CML: Third-Line Treatment Options for Chronic Myeloid Leukemia

Jorge Cortes, MD, breaks down third-line treatment options for patients who progress with chronic myeloid leukemia.


Jorge E. Cortes, MD: The approach for third-line therapy, for a long time and even up until recently, it had been to shift from a second-generation TKI [tyrosine kinase inhibitor] to another second-generation TKI. For example, a patient who had received imatinib moved to a second-generation TKI, and if there was resistance, they moved to another second-generation TKI. Some of that was led by the concerns about the safety of ponatinib, because of arterial occlusive events and the lack of alternative third-line or beyond treatment options. I want to emphasize that strategy of going from one second-generation TKI to another second-generation TKI, when there is resistance, it really has not yielded a good level of response. There will be an occasional patient who responds. Certainly, if it is due to a mutation where another second-generation TKI may have better efficacy, that’s a scenario where you might get some efficacy. But for the most part, the response rates have been less than 20%. Fortunately, we have ponatinib, and it is a very effective drug. There’s a recent study that looked at a strategy of starting with a standard dose, 45 mg, and reducing the dose when the patient responds, and that seems to have reduced significantly the safety concerns of ponatinib. So that definitely has to be considered.

More recently, we have the approval of asciminib, a very novel tyrosine kinase inhibitor, where the difference is that instead of all the other tyrosine kinase inhibitors that bind in the ATP [adenosine triphosphate]-binding pocket, this one binds in the myristoyl domain. It has shown very high levels of activity, both in a phase 1/2 and a randomized study, compared to bosutinib used in the third line or beyond, and with a very good toxicity profile. So we have now that additional option that we didn’t have. I think that when a patient needs to go to a third line, these are the treatment options that have to be considered, taking into consideration comorbidities and risk factors for arterial occlusive events, etc. Then you have, now, very good treatment options for these patients.

We need to remember that transplant is still a good option. We hardly ever use it as frontline therapy, and probably not even in second line much. But it is a good treatment option, and the possibilities of finding donors have improved significantly. The early mortality has decreased significantly. In my practice, what I do is, once I’ve gone beyond a second tyrosine kinase inhibitor, I need to start having a conversation with my patient about the possibility of needing a stem cell transplant. What potential donors do we have? What are the other comorbidities and risk factors for a transplant that the patient may have, etc?

We have done some studies in the past, for example, comparing ponatinib vs a stem cell transplant in patients who have a T359 mutation. We’ve established that the survival is better with ponatinib for those patients if they have that chronic phase. In the accelerated phase, it’s equivalent. If the patient has a blast phase, transplant is definitely better. So in the third line, you may still have, depending on the characteristics of the patient, the disease, etc, still the option to use another TKI, particularly now that we have ponatinib and asciminib as third-line therapies. But you at least have to have that conversation. And if you need to move to a fourth TKI, I think that then transplant jumps up as at least equal in terms of priorities in that scenario.

Transcript edited for clarity.

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