patient care perspectives

Recommendations for Second-Generation Tyrosine Kinase Inhibitors As Frontline Therapy in the Management of Chronic Myeloid Leukemia

by Mark J. Levis, MD, PhD


In addition to the chronic myeloid leukemia (CML) risk category, the choice of a particular tyrosine kinase inhibitor (TKI) therapy for initial treatment includes factors such as side-effect profile, comorbid illness(es), and tolerability. The continuing emergence and US Food and Drug Administration approvals of second-generation TKIs translate into more options for patients and clinicians.

Expert Commentary

Mark J. Levis, MD, PhD

Director, Adult Leukemia Service
Co-Division Director, Hematologic Malignancies
Professor of Oncology
The Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University
Baltimore, MD

“In addition to taking a patient’s medical comorbidities into account, my goal is to match the correct drug with the correct patient to ensure tolerability and good compliance.”

Mark J. Levis, MD, PhD

The data indicate that patients with very high CML risk scores will have better disease control with a second-generation TKI agent instead of the first-generation agent imatinib. And, while that is true, there is more complexity to the decision. At this point, I am still balancing factors such as the patient’s cardiovascular risk with the side-effect profiles of the TKIs, in view of the patient’s age and other factors.

Yes, major molecular response with imatinib in this setting may be suboptimal, and, yes, major molecular response can be linked to longer-term survival in analyses. However, we know that imatinib can still work reasonably well, and, in my experience, the risk of mortality is not increased when imatinib is used first line in select patient groups with higher-risk CML. If it becomes clear that imatinib is not effective, then we know that the patient will likely have a good response to a second-generation TKI.

In addition to taking a patient’s medical comorbidities into account, my goal is to match the correct drug with the correct patient to ensure tolerability and good compliance. In my opinion, compliance plays a much larger role in treatment success than is generally appreciated, regardless of the specific treatment used. If the patient simply cannot tolerate imatinib, you have to look for other options, and there are some instances when starting with a second-generation TKI right from the beginning might make sense. In my practice, for example, we frequently use dasatinib.

Because CML treatment is typically administered as lifelong therapy, patients need to be accepting of the side effects long-term. We know from data that poor compliance is typically the reason for treatment failure. The best way to make a patient noncompliant is to give them a drug that makes them miserable when they take it each day. In my 20 years of managing CML, I have had very few—if any—CML-related deaths in treatment-compliant patients.

The bottom line is that we all know about the risk scores and the data regarding major molecular response. But you also have to get the patient on a medication that they tolerate and can be compliant with. And I will follow the molecular response. If the patient does not meet their milestones, then I am going to recommend switching therapies.


Cortes JE, Jiang Q, Wang J, et al. Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study. Leukemia. 2020;34(8):2064-2073. doi:10.1038/s41375-020-0805-1

Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis [published correction appears in Leukemia. 2021;35(7):2142-2143]. Leukemia. 2021;35(2):440-453. doi:10.1038/s41375-020-01111-2

Oehler VG. First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia? Hematology Am Soc Hematol Educ Program. 2020;2020(1):228-236. doi:10.1182/hematology.2020000108

Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120(19):3898-3905. doi:10.1182/blood-2012-02-410688

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