Results of asciminib therapy as part of managed access program in patients with chronic myeloid leukemia with T315I mutation

Background. The most common mechanism of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is point mutations in the BCR::ABL1 gene. Of particular importance is the T315I mutation, which causes insensitivity of leukemia cells to all ATp-competitive TKIs: imatinib and 2^nd generation TKIs. Asciminib is the first drug of the STAMp inhibitor class that specifically interacts with the myristoyl-binding active site of the bCR::AbL1 molecule. In a phase I clinical trial, asciminib at a dose of 200 mg twice daily showed efficacy in the treatment of chronic phase (Cp) CML patients with T315I mutation. There are no data on the efficacy of asciminib therapy in patients with T315I mutation and additional chromosomal abnormalities (ACA) or advanced disease. The Russian part of the managed access program (MAp) has accumulated its own experience of using asciminib in CML patients with T315I mutation, including those with ACA and history of progression to the acceleration phase / blast crisis.

Aim. To analyze the 3-year results of asciminib therapy as part of MAp in CML patients with T315I mutation.

Materials and methods. In the MAp program to asciminib between October 2019 and January 2022 were included 26 CML patients with T315I mutation who were ineffective or intolerant to ATp-competitive TKIs therapy. Asciminib was administered at a dose of 200 mg twice daily. The efficacy and tolerability of asciminib therapy were assessed in accordance with national clinical guidelines and the 2020 European LeukemiaNet guidelines.

At the time of asciminib therapy initiation, 19 (73 %) patients had Cp. four (15 %) patients had a history of acceleration phase (n = 3) and blast crisis (n = 1). four (15 %) patients had ACA immediately before the start of asciminib therapy, including a patient with a history of blast crisis. To analyze the asciminib therapy results, patients with a history of progression and / or ACA were combined into one group: 2Cp / Cp ^ACA+ (n = 7). More than half of patients (54 %) had previously received ponatinib.

Results. The median duration of asciminib therapy was 31.6 (3.3–50) months. Of the 26 patients, 25 (96 %) are alive, one patient in the 2Cp / Cp ^ACA+ group died from progression of CML to myeloid blast crisis. In the total group, 14 patients (54 %) continued asciminib therapy, 12 (46 %) – discontinued treatment: most patients due to treatment failure (n = 9 (75 %)). In 3 patients (25 %), the reason for treatment discontinuation was allogeneic hematopoietic stem cell transplantation (all three achieved a complete cytogenetic response with asciminib therapy). No patients discontinued treatment due to toxicity. No new mutations, including asciminib resistance mutations, were detected during therapy.

Progression-free survival and survival without therapy discontinuation at 3 years of follow-up in the total group were 92 and 58 %, respectively. when analyzing the Cp and 2Cp / Cp ^ACA+ groups, progression-free survival at 3 years of asciminib therapy was comparable. There was a trend toward decreased survival without therapy discontinuation in 2Cp / Cp ^ACA+ group (28 %) versus Cp group (63 %) (p = 0.0856).

The probability of achieving a complete cytogenetic response / molecular response MR2 in all patients with T315I mutation by the 3^rd year of asciminib treatment was 59 %, in the Cp and 2Cp / Cp ^ACA+ groups – 47 and 80 %, respectively; no significant difference were found between the groups (p = 0.08). The probability of achieving a major molecular response (MMR) in the total group by the 3^rd year of asciminib treatment was 42 %; the probability of achieving MMR in the Cp and 2Cp / Cp ^ACA+ groups was 44 and 33 %, respectively; no significant difference were found between the groups (p = 0.6).

In univariate analysis, significant favorable factors for achieving MMR were the molecular response at the start of asciminib therapy ≤10 %, the best molecular response in prior TKI therapy ≤1 %, and the absence of prior ponatinib treatment. In multivariate analysis, a history of ponatinib therapy was an independent significant factor for achieving MMR with asciminib therapy (p = 0.02; hazard ratio 12.08).

Conclusion. The therapy results of patients in initially unfavorable 2Cp / Cp ^ACA+ group were comparable with Cp group in terms of both survival rates and probability of achieving responses. However, given the small number of patients in our cohort, the asciminib efficacy in patients with T315I⁺ CML with ACA and a history of progression requires further investigation. A factor that significantly reduced the probability of achieving MMR during asciminib treatment was a history of ponatinib therapy.

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