CML Takeaways From ASH 2015: Discontinuing Tyrosine Kinase Inhibitors

Jerald P. Radich, MD


December 22, 2015

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One of the biggest concerns for community physicians these days, and one that patients are going to bring up to you, is the idea of discontinuation. After you have had a good response on imatinib or one of the second-generation drugs, can you actually get off these drugs successfully?

Historically, we thought that people would be on tyrosine kinase inhibitors for life, because in the lab, you can actually take putative CML [chronic myeloid leukemia] stem cells, add tyrosine kinase [inhibitors], and the cells do not die. Essentially, we thought that if that's true, there will always be a reservoir of stem cells, and once you discontinue therapy, patients will just relapse.

Like many things in medicine, we have been proven wrong. There have been a remarkable number of studies now, and it's unique, because there are very few places in medicine where different studies in different centers have yielded almost exactly the same response. What is comforting now, at this ASH [American Society of Hematology meeting], is that almost a dozen studies—either as follow-up of older studies or new studies—have shown the same results.

In summary, those results are that among patients who have been on tyrosine kinase [inhibitor]s for at least 3 years and have had essentially undetectable or very low levels of disease burden by BCR-ABL measurement for at least 2 years, about 40%-60% of those patients can discontinue drug and their disease will not come back. And now that has been followed in some of the larger studies, such as the study out of France, for up to 5 years.[1] If relapses come, most—about 80%—come within the first 3 months; there is only a little nibbling of relapses that occur after a year and a half. Generally, if patients are going to relapse, they are going to relapse early.

A few things are unresolved. One interesting thing is that although the second-generation drugs will get you to a low level [of disease] more than the first-generation drugs, once you are there, it does not seem to make much difference on who relapses or not. This is another indication where if you have a younger person for whom you think that getting them off drug is a goal, these are patients who probably should go on a second-generation drug early on. Older patients who might be suffering some of the cardiovascular side effects of the second-generation drugs and who you really do not want to get off drug for 30 or 40 years because they're starting their diagnosis at age 65 will probably do fine just on imatinib. That is one point.

The other point is that although it appears there are ways to tweak agents, such as adding interferon and the like, to get people into deeper response early on, [in] some studies that have looked at patients who have a suboptimal response and then added another agent to get them into a deeper response, it looks like we don't push that many more patients into that deeper response. And there is always a cost to that, with the added therapy.

Moreover, we do not know whether those patients whom we actually have to push to get a deeper response, if we are able to [then] discontinue them, that this will actually let them have a long period of time without disease like the people who naively go into deep responses. If you have a patient in that line who wants to add other drugs to get into a deeper response, you should really do that on a clinical trial.

It's reassuring that there has only been one case so far among people who have discontinued drug that has gone on to accelerated phase or blast crisis. That is the worry we all had.

After relapse, almost everyone responds after rechallenge very quickly, although often not to the exact same levels of deep response. One has to remember that if unopposed BCR-ABL activity is associated with progression, there may be clones hidden for years that may eventually go to relapse.

This is not completely without risk, and if you have patients who want to discontinue therapy because of a variety of reasons—side effects, pregnancy, and the like—you have to realize that there is a small but probably real risk involved.

Those are the types of issues that we hopefully will be able to resolve as years go on. We are trying to do biological studies now to try to determine up front which patients will be able to successfully discontinue and which patients will not. Right now, none of those are really ready for the clinic.


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