Expert Discusses the Discontinuation of TKIs in Treatment Landscape of CML

Gabriela S. Hobbs, MD

A hot topic in the treatment landscape of chronic myeloid leukemia (CML) is the possibility of discontinuing the use of tyrosine kinase inhibitors (TKIs). The first TKI, imatinib (Gleevec), was approved by the FDA in 2001, and now there are many others approved in the field. However, data now supports the idea of discontinuing this treatment altogether in some patients with CML.

While the side effects of these agents are very low-grade, they can create a burden on the patient. While recent data, acknowledged by the NCCN, supports discontinuation of TKIs, there is still not enough data on the long-term effects of discontinuing a patient's treatment.

If a physician should choose this route for their patient, it is important that they follow up with them regularly, which can result in frequent visits and copays, leading to financial toxicity. Additionally, Gabriela S. Hobbs, MD, says that there is not enough data demonstrating that it is safe to discontinue treatment with a TKI and then put them back on a TKI after relapse.

OncLive: Today, you're discussing treatment options for patients with CML. What is the current treatment landscape in this disease?

In an interview with OncLive at the 2nd Annual Live Medical Crossfire: Hematologic Malignancies, Hobbs, clinical director, Leukemia Service, Massachusetts General Hospital, discussed how discontinuing TKIs will change the treatment landscape and other strategies for treating patients with CML.Hobbs: CML is a disease that has seen a tremendous amount of progress in the last 2 decades. The biggest breakthrough was in 2001 with the approval of the first TKI, imatinib, and since then there has been several others approved. Now, you can say that therapies have become so good and so successful at treating CML that the biggest thing in the last couple of years has been the discontinuation of these medications. The main focus of this talk is who can safely stop these drugs, how does that affect patients, and how does that affect the economics of treating this disease.

Has there been any promising data in CML to come out recently?

What are some challenges you think we still need to overcome in this field?

When you think about the landscape of CML, you think about which drugs to try for the patient, and not just thinking about a drug that will be successful in controlling their disease, but also in giving them the possibility of not having to take these medications at some point. This is a huge shift in the way we think about CML.The most exciting thing to come out recently was a big change in the NCCN guidelines. As you know, the NCCN guidelines are the guidelines that many physicians follow in the United States, but also internationally, to help treat and manage their patients. The NCCN guidelines are very helpful in managing CML. What's been exciting recently is that there's been so much data to support the idea of TKI discontinuation that the NCCN guidelines, as well as the European Leukemia Net Guidelines (ELN), now have acknowledged all those data and have incorporated that into the guidelines. They have taken into account the results of a variety of different clinical trials, including the Stop Imatinib (STIM) data, which are several trials looking at imatinib discontinuation. TWISTER data and the Dasatinib Discontinuation (DADI) study are some of the studies that have been published in the last couple of years that basically all say the same thing-that it's safe to discontinue the use of TKIs if done properly.There are still some things I think we need to overcome, although CML is a disease for which patients have a variety of treatment options and for the most part, patients do very, very well. There are still a few things that require some improvement. Some of it can be overcome with the TKI discontinuation, but it's not for everybody. Patients still have to take a pill every day, and while that may not seem like a big deal, these drugs are not free of side effects. Many times, patients live with these diseases and they have to have these kind of low-grade, nagging side effects indefinitely, so that's really difficult. Some patients don't have side effects, but some patients do really have a lot of side effects.

What are you particularly interested in discussing today during your session?

What kind of advice would you give to a community oncologist treating a patient with CML?

Too many of our patients, especially our younger patients who are still working, living with daily headaches, fatigue, or muscle aches, or issues with nausea and vomiting, can be very challenging, especially long term. If you have to tell a patient you only have to take this drug for a week, then most patients are able to tolerate a lot of side effects, but long term, that can be difficult. That is an area where it would be nice to have medications that really didn't have so many side effects. Although we can talk to our patients about maybe overtime being able to stop these drugs, the truth is that majority of patients will not be able to stop these drugs, and if they do, the majority of them will not be able to stay off of them forever. That's definitely an area where we still need some research to improve the therapy that we have available.There are a few things. I think it's important to review the data that we have, in terms of who are proper patients for discontinuation, and also to remind the audience that when you discontinue these drugs, you need to do a lot of monitoring. Patients are often times switching, they're giving up something for something else. Although they may not have to take their medicine now, these are patients that, probably prior to discontinuation, are only being seen by their doctors every 3 to 6 months, and when they discontinue drugs, they really need to have testing done every month for at least a year. They will need to be seen more frequently. There are some costs associated with that and if that's not done properly, then that can obviously be a problem. Emphasizing who to discontinue and how to follow these patients after discontinuation is really important.First, these patients sometimes seem fine, and it's important to remember that CML patients can have a normal or near-normal life expectancy, but getting your patients to that point does require some effort. Although in a busy oncology practice, the CML patient may not be the sickest patient you have, it's important to remember they can be very sick. Again, the NCCN guidelines and the ELN Guidelines, depending on where you practice, are really important and they really offer a lot of guidance as far as how to follow and monitor these patients. It's important to remember that although these CML patients seem like they're doing okay, frequent and appropriate follow-up of their polymerase chain reactions (PCRs) is really important to know that these patients are achieving optimal responses.

Where do you see this field heading in the next 5 to 10 years?

The number may seem small, but the way a patient may behave long-term with a suboptimal response to their TKI may ultimately translate to really poor outcomes, so it is important to be very vigilant and to make sure that their PCRs are followed frequently to make sure that your patients do have the opportunity to have normal or near-normal life expectancy.As I mentioned, one of the biggest changes has been the discontinuation of TKIs. Now, we are starting to feel more comfortable discontinuing these drugs, but what we don't know yet is if it is safe to do multiple discontinuations. [For example,] you discontinue the drug for a year and then maybe they relapse, you put them back on the drug, but is it safe to do multiple discontinuations? Is it safe a few years from now to discontinue again and then restart it again? We don't know. There's some data, but not a lot to tell us if that is safe long term, so hopefully in the next 5 to 10 years, we will have some more clarity on that.

What else is important to note about this patient population?

Right now, with the insurance landscape the way that it is, most payers don't have a preference for what TKI you choose at the beginning, either imatinib, dasatinib (Sprycel), nilotinib (Tasigna) or bosutinib (Boslif), which are all approved for first-line, but now generic imatinib is on the market and I think in the next 5 to 10 years, there's a possibility that we will see a shift in that and where we need to start with imatinib more often. I think it will be important to know if that is important for everybody, or if we can make an argument that some people need to start with the other drug instead of with imatinib. That is something that still needs to be thought of a little bit more.It's important to remember that there's been a lot of progress for CML in the last couple of decades, and just like any other patient, it's important to follow guidelines for these patients and remember there's a lot of different options for treatment upfront. Although we don't normally think about it this much in oncology, oncology patients are like any other patients and overtime, they also can be noninherent to their medication which can also have devastating outcomes. Especially because these patients take these medicines every day and they have a lot of side effects, some patients don't take these medications as they should.

It's important for all of us to talk to our patients and make sure that they are taking their drug and that if they have side effects, they are well managed because that can help them become adherent to their medication. Sometimes, patients have a lot of copays from their medications and have a hard time then affording their medication. That can also lead them to not taking their medications properly. There really is a lot of help available for patients to be able to get these medications so that they don't have to uncurl this financial toxicity, so having good and open communication with these patients is really important in making sure they are taking the medicine as prescribed so that they can have good outcomes.