Reconsidering dual BCR::ABL1 inhibition in Philadelphia chromosome-positive acute lymphoblastic leukemia: is sequential better than concurrent?

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is a biologically distinct subtype that has long been associated with a poor prognosis. The BCR::ABL1 fusion oncogene confers aggressive disease behavior, and its prevalence increases with age, complicating disease management due to treatment-related toxicity (1). Over the past two decades, the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes compared with conventional cytotoxic chemotherapy alone (Table 1). However, relapse remains a substantial clinical problem, and many patients ultimately require allogeneic hematopoietic stem cell transplantation (allo-HSCT), underscoring the need for continued therapeutic refinement (16).

Luskin et al. recently reported in Blood the results of a phase I trial evaluating the combination of asciminib and dasatinib in patients with Ph+ ALL and chronic myeloid leukemia in the lymphoid blast phase (CML-LBP) (15). Dasatinib is a second-generation adenosine triphosphate (ATP)-competitive TKI that binds to both the active and inactive conformations of ABL1, providing rapid and potent inhibition of BCR::ABL1 signaling. It maintains activity against most imatinib-resistance mutations, except for the T315I gatekeeper mutation (17). In contrast, asciminib is the first-in-class Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibitor, which allosterically suppresses BCR::ABL1 activity independently of the ATP-binding site (18). By pairing two TKIs with distinct binding modes, investigators have aimed to enhance the suppression of BCR::ABL1 signaling and potentially limit clonal evolution. This study represents an important proof of concept for dual BCR::ABL1 inhibition using mechanistically complementary agents. Simultaneously, the results prompted critical consideration of how best to administer asciminib in patients with Ph+ ALL, particularly regarding dosing, sequencing, and patient selection.

Overview of the Luskin et al. study

The phase I trial enrolled 24 patients, including 22 with Ph+ ALL (16 expressing p190 BCR::ABL1 and six expressing p210) and two with CML-LBP. The patients received dasatinib 140 mg daily and prednisone 60 mg/m² daily in combination with escalating doses of asciminib. After the 28-day induction phase, dasatinib and asciminib were continued until allo-HSCT or until treatment was discontinued. The median patient age was 64.5 years, reflecting a population in which treatment-related toxicity poses a significant challenge.

The recommended phase II dose (RP2D) of asciminib was established at 80 mg daily, which is notably lower than the 160–400 mg daily dose required as monotherapy to overcome the T315I mutation. Importantly, this chemotherapy-free backbone with prednisone minimizes treatment-related mortality, particularly in older patients who are often ineligible for intensive chemotherapy. Among the newly diagnosed patients with ALL, complete hematologic remission (CHR) was achieved in 84% by day 28 and 100% by day 84. Although reverse transcription quantitative polymerase chain reaction (RT-qPCR) detected BCR::ABL1 levels <0.1% in 74% of patients, the rate of deeper molecular response (<0.01%) was only 26%. In addition, 89% of the patients were classified as minimal residual disease (MRD)-negative by flow cytometry at the same sensitivity level, which underscores the urgent need for standardized molecular assessments in dual TKI therapy. Overall, dual TKI therapy was feasible, although adverse events such as pleural effusions led to dose reductions in some patients.

However, with a median follow-up of 26.9 months, hematologic relapse occurred in both CML-LBP patients and three Ph+ ALL patients. Notably, emergent T315I mutations were detected in two of these five cases, highlighting the continued difficulty of fully suppressing this resistance mechanism at the current dosage.

Biological rationale for dual BCR::ABL1 inhibition

The clinical rationale for dual inhibition lies in the distinct yet complementary ways these agents neutralize the BCR::ABL1 oncoprotein. While dasatinib rapidly debulks the leukemia by competing for the ATP-binding site, allosteric modulation by asciminib restores the protein’s physiological self-inhibition. By simultaneously or sequentially targeting these two independent regulatory nodes—the ATP-binding site and the myristoyl pocket—the goal is to achieve a more profound vertical inhibition of the kinase activity and prevent the selection of resistant subclones. Beyond direct enzymatic blockade, dasatinib also inhibits Src family kinases (e.g., LCK and FYN) that may further enhance the anti-leukemic effect by reducing regulatory T-cell-mediated immunosuppression (19). In contrast, asciminib exhibits high selectivity for ABL1 with minimal off-target kinase inhibition (18). Since this combination does not excessively impair effector T-cell function, it potentially maintains a favorable immune microenvironment for long-term disease control. However, these immunological benefits remain largely theoretical in the clinical setting and require further validation.

Efficacy signals and unresolved concerns

Despite a strong biological rationale, several aspects of the clinical results warrant careful consideration. Preclinical studies have suggested synergistic antileukemic effects of dasatinib and asciminib owing to their distinct binding sites; however, other reports have indicated potential antagonism, and a consensus has not been reached (20-23). Although the study by Luskin et al. was not designed to formally assess efficacy, the molecular response rate of 26% at day 84 was comparable to, rather than superior to, that reported in prior studies of dasatinib combined with corticosteroid monotherapy (2,9-13).

Moreover, the emergence of T315I-mutated clones remains a primary driver of resistance in dasatinib-based regimens, accounting for the majority (~70%) of relapses with detectable ABL1 kinase domain mutations in this setting (6,9,11). In the current trial (15), T315I mutations were detected in two of the five patients who experienced hematologic relapse, underscoring the clinical relevance of this resistance pathway, even in the setting of dual TKI therapy. Although higher doses of asciminib may be required to effectively suppress T315I-mutated clones (24), such escalation must be balanced against safety considerations.

At the highest tested dose of asciminib (160 mg once per day), asymptomatic grade 3 pancreatic enzyme elevation was observed without clinical pancreatitis. This toxicity was classified as dose-limiting and led to the selection of a lower RP2D. Notably, pancreatic enzyme elevations associated with asciminib typically resolve with treatment interruption alone and often permit the subsequent reintroduction of therapy. Refined toxicity management, such as dose-titration strategies, may enable the use of higher asciminib doses, potentially reconciling the need for safety with the requirement for more potent T315I suppression.

Concurrent versus sequential TKI strategies: a case for rethinking timing

A central question raised by Luskin et al. was whether the concurrent administration of two TKIs from treatment initiation represents the optimal strategy in Ph+ ALL. An alternative approach, the sequential use of TKIs, merits serious consideration.

The rationale for the sequential strategy is supported by the observation that T315I-driven failures during the induction phase are exceedingly rare (9-12). Similarly, several studies have consistently demonstrated high complete remission rates during induction, even with reduced-intensity regimens (2,3,5,6,9-13). For example, studies conducted by GIMEMA and JALSG using prednisone alone and those conducted by CALGB using prednisone plus vincristine and daunorubicin during induction demonstrated rare early mortality and preserved hematological efficacy, underscoring the safety of less intensive induction approaches (9-11).

Importantly, the GIMEMA study demonstrated that post-remission strategies critically influenced long-term outcomes (2). Although induction therapy was effective, relapse rates varied substantially depending on subsequent treatments. Patients who received no further therapy or dasatinib alone after induction experienced the highest relapse rates, whereas those who underwent allo-HSCT had the lowest relapse rates, and chemotherapy plus dasatinib yielded intermediate outcomes. The MRD analyses suggested that insufficient tumor burden reduction after induction was associated with a higher risk of relapse, emphasizing the importance of optimizing post-remission therapies.

Imatinib binds exclusively to the inactive conformation of ABL1, whereas dasatinib preferentially binds the active conformation and exhibits greater conformational flexibility. Dasatinib has been shown to exhibit approximately 100-fold greater inhibitory potency against BCR-ABL than imatinib in vitro, a finding that has been consistently cited in studies of Ph+ ALL (25). Based on the above, dasatinib is considered more suitable than imatinib for use as first-line induction therapy.

Synthesizing these findings, a sequential strategy is supported: employing dasatinib during the induction phase to achieve rapid CHR, followed by a transition to an agent aimed at deepening molecular responses and suppressing clonal evolution. This approach is considered more rational and potentially safer than prolonged combination therapy, as it avoids cumulative toxicities, such as elevated pancreatic enzymes, which may be exacerbated by the concurrent use of both agents.

Asciminib as a post-induction or MRD-guided therapy

In the proposed sequential strategy, dasatinib serves a dual role: achieving rapid CHR and providing central nervous system (CNS) prophylaxis, while subsequent high-dose asciminib aims to eradicate residual disease and overcome T315I-driven resistance. Many BCR::ABL1 mutations described in the literature do not involve the myristoyl pocket targeted by asciminib (26). Although the concurrent combination of dasatinib and asciminib presented by Luskin et al. represented a groundbreaking therapeutic strategy, it has failed to overcome the T315I mutation. This is because the dosages of dasatinib and asciminib at 80 mg once daily might be insufficient to eliminate clones harboring the T315I mutation. According to the results of dasatinib-based clinical trials shown in Table 1, the T315I mutation was identified in approximately 70% of relapse cases following dasatinib treatment, where mutational analysis was performed. Prospective trials have explored the switch to ponatinib in patients who fail to achieve molecular remission after dasatinib-based therapy (jRCTs041190096 and jRCTs071190036). However, ponatinib-resistant compound mutations remain a clinical challenge. Furthermore, given the high frequency of arterial and venous occlusive events associated with ponatinib—which can lead to myocardial infarction, cerebrovascular accidents, and peripheral arterial occlusive disease—the selection of a safer agent is highly desirable (27).

In this setting, allosteric inhibition by asciminib provides a unique therapeutic means to eliminate resistant subclones. A strategy of sequentially incorporating asciminib could be a promising approach, particularly in patients who do not achieve a deep molecular response after dasatinib-based induction therapy.

Notably, mutations observed in patients receiving asciminib include: (I) direct mutations within the myristoyl pocket (e.g., A337V/T, P465S, V468F, I502L, and C464W); (II) mutations at sites distant from the pocket (e.g., M244V) that indirectly induce asciminib resistance through conformational changes in the protein (28); and (III) the T315I gatekeeper mutation. While the first two types of clones may retain sensitivity to ATP-competitive TKIs such as dasatinib and could be eliminated during dasatinib induction therapy, the T315I mutation requires higher doses of asciminib. The RP2D of asciminib was established at a relatively low dose of 80 mg daily. To target the T315I mutant clones that must be overcome, a high dose of approximately 200 mg orally twice daily—based on clinical trial results in chronic phase CML—is considered necessary. The clinical outcomes of 41 patients with relapsed or refractory Ph+ ALL or CML-LBP following prior TKI therapy, who received asciminib either as monotherapy or in combination, have been reported from France (EWALL-OBS22). Among these, 34 patients received asciminib at a dose of 200 mg twice a day (BID), and 20 patients were treated with asciminib monotherapy. Nineteen patients harbored either isolated or compound T315I mutations. Of the 36 evaluable patients, 30 (83%) achieved CHR or CHR with incomplete count recovery; the corresponding rates were 88% (15/17) with ASC monotherapy and 79% (15/19) with combination therapy (29). In the protocol by Luskin et al., asymptomatic pancreatic enzyme elevation was noted as a dose-limiting toxicity (DLT), which may have been exacerbated by the concomitant use of dasatinib. In the international phase I study (30), a wide range of asciminib monotherapy doses (10–200 mg BID) was administered to patients with CML in the chronic phase (CML-CP) who were relapsed, refractory, or intolerant to two or more prior TKIs. The results showed that the maximum tolerated dose (MTD) was not reached, indicating a broad therapeutic window for asciminib. When asciminib is administered at 200 mg BID, it may be safer to use it as monotherapy in a setting of controlled lower tumor burden.

Therefore, initiating treatment with dasatinib to sufficiently reduce the leukemic clone size before introducing asciminib may allow for the use of higher asciminib dosages while avoiding cumulative toxicity. Consequently, sequencing dasatinib followed by asciminib, rather than the reverse, may be safer and is supported by more substantial clinical rationale.

Future directions

The study by Luskin et al. provides a valuable foundation for future clinical investigations; however, several critical gaps remain. A primary concern is the lack of data regarding the penetration of asciminib into the CNS. Given the high incidence of CNS involvement in Ph+ ALL, defining the role of asciminib in CNS prophylaxis and treatment is crucial. In the EWALL-OBS22 study, two isolated CNS relapses were observed, highlighting the limited penetration and efficacy of asciminib in the CNS (29). Prospective trials are required to directly compare concurrent with sequential TKI strategies, ideally by incorporating MRD-guided treatment adaptation. Therefore, future trials should prioritize standardized, high-sensitivity monitoring, such as next-generation sequencing-based MRD assessment, to resolve the discrepancies observed between current flow cytometry and RT-qPCR assays. These studies should define the optimal timing, dose, and duration of asciminib as well as the criteria for switching therapy based on molecular response.

Future trial designs should also include predefined management algorithms for asymptomatic pancreatic enzyme elevation to allow safe exploration of higher asciminib doses when clinically justified. Comprehensive molecular profiling at relapse should be systematically performed to characterize emergent resistance mechanisms and to identify patient subsets that are most likely to benefit from STAMP inhibition. The universal utility of these two TKIs in patients with or without indications for allo-HSCT remains to be validated. Considering the growing evidence that eradicating T315I subclones is essential even for patients undergoing transplantation (31), treatment regimens utilizing both TKIs hold significant therapeutic potential. Although the optimal timing of switching from dasatinib to asciminib may differ between transplant-eligible and -ineligible patients, the sequential strategy proposed here is potentially applicable to both groups, with the goal of achieving deeper molecular remission prior to transplantation in eligible patients and sustained disease control in those who are not. Finally, for the older population, strategies that reduce cumulative toxicity while maintaining potent leukemia suppression, potentially through sequential rather than concurrent TKI exposure, will be the key to improving long-term survival in patients with Ph+ ALL.

In summary, the phase I trial reported by Luskin et al. validated the clinical feasibility of combining asciminib and dasatinib in patients with Ph+ ALL, underscoring the potential of dual BCR::ABL1 inhibition at mechanistically distinct sites. However, these data require further evaluation to determine whether upfront concurrent administration represents the optimal standard of care. A sequential approach leveraging the potent induction and CNS protection of dasatinib, followed by dose-optimized asciminib to eradicate resistant subclones, may achieve a superior balance between antileukemic efficacy and cumulative toxicity. Ultimately, determining the right timing and sequencing for asciminib, combined with more sensitive molecular monitoring, will be key to improving long-term outcomes in patients with Ph+ ALL.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0219/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0219/coif). S.Y. reports receiving honoraria from AstraZeneca and Daiichi Sankyo. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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