Julia Yu. Vlasova1, Elena V. Morozova1, Oleg A. Shukhov2, Maria V. Barabanshchikova1, Tatiana L. Gindina1, Ildar M. Barhatov1, Irina S. Martynkevich3, Vasily A. Shuvaev3, Anna G. Turkina2, Boris V. Afanasyev1
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Cellular Therapy and Transplantation (CTT)
Volume 6, Number 3
Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in he BCR-ABL kinase domain, including
the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors except of ponatinib. The aim of present work was to evaluate the results of different treatment modalities in CML patients with T315I mutation.
Patients and methods
Retrospective analysis of 53 BCR-ABLT315I –positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo-HSCT) was made in 16 pts, whereas 37 pts received only pharmacological therapy (21 pts received TKI as monotherapy or in combination with other drugs, and other 16 pts received hydroxyurea, interferon- α or chemotherapy). At the time of T315I detection, 29 (55%) pts were in CP, 19 (36%) pts had AP and 5 (9%) pts were in BC. Median (Me) age at the time of mutation detected was 47 years (15-76) (38 years in HSCT-group). In allo-HSCT group 11 (69%) pts had unrelated donors, 11 (69%) pts received more than 2 lines TKIs before HSCT, 2 (12%) pts were in BC at the time of HSCT, 5(31.2%) pts were in AP, 7(43.7%) pts were in CP≥2. The number of points on EBMT scale: 3-4 points – 12(75%) pts, 5-7 points – 4(25%) pts. Conditioning regimen in 13 (81%) pts had reduced intensity. Me time to HSCT after T315I detection was 10 months (1-38). 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.
Me follow-up time after T315I detection was 21 months (1-100). 5-years OS in whole group was 42% (Fig. 1A). According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All pts in BC (n=5, 2 in HSCT group and 3 in non-HSCT group) died within first year after T315I indication wherein Me survival time was 1,3 month (Fig. 1B). 5-years OS in non-HSCT group (n=37) was 42% with Me survival time 2,8 years. 5-years OS after allo-HSCT (n=16) was 37% with Me survival time 5 months (Fig. 1C). All living patients after allo-HSCT are in deep molecular response. There was no significant difference in 5-years OS between TKI (n=21) and non-TKI (n=16) pharmacological therapy (non-HSCT) groups (42% and 47% respectively, p=0,53) (Fig. 1D).
Detection of T315I mutation in TKI-resistant patients is extremely unfavorable factor for survival, especially in the advanced phase CML, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo-HSCT can be a potential option for this group of patients in case of good selection taking into consideration transplant risk, especially for patients in CP ≥2.
CML, T315I mutation, allo BMT, therapy resistance.