Molecular monitoring of response to imatinib (Glivec) in chronic myeloid leukemia patients: experience at a tertiary care hospital in Saudi Arabia.
OBJECTIVE
The aim of this study was to evaluate the response and resistance of cases to chronic myeloid leukemia (CML) therapy with tyrosine kinase (TK) inhibitors (imatinib mesylate) and to search for mutations in the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) kinase domain prior to and during therapy.


METHODS
Molecular response was assessed with real-time quantitative reverse transcription-polymerase chain reaction and was expressed as the ratio between BCR-ABL and ABL (k562 cell line) x 100. In addition, we searched for mutations in BCR-ABL kinase domain by amplification and direct sequencing of cDNA products of archived RNA samples.


RESULTS
There were 85 cases of CML Philadelphia-chromosome-positive patients. Major molecular response [corrected] (MMR) of 0.05% was achieved in 40 (47%) of 85 patients and 3-log reduction was achieved in 37 (44%) after 6 months of imatinib therapy. When molecular monitoring was extended to 12 months in a subset of delayed responsive cases (17 cases) who did not achieve an MMR at 6 months, significant changes in BCR-ABL/ABL ratio were noticed. Fifteen de novo CML patients were started directly on treatment and were monitored for BCR-ABL/ABL ratio for a further period of up to 24 months. Their median of BCR-ABL/ABL ratio was 18% at diagnosis, 0.3% after 6 months, 0.2% after 12 months, and 0.01% after 18 and 24 months. Four (27%) of 15 patients achieved MMR as 3-log reduction after 6 months, 6 (40%) after 12 months, 9 (60%) after 18 months, and 7 (46%) after 24 months. No mutation(s) or polymorphism(s) were detected in all tested patients at diagnosis, at 6 months following imatinib and following 12 months for patients showing delayed response.


CONCLUSIONS
BCR-ABL mutations are rare in early chronic phase and increases with CML disease progression. Therefore, search for other causes in resistant cases at this phase should be sought.
Khalil
Salem H
SH
Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Abu-Amero
Khaled K
KK
Al Mohareb
Fahad
F
Chaudhri
Naeem A
NA
D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012189:Retrospective Studies; D012529:Saudi Arabia; D016896:Treatment Outcome; D055815:Young Adult
D001549:Benzamides; D014408:Biomarkers, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl