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3025 Real-World Experience of Asciminib: Factors Associated with Response

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality), drug development, Therapies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Andrew J. Innes, PhD, FRCPath, MRCP1,2*, Chloe Hayden, BSc3*, Victoria Orovboni4*, David Rees5*, Simone Claudiani, MD, PhD1,2*, Fiona Fernando, MBChB1,2*, Afzal Khan1,2*, Jennifer Byrne, PhD, FRCPath6*, Paolo Gallipoli, MD7,8, Sebastian Francis, MBChB, FRCPath, MD9*, Mhairi Copland, PhD, MBBChir, FRCP, FRCPath10, Gillian Horne10*, Manoj Raghavan, MBBS, PhD, MRCP, FRCPath11*, Claire Arnold, MD12*, Angela Collins, MBBS, BSc13*, Tanya Cranfield, MD14*, Nicholas Cunningham12*, Akila Danga, MBBS15*, Peter Forsyth16*, Rebecca Frewin17*, Paula Garland18*, Guy Hannah19*, Sandra Hassan20*, Brian Huntly, MB ChB, FRCPath, FMedSci, PhD21, Jissan Husain22*, Sudhakaran Makkuni23*, Kate Rothwell24*, Letizia Foroni, MD, PhD25*, Jane F. Apperley, FRCP, FRCPath, MB1,2 and Dragana Milojkovic, FRCPath, PhD1,2*

1Centre for Haematology, Faculty of Medicine, Imperial College London, London, United Kingdom
2Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
3North West London Pathology, Imperial College Healthcare NHS Trust, London, United Kingdom
4North West London Pathology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
5Medical School, Faculty of Medicine, Imperial College London, London, United Kingdom
6Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, ENG, United Kingdom
7University of Cambridge, London, United Kingdom
8Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
9Haematology Department, Sheffield Teaching Hospitals NHS trust, Sheffield, United Kingdom
10Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
11Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom
12Belfast City Hospital, Belfast, United Kingdom
13Norfolk and Norwich University Hospital, Norwich, United Kingdom
14Department of Haematology, Queen Alexandra Hospital, Portsmouth, ENG, United Kingdom
15The Hillingdon Hospital, London, United Kingdom
16Raigmore Hospial, NHS Highland, Inverness, CA, United Kingdom
17Department of Haematology, Gloucestershire Royal Hospital, Gloucester, United Kingdom
18Princess Royal University Hospital, London, United Kingdom
19Kings College Hospital, London, United Kingdom
20Queens Hospital, Romford, United Kingdom
21Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, ENG, United Kingdom
22Ashford and St Peter's Hospitals NHS Foundation Trust, Chertsey, United Kingdom
23Mid and South Essex NHS Foundation Trust, Basildon, United Kingdom
24Calderdale and Huddersfield NHS Trust, Huddersfield, United Kingdom
25Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

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.

Disclosures: Innes: Incyte: Speakers Bureau. Byrne: Novartis: Honoraria, Speakers Bureau. Copland: Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cyclacel Ltd: Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hannah: Pfizer: Speakers Bureau; Novartis: Other: Advisory board, Speakers Bureau. Rothwell: Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Other: registration sponsorship. Apperley: Pfizer: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Milojkovic: Novartis: Honoraria; Pfizer Inc.: Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Incyte: Honoraria, Research Funding.

*signifies non-member of ASH