TKIs have transformed patient outcomes in CP-CML to the point where these individuals now have a near-normal life expectancy, provided that they adhere to therapy and the molecular monitoring of their disease. Therefore, there is currently a greater emphasis being placed on maintaining quality of life (QOL) by devising strategies to minimize bothersome and severe side effects that can negatively impact adherence and long-term outcomes. The availability of multiple TKIs provides patients with a greater variety of treatment options, improving their chances of identifying a drug that is both tolerable and efficacious at a given dose. Nonetheless, a substantial proportion of patients still struggle with either resistance or intolerance to multiple TKIs.

Optimizing the TKI dose is important for mitigating side effects, maximizing adherence, and achieving favorable long-term outcomes. For many patients who are responding to TKI therapy but are dealing with unpleasant side effects, it is possible to reduce the dose and maintain efficacy. It is critical for physicians to ask their patients about side effects at each visit. The most common are bothersome lower-grade toxicities such as fatigue, musculoskeletal discomfort, gastrointestinal toxicity, and mental fog; however, there are also potentially serious cardiovascular toxicities that are associated with all TKIs aside from imatinib. For example, nilotinib has been associated with accelerated atherogenesis and ponatinib has been linked to thrombosis, although the prothrombotic mechanisms are not well characterized. In the phase 2 PACE study, which was performed in patients with CP-CML and resistance to prior TKIs, ponatinib achieved deep and durable responses, but arterial occlusive events were observed. Post hoc analyses indicated that these events were dose dependent. Further, since many patients with CML are older, age-associated comorbidities such as cardiovascular disease are relatively common. As such, there are ongoing efforts to understand cardiovascular and thrombotic risk in these individuals, as well as any influence that TKIs may have. Examples of this work are included in abstracts 2996 and 4340 from this year’s ASH meeting.

In abstract 620, Cortes et al provided a 3-year update from the ongoing OPTIC study (NCT02467270), a phase 2 trial evaluating the efficacy and safety of ponatinib using a novel response-based, dose-adjustment strategy in patients with CP-CML who were resistant to 2 or more TKIs or who harbored the T315I mutation. Results demonstrated the robust longer-term efficacy and an improved and manageable safety profile of ponatinib in a highly resistant CP-CML population. Consistent with results from the primary analysis, a ponatinib starting dose of 45 mg per day with a reduction to 15 mg per day upon attainment of BCR::ABL1 IS results of 1% or lower provided the optimal risk-benefit ratio. It remains to be seen, however, whether this dose reduction strategy will maintain responses in patients with the T315I mutation, who clearly benefit from a starting dose of 45 mg daily.

The very first of the post-approval dose optimization studies was actually a trial of dasatinib, and now other US Food and Drug Administration (FDA)–approved TKIs are also being studied at doses and schedules that differ from those in the initial registrational trials. Of course, a “one-size-fits-all” approach seems overly simplistic, and it is reasonable to pursue the individual tailoring of doses to maintain efficacy and improve QOL.

The recently FDA-approved TKI asciminib appears to be quite well tolerated, although more mature data from randomized studies will be required to assess how its profile compares with other TKIs. Unlike the 5 other TKIs that are FDA approved for CML, asciminib targets a distinct pocket within the BCR::ABL1 kinase. This pocket appears to be relatively unique to the ABL1 kinase, and, as a result, asciminib interferes with far fewer kinases than other BCR::ABL1 TKIs in vitro. It is hoped that this will translate to an improved safety profile.

Some patients with CML who struggle with intolerance can achieve satisfactory disease control with treatment, but at the cost of an unsatisfactory QOL. Anecdotally, for at least a few of these individuals, switching to asciminib has dramatically improved their QOL. The ongoing phase 3 ASC4FIRST study (NCT04971226) is evaluating asciminib vs an investigator-selected TKI in patients with newly diagnosed Philadelphia chromosome–positive CP-CML; however, the design of this study will likely not allow for comparisons between asciminib and individual second-generation TKIs. That is, the comparator consists of a pool of patients treated with the investigators’ choice of TKI, and the extent to which imatinib-treated patients are represented in this pool will impact the rates of response and the cardiovascular toxicity of the comparator.

On the contrary, the present ASC4START trial, a phase 3b study of asciminib vs nilotinib in newly diagnosed patients with CP-CML, is expected to be more informative in this regard (abstract 3021). It is hoped that asciminib will display efficacy in the frontline setting that is equivalent or superior to second-generation TKIs but with an improved safety profile, although several years of follow-up will be necessary to demonstrate this.

The Australasian Leukaemia Lymphoma Group CML13 ASCEND-CML trial also aims to assess asciminib in the frontline setting. At ASH 2022, Yeung and colleagues reported the interim results of this single-arm study, which revealed favorable tolerability and efficacy as frontline treatment for CP-CML (abstract 79). Notably, the early molecular response rate appears to be higher than what it has been historically with second-generation TKIs, and, if this finding is accurate, it may translate to improved long-term outcomes and higher rates of deep molecular responses that can potentially improve the likelihood of achieving a treatment-free remission. Cytopenia and lipase elevations were the most commonly reported adverse events in this study, although clinically relevant pancreatitis has not been observed. Two patients developed resistance, 1 of whom had a confirmed loss of major molecular response at 9 months after reaching a nadir of 0.067% at 6 months, without evidence of a kinase domain or a myristoyl site mutation, while the other patient transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T (40%), A337V (10%), and P465S (10%), having previously achieved a BCR::ABL1 of 0.37% at 3 months.