With multiple TKIs available for chronic myeloid leukemia (CML) management, careful drug selection, genetic testing, and dosing strategies are key to maximizing deep remission opportunities, maintaining adherence, and prioritizing safety, according to Michael J. Mauro, MD.
“CML can be a busy disease to manage, and I hope we all continue to work together to optimize guidelines, [facilitate] communication between patients and providers, and use all the tools we have available to us in the current era, [including] molecular testing, technology, and even artificial intelligence, to help streamline and optimize decision-making and management in CML,” Mauro said in an interview with OncLive®.
In the interview, Mauro discussed the evolution of TKIs like ponatinib (Iclusig), asciminib (Scemblix), and others for CML management, including their association with high remission rates and relatively tolerable toxicity profiles. He noted unmet needs for patients with CML, including the goal of increasing deep remission rates and developing treatment strategies that lead to cures. Mauro also described factors for TKI selection, ways that genetic mutations influence treatment efficacy, dosing strategies for TKIs to enhance treatment adherence, and the importance of ongoing research in this disease.
Mauro is an attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.
OncLive: How have TKIs shaped the CML treatment paradigm? What unmet needs remain for these patients?
Mauro: TKIs for CML represent the first example of rationally designed targeted cancer therapy using a small molecule inhibitor. The project started back in the 1990s with the recognition of the potential target, BCR::ABL, that [researchers] seeking a small molecule inhibitor, mainly my mentor, Brian Druker, MD, [of Oregon Health & Science University in Portland], and others, had conceptualized. [2025] marks the 25-year anniversary of the advent of TKIs for CML with the [start of enrollment for the phase 3 IRIS trial (NCT00006343) evaluating] imatinib [(Gleevec) in newly diagnosed chronic-phase (CP)–CML].1
Now we have several approved TKIs both in the United States [US] and globally. That set forward a chain reaction in other cancers where seeking rationally designed targeted therapies for molecular targets was known to be a viable option. The expansion has been great. At the time imatinib was developed, we had only hormonal therapy for breast cancer and prostate cancer, as well as monoclonal antibody therapy with drugs like trastuzumab [Herceptin] and rituximab [Rituxan].
[TKIs have] reshaped cancer [management]. They have reshaped CML because now it is a disease that’s highly treatable. Most patients can get into a safe remission with TKI therapy with low toxicity. It’s often chronic therapy. We have a clear agenda for treatment-free remission.
Some unmet needs include increasing the fraction of patients who have a safe and straightforward achievement of deep remission, which is protective against relapse or progression. That we do well, but we can do even better. The FDA approval of asciminib [for patients with newly diagnosed, Philadelphia chromosome (Ph)–positive CP-CML]2 highlights that; [this is] a drug that’s probably safer but also more effective at putting patients into safe and protective remissions.
The last [unmet need is] the holy grail of curing CML. [Inducing] treatment-free remission that’s successful is the equivalent of a functional cure. Increasing the fraction of patients who can get to that opportunity for treatment-free remission and be successful is something we’re working on.
What are some of the factors to consider when selecting a TKI for patients with CML or mapping out potential treatment sequencing with these agents?
Many people have called the number of TKIs we have available for treatment decision-making for CML a spoil of riches. We have a lot of good options and good problems because we have many drugs. The goals are simple. We want to find a drug that has the highest yield and the lowest risk in getting patients free of the disease with limited or no adverse effects [AEs]. The optimal circumstance would be getting them to the deepest of remissions and the best chance for a functional cure. When we choose [a TKI], that should be our highest agenda.
There are many other factors that should also be taken into consideration: the health of the patient and the goals of the patient. Some patients have a different balance they’re seeking [with treatment], and it’s our job to be open about that. [TKIs are also] chronic maintenance therapy with oral targeted agents. Many [oncologists and patients] discuss cost, and there is a spectrum of different financial scenarios, including low-cost generic options and newer, nongeneric, branded drugs. [Financial considerations] should fall to the bottom [of the priorities list], although they are relevant. We should combine all the agendas to best sequence the drugs and to choose our best, most potent, and safest drugs, most often early on, with a goal toward shortening the therapy to limit costs and to choose the best therapies to limit AEs, which would also be better on all fronts: for patients, for health care costs, etc.
That’s just the first decision. Approximately one-third of patients have some challenge like intolerance or resistance, so sequencing is a question. How do we choose our next drug? What are the risk factors for patients who may not have an ideal response or an ideal tolerability to the first drug?
We have new questions now, as we have new drugs. Asciminib is in a new class of TKIs called allosteric STAMP inhibitors, specifically targeting the myristoyl pocket. We have questions about sequencing, for example, from that class to the ATP-competitive—or active-site—ABL inhibitors. We have much to learn still. The disease, the patient’s remission status, mutations that can affect BCR::ABL [expression], patient comorbidities, and the risk of AEs as we move from one therapy to the next all need to be continually reassessed.
How do genetic alterations play a role in treatment decision-making for CML?
Cancer is [the culmination of] normal cells and normal tissue gone awry. It’s often based in alterations and mutations. CML is the first and most classic example of a human cancer driven by a sole genetic abnormality in Ph. That creates an abnormal protein called BCR::ABL that drives cancer.
BCR::ABL itself can come in different forms, and it can undergo alteration or mutations that directly affects the choice and the efficacy of certain drugs. In some cases, because of the nature of the disease, mutations may occur in an unstable genetic landscape for untreated CML. However, with treatment selection or other factors, we see the emergence of mutations that, to a significant but not major degree, drive our choice of subsequent lines of therapy. This drives us into scenarios, unfortunately, where we have selective resistance mutations, such as the T315I mutation, which affects drugs that bind the active site-ATP–competitive drugs, mostly—and limits our choices, because many drugs cannot bind in the presence of that mutation.
In more recent years, we’ve recognized, as we do in other cancers, that mutations outside of BCR::ABL that are part of the genome and regulation of the myeloid compartment are also relevant. Most recently, examples of mutations we see in other blood diseases like acute myeloid leukemia or acute leukemias and myeloproliferative disorders, such as ASXL1, present a challenge because they may foster higher rates of mutations in the target of our drugs: BCR::ABL. This means that if there are mutations outside of BCR::ABL, that might mean more mutations in BCR::ABL that could lead to challenges with asciminib and other drugs.
However, this may be an opportunity as well. We may have now an entree into saying that maybe a combination can be used in certain higher-risk, genetically unstable, or genetically complex scenarios. Mutation testing remains important to choose drugs, to identify resistance, to understand the complexity of resistance, and now increasingly, to profile the myeloid compartment in general.
When and how often should genetic testing be conducted in CML?
There are a lot of key principles. Testing for disease response and BCR::ABL levels [can be] easily done by blood-based testing. Many years ago, we recognized that we aren’t often testing the basic measure of CML response as often, as accurately, and [as close to the] guidelines as we should. At a basic level, measuring disease response and BCR::ABL levels are important, and guidelines should be followed because they’re practical and vital to patients’ optimal responses.
With resistance and mutation testing, we have to understand the highest yield and the type of testing we want to do. In broad terms, when patients lose significant degrees of response, particularly cytogenetic and hematologic response, there’s an indication for resistance testing. For patients who remain at a high level of disease at a plateau, there’s probably a reason for testing. For patients [who do not] achieve [certain] milestones, [such as] patients who [have not moved] into deeper levels of remission, particularly at higher levels, there’s a rationale for mutation testing.
Where we get into a bit more uncertainty is when we have patients with lower levels of disease who haven’t, for example, moved from a major molecular remission to a deep molecular response. We may not see as much data from standard BCR::ABL mutation testing [in those patients]. However, overall, the landscape of mutation testing—both in the myeloid mutation spectrum to understand risk, and specific BCR::ABL mutations under several circumstances and probably with a low threshold, especially with the advent of more available inhibitors like asciminib as a T315I-active agent with much more safety—remains important.
What are some dosing strategies to increase TKI adherence and tolerance?
The paradigm continues to grow. We’ve had ponatinib for many years, and that drug’s gone through evolution regarding initial standard testing and understanding the efficacious dose and early indications of what AEs might happen. [We have found that we can even] pause treatment and hold the drug when we need to better understand some of the more complex risks, including vascular disease, vascular occlusive events, and metabolic disease.
With ponatinib, we needed to [identify] the ideal dose. Could we start at a lower dose? The results of the phase 2 OPTIC trial [NCT02467270] showed that we needed to stay at our previously established best first dose of ponatinib, generally 45 mg, although there may be some exceptions.3 However, with that drug, there’s the provision to lower the dose once patients achieve response to [reduce toxicity] risk, meaning we’re handling drugs that [are associated with] more specific risks in a specific way to try to minimize AEs.
Asciminib was developed as an alternative [to ponatinib]. This was tested in similar patients and seems to be similar in capacity, particularly for patients with some degree of response, mixtures of intolerance and resistance, etc. Asciminib doesn’t require [the same] type of handling [as ponatinib]. We have different dosing depending on mutation status with asciminib: a lower dose for patients without T315I mutations, and a higher dose for patients with [those mutations]. That’s based on our better understanding and clinical trial data showing that the efficacy of these drugs under certain mutational conditions may vary depending on the dose, access to the kinase, and the ability to inhibit.
How do we ensure adherence and tolerance? The formula for success is regular communication, feedback, and monitoring so we can identify AEs, advise patients, steer them away from [these AEs], and hear from patients about their tolerance. We’re asking them to take chronic oral therapy for extended periods of time, sometimes indefinitely.
Adherence is a key principle in CML therapy. In simply taking less than 90% of your dose or missing a few days a month, for example, you can undermine the ability to achieve a deeper remission. It’s up to us as a health care community and in collaboration with patients to understand the science, the mutations, and the right drug, but then to understand the basic principles of how patients are going to stay on track to take this drug, tolerate it, avoid AEs, and have great communication.
How do you choose between newer TKIs and more established agents?
The quest for more TKIs continues. At present, we have novel agents in clinical trials that are potentially vying to be the best in class for active-site or ATP-competitive inhibitors. Examples of those drugs include a drug that’s been approved and studied in China called olverembatinib [GZD824], and a medication that’s being studied globally with a similar target called ELVN-001. There are novel allosteric inhibitors in clinical development, [such as TGRX-678] and TERN-701. We have preliminary data on these agents, so we may have second-generation allosteric inhibitors [in the future].
I mentioned only a few of the most developed novel ATP-competitive inhibitors. Others have tried to fulfill unmet needs, drugs like vodobatinib [K0706] and vamotinib [PF-114], coming mainly from outside the US. The paradigm continues to grow.
How do we navigate these options? These [novel agents] are on top of our palette of approved drugs, which span from low-cost generic options to agents that are only available under their branded labels. For oncologists, [this decision] should be simple. We should look at the science and the clinical trial data as our first arbiter of choice. What is the best and the lowest-risk choice for a patient under certain conditions when all factors are included: underlying health, disease characteristics, comorbidities, etc?
I try to avoid categorical decision-making based on age, cost, etc. However, nothing is going to be efficacious if a patient cannot gain access to a drug. [CML treatments need to be] accessible, ongoing, affordable, well tolerated, and ones that we agree are the best for the patient. [This decision-making] remains complicated, starting from the initial discussion of what is the best initial treatment, then navigating treatment changes, optimizing response, potentially getting to a deep remission and a functional cure if it’s desirable for the patient, [determining whether this is] successful, [and deciding] what to do beyond it.
Blood Cancer Awareness Month is observed annually in September. What is your main message regarding the importance of staying aware of CML treatment advances as the field continues to evolve?
September 22 is World CML Day, and September is Blood Cancer Awareness Month. 2025 is a special year because 25 years ago, we [initiated the IRIS trial] with imatinib, which was the first of our BCR::ABL-targeted inhibitors. I was part of those original studies. We’ve seen a tremendous example of what we can do in cancer treatment with CML. It’s been highly successful.
[The treatment paradigm] is not perfect. It requires continued thought. We’re still not done. We have work to do to optimize and maximize the deep remission and cure rates, and to continue to whittle away at AEs.
However, we’re blessed with a spoil of riches and many treatment options. The best thing you can do when you have those good problems is to be even more focused and precise about what you do, because you have little reason not to, and you have good tools at your disposal. I hope that the future for patients with CML continues to look up and we see a day at 30 or 50 years of CML TKI therapy where we’re doing even better and have set an even better example of what we can do in cancer therapy.
ReferencesO’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. doi:10.1056/NEJMoa022457FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. FDA. October 29, 2024. Accessed September 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-asciminib-newly-diagnosed-chronic-myeloid-leukemiaCortes J, Deininger M, Lomaia E, et al. Long-term results from the Optic trial: a dose-optimization study of 3 starting doses of ponatinib. Blood. 2023;142(suppl 1):3164. doi:10.1182/blood-2023-178790