Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy.
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Embargo End Date
ICR Authors
Authors
Innes, AJ
Hayden, C
Orovboni, V
Claudiani, S
Fernando, F
Khan, A
Rees, D
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
Avenoso, D
Hassan, S
Huntly, BJP
Husain, J
Makkuni, S
Rothwell, K
Khorashad, J
Apperley, JF
Milojkovic, D
Hayden, C
Orovboni, V
Claudiani, S
Fernando, F
Khan, A
Rees, D
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
Avenoso, D
Hassan, S
Huntly, BJP
Husain, J
Makkuni, S
Rothwell, K
Khorashad, J
Apperley, JF
Milojkovic, D
Document Type
Journal Article
Date
2024-11-01
Date Accepted
2024-09-05
Abstract
Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.
Citation
Leukemia, 2024, 38 (11), pp. 2443 - 2455
Source Title
Leukemia
Publisher
SPRINGERNATURE
ISSN
0887-6924
eISSN
1476-5551
Collections
Research Team
Translational Genomics