaches to massive cell killing produced by chemotherapy.ABBREVIATIONS: ABL = Ableson oncogene found in a strain of mouse leukemia virus; ASH = American Society of Hematology Annual Meeting; BCR = breakpoint cluster region; CCR = complete cytogenetic response; CHR = complete hematologic response; CML = chronic myelocytic leukemia; INF = interferon; MCR = major cytogenetic response; MMR = major molecular response; RT-PCR = reverse transcriptase-polymerase chain reaction; SCT = stem cell transplant.