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TKI Therapy for CML
A Team Approach to Optimizing TKI Therapy for Patients With Chronic Myeloid Leukemia

Released: November 15, 2019

Expiration: November 13, 2020

Jorge Cortes
Jorge Cortes, MD
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The introduction of BCR-ABL–targeted tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) started with imatinib in 2001, and has dramatically changed outcomes and the way we manage patients with CML. Most importantly, TKIs have improved survival to the point where most patients with chronic-phase CML have a life expectancy similar to that of the general population, provided that they have access to these effective therapies, appropriate monitoring of response, and good follow-up throughout their care.

Approved BCR-ABL TKIs for CML
To use these TKIs for maximum clinical benefit, it is important for clinicians to understand key differences between the available TKIs. Factors to consider when making recommendations of a specific TKI include a patient’s clinical presentation characteristics and comorbidities, the relative efficacy and toxicity profiles of the TKIs, and the ability to overcome specific BCR-ABL resistance-inducing mutations. Four different TKIs are approved for first-line therapy of CML: Imatinib was first approved, followed by the second-generation TKIs dasatinib. nilotinib, and most recently, bosutinib in 2017. These 4 TKIs also can be used as second- or later-line therapy, as can another TKI, ponatinib, which is approved only for patients with CML who are resistant or intolerant to the other TKI therapies or who have the ABL T315I mutation. The availability of multiple options allows a great degree of personalization for the patient’s treatment regimen.

Risk Stratification in CML
Risk stratification for disease progression is an important factor for this treatment personalization. The most frequently used risk classifications are the Sokal and the Hasford prognostic scoring systems, which were developed many years ago and classify patients into low, intermediate, and high risk categories. The scores are based on a formula that assigns a given value to baseline characteristics, including age and spleen size, plus some of the blood indices, including the blast count and the basophil count.

This is important because patients in the high-risk category, whether by Sokal, Hasford, or the newer EUTOS scoring system, have a worse prognosis with poorer survival rates. Risk stratification at the start of treatment will help determine patient prognosis, and it has also been suggested as a possible way of identifying which patients are most likely to benefit from the second-generation TKIs (bosutinib, dasatinib, and nilotinib). Generally, patients in the intermediate-risk or the high-risk group should be considered for second-generation TKIs, whereas low-risk patients may have a good outcome with imatinib. In the ENESTnd and DASISION studies, nilotinib and dasatinib, respectively, produced higher rates of major molecular response (MMR), and responses occurred earlier, with less progression to accelerated-phase or blast-phase CML than imatinib. Similar results have more recently been reported with bosutinib from the BFORE trial, although the follow-up is shorter.

Patient Comorbidities and TKI-Associated Toxicity Influence Treatment Choice
A patient’s medical history and comorbidities also are important considerations when selecting TKIs. Because we have multiple effective first-line treatment options, these factors can help determine what treatment might be better suited for each patient or may have a lower risk of TKI-related complications for a particular patient.

For example, nilotinib has been associated with worsening diabetes in patients with the disease, and even the development of diabetes in some patients with hyperglycemia, making it a less desirable choice for these patients. Dasatinib can be associated with pleural effusions or pulmonary hypertension, so patients with a history of lung problems or hypertension, which is a known risk factor for pleural effusion, may want to avoid dasatinib. Patients who have significant liver or bowel issues may want to avoid bosutinib, which has a somewhat higher risk of liver toxicity and diarrhea. Imatinib, and to some extent bosutinib, may be associated with some decrease in renal function, so patients with borderline renal function may not be the best candidates for these agents.

Even though this class of drugs is generally safe and well tolerated, it is important to recognize the various TKI-related adverse events and to manage them properly in those patients who experience them. For more details on the management of the toxicities associated with the TKIs, please see the accompanying text module here.

Treatment Adherence Is Essential
TKIs are oral therapies that are administered for years, so adherence to treatment is essential to maximize their clinical benefit. Patients often need help to remain adherent to their prescribed treatment, which is why a multidisciplinary approach can be so beneficial. Access to medication can be a concern, and the patient’s care team needs to assist the patient and their caregivers with access to drug-assistance programs as needed. In our clinic, we rely on the support of physician assistants, nurse practitioners, and pharmacists, to help us to optimally manage our patients with CML, in addition to continuous communication with patients throughout their journey to address their concerns and manage any co-morbidities and adverse events.

Monitoring of Response and Therapy Change or Discontinuation
Optimal use of TKIs includes adequately monitoring the patient’s response regularly throughout his or her treatment. Bone marrow biopsy is important both for the diagnosis of CML and to confirm a complete cytogenetic response to therapy. Otherwise, patients’ response to therapy can be monitored using quantitative peripheral blood polymerase chain reaction testing at regular intervals. Any warning signs such as changes in BCR-ABL transcript levels should increase caution and trigger an evaluation. Remember, although not ideal, this does not necessarily represent failure or the need to change therapy, but increased monitoring is warranted. A change in therapy is needed for a patient who progresses, who loses their response, or who progresses to the accelerated or blast phase.

On the other side of the spectrum, some patients may have deep and sustained responses robust enough to consider the possibility of treatment discontinuation, whereas other patients may benefit more from switching to a different therapy due to intolerance or resistance (ie, disease progression). It is important that clinicians recognize all of these scenarios and manage them appropriately, while avoiding unnecessary treatment interruptions or changes. For more detailed information on monitoring response and when to consider a change or potential discontinuation of therapy, please see the accompanying text module here.

Overall, treatment of CML has greatly improved in recent years. We have been able to improve treatment options and quality of life for our patients, but it takes active involvement of the entire multidisciplinary team to ensure the best possible outcomes.

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