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Michael J. Mauro, MD, discusses the variety of TKIs available for chronic myeloid leukemia management and how to navigate new formulations.
TKIs have proliferated within the chronic myeloid leukemia (CML) treatment paradigm, with second- and third-generation agents, in addition to alternative formulations, presenting patients with CML with more diverse options, according to Michael J. Mauro, MD.
Mauro specifically highlighted the FDA approval of the generic, small molecule formulation of dasatinib (Phyrago) for patients with CML and acute lymphoblastic leukemia, which is the only approved formulation of the TKI that can be administered concomitantly with proton pump inhibitors (PPIs) and H2 receptor antagonists intended to help patients manage acid reflux.1
“We’ve grown accustomed to counseling patients that they need to follow a certain schedule if they have to take a drug twice a day on an empty stomach to eliminate or minimize the effect of acid blockade, for example,” Mauro said. “With [this newly approved dasatinib] formulation, we can now introduce them in the beginning [of treatment].”
In an interview with OncLive®, Mauro also dived into the phase 3 ASC4FIRST trial (NCT04971226), which evaluated asciminib (Scemblix) for the treatment of CML.2 He also touched on the roles other TKIs, such as ponatinib (Iclusig), bosutinib (Bosulif), imatinib (Gleevec), and nilotinib (Tasigna), play in CML management, and detailed ongoing research aiming to refine TKI use for this patient population.
Mauro is an attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.
Mauro: Managing a patient with CML, at present in 2026, is what we call it a spoil of riches. We have a number of different choices, and a lot depends on where [patients are] at in the course of [their disease]. The most important decision is: how do we choose a frontline therapy, when we have multiple approved options?
We have some compelling data from a recent study, the ASC4FIRST trial, which looked at asciminib vs imatinib or other second-generation TKIs, [and asciminib superiority] was the case. In a well-designed trial, we saw that asciminib offered a lower adverse effect [AE] profile and superior response, which puts it at the top of our list.2 There are questions that people have regarding long-term safety [of asciminib in CML], which should be resolved by looking at long-term data from the phase 1 study [NCT02081378], where we have more than 10 years [of follow-up].
Of course, we also have other [TKIs available in CML] that are viable. We have our second-generation TKI dasatinib, which is the best option based on risk/reward, flexibility, and [the fact that] it's a TKI that can be started at lower doses. Lower doses can be easily adapted if a patient has tolerability issues or if they have a preference.
Other second-generation TKIs are also good in the frontline and offer advantages, but they also [feature] different AEs. We want to steer away from serious and morbid AEs like cardiovascular [AEs]. Imatinib, which was our original TKI, has the longest safety [follow-up, in addition to being] available as a generic. [Imatinib] offers good efficacy and predictable safety.
Frontline therapy is complicated—probably the most complicated [for TKI selection in CML]. [After considering each available TKI,] we look at response, comorbidities, and mutations. [The role of mutations is] becoming a bit more of a prominent story with more use of asciminib, where we have a more selective resistance profile. We don't see more resistance [to asciminib], but we do see a more selective and perhaps a more TKI mutation–dominant resistance signature. [There is also a] question about secondary mutations in the myeloid genome spectrum outside [BCR-ABL1] that may be relevant to choosing a TKI and how a patient is responding.
The patient has to be part of this [treatment] discussion because this is a long journey. It's like running a marathon, [thus] fully assessing the patient's comorbidities, particularly their cardiovascular status, seeing where they're at in their disease course, [and having a] full discussion and communication during treatment [is necessary] because intolerance is an equal challenge to clinical response and clinical benefit. Making careful decisions and striking that balance [between efficacy and safety] is probably the most important thing to remember when approaching TKI selection in CML.
The story of TKI development with CML unfolded with the first principle about developing a small molecule inhibitor against BCR-ABL1. Imatinib was the canonical prototype molecule [for TKIs in CML], which turned out to be safe, highly effective, and revolutionary. [Imatinib is] what we call an active site inhibitor, [which] binds the ATP binding pocket.
[Following imatinib], we developed second-generation ATP competitive inhibitors, which were dasatinib, nilotinib, and bosutinib. [The second-generation agents] have different properties with regard to the way they bind the BCR-ABL1 kinase domain. They also have different AEs, which is where the risk:benefit analysis comes into play.
Imatinib has a predictable AE profile, where musculoskeletal symptoms, gastrointestinal [GI] AEs, and fluid retention [are] challenges to consistent use and the patient quality of life, rather than significant or morbid AEs. As we got into the second- and third-generation inhibitors, we started to see questions about morbid AEs, such as vascular AEs, including vascular occlusion, and pleural and pericardial complications. With bosutinib, we saw more intense versions of the AEs seen with imatinib, such as more intense GI toxicities and liver enzyme elevation.
We then developed the third-generation TKIs, and ponatinib tried to solve the question: what do we [to combat] selective resistance with the presence of a BCR-ABL1 T315I mutation? T315I mutations make binding of the ATP pocket complicated. [However], via a different molecular structure and binding at the active site, ponatinib was able to overcome this mutation and not have any mutations for which resistance would be expected. [Ponatinib] offered a tremendous advantage for patients with highly resistant or heavily pretreated disease.
[Ponatinib,] of course, was studied all the way into the frontline, but unfortunately, the AE profile for the drug carried forward into earlier lines of therapy, [prompting us] to halt those trials. [Thus,] we still relegate ponatinib to later-line therapy when most [other] drugs have already been used, where it serves patients well but has the highest risk of cardiovascular and vascular occlusive AEs.
Asciminib is in its own class. It specifically targets the myristoyl pocket, [which] is another region in the BCR-ABL1 kinase domain that is targetable and was known from the beginning to be a way to essentially inactivate BCR-ABL1. By correcting a defect called the myristoyl pocket, which occurs with BCR-ABL1 fusion, [asciminib] essentially puts the kinase into an inactive state, generating programmed cell death.
Eventually, oral, safe, small molecules were developed. The biggest challenge moving forward now is going to be: how do we use [these TKIs] together? How do we choose [between all TKIs]? There are also other drugs in development, including novel allosteric inhibitors. For a while, we have seen the search for a better active site inhibitor, and there's some good candidates that are far along in clinical development.
In addition to the continued development of specific and alternative approaches to BCR-ABL1 inhibition, we've seen a nice addition with multiple alternative formulations of available drugs. We've seen approval of alternative forms of nilotinib, which are able to be taken without food exclusion. Importantly, we have a [newly approved] formulation of dasatinib, with several others in development [The generic, small molecule approval of dasatinib now allows patients to have concomitant therapy to block stomach acid and correct for stomach pH through histamine blockade or more commonly PPI.
[These formulations] allow for a patient to overcome barriers. It can often be a challenge to getting full adherence, absorption, and effect from their TKI. [Full absorption and adherence to TKIs] can be unknowingly or knowingly undermined by concomitant medications, dosing difficulties, and requirements such as fasting.
[There is also] an oral liquid formulation of imatinib, which could be a very significant advance for pediatric patients or older patients who might have issues with the mechanics of oral medications. [Ultimately, there] will be more to come, and this is an important space to develop—not just to develop better and more potent TKIs, but rather to optimize the drugs and compounds that are already available.
If a patient needs a drug for their CML and there's an alternative formulation, at present, with multiple iterations available, a discussion is always important. We’ve grown accustomed to counseling patients that they need to follow a certain schedule if they have to take a drug twice a day on an empty stomach to eliminate or minimize the effect of acid blockade, for example. With [the newly approved dasatinib] formulation, we can now introduce [PPIs] in the beginning [of treatment]. We have our standard formulations, which have certain requirements, and if that isn't feasible, one can quickly pivot to alternate formulations.
What is most important is looking at the bulk of patients who remain on treatment who may have questions about their ability to easily and effectively take their drug, [in addition to] raising awareness. There may not be as much awareness of these novel agents, which are in the mix with generic forms of dasatinib and may not be as well understood. There is different dosing, for example, for one of the alternative formulations of nilotinib, and there's different dosing for certain forms that may be developed regarding dasatinib. We don't want confusion about the dose; we want to make it clear that we have multiple options and want to prescribe the right drug for the right patient and circumstance.
We now have a new class of therapy with allosteric inhibitors, which we've seen better efficacy and safety [early in development]. The holy grail for CML is: can we increase the cure fraction if we're able to increase the number of patients who are eligible for what's called a treatment-free remission? [Treatment-free remissions are] when patients have had sufficient length of treatment and deep remission that meets defined requirements, who then elect to be closely monitored off therapy.
There's some speculation that asciminib, for example, may increase the success of treatment-free remission for patients with the same remission they might have achieved with one of our earlier-generation TKIs. This remains to be proven, but it is exciting to think about.
Despite better and safer drugs, we still have patients with resistance and intolerance. [Thus,] continued development of alternate active site inhibitors [is important]. I'm excited about a drug [ELVN-001] from a company called Enliven Therapeutics, which is an ATP competitive agent and is moving through trials nicely, proving to be safe and highly effective in challenging cases.
We have drugs that are in similar spaces, that have been approved outside the US, such as olverembatinib, which has been studied primarily in Asia but requires further scrutiny and may have some unique features regarding its dosing and AEs. Alternative allosteric inhibitors are the [fastest-growing] area of development. We have a nice dossier from a company called Terns Pharmaceuticals with a drug TERN-701, which may offer advantages over asciminib. With data in patients who had previous asciminib and ponatinib exposure, the patients seem to be doing quite well comparatively with earlier data. We may have a second version of allosteric inhibitors that could offer advantages over asciminib. There are other allosteric inhibitors in development, as well.
We’re not done. We have still unmet needs, particularly in the fact that the more options we have for our patients, the better this spoiler riches will be for our patients, [so we can] offer them as many options as we can. CML should be a highly treatable and functionally curable disease, and the more options we have, the better.
Treatment for CML is like a marathon. You have to be prepared, knowledgeable, thoughtful, and patient. You have to check in along the way because [CML seems] like it may be easy to treat, but we get lost sometimes when we're not paying attention to AEs or response trajectories. We want we want to stay on course, stay in the game, engage in dialogue, and follow-up [with patients to ensure] tremendous success.
