AUTHORS
David Yeung, M.D., Ph.D., Naranie Shanmuganathan, MBBS, DPhil, FRACP, FRCPA2, Andrew P Grigg, MD, MBBS, FRACP, FRCPA3, Yu Jin Kim, PhD4, Susan Branford, PhD5, Jake Shortt, MBBS, FRACP, FRCPA, PhD6, Lynette C.Y. Chee, PhD, MBBS, FRACP, FRCPA7, Ilona Cunningham8, Richard Blennerhassett, MBBS9, Carolyn S. Grove, MBBS, PhD, FRACP, FRCPA10, Nicholas Viiala, BS, MB11, Agnes Yong I, MD, PhD12, Anthony Mills, MBBS, FRACP, FRCPA13, David M. Ross, MBBS, PhD14, Nilu Perera15, Rosemary Anne Harrup, MBBS, FRACP, FRCPA16, Andrew Charles Perkins, MBBS, PhD17, Deepmala Mazumdar18, Mannu Walia Sr19, John Reynolds, PhD20, Peter J. Browett, MBChB, FRACP, FRCPA21, Anthony Schwarer22, Timothy P Hughes, MD, MBBS, FRACP, FRCPA23
AFFILIATIONS
1 Adelaide Medical School, Adelaide, South Australia, Australia, Royal Adelaide Hospital, Adelaide, South Australia, Australia, SAHMRI, Adelaide, South Australia, Australia
2 Adelaide Medical School, Adelaide, South Australia, Australia, Royal Adelaide Hospital, Adelaide, South Australia, Australia, SAHMRI, Adelaide, South Australia, Australia
3 Austin Hospital, Melbourne, Victoria, Australia, University of Melbourne, Melbourne, Victoria, Australia
4 Bayside Health and Monash University, Melbourne, Victoria, Australia
5 Adelaide Medical School, Adelaide, South Australia, Australia, SA Pathology and Centre for Cancer Biology, Adelaide, South Australia, Australia
6 Monash Medical Centre, Melbourne, Victoria, Australia, Monash University, Melbourne, Victoria, Australia
7 Royal Melbourne Hospital and Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia, University of Melbourne, Melbourne, Victoria, Australia
8 Concord Hospital, Sydney, New South Wales, Australia, University of Sydney, Sydney, New South Wales, Australia
9 Central Coast Haematology, Gosford, New South Wales, Australia, Newcastle University, Newcastle, New South Wales, Australia
10 Sir Charles Gardiner Hospital and Pathwest, Perth, Western Australia, Australia, University of Western Australia, Perth, Western Australia, Australia
11 Liverpool Hospital, Sydney, New South Wales, Australia, University of New South Wales, Sydney, New South Wales, Australia
12 Royal Perth Hospital, Perth, Western Australia, Australia, University of Western Australia, Perth, Western Australia, Australia
13 Princess Alexandra Hospital, Brisbane, Queensland, Australia
14 Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia
15 Royal Brisbane & Womens Hospital, Brisbane, Queensland, Australia
16 Royal Hobart Hospital and University of Tasmania, Hobart, Tasmania, Australia
17 Monash University, Melbourne, Victoria, Australia, The Alfred Hospital, Melbourne, Victoria, Australia
18 Australasian Leukaemia and Lymphoma Group, Melbourne, Victoria, Australia
19 Australasian Leukaemia and Lymphoma Group, Melbourne, Victoria, Australia
20 Bayside Health and Monash University, Melbourne, Victoria, Australia
21 Auckland City Hospital, Auckland, North Island, New Zealand, University of Auckland Faculty of Medical & Health Sciences, Auckland, North Island, New Zealand
22 Box Hill Hospital, Melbourne, New South Wales, Australia, Monash University, Melbourne, Victoria, Australia
23 Adelaide Medical School, Adelaide, South Australia, Australia, Royal Adelaide Hospital, Adelaide, South Australia, Australia, SAHMRI, Adelaide, South Australia, Australia
ABSTRACT
Asciminib, a first in class myristoyl pocket BCR::ABL1 kinase inhibitor, is now in clinical use for newly diagnosed chronic phase chronic myeloid leukemia (CML-CP). It has a favourable safety profile and leads to high molecular response rates. However, BCR::ABL1 mutations, mainly in the myristoyl pocket, have emerged as a predominant cause of resistance in the first 12-18 months of therapy. Additional genomic abnormalities (AGA) at diagnosis, especially ASXL1 variants, were strongly associated with these emergent mutations in recent frontline asciminib trials (ASCEND, ASC4FIRST). AGAs, together with high risk additional cytogenetic abnormalities (ACAs) [+8, +Ph, i(17q), +19, 3q26 rearrangements], identify patients at high risk of treatment failure. We hypothesised that patients with high risk ACAs and AGAs would benefit from a combination of asciminib and low-dose dasatinib, which would provide safe and effective cover against low-level BCR::ABL1 mutants in both the ATP and the myristoyl pockets to minimise emergent resistance and treatment failure.
ASCENDANCE is a phase II single arm 100 patient study. All patients started asciminib 80mg daily. After 1 month, dasatinib 50mg QD was added in high-risk patients (AGAs + high risk ACAs detected at diagnosis). AGAs were as previously defined by Shanmuganathan et al, Blood 2025, at variant allele frequency of >5%. Combination therapy was given for a maximum of 18 months; patients de-escalated to asciminib monotherapy once confirmed MR4 (BCR::ABL1 < 0.01%) was achieved. Dasatinib was also added for patients with treatment failure (BCR::ABL1 >10% at 3 or 6 months; BCR::ABL1 >1% at 12 or 18 months). The co-primary end points were early molecular response (EMR, BCR::ABL1 ≤10% at 3 months) and MR4 at 12 months (BCR::ABL1 ≤0.01%).
Data cut off for this per protocol analysis was Jun 15, 2026. The median follow-up was 9 months (range 3-19). Median age was 57 years (19-88), and 52 were female. EMR was achieved in 95 patients; one withdrew prior to 3 months, 1 missed testing, and 3 had BCR::ABL1 >10%. ELTS score was high in 16%, intermediate in 27%, and low in 57%. The cumulative incidence of MMR, MR4 and MR4.5 by 12 months was 88% (95% CI 77-94%), 50% (95% CI 39-61%) and 40% (95% CI 28-52%), respectively. In the 43 patients with >12 months of follow up, the MMR, MR4 and MR4.5 at 12 months were 89%, 47% and 31% respectively.
Seven patients had ACAs, none were high risk (2 had -Y, 5 had variant translocations). AGAs were reported in 17 patients: ASXL1, 9; DNMT3A, 3; TET2, 2; STAG2, 1; RUNX1, 1; PPM1D, 1. One patient with DNMT3A variant also had mutated CALR (was diagnosed as CML morphologically at study entry, but developed myelofibrosis (MF) at 9 months, after achievement of MMR and suppression of Ph+ clone). Cumulative incidence of MR4 by 12 months were similar in patients with AGA vs those without (34% vs 53%, p=0.31), as were MMR rates (82% vs 85%). Of the 17 patients with AGAs, 6 have since reverted to asciminib monotherapy (4 achieved MR4, 2 had cytopenia to combination); and 2 withdrew from study (1 lost to follow up, 1 developed MF). Notably, none of the 17 patients with AGAs have developed BCR::ABL1 mutations (median follow up 10.5 months).
The most common adverse events were upper respiratory tract infections (23%), fatigue (22%), increased lipase (20%), nausea (19%), and thrombocytopenia (19%). Anaemia and neutropenia were reported each reported in 8 patients. The most common Grade 3/4 AEs were thrombocytopenia (7%), anaemia (6%), neutropenia (5%), increased lipase (4%) and hypertension (3%). Of 100 trial patients, five have discontinued asciminib: 2 lost MMR with a myristoyl site (A337T) mutation at months 9 and 10 (neither had AGAs and were on asciminib monotherapy), one for MF (above), one from liver enzyme elevation at month 4 and one was lost to follow up at month 3. No deaths nor progression to blast crisis have been reported.
This early analysis of ASCENDANCE demonstrates high achievement of molecular response in newly diagnosed CP-CML patients, with genomics risk-based approach towards intensification of kinase inhibition. The asciminib / dasatinib combination appears to be well tolerated. Longer follow up will determine whether our approach reduces the risk of BCR::ABL1 mutation acquisition and treatment failure in patients with AGAs.
DISCLOSURES
David Yeung, M.D., Ph.D.: Novartis - Honoraria; Bristol Myers Squibb - Honoraria; Ascentage - Honoraria; Amgen - Honoraria; Bristol Myers Squibb - Research Funding; Novartis - Research Funding