[Resistance to tumor specific therapy with imatinib by clonal selection of mutated cells].
METHODS
A 60-year-old woman presented with night-sweats and increasing weakness. Physical examination revealed no abnormalities. For 27 years she had been treated for Philadelphia-positive chronic myeloid leukemia (CML). Because of progressive disease treatment with the tyrosine kinase inhibitor imatinib (STI571, Glivec (R)) had been started 9 months before. She had achieved complete hematological remission within 8 weeks, but not a cytogenetic response.


METHODS
Elevated WBC count (26.7/nl) with a differential displaying typical features of acceleration in bone marrow aspirate confirmed CML in accelerated phase. Sequencing of the ATP binding site of the BCR-ABL gene, which - at protein level - is the target for imatinib, revealed the clonal selection of cells harboring a point mutation leading to the exchange of amino acid 253 from tyrosine to histidine. This was considered to be the cause of resistance to imatinib.


METHODS
Dose increase of imatinib up to 600 mg daily and administration of cytarabine did not overcome resistance. Imatinib therapy was discontinued; hematologic remission was induced by oral therapy with hydroxyurea and mercaptopurine. In the course of the following 6 months a gradual decrease of the resistant clone from 100 % down to lower than the detection limit of the method was demonstrated.


CONCLUSIONS
Clonal mutations are often the cause of resistance to imatinib therapy. They can be detected by sequencing of the ATP binding site of BCR-ABL in specialized laboratories. This case shows that discontinuation of imatinib therapy can significantly reduce the mutated (resistant) clone and thereby restore sensitivity to imatinib.
Müller
M C
MC
III. Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim. mueller@uni-hd.de
Lahaye
T
T
Hochhaus
A
A
D019943:Amino Acid Substitution / Q000235:genetics; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides; D002999:Clone Cells / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006639:Histidine / Q000235:genetics; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D015122:Mercaptopurine / Q000008:administration & dosage; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000187:drug effects / Q000235:genetics; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D017354:Point Mutation / Q000235:genetics*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012641:Selection, Genetic; D014443:Tyrosine / Q000235:genetics
D000970:Antineoplastic Agents; D001549:Benzamides; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; C406060:abl-bcr fusion protein, human; D014443:Tyrosine; D006639:Histidine; D000068877:Imatinib Mesylate; D015122:Mercaptopurine; D016044:Fusion Proteins, bcr-abl; D006918:Hydroxyurea