Integrating Asciminib into the Evolving Treatment Landscape of Chronic Myeloid Leukemia: A Canadian Perspective

Abstract

Five years after the first readout of the ASCEMBL trial, asciminib evidence has rapidly expanded across the chronic myeloid leukemia (CML) treatment landscape. Subsequent studies and growing real-world experience have also clarified its efficacy and tolerability in earlier treatment lines. As the first allosteric inhibitor targeting the BCR::ABL1 myristoyl pocket, asciminib provides a mechanistically distinct approach that may reduce cross-resistance and toxicity associated with ATP-competitive TKIs. At a time when treatment goals in CML emphasize long-term tolerability, quality of life, and the potential for treatment-free remission (TFR), asciminib’s unique molecular and clinical profile justify its inclusion in CML treatment considerations. In this expert opinion review, we synthesize emerging clinical and real-world evidence for asciminib and discuss practical considerations for its integration into contemporary CML management, including its potential im-plications for TFR eligibility. We also explore the role of next-generation sequencing in detecting salvageable resistance mutations, the prognostic significance of co-mutations such as ASXL1, and the concept of mutation-guided treatment sequencing. Collectively, these data position asciminib as an established later-line therapy and an emerging frontline option, with the potential to improve long-term treatment sustainability through favorable tolerability and early molecular response kinetics.

Graphical Abstract

Introduction

The development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) transformed chronic myeloid leukemia (CML) from a fatal malignancy into a chronic disease with near-normal life expectancy for many patients. However, TKI therapy is often lifelong; thus, cumulative toxicities and chronic low-grade adverse events (AEs) significantly influence quality of life, adherence, and long-term treatment sustainability. Thus, treatment priorities have shifted toward long-term tolerability and treatment-free remission (TFR).¹ In this evolving therapeutic landscape, a central clinical question is how asciminib should be optimally positioned across lines of therapy in CML. Despite their effectiveness, adenosine triphosphate (ATP)-competitive TKIs for CML (ie, imatinib, dasatinib, nilotinib, bosutinib and ponatinib) are associated with persistent toxicities that can significantly affect quality of life and treatment sustainability. Population-based studies show that quality-adjusted life expectancy remains reduced among patients with CML, largely reflecting the cumulative burden of chronic therapy rather than acute toxicity.² Patient-reported outcome studies consistently identify fatigue and other low-grade symptoms as key contributors to impaired daily functioning and reduced work productivity.^3–5 In routine clinical practice, these factors frequently lead to treatment modification, with real-world cohorts reporting TKI switching or discontinuation in approximately 25–45% of patients within five years.^6,7 In a prospective Quebec registry of 661 patients, nearly half required switching during first-line (1L) therapy, again primarily driven by treatment intolerance with similar patterns observed in all subsequent lines of treatment.⁸ Switching rates in real-world practice may exceed those reported in clinical trials and vary across clinical settings, likely reflecting broader definitions of intolerance and a lower threshold to change therapy when multiple treatment options are available.^9–11 Taken together, these findings highlight the challenge of balancing durable disease control with long-term toxicity and quality of life when using ATP-competitive TKIs with overlapping resistance and toxicity profiles.

Asciminib introduces a mechanistically distinct approach to BCR::ABL1 inhibition by targeting the myristoyl pocket rather than the ATP-binding site (Figure 1). This offers the potential to maintain antileukemic efficacy while reducing cross-resistance and minimizing toxicities associated with ATP-competitive TKIs.^12–14 As clinical experience with asciminib expands across treatment lines, key questions remain regarding its optimal positioning within existing treatment algorithms, its long-term safety profile, and its potential role in strategies aimed at achieving durable TFR. In this review, we synthesize clinical and real-world evidence and suggest an approach to the integration of asciminib into individualized CML treatment selection and sequencing. We first review the evidence supporting asciminib across treatment lines, including 1L, second-line (2L), and later-line settings, followed by discussion of its role in TFR and post-asciminib sequencing, before outlining practical principles for individualized treatment selection and highlighting emerging considerations, including combination strategies, special populations, and biomarker-informed risk assessment.

Figure 1.

ATP-site versus myristoyl-pocket inhibition of BCR::ABL1. The BCR::ABL1 fusion protein is constitutively active because normal ABL1 autoinhibitory regulation is disrupted, allowing persistent ATP-dependent kinase activity. ATP-competitive TKIs bind directly to the ATP-binding site and inhibit kinase activity by competing with ATP. In contrast, asciminib binds the myristoyl pocket and allosterically stabilizes BCR::ABL1 in an inactive conformation, thereby suppressing kinase activity without directly occupying the ATP-binding site. The X indicates inhibition of ATP-dependent kinase activity.

Abbreviations: ABL1, Abelson murine leukemia viral oncogene homolog 1; ATP, adenosine triphosphate; BCR, breakpoint cluster region; TKI, tyrosine kinase inhibitor.

What Is Known About Asciminib Treatment

Asciminib development has progressed from heavily pretreated CML into progressively earlier treatment settings as evidence on efficacy and tolerability has accumulated. Figure 2 provides a chronological overview of selected clinical studies and regulatory milestones, while Table 1 summarizes the key efficacy and tolerability findings from the pivotal studies discussed in this section.

Figure 2.

Key milestones in asciminib clinical development and regulatory evolution.

Abbreviations: 1L, first line; 2L, second line; CML-CP, chronic myeloid leukemia in chronic phase; EMA, European Medicines Agency; FDA, US Food and Drug Administration; TKI, tyrosine kinase inhibitor; W, week.

Table 1.

Summary of Key Asciminib Trials and Clinical Outcomes

Study	Setting and Design	Primary Endpoint	Follow-Up Readout	Last Readout	AE-Related Discontinuation
ASCEMBL Phase III NCT0310677915–17	≥3L CML-CP ASC n=157 vs BOS n=76	MMR at W24 25.5% vs 13.2%	MMR at W96 37.6% vs 15.8%	MMR at W156/EOS 33.8% vs 10.5%	At W156/EOS 8.3% vs 27.6%
ASC4FIRST Phase III NCT0497122618–20	1L CML-CP ASC n=201 vs IS-TKI n=204 IMA stratum: 101 vs 102 2G-TKI stratum: 100 vs 102	MMR at W48 Overall: 67.7% vs 49.0% IMA: 69.3% vs 40.2% 2G TKI*: 66.0% vs 57.8%	MMR at W96 Overall: 74.1% vs 52.0% IMA: 76.2% vs 47.1% 2G-TKI: 72.0% vs 56.9%	MMR at W144 Overall: 77.1% vs 53.4% IMA: 79.2% vs 47.1% 2G TKI: 75.0% vs 59.8%	At W144 ASC: 6.0% vs IMA: 13.1% vs 2G TKI: 13.7%
ASC4START Phase IIIb NCT0545619121	1L CML-CP ASC n=284 vs NIL n=282	TTDAE HR 0.45 (95% CI, 0.25–0.81; nominal P=0.004)	NA	NA	At W48 7.7% vs 16.0%
ASC2ESCALATE Phase II single-arm dose escalation NCT0538458722	2L CML-CP N=101	MMR at W48 55.6%†	NA	NA	At W48 7.9%†

Notes: *The comparison versus pooled 2G TKIs was a secondary analysis rather than a co-primary comparison. ^† ASC2ESCALATE results represent an updated interim analysis; W48 efficacy was evaluable in 72 of 101 enrolled patients, whereas safety analyses included all 101 patients.

Abbreviations: 1L, first line; 2G, second generation; 2L, second line; ≥3L, third line or later; AE, adverse event; ASC, asciminib; BOS, bosutinib; CI, confidence interval; CML-CP, chronic myeloid leukemia in chronic phase; EOS, end of study; HR, hazard ratio; IMA, imatinib; IS-TKI, investigator-selected tyrosine kinase inhibitor; MMR, major molecular response; NIL, nilotinib; TKI, tyrosine kinase inhibitor; TTDAE, time to treatment discontinuation due to adverse events; W, week.

Asciminib in Heavily Pretreated Patients

Evidence: The Phase 3 ASCEMBL trial established asciminib as an effective option for patients with chronic-phase CML previously treated with at least two TKIs.^15–17 In this randomized study, asciminib demonstrated superiority to bosutinib for major molecular response (MMR) at week 24 (25.5% vs 13.2%; primary endpoint) and continued deepening of responses with longer follow-up (37.6% vs 15.8% at week 96).^15,16 Molecular responses were generally durable once achieved, and treatment discontinuations due to AEs were substantially lower with asciminib than with bosutinib (8.3% vs 27.6% at week 156).¹⁷ Consistent efficacy and tolerability of asciminib have also been reported in Canadian real-world cohorts of heavily pretreated patients, with one-year MMR rates of approximately 42%.²³

The safety profile of asciminib in later-line settings is characterized primarily by hematologic toxicities, most commonly thrombocytopenia (grade ≥3: 22.4%; all grades: 29.5%), and less frequently elevations in pancreatic enzymes (lipase grade ≥3: 3.8%, all grades: 5.1%; amylase grade ≥3: 0.6%, all grades: 5.8%).¹⁷ These events typically occur early within the first weeks to months of treatment initiation and are generally manageable with dose interruption or modification. Importantly, longer-term safety data have not identified a clear signal for cumulative cardiovascular (CV), metabolic, and pulmonary toxicities as associated with ATP-site TKIs. Extended 4-year follow-up from ASCEMBL and 8-year follow-up from Phase I studies in heavily pretreated CML patients have not identified clear emerging CV safety signals.^17,24,25 However, continued long-term surveillance remains warranted given the experience of late-onset vascular toxicity observed with other TKIs after prolonged exposure.²⁶

Expert opinion: In clinical practice, ASCEMBL supports asciminib as a key later-line option, particularly for patients with treatment intolerance or those requiring improved long-term tolerability. However, in patients with more resistant disease, treatment selection remains individualized. In these cases both asciminib and ponatinib are commonly considered after multiple TKIs, with asciminib generally favored in patients with prior intolerance or increased CV risk, and ponatinib preferred in selected high-risk situations requiring rapid disease control. While indirect comparisons have not shown clear superiority of either agent, some clinicians may favor ponatinib in selected high-risk situations—such as younger patients requiring rapid disease control over a short treatment interval (eg, as a bridge to transplant)—because of its perceived greater potency.^27,28 However, ponatinib’s association with arterial occlusive and metabolic complications can limit its use in patients with elevated CV risk, making asciminib an attractive option for many patients requiring later-line therapy.²⁹ In Canada, asciminib is publicly accessible in the third-line and later setting across all provinces and has become an established option after failure or intolerance of ≥2 TKIs.

Moving into Frontline Therapy

Evidence: The favorable efficacy and tolerability of asciminib in heavily pretreated patients prompted evaluation earlier in the treatment sequence. In the phase 3 ASC4FIRST trial, asciminib was compared with investigator-selected TKIs (imatinib or pooled second-generation [2G] TKIs [ie, dasatinib, nilotinib, bosutinib]) as initial therapy for newly diagnosed chronic-phase CML.¹⁸ At 48 weeks, asciminib achieved higher MMR rates than investigator-selected TKIs (67.7% vs 49.0%), with a particularly marked advantage over imatinib (69.3% vs 40.2%). Higher MMR rates were maintained at week 96 (74.1% vs 52.0% overall; 76.2% vs 47.1% versus imatinib).¹⁹ While the analysis versus pooled 2G TKIs was not powered for formal statistical comparison, the treatment difference in MMR favored asciminib by 8.2 percentage points at week 48 (95% confidence interval [CI], −5.1 to 21.5) and increased to 15.1 percentage points at week 96 (95% CI, 2.3–28.0; one-sided P<0.05), with this difference maintained at week 144 (15.2 percentage points; 95% CI, 2.6–27.8).^18–20 Importantly, efficacy was consistent across prespecified clinical subgroups, including patients older than 75 years.

Safety outcomes were consistent with prior studies, with cytopenias and lipase elevations as the most frequent AEs. In ASC4FIRST, grade ≥3 AEs and treatment discontinuations at 144 weeks were less frequent with asciminib than with imatinib or pooled 2G TKIs (49.0% vs 51.5% and 62.7%; discontinuations 6.0% vs 13.1% and 13.7%), with fewer dose modifications and sustained improvements in patient-reported quality of life.²⁰ These findings were supported by the phase 3b ASC4START trial, which used time to treatment discontinuation due to AE (TTDAE) as the primary endpoint and showed a lower risk of discontinuation with asciminib versus nilotinib at 10-month median follow-up (5.6% vs 12.1%; hazard ratio [HR] 0.45; 95% CI, 0.25–0.81; P=0.004).²¹

Expert opinion: Together, these data establish asciminib as a compelling frontline option, with superior molecular efficacy versus imatinib and consistently higher response rates versus pooled 2G ATP-site TKIs. Its favorable tolerability profile has also translated into improved patient-reported quality-of-life outcomes in ASC4FIRST.³⁰ Notably, the consistent benefit observed across prespecified subgroups, including patients older than 75 years, suggests that asciminib may be broadly applicable across diverse patient populations rather than restricted to a specific clinical niche. If confirmed with longer follow-up, including overall survival benefit and long-term safety durability, these findings would further solidify the role of asciminib in the frontline setting. However, it should be noted that frontline real-world experience remains limited and that ASC4FIRST was not powered for definitive head-to-head comparisons against individual 2G TKIs, including lower-dose strategies such as dasatinib 50 mg/day, which are used in clinical practice to optimize tolerability. Uptake may nonetheless be influenced by cost and access considerations, although health-economic analyses suggest asciminib is associated with 53% more adverse-event–symptom-free days and a lower cost per symptom-free day compared with 2G TKIs.³¹ In Canada, access to frontline asciminib is evolving rapidly. Since the positive CDA-AMC reimbursement recommendation in October 2025, public reimbursement for newly diagnosed patients has become available in selected provinces, including Québec and Ontario through their respective access programs. As access becomes more streamlined across provinces, asciminib may become increasingly integrated into frontline treatment strategies.

Asciminib in 2L Treatment Setting

Evidence: Sequential switching among 2G TKIs often provides limited benefit and may increase cumulative toxicity, making the 2L setting an important point to consider a mechanistically distinct therapy. The Phase II ASC2ESCALATE trial evaluated asciminib in patients who discontinued one prior TKI due to intolerance or lack of efficacy.²² Among 101 patients—most previously treated with imatinib or dasatinib—84% remained on asciminib at the May 2025 cutoff, with fewer than 8% discontinuing due to AEs and only one for lack of efficacy.²² At 48 weeks, the MMR rate was 55.6%. Early responses at week 24 were more frequent among patients switching for intolerance, but responses continued to deepen with longer follow-up in those switching for lack of efficacy, resulting in similar MMR rates across both groups at week 48 (58.1% vs 53.7%). These findings are supported by real-world data showing higher molecular response rates and fewer treatment discontinuations with 2L asciminib compared with ATP-competitive TKIs (MMR 68.3% vs 58.1%; deep molecular response [DMR] 40.6% vs 21.0%).^32,33

Expert opinion: Clinically, asciminib is particularly compelling in patients switching therapy because of intolerance, where further cycling among ATP-site TKIs frequently reproduces toxicity without meaningfully improving disease control. Early activity observed in ASC2ESCALATE demonstrates that clinically meaningful molecular responses can be achieved with asciminib after 1L TKI failure, including in patients for whom ponatinib might otherwise be considered—a meaningful consideration given ponatinib’s vascular toxicity profile. This approach aligns with emerging ELN 2025 guidance supporting earlier introduction of mechanistically distinct therapies rather than sequential cycling of 2G TKIs.¹ In Canada, however, the ability to implement this strategy in 2L remains jurisdiction dependent. Québec expanded public reimbursement of asciminib to eligible patients after one prior TKI in June 2026. In Ontario, earlier-line access is available through the Exceptional Access Program for selected patients with documented mutational resistance that makes imatinib, dasatinib, and nilotinib clinically inappropriate. Routine 2L public reimbursement remains more limited elsewhere in Canada, following the negative CDA-AMC reimbursement recommendation for the 2L indication. Thus, despite Health Canada approval after ≥1 prior TKI, the practical position of asciminib in 2L currently differs across Canadian jurisdictions.

What is Not Yet Known About Asciminib Treatment

Treatment-Free Remission

In practice, TFR success remains modest regardless of the TKI used, with only about one in four patients achieving durable remission.³⁴ This largely reflects the fact that only a minority of patients achieve and sustain the deep molecular responses required for TFR eligibility—typically MR4 or deeper for ≥2 years—and even after five years of therapy with 2G TKIs, only about 42–68% of patients reach this threshold for TFR eligibility.^35–42 In contrast to the extensive TFR experience with other TKIs across multiple trials, dedicated asciminib discontinuation TFR data are not yet available.

In the absence of asciminib-specific TFR data, its potential impact on achieving TFR eligibility can be inferred indirectly. Early molecular responses (eg, BCR::ABL1 ≤10% at 3 months and ≤1% at 12 months) are known to predict later achievement of deep molecular remission and the likelihood of achieving TFR eligibility, with reported success rates of approximately 24–26% for those who achieve these milestones versus 3–6% for those who do not.^43,44 Asciminib’s ability to induce rapid and durable molecular responses, as demonstrated in ASC4FIRST, could plausibly increase the proportion of patients who ultimately meet eligibility criteria for TFR.¹⁸ In addition to higher MMR rates at week 96, asciminib was associated with higher rates of early molecular response at 3 months (89.6% vs 70.1% [IS TKI stratum]; 88.1% vs 59.8% [imatinib stratum] and 91.0% vs 80.4% [2G TKI stratum]) and higher rates of deep molecular response at 96 weeks (MR4/MR4.5: 48.8%/30.9% vs 27.5%/17.7% [IS TKI stratum]; 52.5%/35.6% vs 23.5%/11.8% [imatinib stratum]; 45.0%/26.0% vs 31.4%/23.5% [2G TKI stratum]).⁴⁵ Improved tolerability may further support this trajectory by enabling sustained treatment exposure, as reflected by approximately half the rate of treatment discontinuation due to AEs at 144 weeks (6.0% with asciminib vs 13.1% with imatinib vs 13.7% with 2G TKIs) and fewer dose modifications with asciminib relative to imatinib and 2G TKIs.²⁰ Whether asciminib influences the likelihood of maintaining remission after discontinuation remains unknown and will require dedicated TFR studies. TFR eligibility and success rates with asciminib in 1L are currently being explored in ongoing clinical trials including ASC4FIRST and ASC4START to better inform clinical practice.

Expert opinion: It is generally accepted that once standard eligibility criteria are met, the probability of maintaining TFR after discontinuation is broadly similar across TKIs.⁴⁶ Any potential advantage of asciminib with respect to TFR is more likely to arise from increasing the pool of patients eligible to attempt discontinuation rather than altering relapse biology after treatment cessation. This distinction is particularly relevant in light of commonly adopted cost-driven strategies such as a “generic-first, switch-later” approach, which may delay deep molecular response and potentially reduce the proportion of patients who ever become eligible to attempt TFR, since response rates decrease with later-line use.^47,48 In the Canadian publicly funded setting, this creates an important tension between minimizing upfront drug acquisition costs and selecting therapy with the longer-term objective of achieving deep molecular response and TFR eligibility. Earlier use of asciminib may therefore represent a rational, albeit as yet unproven, strategy to increase TFR eligibility. Whether it improves the likelihood of maintaining remission after treatment discontinuation remains unknown, as TFR is also influenced by residual leukemic stem cells, immune surveillance, and underlying disease biology.

Treatment Sequencing After Asciminib

When asciminib treatment fails, it is important to distinguish intolerance from resistance, as subsequent management differs. Intolerance generally allows transition to another TKI, whereas resistance requires mutation-guided therapy based on ABL1 kinase-domain alterations. Treatment-emergent BCR::ABL1 mutations remain relatively uncommon (5%) but may be more heterogeneous in later-line disease.¹⁹

In ASC4FIRST (frontline setting), resistance to asciminib most commonly involved myristoyl-pocket mutations (eg, A337T, F497L, L340Q), which selectively reduce asciminib sensitivity but usually remain responsive to ATP-site TKIs such as dasatinib, bosutinib, or ponatinib.^19,49,50 In later-line disease, resistance more often involves ABL1 kinase-domain mutations, including M244V and F359 variants, which can disrupt interaction between the myristoyl and ATP-binding sites and may produce partial cross-resistance across inhibitor classes.^51,52 In these cases, mutation-guided therapy is essential to limit clonal evolution (Figure 3).

Figure 3.

ELN2025/NCCN2027 recommendations for actionable mutations.^1,53 ✓ indicates a TKI considered appropriate for the indicated mutation; X indicates a TKI not recommended because the mutation is associated with resistance or reduced sensitivity. Blank cells indicate that no specific mutation-directed recommendation is shown. (*) Asciminib used at higher dose of 200 mg BID.

Abbreviations: BID, twice daily; ELN, European LeukemiaNet; NCCN, National Comprehensive Cancer Network.

Expert opinion: Emerging data suggest that high-potency ATP-site TKIs, particularly dasatinib and ponatinib, can suppress some asciminib-resistant clones, although outcomes depend on overall mutational burden and clonal complexity.^51,52 Most mutations detected after asciminib failure are not directly actionable; only a limited subset (eg, T315I/A, F359 variants, E255K/V, Y253H, V299L) currently guide treatment switching.^1,54,55 Early detection is critical, as low-level resistant clones (eg, M244V, E255K) may expand under treatment pressure before becoming detectable by Sanger sequencing.^52,54 Accordingly, ABL1 mutation testing may be performed before initiating asciminib in later lines and repeated at loss of response. Next-generation sequencing (NGS) is preferred when available because of its greater sensitivity (≈1–5%), while digital droplet polymerase chain reaction (ddPCR) may allow highly sensitive monitoring of known mutations.^56,57 This has particular practical relevance in Canada, where access to sensitive BCR::ABL1 mutation testing is not uniform and testing remains centralized. Moreover, conventional kinase-domain assays may not interrogate the myristoyl-pocket region implicated in asciminib resistance, creating a need for validated assays that extend beyond the ATP-binding kinase domain. Broader and more standardized access to appropriately designed NGS-based testing across Canada may therefore facilitate earlier identification of actionable resistance and help preserve subsequent treatment options.

Asciminib in T315I-Mutated CML

T315I represents a special case among actionable mutations because it confers resistance to all first- and 2G ATP-competitive TKIs. Ponatinib remains the most extensively studied therapy in this setting, with the PACE trial demonstrating substantial and durable responses in patients with T315I-mutated CML.⁵⁸ Its use, however, has historically been limited by cardiovascular toxicity, particularly arterial occlusive events. More recent data from OPTIC suggest that a response-adapted dosing strategy (initiating ponatinib at 45 mg/day and reducing to 15 mg/day after achieving BCR::ABL1 ≤1%) can improve the benefit/risk profile while preserving efficacy, including in patients with T315I-mutated disease.⁵⁹

While ponatinib has historically been the primary option, asciminib also demonstrates clinically meaningful activity at higher doses (200 mg BID).⁶⁰ Although AEs were more frequent with the higher dose, treatment discontinuation due to toxicity was uncommon (6%), supporting a manageable safety profile. Based on these results, asciminib 200 mg BID was approved in the US and Europe (but not in Canada) for T315I-mutated chronic-phase CML. Since then, after a median 3.5 years of asciminib exposure, 53.3% of evaluable patients achieved MMR, including 73.7% of ponatinib-naïve and 38.5% of ponatinib-pretreated patients.⁶¹ Importantly, responses were durable, with no new safety signals identified.⁶¹ Consistently, in a real-world Italian managed-access cohort, the 3-month DMR rate was 60% in the 11 patients with T315I, all of whom had prior ponatinib exposure, with low discontinuation due to intolerance or resistance (2.6% each in the overall cohort).⁶²

Expert opinion: In practice, asciminib may represent a reasonable option for patients in whom ponatinib is undesirable, although treatment choice should be individualized in the absence of direct comparative data. Ponatinib remains the reference therapy for T315I-mutated CML because of the largest body of clinical evidence and longest follow-up, whereas asciminib expands therapeutic options for T315I-mutated CML by providing a mechanistically distinct alternative, particularly for patients in whom ponatinib is unsuitable due to cardiovascular risk or intolerance. In Canada, however, access to asciminib for T315I-mutated CML remains a particular challenge. Unlike the United States, the current Health Canada monograph does not include a T315I-specific indication or the 200 mg twice-daily regimen evaluated in this population.

ASXL1 Somatic Mutations

ASXL1 mutations are detected in approximately 5–10% of patients with chronic-phase CML at diagnosis, but their clinical significance remains incompletely defined.⁶³ Current evidence suggests that ASXL1 acts primarily as a risk modifier rather than a direct driver of resistance.⁶³ ASXL1 mutations often reflect underlying clonal complexity or genomic instability. In some cases, these variants arise in BCR::ABL1-negative clones, consistent with age-related clonal hematopoiesis, and may not be directly related to CML biology.

Available data indicate that ASXL1 mutations do not preclude response to asciminib, but may be associated with a higher risk of treatment failure and subsequent development of BCR::ABL1 mutations over time.^64,65 Exploratory analyses from ASC4FIRST showed that most baseline ASXL1 clones were cleared during therapy (74%, 29/39 patients), and treatment failure was more common among patients with persistent ASXL1 mutations (5/6 patients) than those with mutation clearance (4/29 patients; P=0.03).⁶⁶ Importantly, the adverse prognostic effect of ASXL1 was observed across both asciminib and investigator-selected TKI arms, indicating that ASXL1 is not a therapy-specific resistance factor.

Expert opinion: ASXL1 mutations should not be considered a contraindication to asciminib but may serve as a risk marker warranting closer molecular monitoring and consideration of repeat genomic testing if response becomes suboptimal. In Canada, where access to broad NGS-based profiling in CML remains variable, ASXL1 status should therefore be used to refine risk assessment when available rather than as a prerequisite for treatment selection.

Principles of Individualized TKI Selection in Contemporary CML Practice

Initial TKI Selection

Long-term outcomes in CML depend not only on molecular efficacy but also on treatment persistence, which may be limited by chronic low-grade toxicities and evolving comorbidities. Initial TKI selection is guided by baseline disease risk (ELTS or Sokal score) and patient goals, such as prioritization of rapid deep molecular response or TFR eligibility.^67,68 Patients with low-risk disease may reasonably prioritize long-term tolerability, whereas those with higher-risk disease or explicit TFR goals may favor agents associated with faster and deeper molecular responses. Comorbidities, including CV, pulmonary, metabolic, and drug–drug interaction risks, also remain key considerations (Figure 4).

Figure 4.

Summary of TKI characteristics to guide individualized therapy.

Abbreviations: 1L, First-line; 2G, Second-generation; 3L+, Third-line or later; AE, Adverse event; ASCVD, Atherosclerotic cardiovascular disease; BID, Twice daily; CV, Cardiovascular; DMR, Deep molecular response; GI, Gastrointestinal; MMR, Major molecular response; OSA, Obstructive sleep apnea; QOL, Quality of life; QT, QT interval; TFR, Treatment-free remission; TKI, Tyrosine kinase inhibitor; VTE, Venous thromboembolism.

The emergence of asciminib raises the possibility that the traditional comorbidity-driven framework may evolve. In ASC4FIRST, asciminib demonstrated favorable efficacy and tolerability across prespecified clinical subgroups, including ELTS risk and baseline CV risk categories.^19,20 These findings suggest that asciminib could function as a broadly applicable frontline option rather than being restricted to specific clinical phenotypes. However, confirmation of this potential paradigm shift will require longer follow-up, broader real-world experience, and consideration of system-level factors such as access and cost.

Treatment Adaptation and Sequencing

Beyond initial agent selection, treatment strategies frequently evolve over time in response to intolerance, suboptimal response, or emerging resistance. In the 2L setting, asciminib may be particularly attractive for patients switching because of intolerance, where sequential cycling among ATP-site TKIs often reproduces toxicity without meaningfully improving disease control. Introducing a mechanistically distinct inhibitor at this stage may allow continued disease control while limiting cumulative toxicity. In later-line disease, asciminib is frequently considered alongside ponatinib for resistant CML. While indirect comparisons have not demonstrated clear efficacy superiority for either agent, ponatinib may be favored in selected high-risk situations requiring rapid cytoreduction, whereas asciminib may be preferred in patients with elevated CV risk given its more favorable vascular safety profile.

Dose optimization also plays an important role in maintaining long-term treatment tolerability. Alternative dosing approaches for several ATP-site TKIs have improved safety without compromising disease control. For example, low-dose dasatinib (50 mg daily) reduces pleural effusion and hematologic AEs while maintaining efficacy, and response-adapted dosing has transformed ponatinib use by mitigating vascular risk once BCR::ABL1 levels fall below 1%.^69–71 Similar strategies, including bosutinib dose titration and imatinib or nilotinib dose reductions after response achievement, reflect a broader shift toward identifying an “optimal biologic dose” for long-term therapy.⁷² In contrast, published data on dose-modification strategies for asciminib remain limited, although further insights are anticipated from ongoing clinical trials and real-world experience.

Taken together, these considerations support a dynamic treatment framework rather than a static choice of TKI. As illustrated in Figure 5, expert management emphasizes selection of a safe and effective initial agent informed by disease risk and comorbidity filters, close molecular monitoring, early intervention for intolerance through dose optimization, and mutation-guided switching when response becomes suboptimal.

Figure 5.

CML TKI selection and troubleshooting pathway.

Abbreviations: CV, Cardiovascular; GI, Gastrointestinal; MoA, Mechanism of action; TFR, Treatment-free remission; TKI, Tyrosine kinase inhibitor.

Future Directions for Asciminib

Combination Strategies

Combining TKIs in CML has long been explored to deepen molecular responses and reduce resistant clones by targeting different regions of the ABL1 kinase. Preclinical studies show that simultaneous inhibition of the ATP-binding site and the myristoyl pocket can achieve more complete BCR::ABL1 suppression than either approach alone.¹⁴ However, translating this strategy into clinical practice has been challenging due to additive toxicity, particularly when full-dose ATP-site TKIs are maintained.⁷³ This limitation was highlighted in FASCINATION, where deeper molecular responses were observed but tolerability became a key constraint when asciminib was added to standard-dose imatinib or 2G TKIs.⁷⁴ In contrast, ASC4MORE suggests that an asciminib add-on strategy to imatinib may represent a more favorable approach in selected patients, achieving higher rates of deep molecular response and treatment persistence than switching to nilotinib, with a manageable tolerability profile, although this strategy remains investigational.⁷⁵

To mitigate tolerability limitations, an “inverse dosing” strategy (ie, using full-dose asciminib as the therapeutic backbone with de-escalated doses of ATP-site TKIs) has emerged as a more rational approach considering asciminib’s superior tolerability. Han et al demonstrated in vitro that the addition of asciminib enabled reduced concentrations of potent ATP-site inhibitors while maintaining or enhancing growth inhibition across wild-type and multiple ABL1 kinase-domain mutant models, including M244V.⁷⁶ Several ongoing clinical studies, including ASCEND-CML (Australasian Leukaemia and Lymphoma Group chronic myeloid leukemia 13 [ALLG CML13]) and ASCENDANCE, are now exploring this strategy by evaluating asciminib-based backbones with selective addition of ATP-site TKIs in the frontline setting.^77,78 At present, combination strategies may ultimately be most relevant in higher-risk disease beyond chronic myeloid leukemia in chronic phase (CML-CP), where treatment is time-limited and treatment intensification may be justified, with early data suggesting activity of asciminib-based combinations in these settings.^79,80

Special Populations: Pregnancy, Fertility, and Pediatric CML

Management of CML in special populations—including pregnancy/fertility, and pediatric disease—requires balancing disease control with long-term safety. During pregnancy, TKIs are generally avoided because of potential teratogenicity. Management typically involves planned conception in patients with stable deep molecular response, interruption of TKI therapy during early pregnancy, and use of interferon if treatment is required.¹ While imatinib and, in selected cases, nilotinib have been cautiously reintroduced after organogenesis, other TKIs are generally avoided because of reported fetal harm or limited human safety data.^81–85 Experience with asciminib during pregnancy remains limited. In a multicenter series of 34 pregnancies with maternal exposure, 23 had known outcomes, including 12 live births (one twin pregnancy), 3 miscarriages, and 10 elective terminations following early drug discontinuation.⁸⁶ Although no clear safety signal has emerged, available data remain insufficient to define fetal risk and current guidance continues to recommend avoiding asciminib during pregnancy. This approach is consistent with a recent comprehensive review of CML management during pregnancy, with the relative evidence across TKIs summarized in Table 2.⁸⁷

Table 2.

Interpretation of Available Evidence for BCR::ABL1 Inhibitors in Selected Special Populations

TKI	Maternal Pregnancy	Paternal Conception	Pediatrics
Imatinib	●●● Most established Later use may be considered after organogenesis	●●● Reassuring Interruption generally not required	●●● Most established Extensive pediatric experience
Dasatinib	●●● Established evidence of fetal risk Avoid throughout pregnancy	●●● Reassuring Treatment interruption generally not required	●●● Established pediatric option
Nilotinib	●●○ Moderate evidence: reassuring later-pregnancy experience	●●● Reassuring Treatment interruption generally not required	●●● Established pediatric option
Bosutinib	●○○ Limited Insufficient evidence to support use	●○○ Limited	●●○ Developing Prospective pediatric data available, but clinical experience is less mature than with imatinib, dasatinib, or nilotinib
Ponatinib	●○○ Limited/concerning Preclinical fetal toxicity and concerning human outcomes; use not recommended	●○○ Limited	●○○ Limited Mainly for resistant/T315I disease
Asciminib	●○○ Limited Insufficient pregnancy experience	●○○ Limited But reassuring early experience	●○○ Limited Longer follow-up required

Notes: Symbols indicate the relative maturity of available clinical evidence: ●●● = established/extensive evidence; ●●○ = moderate/developing evidence; ●○○ = limited evidence. Symbols do not indicate treatment efficacy, safety, or a formal evidence grade.

For paternal exposure, accumulated experience across TKIs has not demonstrated increased rates of congenital anomalies in pregnancies fathered by men receiving therapy, and current guidelines do not recommend treatment interruption when men on TKIs attempt conception. Limited data specific to asciminib are reassuring. Among 13 pregnancies following paternal asciminib exposure, 11 have known outcomes, 8 resulting in live births (including one twin pregnancy) with no congenital anomalies reported; the remaining outcomes included two miscarriages and one ectopic pregnancy.⁸⁶

Pediatric CML presents distinct long-term management challenges, as treatment may extend across critical periods of growth and development. Imatinib has the most established pediatric experience, while dasatinib, nilotinib, and bosutinib are also established treatment options; current international expert recommendations support the use of first- or 2G TKIs according to disease risk and patient-specific considerations.⁸⁸ Although these agents provide effective disease control, prolonged TKI exposure has been associated with growth deceleration and potential effects on bone, endocrine, and reproductive health, underscoring the importance of long-term toxicity monitoring.⁸⁸ Evidence for asciminib in pediatric CML remains limited, but interim results from the ASC4KIDS study indicate that pediatric dosing can achieve drug exposures comparable to adults with a reassuring early safety profile.⁸⁹ Its distinct mechanism and safety profile may therefore make asciminib an attractive additional option in pediatric CML. However, longer follow-up is required to determine whether this translates into meaningful long-term safety advantages over established TKIs (Table 2).

Biomarker Testing in Risk Assessment

Beyond BCR::ABL1 transcript monitoring and established clinical risk scores, baseline cytogenetic assessment remains a mandatory component of CML evaluation, allowing identification of additional chromosomal abnormalities with prognostic significance. In parallel, there is growing interest in how co-occurring somatic mutations may influence disease biology and treatment outcomes in CML. High-sensitivity NGS studies indicate that approximately 20% of newly diagnosed patients harbor at least one additional myeloid-associated mutation, most commonly involving epigenetic regulators such as ASXL1, TET2, or DNMT3A, with smaller subsets affecting signaling or transcription factor pathways (eg, RAS, RUNX1).⁶⁴ These mutations have been associated with higher rates of treatment failure and disease progression, particularly when involving activated signaling or transcription factor pathways. However, these effects appear most pronounced in patients treated with imatinib rather than 2G TKIs. While somatic mutation profiling may identify patients with higher biological risk, and may argue against very conservative frontline strategies such as low-intensity imatinib in younger or high-risk patients, it does not currently define a specific treatment algorithm or mandate selection of asciminib or a particular ATP-site TKI. Accordingly, the most pragmatic approach is to view co-occurring somatic mutations as risk modifiers rather than deterministic biomarkers. Their presence should prompt closer molecular monitoring, heightened vigilance for suboptimal response, and a lower threshold for repeat genomic reassessment, particularly in the setting of delayed molecular milestones or emerging resistance.

Conclusion

Asciminib represents an important advance in CML therapy as a mechanistically distinct option that provides effective molecular responses and a favorable safety profile compared with ATP-site TKIs. Low discontinuation rates across trials and emerging real-world experience highlight its value in settings where treatment persistence and quality of life are critical to long-term outcomes. Growing understanding of resistance biology, including myristoyl-pocket mutations, ABL1 kinase-domain alterations, and co-occurring mutations, underscores the importance of sensitive mutational testing to guide treatment sequencing and limit clonal evolution. Although questions remain regarding its impact on TFR and its role in resistant disease, asciminib expands the therapeutic landscape and enhances choice in an individualized approach to CML management.

Funding Statement

No author has received compensation for the writing of this paper. liV Agency Inc. received an unrestricted educational grant to support logistics and medical writing from Novartis Pharmaceuticals Canada Inc.

Ethics/Consent Statement

All experts whose perspectives are included in this manuscript have provided informed consent for publication of their views. Consent forms have been obtained and are available upon request from the corresponding author.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, manuscript design, execution, literature search, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Dennis Dong Hwan Kim reports Support for the manuscript from liV, Medical Education Agency, during the conduct of the study; Grants or contracts from Pfizer, Enliven Therapeutics, AbbVie, Ascentage, Sanofi, Novartis; Consulting fees from Ascentage, Daiichi Sankyo, Astellas, AbbVie, Sanofi, Novartis; Honoraria from Enliven Therapeutics, Novartis, Sanofi; Meeting/travel support from Sanofi, BeOne; Data safety/advisory board participation from Ascentage, Sanofi, Novartis, outside the submitted work. Lambert Busque reports Support for the manuscript from Novartis, during the conduct of the study; Grants or contracts from Novartis; Consulting fees from Takeda, Novartis; Honoraria from Novartis, outside the submitted work. Christopher Hillis reports Honoraria from Novartis; Leadership or fiduciary roles from Canadian Hematology Society, outside the submitted work. Pierre Laneuville reports Support for the manuscript from Novartis, during the conduct of the study; Honoraria from Novartis; Data safety/advisory board participation from Novartis; Equipment/materials/services from Novartis, outside the submitted work. Mary Lynn Savoie reports Support for the manuscript from Novartis, during the conduct of the study; Consulting fees from Jazz, BMS, Novartis, outside the submitted work. The authors report no other conflicts of interest in this work.