The Updated Results of Asciminib Managed-Access Program (MAP) in Patients with Chronic Myeloid Leukemia in Russia

Background: Therapy choice in chronic myeloid leukemia (CML) patients (pts) with ≥2 lines of tyrosine kinase inhibitors (TKIs) failure or in pts with T315I mutationis a relevant problem. Efficacy and good tolerability of a first-in-class BCR::ABL1 allosteric inhibitor Asciminib (ASC) in chronic phase (CP) CML pts were confirmed in clinical trials. The out-study world data of ASC use in Managed Access Program (MAP) is of particular interest.

Aim: to report the updated results of the ASC use within MAP in 3 clinical centers of Russia.

Methods : Adult (≥18 years) CML pts with the lack of efficacy or intolerance to ≥2 lines of TKIs or T315I-positive pts after ≥1 prior TKI were included into a MAP. Inclusion criteria for our analysis were: CML-CP, ASC therapy for >3 months (mo). Two dosing regimen were used: 40 mg BID in BCR::ABL1 ^T315I-negative pts (40BID group) and 200 mg BID in BCR::ABL1 ^T315I-positive pts (200BID group). Complete cytogenetic response (CCyR, equivalent of MR2 or BCR::ABL1≤1%), major molecular response (MMR) and deep molecular response (MR4) achievement was assessed by cumulative incidence function (CIF) with Gray's test for comparison. Survival analysis was performed by Kaplan-Meier method according to “intention-to-treat” principle.

Results: A total 82 pts received ASC in the MAP, 68 of them met the criteria for analysis (baseline characteristics are in table 1), while 14 were excluded. The median follow-up was 26 mo (range 4-49).

The 2-year overall survival was 93% and 83%, the progression free survival was 90% and 70% in 40BID and 200BID groups, respectively. In 40BID group 17/43 pts discontinued ASC: 2 progressed to AP/BP, 2 - for bone marrow transplantation (BMT), 13 - failure (3 pts died due to CML after ASC discontinuation). In 200BID group 12/25 pts discontinued ASC: 2 developed AP, 3 -BMT, 7 - failure (one pt died).

CIF of CCyR/MMR/MR4 by 24 mo was 58%/68%/19% in 40BID group and 65%/56%/32% in 200BID group. The achieved CCyR was preserved in 93% (14/15) and 77% (10/13) pts in 40BID and 200BID group, respectively. CIF of MMR in ponatinib-naïve pts was higher in both groups than in ponatinib-pretreated pts (picture).

Dose escalation to 80-100 mg BID in 8/43 pts of 40BID group (due to lack of efficacy) resulted in achieving MMR for 2/8 pts with no MMR before escalation. Dose reduction in two groups was done both for adverse events (AEs) grade 3-4 (n=8) and stable MR4,5. In 4 pts (200BID) with no AEs and having a stable MR4,5 for >1 year, no MR4,5 loss was observed after ASC dose reduction to 100 mg BID.

Subclone with emerging a new mutation was detected in 3 pts of 40BID group (A337T, G250A, T315I) while no new mutations were found in 200 mg BID group.

AEs associated with ASC have been identified in 27/43 pts and 13/25 pts in 40BID and 200BID group, respectively, with no significant difference in AE spectrum and frequency. Most common (≥5%) AEs in two groups were: thrombocytopenia (29%), neutropenia (18%), cholesterol high (13%), anemia (6%), skin rash (5%). AEs grade 3-4 were detected in 13 (30%) and 4 (16%) pts in 40BID and 200BID group, respectively, and mostly presented by hematologic/cytopenic AEs (24%). No pt discontinued ASC due to toxicity, no arterial occlusive AEs were observed.

Conclusion: ASC shows effectiveness and good safety profile in pts after prior failure to TKIs and those with T315I mutation. The CIF of any response was higher in ponatinib-naive pts at any dose. Different mutational subclones evolution was observed, including emergence of myristoyl-site mutation in 1 pt. ASC half dose reduction was safe in pts with previous MR4,5 stable response.