Case 1: Managing intolerance – achieving stability with asciminib
A 78-year-old male with pre-existing comorbidities, including diabetes, hypertension and ischaemic heart disease (IHD), exemplified the real-world challenges of long-term tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukaemia (CML).
Initial treatment course, and clinical outcomes with AEs
Treatment with dasatinib was initiated, but the patient required dose reduction due to cytopenia. He eventually achieved major molecular response (MMR). However, he developed pleural effusion around 2.5 years after starting dasatinib, prompting a switch to imatinib. Although imatinib maintained MMR, the patient experienced adverse events (AEs) such as fluid retention (ie, periorbital and lower limb swelling) and renal impairment after starting imatinib.
Switching to asciminib
Due to the patient’s intolerance to imatinib, which impacted his quality of life (QoL) and renal function, treatment was switched to asciminib (80 mg QD). Following the transition, the patient’s clinical status improved: fluid retention resolved, kidney function returned to baseline, and molecular response remained deep and stable.
To date, the patient has been adherent to asciminib, experiencing better QoL with no complications. His heart condition remains stable on medical therapy. Despite established cardiovascular (CV) risk factors, the patient showed no worsening of existing IHD, and blood pressure remained stable. There was no recurrence of pleural effusion.
Asciminib maintained deep molecular response at MR4 (BCR::ABL1 transcript level ≤0.01 percent) and mitigated intolerance-driven complications from prior TKI(s), suggesting its safety in elderly patients with comorbidities.
Case 2: Managing resistance – restoring response in a patient with complex history
The patient was a 66-year-old male with a long-standing history of CML who had failed multiple TKIs.
Initial treatment course, and clinical outcomes with AEs
Initial response to imatinib and dasatinib was poor. At the time, the patient was still relatively young and fit and thereby offered allogeneic haematopoietic stem cell transplantation (allo-HSCT), but he refused.
Treatment was switched to nilotinib due to suboptimal response to previous TKIs. Improvements were initially slow, but the patient eventually achieved MMR after being put on a relatively high dose of nilotinib (400 mg BID). However, the patient subsequently developed CV events, including IHD and transient ischaemic attack (TIA). IHD was managed with medication and nilotinib was continued concurrently.
The patient eventually demonstrated resistance with a confirmed loss of MMR. Kinase domain (KD) mutation testing did not reveal any identifiable mutation. Three treatment options were thus considered: allo-HSCT, ponatinib or asciminib. As the patient refused allo-HSCT, and ponatinib was not preferred due to existing IHD and ponatinib’s association with arterial occlusive events (AOEs), asciminib was chosen.
Switching to asciminib
Transition to asciminib 80 mg QD led to MMR within 2 months. The rapid response confirmed asciminib’s capacity to restore molecular control even after multi-TKI resistance, with improved safety in patients for whom ponatinib was contraindicated.
Discussion
CML has transformed from a fatal disease into a manageable condition, yet achieving durable molecular control remains a challenge when treatment intolerance or resistance arises. Asciminib, a first-in-class TKI that specifically targets the ABL myristoyl pocket (STAMP), represents a novel therapeutic approach distinct from ATP-competitive TKIs.1,2 Recently approved in Hong Kong for first-line (1L) as well as second-line and beyond (≥2L) treatment of chronic-phase CML (CML-CP), asciminib has demonstrated efficacy and tolerability across pivotal phase III trials.2-4 To build local evidence and guide clinical practice, a retrospective real-world study was conducted by Dr Carol Cheung in 17 CML-CP patients treated with asciminib in ≥2L setting.2 (Figure) The aim was to evaluate treatment outcomes, safety and mutation profile correlations, and to contextualize these findings within the Hong Kong clinical landscape.2
The cohort reflected the complexity of later-line CML management. Patients were heavily pretreated – 88 percent (n=15/17) had received ≥2 prior TKIs, and half had prior ponatinib exposure. Six patients harboured known KD mutations, including T315I, F359V, Y253H, F317L, G250E and Q252H. At treatment initiation, one-third of patients were in MMR, having switched primarily due to intolerance. (Figure) The remaining patients had resistance or suboptimal response to prior therapy.2
Asciminib consistently sustained deep response in all patients who began treatment in MMR, with each maintaining or further improving their molecular status over 12 months. Among those not in MMR at baseline, 30 percent (n=3/10) achieved MMR or deeper response by 6 months, while 20 percent (n=2/10) maintained stable disease with complete haematologic response. The remaining patients failed ponatinib prior to asciminib switch; all except one had documented KD mutation, while three had subsequent blastic transformation. Such outcomes revealed a clear high-risk subgroup: patients with genuine multi-TKI resistance after ponatinib – reflecting the aggressive nature of the disease.2
The safety profile of asciminib remained favourable, with infrequent, mostly mild AEs managed by dose adjustment and no discontinuations. Overall, the findings reinforced asciminib as a well-tolerated option capable of maintaining or improving molecular control in everyday practice.2
These findings provide important clinical context of how asciminib performs across very different patient scenarios.
Key takeaways for clinical practice
Asciminib is a viable option for TKI-intolerant or -resistant patients (including those with T315I mutations), particularly when comorbidities or allo-HSCT ineligibility limit treatment options.
In TKI-intolerant or -resistant patients, timely switch to alternative TKI is recommended to optimize patient outcomes. Clinicians are encouraged to monitor metabolic profile, CV risk and blood pressure alongside standard TKI surveillance, and inform patients of the possibility of transient constitutional symptoms (fever, myalgia) that typically resolve within 1–2 weeks.
