Managing Treatment Toxicity in CML and MPNs

Jorge E. Cortes, MD

TKIs have significantly shifted the treatment paradigm for patients with chronic myeloid leukemia (CML), although patients must be closely monitored to address any adverse events (AEs) that should the arise, explained Jorge E. Cortes, MD.

Further, there needs to be awareness of a patient’s comorbidities prior to starting TKIs to adequately assess the risk and choose the right agent. Optimizing the drug efficacy while controlling AEs in CML can often be managed through dose adjustment, according to Cortes.

“We need to use the drugs properly. I don't stay away from any of these drugs when it is appropriate for my patient, but it is very important to monitor the patients closely,” said Cortes. “If we manage patients well, we decrease the risks and make the best possible outcome for our patients.”

Similar to the impact of TKIs in CML, JAK inhibitors have greatly influenced therapy for patients with myeloproliferative neoplasms (MPNs). Ruxolitinib (Jakafi) and fedratinib (Inrebic) are generally well tolerated, though patients need to be monitored for anemia, thrombocytopenia, and some neutropenia, which can usually be managed through dose modification.

OncLive: How have TKIs impacted the field of CML?

In an interview with OncLive, Cortes, director of the Georgia Cancer Center at Augusta University, discussed managing treatment toxicities to optimize therapeutic outcomes in patients with CML and MPNs.Cortes: TKIs have changed everything in CML. The prognosis is very good and the responses are great; however, because of the long-term treatment, we've started to focus more on the potential complications that we see in some of these patients, including some cardiac toxicity or some arterial occlusive events. The events of most concern recently have been cardiovascular, strokes, or peripheral arterial disease, which occur mostly on patients who have other risk factors for these same issues. Examples include patients who are diabetic, have hypertension, have hypercholesterolemia, or other things. It's a sum of all these risk factors that increases the risk of developing one of these events.

How can toxicity from TKIs be managed?

It is important is to recognize that the risk exists, and it is important to manage those comorbidities so that the patient has better control because they need their TKIs and to use the TKIs properly. With ponatinib (Iclusig), there have been many instances where the physician or the patient may want to stay away from ponatinib [due to toxicity] when it's clearly indicated and may be the best choice for the patient. We don't have to stay away from it. We just need to manage the patient properly so that we can provide the treatment that's most appropriate for patients.We don't understand the mechanism of action—how these events occur, or why. We believe that it is an on-target problem because it happens across the board with all the TKIs, suggesting that it's probably mediated by ABL, although we don’t understand how and, because of that, we do not know exactly how we should manage the risk. The one thing that we know would work the best is to manage all the comorbidities. If a patient is diabetic, we need to make sure that we control the diabetes. If the patient is hypertensive or develops hypertension while on therapy, we need to manage that aggressively and control their cholesterol.

It has been controversial whether the use of aspirin works. There is no good prospective data. The use of aspirin is a low risk intervention and many times we use it, but we don't know that it works. Another extrapolation of data suggest that the use of statins may help many patients if they have high cholesterol, even patients who don't. Again, there's no prospective data and there's no validation of that hypothesis.

We know that we have the dose of the TKI more directly tested in the frontline ENESTnd study where we had a randomization between nilotinib (Tasigna) and imatinib (Gleevec), but there were 2 different doses of nilotinib. The risk of both doses of the nilotinib was significantly higher than imatinib, but there is more of a risk with the higher dose than with the lower dose. That suggests that there is a dose effect with nilotinib, but you would imagine that the same is true with ponatinib or dasatinib (Sprycel).

Frequently, we have dose-adjusted ponatinib and there are 2 ways of doing it. One of them is decrease the dose once the patient achieves a certain level of response, and we do that very routinely. The second one is to start with a lower dose. To that effect, we don't know the exact ideal dose.

In the MPN space, where does ruxolitinib fit?

What is the safety profile of ruxolitinib?

There is a study called the OPTIC trial, which randomized patients to receive, from the start, 45, 30, or 15 mg [of ponatinib] daily. The study has completed enrollment and the results will be available very shortly. We want to improve the safety but not lose too much of the efficacy. The trial will tell us the right balance of these 2 elements, but I think between comorbidities and proper management of the dose, and perhaps aspirin studies, that's how we need to manage these patients.Ruxolitinib is very effective in patients with myelofibrosis, particularly patients who have either a large spleen or who are symptomatic. Those are the 2 benefits of ruxolitinib. It does not simply change the natural history of diseases and eliminate the disease. For a patient who doesn't have either one of these problems, ruxolitinib is probably not going to help. Ruxolitinib is very effective in a lot of patients who have a large spleen and/or symptoms. We also have it approved for polycythemia vera and essential thrombocythemia for patients who have not responded to the initial therapy.Ruxolitinib is generally very well tolerated. The main problem is the myelosuppression. There is anemia, thrombocytopenia, and some neutropenia, and these have to be monitored. It is very dose dependent. If patients develop these symptoms, we need to decrease the doses to find the proper balance between having a good control of the symptoms while maintaining them [on the treatment]. We don't want to push them to a scenario where they're going to be transfusion dependent and all that because that would probably make us lose some of the benefits that we have.

What other challenges are there with using ruxolitinib in this space?

Other than that, [ruxolitinib] is very well tolerated. There's been concern about patients who end up having to stop therapy, whether they could go into sort of a withdrawal syndrome. There was much discussion about that earlier on. I haven't seen it as much, but you want to be careful if you stop the therapy. Make sure that you monitor your patient because perhaps at least some patients may develop into some decompensation. Keep in mind that ruxolitinib decreases a whole variety of cytokines, so these symptoms may be related to a rapid bounce back of the cytokine levels. Some of those can cause some of the symptoms of shortness of breath, fevers, and hypertension. Closely monitor the patient so, if the patient is having problems, we can identify them early.One of the problems is for patients who start with thrombocytopenia. For example, if they have platelets less than 100,000, ruxolitinib can lower the platelets, creating a challenging scenario for the patients if they have already a significant anemia. What do you do if the patient has a big spleen, a lot of symptoms, but has thrombocytopenia? There have been studies that if you start with a lower dose and slowly escalate to find a happy medium, you can do that. For example, there was a study that started with 5 mg twice a day, instead of with 25 mg. Many patients were able to then get some benefits. Sometimes in those patients, you may not push for the optimal benefit or for the most benefit, but if you can at least get some benefits, that still helps the patient. They still feel better, even if the spleen doesn't become completely undetectable. It shrinks enough that they don't feel that discomfort and pain.