The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis

Abstract

The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact of this mutation on survival in early stages of disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64 patients with chronic phase chronic myelogenous leukemia harboring a T315I mutation and resistant to imatinib mesylate was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according to age at diagnosis, interval between disease diagnosis and start of imatinib treatment, and duration of imatinib therapy. Kaplan-Meier survival analyses demonstrated the significant negative impact of the presence of the T315I mutation on overall survival (since imatinib-resistance: 48.4 months for T315I(+) patients versus not reached for T315I(-) ones; P=0.006) and failure-free survival (since imatinib-resistance: 34.7 months for T315I(+) patients versus not reached for T315I(-) patients; P=0.003). In addition, Cox proportional hazard models adjusted on overall survival demonstrated the negative influence of the T315I mutation (P=0.02, HR=2.54). These results confirm early assumptions concerning the poor prognosis of chronic phase chronic myelogenous leukemia patients with the T315I mutation who are not eligible for allogeneic transplantation, and demonstrate the need for more therapeutic options.

Figure 1.

Overall survival of chronic phase CML patients resistant to IM, since IM-initiation (A), since IM-resistance (B), and since TKI2 initiation (C) in months according to T315I status (dashed line patients with T315I mutation, plain line patients without T315I mutation). N: number of patiens.

Figure 2.

Failure-free survival of chronic phase CML patients resistant to IM, since IM-initiation (A), since IM-resistance (B), and since TKI2 initiation (C) in months according to T315I status (dashed line patients with T315I mutation, plain line patients without T315I mutation). N: number of patients.

Figure 3.

Failure-free survival of CP CML patients resistant to IM harboring a T315I mutation, in months, according to the time of detection of the mutation before (dotted line) of after (dashed line) exposure to the TKI2. N: number of patients.

Figure 4.

(A) Forest plot (log scale) showing the results of the multivariate analysis with Cox model, adjusted on overall survival since IM-resistance for the whole population of CP CML patients resistant to IM studied here. Horizontal bars represent the 95% confidence intervals. P values for each variable are indicated, the hazard ratio (HR) is stated for the each variable “Hazard Ratios” and numbers in brackets indicate the exact 95% confidence intervals. (B) Forest plot (log scale) showing the results of the multivariate analysis with Cox model adjusted on overall survival since IM-resistance for the T315I⁺ population of CP CML studied here. Horizontal bars represent the 95% confidence intervals. P values for each variable are indicated. The hazard ratio (HR) is stated for each variable and the numbers in brackets are the exact 95% confidence intervals.