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

Abstract

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.

• Authors: Gabriel Etienne, Stéphanie Dulucq, Françoise Huguet, Anna Schmitt, Axelle Lascaux, Sandrine Hayette, Marie-Pierre Fort, Pierre Sujobert, Fontanet Bijou, Stéphane Morisset, Suzanne Tavitian, Audrey Bidet, Beatrice Turcq, Fanny Robbesyn, Claudine Chollet, Francis Belloc, Françoise Durrieu, François-Xavier Mahon, Franck E Nicolini
• Journal: Cancer medicine (Cancer Med) Vol. 8 Issue 11 Pg. 5173-5182 (Sep 2019) ISSN: 2045-7634 [Electronic] United States
• PMID: 31350815 (Publication Type: Journal Article)
• Copyright: © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

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

Topics

• 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, genetics, mortality)
• Male
• Middle Aged
• Mutation
• Mutation Rate
• Prognosis
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Survival Analysis
• Young Adult