ISSN 1866-8836
Клеточная терапия и трансплантация

CML patients with T315I mutation: characteristics and outcomes of the treatment

Julia Yu. Vlasova, Elena V. Morozova, Maria V. Barabanshchikova, Tatyana L. Gindina, Ildar M. Barhatov, Alexandr L. Alyanskiy, Elena I. Darskaya, Ivan S. Moiseev, Boris V. Afanasyev
R. M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, First St. Petersburg State I. P. Pavlov Medical University, St. Petersburg

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Cellular Therapy and Transplantation (CTT)
Volume 7, Number 3
Contents 

Summary

Background

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.

Aims

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.

Results

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).

Conclusion

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.

Keywords

Chronic myeloid leukemia, T315I mutation, allo-BMT, drug resistance.


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