TKI rotation-induced persistent deep molecular response in multi-resistant blast crisis of Ph+ CML

Oncotarget. 2017 Apr 4;8(14):23061-23072. doi: 10.18632/oncotarget.15481.


In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions. We therefore switched from ponatinib to bosutinib. During bosutinib, platelet counts recovered. However, after 6 months, BCR-ABL1 mRNA levels increased to > 1%. Therefore, we ´switched back´ to ponatinib, and this was again followed by disappearance of BCR-ABL1 and a decrease in platelets. During the next 2 years, we applied ponatinib and bosutinib in continuous rotation-cycles and added hydroxyurea in order to suppress all sub-clones and to balance between efficacy and potential side effects following the principle of personalized medicine. With this approach the patient remained in complete molecular response and reached normal blood counts and a normal quality of life without vascular or other side effects. In conclusion, TKI rotation is a novel potent approach to suppress multiple resistant sub-clones and to balance between clinical efficacy and side effects in patients with advanced CML. Clinical trials are now warranted to show that TKI-rotation is in general safe and effective in these patients.

Keywords: BCR-ABL1 mutations; CML; drug resistance; nilotinib; ponatinib.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Aniline Compounds / administration & dosage
  • Aniline Compounds / adverse effects
  • Blast Crisis / drug therapy*
  • Blast Crisis / genetics
  • Blast Crisis / pathology
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Drug Substitution / adverse effects*
  • Drug Substitution / methods
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / adverse effects
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Multiple Chronic Conditions / drug therapy
  • Nitriles / administration & dosage
  • Nitriles / adverse effects
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Pyridazines / administration & dosage
  • Pyridazines / adverse effects
  • Quinolines / administration & dosage
  • Quinolines / adverse effects


  • Aniline Compounds
  • Imidazoles
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyridazines
  • Quinolines
  • ponatinib
  • bosutinib