Evolution of therapeutic approaches in patients with chronic myeloid leukemia and T315I mutation

Background. The T315I mutation in BCR::ABL1 kinase domain determines the resistance of leukemia cells to tyrosine kinase inhibitors (TKIs) – imatinib and secondgeneration TKIs – in patients with chronic myeloid leukemia (CML). The impact of new T315I-targeted approaches on treatment outcomes is being actively studied.

Aim. To evaluate the clinical characteristics and therapy approaches in chronic-phase CML patients with T315I mutation in clinical practice. An additional objective is to evaluate overall survival (OS) by considering the therapy provided.

Materials and methods. The non-interventional retrospective multicenter study included 88 adult patients with chronic-phase CML and the T315I mutation identified between January 2015 and November 2023, with a follow-up period of ≥3 months from 6 hematology clinics in Russia. T315I-targeted therapy refers to TKIs registered in Russia with clinically proven efficacy against the T315I mutation – ponatinib and asciminib, as well as allogeneic hematopoietic stem cell transplantation.

Results. The median time from diagnosis to T315I mutation detection was 47 (6–192) months. Patients with T315I received 1–6 lines of therapy; most often, the T315I mutation was detected after 2–3 lines of therapy. After T315I mutation detection, 68 (77 %) patients received T315I-targeted therapy. The probability of receiving T315I-targeted therapy was 51; 61; 74 and 84 % at 6; 12; 24 and 36 months after T315I mutation detection, respectively, and was statistically significantly higher in patients with a detected mutation in 2018–2019 and 2020–2023 compared to 2015–2017 (p = 0.0256). The time to the first T315I-targeted approach was significantly reduced by year of mutation detection (p = 0.0002); the median time to T315I-targeted therapy over these periods was reduced from 17.8 to 2 months. Allogeneic hematopoietic stem cell transplantation was performed in 22 (25 %) of 88 patients: in 9 (41 %) – as the 1st T315I-targeted therapy; in 13 (59 %) patients, asciminib or ponatinib were used as bridge-therapy before it. Overall survival in the total group (n = 88) was 95; 79 and 68 % at 12; 36 and 60 months, respectively. The OS of patients with identified T315I mutation after 2020 was higher than in 2015–2017 and 2018–2019 periods, but the differences were not statistically significant (p = 0.1625).

Conclusion. Selection of resistant clones with the T315I mutation can occur after any line of 1st–2nd generation TKI therapy. Improved availability of T315I-targeted therapy in Russia has been demonstrated depending on the period of T315I mutation detection. When the time to T315I-targeted therapy was reduced, a trend towards improved OS was observed. The differences in OS estimates identified may be related to selection factors given the retrospective nature of the study. Detailed prospective studies are required to evaluate the efficacy of different T315Idirected therapy protocols.

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