CML patients with T315I mutation: characteristics and outcomes of the treatment
Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in the BCR-ABL kinase domain, including the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors except ponatinib.
To evaluate the results of different treatment modalities in CML patients with T315I mutation.
Patients and methods
A retrospective analysis of 79 BCR-ABLT315I –positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo-HSCT) was made in 20 pts, 59 pts received only pharmacological therapy (41 pts received TKI as monotherapy or in combination with other drugs, 10- α-IF, other 8 pts received hydroxyurea or chemotherapy). At the time of allo-HSCT 6 pts were in CP 1, 7- CP≥2, 6 pts had AP and 3 pts were in BC. Median age at the time of mutation detected was 42 years (13-75) (38 years in HSCT-group). In allo-HSCT group 13 pts had unrelated donors, 13(65%) pts received more than 2 lines TKIs before HSCT. The EBMT scores were as follows: 3-4 points, 16 pts; 5-7 points, 6 pts. Conditioning regimen in 13 (70%) pts had reduced intensity. Median time to HSCT after T315I detection was 7 months (0-72). The BCR-ABL mutation analysis was performed by Sanger sequencing. Overall survival (OS) was estimated by Kaplan-Meier method with log-rank test for comparison between groups. Cox regression was used for multivariate survival analysis that included next covariates: age, phase on the time of mutation detection, performance of allo-HSCT, time to T315I detection from TKI start.
Median follow-up time after T315I detection was 21 months (1-100). 5-years OS in whole group was 42%. According to multivariate analysis, only CML phase at the time of mutation detection did significantly affect survival in the entire group. All the pts in BC (n=7), 3 in HSCT group, and 4, in non-HSCT group, died within first year after the T315I detection, whereas the median survival time was 1.3 months. The 5-year OS in non-HSCT group (n=59) comprised 42%, with median survival time of 2.8 years. The 5-year OS after allo-HSCT (n=20) was 37%, with median survival time of 5 months. However, 7 pts lived for more than 2 years after allo-HSCT; 2 patients survived for more than 6 years. All living patients after allo-HSCT are in deep molecular response. The patients in 2nd chronic phase have OS rate of 47% (CI 95% 29-53%), p = 0.46. There was no significant difference in 5-year OS between the non-HSCT groups with TKI (n=41) and non-TKI (n=18) therapy (42% and 47%, respectively, p=0.53). the The 5-year overall survival (OS) among the patients who received α-interferon combined with other drugs (n=10) was higher than in the group that was not treated with interferon (n = 49), 72% vs 45%, respectively (p = 0.21).
Presence of T315I mutation in TKI-resistant patients is extremely unfavorable factor for survival, and it is a major reason for switching to ponatinib or other new potentially available drugs, if possible. Allo-HSCT is an effective method of treatment for this group of patients in case of good selection, however, taking transplant risks into consideration, especially for patients in CP ≥2 . Administration of pharmacological therapy in the 1st CP is an effective method of treatment, which allows to control the disease for a long time.
Chronic myeloid leukemia, T315I mutation, allo-BMT, drug resistance.