Role of Tyrosine Kinase Inhibitors in Treatment of CML

Daniel DeAngelo, MD, PhD, highlights the role that tyrosine kinase inhibitors play in the CML treatment paradigm.


Daniel J. DeAngelo, MD, PhD: The treatment for patients with chronic myeloid leukemia is all based on tyrosine kinase inhibitor therapy. CML [chronic myeloid leukemia] is an unusual disease. It’s a single-gene disease. It’s all driven by BCR-ABL, BCR-ABL. We’re focusing on the chronic phase. However, even in patients who’ve progressed into accelerated and blast phase, all the therapy is still inhibiting that BCR-ABL signal, which is in deference to other diseases. With that being said, therapies include first-, second-, and third-generation tyrosine kinase inhibitors [TKIs], first-generation with imatinib, second generation with nilotinib, dasatinib, and bosutinib. All are approved for frontline therapy.

There are some specific differences, in terms of how one chooses a particular agent for a particular patient, and a lot of that has to do with what are the goals of therapy? Is it a young patient who wishes to enter in a TKI discontinuation rapidly? Is it an older patient with lots of comorbidities? What types of comorbidities? It’s true that on all 3 randomized studies comparing the second generation to first generation, one sees a deeper response, a more rapid response, to the second-generation TKI. But what one doesn’t see is an improvement in overall survival. That may have a lot to do with the fact that there are lots of salvage therapies; nevertheless, overall survival seems to be similar regardless of whether one chooses a first or second generation.

In terms of subtleties, patients with higher-risk disease by the Sokal, Hasford, or EUTOS [European Treatment and Outcome Study] score seem to respond better if they use a second-generation TKI. Certain cardiovascular toxicities are specific to each TKI, specifically some of the second generations that you may want to avoid depending on the patient’s comorbidities and characteristics. That is, for a patient with a newly diagnosed chronic phase CML, all things being equal, I tend to use second-generation TKIs for my younger patients. I tend to use first-generation TKIs for my low-risk patients, specifically for lower-risk adults, and more specifically for older adults.

The long-term data with various TKIs are starting to accumulate. Imatinib has been in clinical trials since the late 1990s and was approved in 2001, so that has the most long-term data, but we have long-term data with first-, second-, and even third-generation TKIs. What we’ve learned with imatinib is that we’re not seeing any deleterious cardiovascular toxicities with long-term usage. We’re seeing a signal in terms of a modest reduction in renal function, which is something I need to understand. What we also see with imatinib is the accumulation of some mild grade 1 toxicities. To the clinician, they may not be an issue because they’re seldom life threatening, but for the patient they may alter their quality of life. That’s very important and also may affect their compliance.

With second-generation TKIs, we’re seeing some late cardiovascular toxicity, which are specific to each agent, whether it’s nilotinib, dasatinib, or bosutinib. Bosutinib has the least or the shortest long-term follow-up. That seems to be mostly diarrhea and antibiotic toxicity, although fusions have been seen. These later long-term adverse effects with some of the second-generation TKIs in deference to the first generation is something that one has to weigh in terms of choosing first vs second generation. However, what we’ve also learned is a dose modification and early recognition of toxicities can really mitigate some of these difficulties.

Transcript edited for clarity.

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