[Resistance to tumor specific therapy with imatinib by clonal selection of mutated cells]

Dtsch Med Wochenschr. 2002 Oct 18;127(42):2205-7. doi: 10.1055/s-2002-34939.
[Article in German]


History and clinical findings: 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.

Investigations: 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.

Treatment and course: 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.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Substitution / genetics
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benzamides
  • Clone Cells / drug effects*
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Fusion Proteins, bcr-abl*
  • Histidine / genetics
  • Humans
  • Hydroxyurea / administration & dosage
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Mercaptopurine / administration & dosage
  • Middle Aged
  • Oncogene Proteins, Fusion / drug effects
  • Oncogene Proteins, Fusion / genetics
  • Piperazines / adverse effects
  • Piperazines / therapeutic use*
  • Point Mutation / genetics*
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use*
  • Selection, Genetic*
  • Tyrosine / genetics


  • Antineoplastic Agents
  • Benzamides
  • Oncogene Proteins, Fusion
  • Piperazines
  • Pyrimidines
  • abl-bcr fusion protein, human
  • Tyrosine
  • Histidine
  • Imatinib Mesylate
  • Mercaptopurine
  • Fusion Proteins, bcr-abl
  • Hydroxyurea