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.

Citation

Innes, A. J., Hayden, C., Orovboni, V., Rees, D., Claudiani, S., Fernando, F., Khan, A., Byrne, J., Gallipoli, P., Francis, S., Copland, M., Horne, G., Raghavan, M., Arnold, C., Collins, A., Cranfield, T., Cunningham, N., Danga, A., Forsyth, P., Frewin, R., Garland, P., Hannah, G., Hassan, S., Huntly, B. J. P., Husain, J., Makkuni, S., Rothwell, K., Foroni, L., Apperley, J. F., & Milojkovic, D. (2022). Real-world experience of asciminib: Factors associated with response. Blood, 140(Supplement 1), 6796–6797. https://doi.org/10.1182/blood-2022-165501

DOI

10.1182/blood-2022-165501

URI

https://hdl.handle.net/20.500.14709/673