Incidence and outcome of BCR-ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors

Cancer Med. 2019 Sep;8(11):5173-5182. doi: 10.1002/cam4.2410. Epub 2019 Jul 27.


Purpose: To assess the incidence of BCR-ABL kinase domain (KD) mutation detection and its prognostic significance in chronic phase chronic myeloid leukemia (CP-CML) patients treated with tyrosine kinase inhibitors (TKIs).

Patients and methods: We analyzed characteristics and outcome of 253 CP-CML patients who had at least one mutation analysis performed using direct sequencing. Of them, 187 patients were early CP (ECP) and 66 were late CP late chronic phase (LCP) and 88% were treated with Imatinib as first-line TKI.

Results: Overall, 80 (32%) patients harbored BCR-ABL KD mutations. A BCR-ABL KD mutation was identified in 57% of patients, who progressed to accelerated or blastic phases (AP-BP), and 47%, 29%, 35%, 16% and 26% in patients in CP-CML at the time of mutation analysis who lost a complete hematologic response, failed to achieve or loss of a prior complete cytogenetic and major molecular response, respectively. Overall survival and cumulative incidence of CML-related death were significantly correlated with the disease phase whatever the absence or presence of a mutation was and for the latter the mutation subgroup (T315I vs P-loop vs non-T315I non-P-loop) (P<.001). Considering patients who were in CP at the time of mutation analysis, LCP mutated patients had a significantly worse outcome than ECP-mutated patients despite a lower incidence of T315I and P-loop mutations (P<.001). With a median follow-up from mutation analysis to last follow-up of 5 years, T315I and P-loop mutations were not associated with a worse outcome in ECP patients (P = .817).

Conclusion: Our results suggest that early mutation detection together with accessibility to 2nd and 3rd generation TKIs have reversed the worst outcome associated with BCR-ABL KD mutations whatever the mutation subgroup in CP-CML patients.

Keywords: BCR-ABL kinase domain mutation; chronic myeloid leukemia; tyrosine kinase inhibitors.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Female
  • Fusion Proteins, bcr-abl / genetics*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / mortality*
  • Male
  • Middle Aged
  • Mutation Rate
  • Mutation*
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Survival Analysis
  • Young Adult


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Fusion Proteins, bcr-abl