Asciminib for Ph⁺ ALL: a step forward?

In this issue of Blood, Luskin et al present results of the first phase 1 trial combining asciminib, an allosteric BCR::ABL1 inhibitor, with the tyrosine kinase inhibitor (TKI) dasatinib for patients with Philadelphia chromosome-positive (Ph⁺) acute lymphoblastic leukemia (ALL).¹ Their dose-finding study provides firm evidence for the feasibility and safety of this drug combination for patients with newly diagnosed Ph⁺ ALL and chronic myeloid leukemia (CML) in lymphoid blast phase. Within the constraints of a phase 1 trial hematologic and molecular responses are encouraging, but response rates with established targeted therapies are similarly high, emphasizing the need for controlled, randomized trials to reliably assess its efficacy. Overall, this early phase trial provides a strong incentive for a greater focus on Ph⁺ ALL in future studies of asciminib, which so far has been systematically developed and clinically approved only for patients with CML who failed prior TKI therapy.² In the frontline setting, a single recently published, prospective, randomized phase 3 trial compared asciminib with classical TKIs for patients with CML in chronic phase.³ 

To date, 3 successive generations of conventional, ABL1-directed TKIs have played a central role in improving the outcome of patients with Ph⁺ ALL, by providing pronounced antileukemic efficacy in conjunction with limited toxicity.⁴ More recently, TKIs including dasatinib have been successfully combined with immunotherapy, most notably the bispecific T-cell engager blinatumomab, raising the possibility that cytotoxic chemotherapy and allogeneic hematopoietic cell transplantation may no longer be needed as a curative approach in all patients with this highly aggressive type of leukemia.⁵ Despite considerable enthusiasm for these TKI plus immunotherapy–based strategies, numerous patients with Ph⁺ ALL do not achieve sufficiently deep molecular responses to warrant transplant-free postremission therapy, and relapse continues to be a major cause of treatment failure.

All conventional TKIs used to treat Ph⁺ ALL inhibit the catalytic site of the BCR::ABL1 oncoprotein and thus are susceptible to the same resistance mechanisms, among which mutations in the tyrosine-kinase domain figure most prominently. Thus, although these TKIs differ in their potency, side effect profile, and the spectrum of relevant resistance mutations, the impact of second- and third-generation TKI has been more incremental, allowing a nuanced approach depending on patient characteristics and clinical context.

Asciminib’s mechanisms of action (MoAs) differs in that it does not bind to the kinase domain of BCR::ABL1 but to an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe referred to as myristoyl-binding pocket, thereby reestablishing autoinhibition of the ABL1 kinase that was lost with the BCR::ABL1 gene translocation.⁶ The rationale for combining asciminib with dasatinib in the study by Luskin et al is further supported by preclinical data showing synergistic antileukemic activity between these 2 agents, as well as non-cross-resistance to mutations. Moreover, several studies of asciminib, alone and in combination with classical TKIs, have demonstrated clinical activity in patients with CML and displayed a favorable safety profile.^6,7 However, as a caveat correctly highlighted by the authors in their discussion, some preclinical data suggest that asciminib and dasatinib might not be synergistic and maybe possibly even be antagonistic.⁸ These conflicting results could have a methodological basis but need to be considered in the design of future studies. Although the responses observed in the current study are encouraging, its design as single-arm phase 1 trial precludes any assessments of synergy, neutral effects, or antagonism between the 2 drugs.

Mutational analysis of 5 patients with overt or molecular relapse revealed the T315I mutation in 2 cases. None of the myristoyl-binding site mutations expected to convey resistance to asciminib were detected, although the sequencing panel only covered mutations previously linked to asciminib resistance. The importance of comprehensive mutational analyses during such clinical trials is highlighted by a recent report that several TKI resistance mutations located in the BCR::ABL1 kinase N-lobe, distant from the asciminib-binding pocket, unexpectedly confer in vitro resistance to asciminib.⁹ 

Detection of the T315I mutation is relevant because the recommended phase 2 dose (RP2D) of asciminib was determined to be 80 mg daily, which is well below the 160 mg daily required to overcome T315I-mediated resistance in CML. It would have been of interest to see whether the plasma levels at the 80-mg dose were above or below the 50% inhibitory concentration for T315I, but the study did not include pharmacokinetic analyses. Likewise, asciminib levels in the cerebrospinal fluid were not measured, which would have addressed whether the drug could pass the blood-brain barrier, an issue of special interest for patients with ALL. The continued importance of administering central nervous system (CNS)-directed intrathecal chemotherapy to prevent CNS relapse in patients with Ph⁺ ALL cannot be overemphasized.

This too low RP2D is attributable to lipase elevations in numerous patients receiving asciminib 160 mg daily in combination with dasatinib 140 mg daily that met the criteria for dose-limiting toxicity, defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4 as any grade 3 or higher elevation (>2× upper limit of normal) of amylase or lipase even in the absence of clinical symptoms. This is unfortunate as safety data generated in other trials and real-world experience show that modest elevations of lipase and amylase are frequent but transient and very rarely associated with clinical pancreatitis. As the authors correctly point out, future studies of asciminib in ALL should investigate higher doses of asciminib, in recognition of the importance of preventing resistance associated with mutations such as T315I. In the context of T315I-mediated resistance, combined asciminib and ponatinib therapy may have superior efficacy against this and other high-resistance BCR::ABL1 mutations.¹⁰ 

The dramatic improvements in treatment of patients with Ph⁺ ALL have been achieved first and foremost by combining highly effective drugs with different MoAs and low or modest toxicity as first-line induction therapy. The article by Luskin et al provides the foundation for the design of future studies for Ph⁺ ALL in which a third targeted agent is added to a classical TKI-blinatumomab doublet as induction therapy. Moreover, although this study was devised exclusively as an induction trial, asciminib should also be explored as a component of postremission regimens.

Conflict-of-interest disclosure: F.L. declares consultancy with and honoraria from Bristol Myers Squibb, Incyte, and Celgene and consultancy with and honoraria and research funding from Novartis. O.G.O. declares consultancy with and honoraria from Incyte; consultancy with and honoraria and research funding from Novartis; and consultancy with and honoraria from Autolous.