P673: asciminib managment in chronic myeloid leukemia (cml) patients with t315i mutation.

Background: Asciminib mechanism of action differs from other tyrosine kinase inhibitors (TKIs) for it is a Specifically Targeting the ABL Myristoyl Pocket (STAMP) ABL kinase inhibitor, that has a potential efficacy against BCR::ABL1 clones with ATP-binding site mutations, including T315I. In clinical trials in patients (pts) with Ph-positive chronic myeloid leukemia (CML) with T315I mutation, failing other TKIs, it has shown an efficacy and a good safety profile. Asciminib is in use in clinical practice in Russia in Managed Access Program (MAP) supported by Novartis Aims: To present the updated results of the asciminib use in CML patients with the T315I mutation under the MAP in 3 centers of Russia. Methods: In total 82 pts received asciminib in MAP with doses 40/200 mg BID. Twenty-nine were in a 200 mg BID dose group, the data of 24 of them are presented, while 5 pts, who undergone bone marrow transplantation, were excluded from the analysis. Twenty-three pts had T315 mutation, one patient had F317L (T315I detected, but later not confirmed). All pts were adult (>18 years) with Ph-positive CML in chronic phase (CP): 3 were in a second CP after an accelerated phase and 1 – after a blast crisis, all of them had no alternative therapeutic options. Response monitoring and toxicity control were performed according to the MAP treatment plan. Complete cytogenetic response (CCyR - corresponded to BCR::ABL1 ≤1% or MR2), major molecular response (MMR) and deep molecular response (MR4) were assessed by cumulative incident function (CIF) with Gray’s test for comparison responses in subgroups. Survival analysis was performed by Kaplan-Meier method. Results: Median (Me) age at asciminib start was 49 years (range 32-71), the female proportion was 63%. Me of CML duration before asciminib was 6,9 years (range 1-34). All pts received ≥2 prior TKIs, 45% had ≥ 4 prior TKIs. With the Me follow-up period of 21 months (range 6-39); 5 (21%) pts discontinued asciminib (4 due to resistance, 1 due to a clinician decision in achieved MR4). Nine pts had additional chromosomal abnormalities (ACAs) and/or additional BCR::ABL1 mutations in an anamnesis; their responses are presented in a table 1. Six (25%) of 24 pts had ACAs before asciminib, 4 of them achieved MMR, and one of them (№1) was resistant and lost CCyR. Six pts had additional BCR::ABL1 mutations in an anamnesis, 5 of them achieved MMR and 1 pt (№9) was resistant to therapy. Two-years overall survival at 24 months was 100%. Survival rate without treatment discontinuation was 74%. CIF of CCyR, MMR and MR4 at 24 month was 57%, 57% and 34%, respectively. Thirteen (54%) pts were ponatinib-pretreated, and CIF of MMR in ponatinib-naive pts compared to ponatinib-pretreated pts was significantly higher: 90% vs. 25% (p=0.001). In total 4 pts lost CCyR or MMR (table 1). Thirteen (54%) pts experienced adverse events (AEs) of any grade and 4 (17%) had AEs of grade 3 (neutropenia, hypercholesterinemia). No one discontinued treatment due to toxicity. Summary/Conclusion: Highly pre-treated CML pts with T315I mutation are able to achieve a response with asciminib 200 mg BID, especially in ponatinib-naive group. In our pts a safety profile was good with no evidence of severe toxicity. Asciminib shows effectiveness in highly resistant pts with T315I mutation with/without other genetic events (combined mutations, ACAs), though some of them still a challenge for clinicians. Overcoming the resistance by adding other therapy should be investigated.Keywords: Mutation status, BCR::ABL, Asciminib, Chronic myeloid leukemia