Aim. To assess the efficacy and tolerability of asciminib in chronic myeloid leukemia (CML) patients after failure of ≥ 2 lines of tyrosine kinase inhibitors (TKIs) therapy under the МАР (Managed Access Program, NCT04360005) in Russia. Materials & Methods. The study enrolled 68 patients with Ph-positive CML chronic phase (CF), over 18 years of age, after failure of ≥ 2 lines of TKI therapy. The analysis was conducted on data from 50 patients who were followed-up for at least 3 months and did not undergo allo-HSCT. Dosing regimens were prescribed depending on T315I mutation. Asciminib 200 mg per os was administered twice a day to 20 patients with this mutation, and asciminib 40 mg per os was administered twice a day to 30 patients without this mutation. By the time of admission into the MAP, there were 42 (82 %) CF CML patients as well as 8 patients with second CF after accelerated phase (AF, n = 7) and myeloid blast crisis (BC, n = 1). None of them could be treated with any therapeutic alternative. 92 % of patients had received ≥ 3 lines of prior TKI therapy. Overall survival (OS) and discontinuation-free survival were estimated by the Kaplan-Meier method. A cumulative incidence function (CIF) was used to calculate the probability of achieving response. Multivariate analysis was based on Cox regression model. Results. The median asciminib treatment duration was 11 months (range 4–30 months). The probable 2-year OS was 96 %. After 12 and 24 months, discontinuation-free survival was 92 % and 70 %, respectively. On asciminib therapy, complete cytogenetic (CCyR/МR2), major molecular (MMR), and deep molecular (MR4) responses were achieved in 17 (42 %), 14 (30 %), and 9 (19 %) patients who had not responded to prior treatment at the point of enrollment. After completing the 12- and 24-month therapy, the probability of CCyR/МR2 achievement was 44 % and 62 %, that of MMR achievement was 32 % and 40 %, and that of MR4 achievement was 26 % and 37 %, respectively. The patients treated with different doses did not significantly differ in achieving either CCyR/МR2 or MMR. By multivariate analysis, the independently significant factor impacting the probability of achieving MMR on asciminib treatment was the best MR (BCR::ABL1 < 1 % vs. 1–10 % vs. ≥ 10 %) after prior TKI therapy (hazard ratio 7.5873; p = 0.0072). In 22 (44 %) patients, adverse events (AEs) of all grades were observed, and 8 (16 %) patients showed AEs grade 3/4 (predominantly thrombocythemia and neutropenia). None of the patients discontinued asciminib treatment due to AEs. Conclusion. Asciminib demonstrated highly promising efficacy in previously TKI-treated patients with T315I mutation (200 mg BID) and without it (40 mg BID). Asciminib can be regarded as therapeutic option after failure of other TKIs. Different doses of asciminib were equally well tolerated, which makes it applicable for patients with intolerance to other TKIs and also provides ground for considering dose increases in non-responders. Good prospects are also expected for studying asciminib efficacy at earlier treatment stages (in first or second lines) as well as in combination with ATP-binding TKIs in CML patients with insufficient response to TKI treatment.
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