Real-World Experience of Asciminib: Factors Associated with Response

Background – Asciminib is an allosteric BCR::ABL1 inhibitor with proven efficacy in multiply treated CML. Prior to licensing, the drug was available in the UK through a Novartis supported managed access program since 2017. Here we report our national real-world experience of asciminib, with a focus on identifying factors associated with response.

Patient cohort – Fifty-three patients from 14 centres were included. The median age was 57 [23-88] years, and 29 (55%) were male. The median time from diagnosis to asciminib treatment was 69 [11-386] months, and the median number of prior tyrosine kinase inhibitors was 4 [2-5], with 33 (62%) of patients having received ponatinib. The reason for stopping the last TKI was intolerance in 33 (62%) and resistance in 20 (38%) patients. Baseline BCR:ABL1 PCRs were greater than 10% in 21 (40%) patients, 1-10% in 13 (25%), 0.1-0.999% in 8 (15%), less than 0.1% in 9 (17%) and unknown in 2 (4%). A history of tyrosine kinase domain mutations (TKDM) was present in 22 (42%) patients. T315I was most common (n=13, 25%) but non-T315I mutations were seen either alone (n=9, 17%) or in combination with a T315I mutation (n=2, 4%). Medical comorbidities were common in the group, with 30 (57%) patients having at least one cardiovascular or vascular disorder (hypertension n=18 (34%), peripheral vascular disease n=10 (19%), ischaemic heart disease n=8 (15%), atrial fibrillation n=6 (11%), stroke or transient ischaemic attack n=4 (8%)). Nine (17%) patients had chronic kidney disease and 4 (8%) had diabetes.

Results – Thirty-four patients (64%) continued on treatment at the time of reporting, while 9 (17%) had stopped for resistance and 7 (13%) for intolerance. One patient had stopped for a treatment free remission attempt, one for pregnancy and one for poor compliance. The median treatment durations were 14.4 [3-51] months for those still on treatment, and 5 [1-24] and 2 [1-26] months for those stopping for resistance and intolerance, respectively.

Cytogenetic response (CCyR; BCR::ABL1 PCR <1% IS) or better was achieved in 32 (58%) patients, and 29 (52%) achieved major molecular response (MMR; BCR::ABL1 PCR <0.1% IS) or better. Higher rates of MMR were seen in patients who has previously achieved a CCyR with any prior therapy (69% vs 25%, p<0.01), stopped their last TKI for intolerance rather than resistance (70% vs 30%, p<0.01), and in those with a baseline BCR::ABL1 PCR at the initiation of asciminib of less than 10% (84% vs 17%, p<0.01). While no difference was seen in the rate of MMR between those harboring a T315I mutation or not (54% vs 55%, p=0.68), a history of a non-T315I-TKDM was associated with a lower rate of MMR (27% vs 62%, p=0.014). No significant differences were seen between those who had previously received ponatinib or not (48% vs 65%, p=0.450), although those with ponatinib resistance, rather than intolerance, had a tendency toward a lower rate of MMR (33% vs 65%, p=0.11).

While asciminib was generally well tolerated, haematological toxicity of any grade was seen in 18 (33%) patients, with grade 3-4 in 10 (18%). The commonest non-haematological toxicities were fatigue, fluid retention, rash, nausea, insomnia, bone pain and deranged liver function tests. One patient had recurrence of a pleural effusion thought to be related to treatment. One patient suffered a myocardial infarction, and one a recurrence of a DVT whilst on treatment but causative relationships to the drug were unclear.

Discussion – Asciminib is a well-tolerated therapy for CML in a previously heavily treated group with multiple comorbidities. Prior responses to therapy appear an important predictor of response to asciminib, with those resistant to the last TKI, and those never achieving a CCyR on any prior therapy showing a lower rate of MMR. While the presence of T315I mutations does not appear to significantly impact on the response to asciminib, the presence of non-T315I mutations is associated with a lower rate of MMR. Importantly the standard dosing regimen in patients with T315I mutations is fivefold higher but whether this explains the discrepant responses to T315I and non-T315I mutations requires further investigation.