As early molecular response to TKI therapy has been associated with an increased chance of achieving DMR and improved overall and progression-free survival for patients with CML [5-8], a standardized detection method of leukemic burden and specific target of molecular response based on which therapeutic decisions are made is required. Cytogenetic and molecular milestones for patients with CP-CML treated with TKIs have been recommended by several guidelines (Table 1) [9-11]. Although definitions of optimal response and treatment failure are inconsistent among recommendations, a BCR::ABL1 transcript level of over 1% at 12 months of treatment is generally considered a TKI-resistant disease [9-11]. If treatment failure is identified, mutational analysis of the BCR::ABL1 kinase domain and a treatment switch to alternative TKI or allogeneic hematopoietic cell transplantation (HCT) should be considered. According to the European Leukemia Net (ELN) recommendations, a treatment change may be considered if a major molecular response (MMR), which is defined as BCR::ABL1 transcript (International Scale) ≤0.1%, is not achieved by 36–48 months of treatment.

In the 10-year follow-up of the IRIS study, 183 of 553 (33.1%) patients in the imatinib arm discontinued therapy owing to adverse events (AE, N=37, 6.7%), unsatisfactory therapeutic effects (N=29, 5.2%), HCT (N=8, 1.4%), death (N=2, 0.4%), and other causes (N=107, 19.3%) [12]. Progression to AP/BP was observed in 38 (6.9%) patients in the imatinib arm, showing the estimated annual rate of treatment failure of 3.3% in the first year, 7.5% in the second year, 4.8% in the third year, 1.5% in the fourth year, and 0.9% in the fifth year [12, 13]. In a phase 3 trial of dasatinib, DASISION, 100 of 258 patients (38.8%) in the dasatinib arm discontinued treatment. Reasons for discontinuation included treatment-related or unrelated toxicities (N=64, 21%), progression or treatment failure (N=28, 11%), and other causes (N=18, 7%). At the 5-year follow-up, 5% of patients receiving dasatinib transformed AP/BP [7]. In a 10-year follow-up of the ENESTnd trial comparing nilotinib to imatinib, of 282 patients of nilotinib 300 mg twice daily arm, 175 patients (62.1%) discontinued the treatment because of AE (N=53, 18.8%), suboptimal response or treatment failure (N=37, 13.1%), disease progression to AP/BP (N=2, 0.7%), death (N=9, 3.2%), and other causes (N=72, 26.2%), respectively [14]. Progression to AP/BP was observed in 11 (3.9%) patients during the study period. In the BFORE trial, which compared the efficacy and safety of bosutinib and imatinib, 268 patients were assigned to the bosutinib arm. The discontinuation rate of the bosutinib arm was 40.3% (N=108), and the causes of treatment discontinuation included AE (N=67, 25%), suboptimal response or treatment failure (N=13, 4.8%), disease progression to AP/BP (N=2, 0.7%), death (N=3, 1.1%), and others (N=23, 8.6%) [15]. In summary, the treatment discontinuation rate of first-line (1 L)-TKI therapy in patients with CP-CML was estimated to be between 28–40%, of which approximately 10% is associated with a suboptimal response or treatment failure. The treatment discontinuation rate due to AEs was reported to be higher with 2G-TKIs (20–25%) than with imatinib (less than 10%).

Beyond the second-line (2 L) setting, the discontinuation rates of TKI therapy were reported to be much higher than those of 1 L-treatment, most of which were due to disease progression or lack of efficacy. In a phase 3 CA180-034 study that evaluated the efficacy of dasatinib in patients with imatinib-resistant or-intolerant CP-CML, 110 of 166 patients (66.3%) discontinued treatment due to protocol-defined progression (N=35, 21.1%), drug-related or unrelated AE (N=49, 29.3%), and investigator or patient request (N=26, 15.6%), except for other reasons, including study termination [16]. In a phase II study of 321 CP-CML patients with imatinib resistance or intolerance who were treated with nilotinib, the discontinuation rate was 69.8% at the 2-year follow-up. The reasons for treatment discontinuation included disease progression (N=96, 29.9%), drug-related or unrelated AE (N=66, 20.6%), death (N=4, 1.2%), and others (N=58, 18.1%), respectively [17]. Bosutinib was studied in patients with CP-CML in whom imatinib failed, followed by dasatinib or nilotinib as third- or fourth-line therapy. Of the 119 patients, 90 (75.6%) discontinued treatment for 4-year because of disease progression (N=24, 20.1%), lack of efficacy (N=22, 18.5%), or AE (N=28, 23.5%) [18]. In the PACE trial evaluating the efficacy of ponatinib in CP-CML with 2G-TKI failure or T315I mutation, treatment discontinuation was observed in 63.3% of the patients, with the most common reason being the discontinuation of AE (N=57, 21.1%), followed by disease progression (N=29, 10.7%), lack of efficacy (N=15, 5.6%), and others (N=70, 25.9%), except for study closure [19].

Patients in whom multiple lines of TKI treatment fail tend to show worse outcomes [20, 21]. In a retrospective study from a single institute that included 206 patients with CML, only 37% maintained their initial TKI therapy, whereas 35% and 28% were treated with two and>two TKIs, respectively [22]. In this study, the number of TKIs administered significantly predicted progression-free and overall survival. Patients treated with fifth-line TKI showed worse survival outcomes, with an estimated 10-year overall survival of 55%, significantly lower than those treated with between two and four TKIs. In this regard, there is a need for more effective therapeutic options with acceptable toxicity profiles for CML patients who exhibit resistance or intolerance to 1 L- or, particularly, beyond 2 L-TKI treatment.

Treatment changes are imperative in patients when 1 L-therapy fails due to TKI resistance [23]. In case of treatment failure, physicians should evaluate the presence of BCR::ABL1 kinase domain mutations, as well as patient compliance and drug interactions, followed by switching TKI. If a known BCR::ABL1 kinase domain mutation exists, treatment decisions should be made based on the mutation profiles (Table 2) [9]. The 2G-TKIs are preferred for patients treated with imatinib as 1 L-treatment. In case of resistance to 2G-TKI without specific kinase domain mutations, the ELN recommendation states that ponatinib is the preferred option rather than an alternative 2G-TKI [11]. The ELN statements also recommend the same definitions for monitoring milestones in patients receiving 2 L-treatment.

Although there is no standardized treatment recommendation or definition of acceptable response for beyond 2 L-treatment, a BCR::ABL1 transcript level ≤1% or complete cytogenetic response is generally considered a minimum requirement. The choice of TKI should be based on the mutational profile or BCR::ABL1 kinase domain mutations, and allogeneic HCT should be considered if the second- or third-line treatment shows a suboptimal response. To date, ponatinib, a third-generation TKI, is considered a potent therapeutic option as a third-line treatment for patients with resistance to 2G-TKIs, including those with T315I mutations.

In CML, constitutive activation of tyrosine kinase is caused by BCR::ABL1 oncoprotein formation, with loss of the regulatory N-terminal cap of ABL1. Conventional TKIs compete with ATP (adenosine 5′-triphosphate) for binding to the catalytically active or inactive conformations of the kinase domain of ABL1. Kinase activity can also be suppressed by inhibitors that bind in an allosteric manner to ABL1 in addition to the ATP-binding site. Asciminib is a first-in-class specific allosteric inhibitor of BCR::ABL1 that selectively binds to a myristoyl pocket, leading to conformational changes induced by myristate-binding to the N-terminus of ABL1 under normal conditions (Fig. 1) [24].

Conventional TKIs frequently show off-target effects because they are not specific for targeting BCR::ABL1 but bind to other tyrosine kinases, including PDGFR, c-KIT, CSF1R, and the Src family [25]. As against conventional TKIs, asiminib has fewer off-target effects because of the limited number of tyrosine kinases containing myristate-binding sites. When viability was assessed in a diverse panel of human cancer cell lines, it selectively inhibited the proliferation of BCR::ABL1 expressing leukemic cell lines but showed minimal or no effect on cells not expressing BCR::ABL1 [26, 27].

Asciminib displayed anti-proliferative activity against cell lines with several ABL1 kinase domain mutations, including T315I, a gatekeeper mutation that leads to resistance to most conventional TKIs, except ponatinib [24, 27, 28]. It also demonstrated tumor regression of xenografts implanted with T315I harboring KCL-22 cell, a CML blast-phase cell line, when treated with 30 mg/kg twice daily [27]. However, cell lines with compound mutations (two mutations within the same allele of BCR::ABL1) with or without the T315I mutation exhibited resistance to asciminib, unlike most kinase domain mutations, which were effectively suppressed by single-agent asciminib at nanomolar concentrations [28].

Resistance to asciminib has been observed in several preclinical studies. Point mutations in BCR::ABL1 within or near the myristoyl pocket, including A337V, P465S, V468F, F359C/I/V, and C464W, have been reported to confer asciminib resistance [27-29]. In addition to the BCR::ABL1 mutation, in asciminib-resistant K562, LAMA84, and KYO1 cell lines, which were generated by treatment with increasing concentrations of asciminb, ABCG-2 mediated drug efflux was found to be a major driving mechanism of resistance [29]. Combined treatment with asciminib and conventional TKIs has shown preclinical evidence for overcoming asciminib resistance. When asciminib was co-administered with nilotinib, durable and complete tumor regression was observed in KCL-22 xenograft mice, as against sequential or single-agent treatment, which showed emerging resistance due to T315I, A337V, or P223S mutations [27]. Notably, ponatinib and asciminib combination treatment at therapeutically relevant concentrations showed synergistic anti-leukemic effects in cell lines harboring BCR::ABL1 compound mutations and in the primary cells of patients with T315I mutated CML [28, 30].

First, the safety and efficacy of asciminib monotherapy were evaluated in a phase I, open-label study (NCT02081378) in patients with Philadelphia chromosome-positive adult CML who relapsed or were refractory to two or more previous TKIs and those with T315I mutation treated with one or more TKI and having no other effective treatment [3]. In this phase I study, 141 patients with CP-CML and nine patients with AP-CML were enrolled and treated with asciminib at doses between 10 and 200 mg twice daily or between 80 and 200 mg once daily in the dose escalation and dose expansion phases. Of the 150 enrolled patients, 105 (70%) had been previously treated with at least 3 previous TKIs, and 49 (32.7%) had been exposed to ponatinib. The maximum tolerated dose was not reached, and a dose of 40 mg twice daily was recommended for patients with CP-CML without the T315I mutation based on a pharmacokinetic-pharmacodynamic model. At the time of analysis, 110 patients (73.3%) continued with the study treatment, with a median follow-up duration of 59 weeks. The commonly observed non-hematologic AEs during treatment were asymptomatic elevation of lipase or amylase levels (26.7% and 12.7%, respectively), rash (23.3%), and constitutional symptoms, including fatigue (29.3%), headache (28%), and arthralgia (24%). Hypertension (19.3%) was the most common cardiovascular AE, and thrombocytopenia, anemia, and neutropenia were observed in 22%, 11.3%, and 10.7% of the patients, respectively. Most AEs were of grade 1 or 2 and were reversible. Among the 113 evaluable patients with CP-CML without the T315I mutation, 91.9%, 54.4%, and 36.1% of patients without complete hematologic response (CHR), complete cytogenetic response (CCyR), and MMR at enrollment, respectively, achieved CHR, CCyR, and MMR during treatment. The response was rapid and durable, with a median time to MMR of 20 weeks (range, 2–120 wk), and the median response duration was >61 weeks (range, 4–154 wk). Among the 28 CP-CML patients with the T315I mutation, 87.5%, 40.9%, and 23.5% of patients without CHR, CCyR, and MMR at enrollment achieved CHR, CCyR, and MMR, respectively. Myristoyl- pocket point mutations, including V468F, G463S, P465S, and F359I, developed in four patients, two of whom experienced disease progression, while two showed no evidence of progressive disease at the time of analysis.

The safety and efficacy of asciminib combination therapy with imatinib, nilotinib, or dasatinib has also been evaluated in separate cohorts within the same study based on the additive effects of asciminib on conventional TKIs in preclinical studies. In the imatinib cohort, asciminib with doses of 40 mg, 60 mg, 80 mg once daily, or 40 mg twice daily was administered with imatinib 100 mg to 25 patients with CP-CML. Among these patients, any-grade drug-related AEs were observed in 22 patients (88%) and grades 3 to 4 in 11 patients (44%). Of 19 patients without MMR at baseline, 8 patients (42.1%) achieved MMR and 3 patients (15.8%) achieved MR^4.5, which is defined as a BCR::ABL1 transcript level of ≤0.0032%, by 48 weeks of treatment [31]. In the dasatinib and nilotinib cohorts, 17 patients were enrolled in each treatment arm. The rates of any-grade and grade 3/4 drug-related AEs were reported to be 82.4% (14 of 17) and 52.9% (9 of 17) in nilotinib cohort, and 88.2% (15 of 17) and 29.4% (5 of 17) in dasatinib cohort, respectively. Of the 13 and 14 patients without MMR at baseline, 4 patients (30.8%) and 5 patients (35.7%) achieved MMR by 48 weeks of treatment, respectively [32].

A subsequent phase 3, open-label, randomized trial compared asciminib 40 mg twice daily with bosutinib 500 mg once daily in patients with CP-CML previously treated with two or more prior TKIs without the T315I or V229L mutation [4]. Patients who were intolerant to the most recent TKI must have BCR::ABL1 transcript over 0.1% at screening which was amended from initial criteria requiring ≥1% of BCR::ABL1 transcript. The patients were randomly assigned in a 2:1 ratio to either the asciminib arm (N=157) or the bosutinib arm (N=76). Of the total patients, 121 (51.9%) had received 3 or more previous TKIs, and the reasons for discontinuation of the last TKI included lack of efficacy (63.9%) and intolerance (34.8%). After a median follow-up duration of 14.9 months from randomization, treatment was ongoing in 97 (61.8%), and 22 (28.9%) patients in the asciminib and bosutinib arms, respectively, and the most common cause of discontinuation was lack of efficacy (33 of 59 for asciminib and 22 of 54 for bosutinib). The primary endpoint of the study was the MMR rate at week 24, which was observed in 25.5% and 13.2% of patients receiving asciminib and bosutinib, respectively (P=0.029). The rate of MR^4.0, defined as a BCR::ABL1 transcript level of ≤0.01%, and MR^4.5 at 24 weeks was 10.8% and 8.9% in the asciminib arm and 5.3% and 1.3% in the bosutinib arm, respectively. In a subgroup analysis, asciminib was superior in terms of achieving MMR, irrespective of the number of prior TKI treatments and in patients who discontinued the last session of the prior TKI due to treatment failure. Asciminib was well tolerated in terms of fewer AEs and a lower discontinuation rate due to AEs of 5.8% compared with 21.1% in the bosutinib arm. Grade ≥3 AEs were observed in 50.6% of patients receiving asciminib, which included thrombocytopenia (21.8%), neutropenia (17.9%), hypertension (5.8%), and amylase elevation (3.8%). Overall, asciminib showed improved efficacy with favorable toxicity profiles compared with bosutinib as a later-line treatment for CP-CML who failed 2 or more previous TKIs.

Since asciminib showed significant efficacy with an acceptable safety profile as a later-line treatment for CP-CML with or without the T315I mutation, and preclinical data support the potential of asciminib with synergistic effects when combined with conventional TKIs in resistant CML, several trials are currently evaluating this treatment, as listed in Table 3.

In Korea, the Ministry of Food and Drug Safety approved the use of asciminib in July 2022 as a third-line treatment for patients with CP-CML, irrespective of T315I mutation status. Although patients with the T315I mutation have limited access to asciminib as an early treatment option in Korea, those who have failed two or more prior TKIs, particularly those with a high cardiovascular risk or medical frailty, may benefit from asciminib, given its relatively favorable safety profile and efficacy in heavily treated CML-CP. Furthermore, current studies are evaluating various approaches to using asciminib in multiple clinical settings, including 1 L- or 2 L-treatment, adjunctive treatment to achieve DMR, and prior to attempting TFR. These investigations suggest that asciminib has potential applications in multiple therapeutic contexts in the near future.