Tinajero

“Pharmacists are uniquely equipped to not only counsel and educate patients on the importance of adherence to therapy, but [we can] also help identify and mitigate toxicities associated with these agents.”

Jose Tinajero, PharmD, BCOP, a bone marrow transplant and hematology clinical pharmacist at City of Hope, outlined the essential role of the oncology pharmacist in the management of chronic myeloid leukemia (CML).

As treatment has evolved from first-generation TKIs to multiple second- and third-generation options and, more recently, allosteric inhibition, pharmacists have become increasingly integral to treatment planning, toxicity management, and patient adherence, he said.

Tinajero emphasized that pharmacists are uniquely positioned to counsel and educate patients on the importance of strict adherence to TKIs, which remains a critical determinant of response durability and long-term disease control. Given that CML therapy is almost exclusively oral and requires consistent, long-term daily administration, pharmacists play a central role in reinforcing adherence expectations, addressing barriers such as complex dosing requirements, and ensuring patients understand drug-food and drug-drug interactions. These interactions are particularly relevant in CML, where agents such as imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), ponatinib (Iclusig), and asciminib (Scemblix) each carry unique administration parameters and metabolic pathways.

Beyond education, pharmacists help identify, monitor, and mitigate treatment-related toxicities. As Tinajero noted, adverse effects—including cytopenias, hepatotoxicity, cardiovascular risk, and gastrointestinal intolerance—may significantly impact quality of life and adherence. Pharmacists assess toxicity patterns early, intervene with supportive care measures, and collaborate with advanced practice providers and the broader oncology team to adjust therapy when necessary. When toxicities become difficult to manage, pharmacists contribute to decisions regarding dose modifications or switching to alternative TKIs with more favorable toxicity profiles.

Pharmacists also support therapeutic sequencing. With multiple TKIs now approved, treatment selection requires careful evaluation of disease risk category, patient comorbidities (particularly cardiovascular), prior intolerance or resistance patterns, and concomitant medications. Pharmacists assist in evaluating these variables, ensuring that each TKI selection aligns with clinical guidelines and patient-specific considerations.

Tinajero highlighted that ongoing communication between pharmacists, clinicians, and patients is essential to maintaining adherence, addressing evolving toxicity or interaction concerns, and optimizing long-term outcomes. As CML care continues to advance, the pharmacist’s role in education, toxicity mitigation, therapeutic sequencing, and collaborative care remains central to effective disease management.

Videos

Jose Tinajero, PharmD, BCOP, discusses the role of the pharmacist in treatment planning and management in chronic myeloid leukemia.

Dr Tinajero on the Role of Pharmacists in Treatment Planning and Management in CML

The input of a pharmacist is crucial to proper therapy selection for the treatment of patients with chronic myeloid leukemia (CML), as they can provide patient education to improve treatment adherence and aid oncologists with frontline treatment choices, especially as new agents continue to emerge, according to Jose Tinajero, PharmD, BCOP.

“Pharmacists are uniquely equipped to not only counsel and educate patients on the importance of adherence to therapy, but [we can] also help identify and mitigate toxicities associated with these agents,” Tinajero, a bone marrow transplant and hematology clinical pharmacist at City of Hope in Duarte, California, said in an interview with 

®. “Additionally, we provide valuable support and collaboration with advanced practice providers and visiting teams regarding sequencing, selection, and even switching therapies.”

In the interview, Tinajero discussed his approach to frontline TKI selection, strategies to enhance patient treatment adherence, how pharmacists aid in the implementation of new agents and formulations, and the importance of the pharmacist-oncologist relationship in treating patients with CML.

: Within the CML space, there are several TKIs approved across the spectrum, with other potentially on the way. With all these options, how do you approach selecting the right agent for the right patient?

: CML management has evolved since the development of the first-generation TKI, imatinib [Gleevec].

 Now we have second-generation options such as dasatinib [Sprycel] and nilotinib [Tasigna], third-generation options like ponatinib [Iclusig], and allosteric inhibitors such as asciminib [Scemblix].

The current treatment landscape focuses on frontline TKI selection, considering factors such as patient risk scores, age, and comorbidities, like cardiovascular risk. We also account for drug-drug and drug-food interactions, as well as [treatment] adherence.

What strategies help to ensure patient adherence, and how do you adjust when patients struggle to stay on treatment?

Our role is to educate and empower patients about the importance of consistent medication use. If patients struggle due to interactions, toxicities, or adverse effects, we counsel them and work to mitigate these issues. When toxicities become burdensome, we may switch patients to more tolerable options. Ongoing follow-up and communication between patients and the care team are key to maintaining adherence.

In terms of dose optimization and adjustments—keeping patients on effective therapy while minimizing toxicity—how do you approach this, and how do you work with oncologists and patients to achieve the right balance?

Dose optimization is critical. We aim to minimize therapy interruptions and manage interactions. Some TKIs have meal-related requirements—for example, some are best taken on an empty stomach, while others should be taken with food for proper absorption.

Drug-drug interactions are also important, particularly since many patients with CML are older and often on multiple medications. Pharmacists help screen for interactions to prevent overdosing or underdosing. Many factors contribute to maintaining optimal dosing.

How important is the multidisciplinary team in ensuring effective treatment planning and patient management from diagnosis through treatment completion?

This is a long journey. We assess milestones at [approximately] 3, 6, and 12 months. Having a multidisciplinary team is essential—pharmacists counsel patients and provide expertise on drug therapies, and advanced practice providers, physicians, nurses, and other health care [team] members reinforce these concepts. An all-hands-on-deck approach ensures optimal outcomes, as shown across various studies.

Although the role of TKIs has been established in CML, new approvals continue to emerge and shake up the treatment paradigm. When new agents become available, what role do you play in education and implementation?

When new agents reach the market, we’re involved in onboarding and ensuring their safe and appropriate use. This includes educating nursing staff, specialty pharmacists, physicians, and advanced practice providers through in-services and training sessions. We also participate in pharmacy and therapeutics committees to evaluate new agents and place them appropriately in treatment pathways based on clinical trial data.

I encourage my colleagues to stay equally involved in these efforts, as education and collaboration are key.

For community oncologists who may not have the same level of daily interaction with pharmacists as those in academic centers, what is the importance of that relationship?

Community oncologists can greatly benefit from pharmacy support. Many centers are now incorporating clinical pharmacists into decision-making, counseling, and education. Pharmacists can assist with prior authorizations for newer agents, identify and manage drug interactions, and help address toxicities.

Having a strong pharmacist-oncologist relationship enhances patient safety and outcomes, and there’s significant opportunity for growth in this area within community settings.

Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. 

Sprycel. Prescribing information. Bristol Myers Squibb. 2024. Accessed November 7, 2025. https://packageinserts.bms.com/pi/pi_sprycel.pdf

Tasigna. Prescribing information. Novartis. 2024. Accessed November 7, 2025. https://www.novartis.com/us-en/sites/novartis_us/files/tasigna.pdf

Iclusig. Prescribing information. Takeda. 2024. Accessed November 7, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/203469s037lbl.pdf

Scemblix. Prescribing information. Novartis. 2024. Accessed November 7, 2025. https://www.novartis.com/us-en/sites/novartis_us/files/scemblix.pdf

Articles

Pharmacists Play Key Role in Patient Education and Treatment Adherence in CML Management

As TKIs have continued to play an integral role in the management of Philadelphia chromosome–positive (Ph-positive) acute lymphoblastic leukemia (ALL), molecular markers and other prognostic factors have helped drive treatment decisions, according to Wendy Stock, MD.

“The appearance of the TKIs approximately 25 years ago revolutionized the way we treat Ph-positive ALL and has completely changed the paradigm and our survival rates, which have improved dramatically,” Stock said.

 Stock discussed the growing role of TKIs in Ph-positive ALL, the impact of molecular monitoring on treatment optimization, and ongoing efforts to refine dosing and treatment approaches to maximize efficacy and safety/quality of life.

Stock serves as co-chair of the Leukemia Committee for the National Cancer Institute-supported Alliance for Clinical Trials in Oncology and a co-leader of the Clinical and Experimental Therapeutics research program at the University of Chicago Medicine Comprehensive Cancer Center in Illinois.

: Within the Ph-positive ALL treatment paradigm, how have TKIs shaped current management strategies, and what unmet needs remain for these patients?

: At the moment, the beauty of Ph-positive ALL is that we have many effective therapies in addition to the TKIs. The TKIs, of course, are an integral part of that treatment, but we are now exploring the possibility that we may get by with very minimal amounts of traditional chemotherapy by incorporating the antibody therapies that we’ve also developed against B-ALL [targeting] CD19- and CD22-positive [disease].

The combination of the TKI with antibody therapies, particularly studies that have shown benefit of third-generation TKIs—ponatinib [Iclusig]

 in particular—with blinatumomab [Blincyto]

 and intensive intrathecal therapy, have revolutionized the way we treat [Ph-positive ALL] and are allowing us to move away from the need for an allogeneic transplant to ensure long-term disease-free survival. There are still some challenges in the area, for sure, including isolated [CNS] nervous system relapses and certain potentially high-risk subsets who may need specific attention.

What factors influence treatment selection and sequencing considerations with these agents in Ph-positive ALL?

There are a number of studies [underway] worldwide that are looking at sequencing. [In the United States], we tend to incorporate the TKIs first, but very quickly—and sometimes simultaneously—start targeting with monoclonal antibodies. There are [ongoing] randomized studies evaluating the benefit of adding chemotherapy vs using TKI plus antibody therapy alone.

In Europe, the Italians have [led] the way in Ph-positive ALL with studies that have incorporated steroids, TKI, and blinatumomab, but they use a longer introductory phase of TKI plus steroids. Both [approaches] have merit and are being investigated.

What is the current role of molecular testing in Ph-positive ALL, and how often should clinicians assess for these alterations during treatment?

In Ph-positive ALL, unlike chronic myeloid leukemia, many patients experience an early emergence of resistance mutations, particularly the 

 T315I mutation. This is why, in the current [treatment] era, we’ve started to incorporate the third-generation TKI ponatinib up-front to try to prevent the emergence of resistant clones, especially the T315I clone.

We do not traditionally test for the presence of that [

 T315I] mutation at baseline, but of course, if there’s any sign or hint of treatment resistance, one might look for that clone—particularly if incorporating a second-generation TKI, like dasatinib [Sprycel], as frontline treatment.

In terms of other molecular features of concern for higher risk, there’s the Ikaros-plus signature, which involves mutation or deletion of the 

 gene, which is very common in Ph-positive ALL. Approximately 80% of patients have a loss or mutation of 

, such as the p15 and p16 genes, which are part of the Ikaros-plus signature, along with other potential gene mutations. Some people will test for the Ikaros-plus signature up-front, and it’s something we’re considering in terms of how to move forward with therapeutics, in terms of whether risk stratification is necessary or additional chemotherapy is needed for those patients.

Another important prognostic factor is an initially high white blood cell count, which is an old but true prognosticator. A count over 70,000 is considered adverse.

For response monitoring, in addition to morphologic evaluation via serial bone marrow exams, we now have much more sensitive molecular techniques, including RT-PCR for 

 and, importantly, next-generation sequencing to track immunoglobulin gene rearrangement that is part of the leukemic clone. That seems to be the most important prognosticator: eradication of this trackable clone is an excellent prognostic markers for DFS.

What key factors guide your approach to dosing and treatment sequencing with TKIs in patients with Ph-positive ALL, particularly regarding dose modifications or treatment holds to support adherence and minimize adverse effects?

A concern with ponatinib when used up-front was that at its originally prescribed doses, this drug can be quite toxic cardiovascularly.] Even now, we usually start at a lower dose than was originally recommended. However, it is possible, once patients achieve complete or significant molecular remission, to reduce the TKI to a lower dose. Typically, for patients receiving ponatinib up-front, once they’re in remission, we reduce the dose from 30 mg to 15 mg.

In general, blinatumomab is quite well tolerated. Initially, [some patients may experience] cytokine-mediated effects with first exposure, but these are [well understood and manageable.] Overall, treatment is quite straightforward these days.

Another important point is to always incorporate intrathecal therapy early and frequently, due to the risk of isolated CNS relapse. Ponatinib, blinatumomab, nor inotuzumab ozogamicin [Besponsa]—if that is the antibody is being incorporated in frontline treatment—penetrate the CNS. That raises the question of whether [using] some traditional chemotherapy agents that do penetrate the CNS, such as prophylactic doses of methotrexate or high-dose cytarabine, are useful and needed, particularly for high-risk patients. These are among the questions being explored by cooperative groups worldwide regarding next steps in treatment.

Finally, who needs an allogeneic transplant? Does such a transplant remain appropriate as frontline therapy? This is being investigated in several studies, particularly in Europe, and [we want to determine if we can] identify high-risk patients who should definitely be directed toward transplant if they are eligible candidates.

What are your thoughts on the emerging research suggesting that some patients with Ph-positive ALL who achieve deep, minimal residual disease (MRD)–negative remission following chemotherapy-free regimens and intensive intrathecal therapy may eventually discontinue TKI treatment and maintain durable, treatment-free remissions?

Another exciting and early emerging area of research is whether, with these novel approaches that are largely chemotherapy free, patients who are complete responders—[those who are MRD-negative by ClonoSEQ or NGS sequencing—and have completed rigorous intrathecal therapy courses can eventually discontinue TKI therapy. There are now case reports in the literature suggesting that this might actually be possible. We may be able to completely eradicate the disease and achieve treatment-free intervals following these intensive regimens without transplant.

This question will be examined carefully in prospective studies over the next number of years. It’s a truly exciting area where we can potentially think about curing the disease and [achieving] treatment-free remissions that are durable, similar to what has been observed in CML with the successful discontinuation of TKIs in a large percentage of patients.

Iclusig. Prescribing information. October 2025. Accessed November 3, 2025. https://www.iclusig.com/hcp/sites/default/files/2022-10/ICLUSIG-Prescribing-Information.pdf

Blincyto. Prescribing information. October 2025. Accessed November 3, 2025. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/blincyto/blincyto_pi_hcp_english.pdf

Wendy Stock, MD, discusses how TKI-based, chemotherapy-free regimens are advancing Ph-positive ALL care toward durable, treatment-free remission.

Evolving Role of TKIs and Antibody-Based Strategies Refines Ph-Positive ALL Management

Dr Stock on the Multifaceted Role of Molecular Testing in Ph+ ALL

“In Ph-positive ALL, unlike in CML, many patients experience an early emergence of resistance mutations, particularly the [

] T315Imutation. This is why, in the current [treatment] era, we’ve started to incorporate the third-generation TKI ponatinib up front to try to prevent the emergence of resistant clones, especially the T315I clone. We do not traditionally test for the presence of that mutation at baseline, but if there’s any hint of treatment resistance, one might look for that clone—particularly if incorporating a second-generation TKI, like dasatinib [Sprycel], as frontline treatment.”

Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine at UChicago Medicine and co-leader of the Clinical and Experimental Therapeutics research program at the University of Chicago Medicine Comprehensive Cancer Center, discussed best practices for molecular testing in patients with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL).

One factor that distinguishes Ph-positive ALL from chronic myeloid leukemia is the frequent and early emergence of resistance mutations, particularly the 

 T315I clone, Stock began. To counteract this rapid resistance development, hematologists have begun integrating the third-generation TKI ponatinib (Iclusig) in the up-front setting to try to avoid the development of those resistant clones, she said.

 T315I mutation is not traditionally tested for at initial diagnosis, Stock explained. However, if there is any indication of emerging treatment resistance during therapy, testing for this clone becomes necessary, she emphasized. This is particularly crucial if a second-generation TKI, such as dasatinib (Sprycel), is incorporated as initial frontline treatment, she noted.

Furthermore, high-risk stratification in Ph-positive ALL requires identifying other molecular features, collectively known as the Ikaros-plus signature, according to Stock. The mutation or deletion of the 

 gene is common in this disease, affecting approximately 80% of patients, she reported. The Ikaros-plus signature constitutes the loss or mutation of 

 in combination with deletions or mutations in other genes, including the 

 genes, she added. Although testing for the Ikaros-plus signature is not universally performed up-front, it is considered a reasonable approach to take, she continued. Determining the presence of this signature is instrumental in guiding therapeutic decisions regarding necessary risk stratification and assessing whether the patient requires additional chemotherapy, she stated.

Beyond molecular genetics, a nonmolecular feature serving as an important prognosticator is initial white blood cell count, which is considered one of the more adverse prognosticators for outcome, she explained. Monitoring treatment response relies on serial bone marrows for morphologic monitoring of the disease, supplemented by much more sensitive molecular techniques, she summarized. Next-generation sequencing is now being employed in Ph-positive ALL to track the immunoglobulin gene rearrangement, she noted. Since this rearrangement is an intrinsic component of the leukemic clone, the eradication of this trackable clone might be the most important prognostic marker for achieving excellent disease-free survival, she concluded.

Wendy Stock, MD, discussed the role of molecular testing in Ph-positive ALL and best practices for implementing this testing across clinical scenarios.

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 

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.

: How have TKIs shaped the CML treatment paradigm? What unmet needs remain for these patients?

: 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, 

 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].

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 

 [for patients with newly diagnosed, Philadelphia chromosome (Ph)–positive CP-CML]

 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 

 [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 

 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 

 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 

, present a challenge because they may foster higher rates of mutations in the target of our drugs: 

. This means that if there are mutations outside of 

 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 

 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

 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 

 mutation testing [in those patients]. However, overall, the landscape of mutation testing—both in the myeloid mutation spectrum to understand risk, and specific 

 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.

 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.

O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. 

. 2003;348(11):994-1004. doi:10.1056/NEJMoa022457

FDA 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-leukemia

Cortes J, Deininger M, Lomaia E, et al. Long-term results from the Optic trial: a dose-optimization study of 3 starting doses of ponatinib. 

. 2023;142(suppl 1):3164. doi:10.1182/blood-2023-178790

Michael J. Mauro, MD, discusses the evolution of TKIs for CML, factors for TKI selection, and ways that genetic mutations influence treatment efficacy.

TKI Advances and Patient-Centered Decision-Making Guide the Path Toward Functional Cures in CML 

Dr Mauro on How Genetic Alterations Impact TKI Decisions in CML  

"Mutation testing still remains important [for] choosing drugs, identifying resistance and understanding the complexity of resistance. Now, [it is] increasingly [utilized] to profile the background."

Michael J. Mauro, MD, a hematologist and director of the Myeloproliferative Neoplasms Program, Leukemia Service at Memorial Sloan Kettering Cancer Center, discussed the prevalence of 

 mutations in chronic myeloid leukemia (CML) and how they inform the use of TKIs for patients with this tumor type.

CML is recognized as the first and most classic example of a human cancer driven by a single genetic abnormality, known as the Philadelphia chromosome, Mauro began. This genetic change results in the creation of an abnormal protein called 

, which functions as the driver of the cancer. Critically, 

 can exist in different forms and may undergo alteration or mutation that directly impacts the choice and efficacy of certain drugs, he noted.

Mauro explained that mutations may occur early on simply due to the nature of the disease, reflecting an unstable genetic landscape for untreated CML. However, the emergence of mutations is certainly observed with treatment, driven perhaps by selection or other factors. These resistance-driving mutations significantly, although not in the majority of cases, influence the choice of subsequent lines of therapy and push patients into scenarios of selective resistance.

A particularly challenging example discussed is the 

 T3151 mutation. This specific mutation affects drugs that bind the active site, namely ATP-competitive drugs. The presence of T3151 severely limits treatment choices because many conventional TKIs are rendered unable to bind effectively.

In recent years, experts have expanded the focus beyond just 

 mutations to recognize alterations outside of the primary target that are part of the genome and regulation of the myeloid compartment. For example, mutations seen in other blood diseases, such as acute myeloid leukemia and myeloproliferative disorders—specifically 

—are relevant. Mauro noted that these external mutations may foster higher rates of mutations in the target of the drugs, BCR::ABL. This implies that if mutations exist outside of 

 itself, which presents challenges for the summation of treatment and other drugs.

Despite this complexity, Mauro suggested that this situation may also present an opportunity, potentially allowing for combinations of therapy to be used in genetically unstable or complex scenarios, particularly those considered higher risk. Ultimately, mutation testing remains crucial not only to choose drugs and identify resistance, but also to understand the complexity of resistance, and increasingly, to profile the overall background of the myeloid compartment.

Michael J. Mauro, MD, discusses how genetic alterations, such as BCR::ABL mutations, inform treatment decisions in CML. 