When to Transition Therapy

Lindsey Lyle

In your practice, how do you typically decide when to transition a patient to a different therapy and what factors play a role in this decision, particularly now that we have a number of treatment options for these patients?

Lindsey Kalhagen

I think that's such a good question. We need to take into consideration the goals of treatment and factors at play when assessing if a therapy is effective and thus whether or not we should consider a change in therapy. We know that the JAK inhibitors were approved on the basis of improvement in total symptom score and spleen volume response. The trials did not include overall survival or delay of disease progression as prespecified endpoints; however, over time we have seen improvement in overall survival in those treated with ruxolitinib.^1,2 But obviously, when we're taking the entire patient into consideration, we have to balance both control of symptoms and splenomegaly with the development of cytopenias or other adverse effects. Whether we continue the current therapy as is, dose adjust based on blood counts, or decide to pursue a second-line treatment is a decision made by the team, including the patient, and taking all of these factors into consideration.

Lindsey Lyle

You hit on a good point: Do we transition to a new therapy, or do we try to modify the current therapy? With this mind, I'd like your input on a case. Mrs. M is a 74-year-old female with a past medical history significant for congestive heart failure and chronic kidney disease. She has intermediate-2 high-risk myelofibrosis, and she's been maintained on ruxolitinib at varying doses for the past five years. But over the course of her treatment, the dose of ruxolitinib has been decreased due to slowly progressive cytopenias. So right now, in my clinic, she's on ruxolitinib 10 mg, twice daily, with a white blood cell count of 5,000, 3% blasts, hemoglobin of 9 g/dL, and platelets of 75,000. I saw her last week, and she reported increasing frequency of night sweats, which are now occurring nearly every night. She also has increased abdominal discomfort in certain positions and early satiety, limiting her food intake. And she's had some weight loss as a result of this. So, would you think that another therapy is warranted for Mrs. M at this point?

Lindsey Kalhagen

Certainly my concern for her would be that it seems her disease was fairly well controlled in the past, but she has now developed symptoms related to an enlarging spleen. My other concern is that now she also has platelets below 75,000, so we're limited in terms of what exactly to do with her current therapy. If we increase her ruxolitinib dose, that’s likely to worsen the thrombocytopenia, putting her in a tricky position. This is someone I may consider as having a loss of response to ruxolitinib and consider changing therapy. How would you approach Mrs. M’s case?

Lindsey Lyle

This is one of those difficult situations. You could try increasing the ruxolitinib dose with really close monitoring of platelets, because that would be the dose-limiting factor. But knowing that she initially had a response from a symptom, spleen, and count perspective followed by many years of stable disease, and now a loss of response at 5 years, I would certainly think she needs a change in therapy. 

Lindsey Kalhagen

From a practice standpoint, what defines loss of response? Is it intolerance, or someone who's refractory to ruxolitinib?

Lindsey Lyle

In my opinion, these are three separate scenarios. A loss of response is similar to this patient case: initial response followed by subsequent spleen growth, return of symptoms, or increased leukocytosis. Certainly, this can happen, especially as the length of time on ruxolitinib increases. That being said, I've been able to follow patients, as I'm sure you have, for many, many years on ruxolitinib with well-controlled disease. Intolerance is when a patient develops serious adverse events or significant cytopenias including the need for frequent blood transfusions. Oftentimes, in this situation, the dose of ruxolitinib cannot be increased, although from a symptom or spleen perspective, the increased dose may provide additional benefit. A patient being primary refractory is pretty rare, in my experience. One particular situation I could see this being the case is when a patient presents with cytopenias limiting the up-front dose of ruxolitinib, therefore possibly reducing the degree of spleen volume response.  

Proactively monitoring blood counts, spleen size, and symptoms for signs of disease progression is an important part of the management of these patients. From a timeline perspective, how long would you continue ruxolitinib before calling it a failure?

Lindsey Kalhagen

That’s a really good question. Baseline labs and symptoms are important here. From a clinical practice perspective, there are strong guidelines for dose reduction based on cytopenias.³ But it’s important to also take into consideration and counsel patients that counts may temporarily worsen before they get better, and that occasional transfusion may be warranted during this time.

In my practice, we would likely keep a patient on ruxolitinib for at least a few months before calling it a failure, unless severe adverse events occurred. Again, it all depends on the overall clinical status of the patient. If a patient had a major adverse event, that would require more abrupt discontinuation. However, if ruxolitinib, for example, was not producing the degree of reduction of splenomegaly we had hoped for in, say, 2 to 3 months and the patient is tolerating it, giving it a little more time to see if there is an effect may be reasonable.

Lindsey Lyle

Great points. Going back to Mrs. M, let's just say we try to increase the dose of ruxolitinib, but her platelets get worse. And so now we're thinking, “Now we really should try to transition her to the next line of therapy.” I am curious as to how you safely do this from the perspective of potential rebound symptoms and cytopenias.

Lindsey Kalhagen

I think that the transition between therapies is something that we are still learning about now that there are more FDA-approved options for this disease, which is great—particularly for patients who become unresponsive to one therapy or who do not tolerate one of the therapies. But based on what we know about ruxolitinib, I would consider trying to taper that down and then start fedratinib, for example, to avoid potential rebound symptoms and overlapping cytopenias from both medications.^3,4 I also think we always take into consideration the risk-benefit balance for any new medication or change in therapy in terms of labs, baseline symptoms, and how potential adverse effects for each medication would impact an individual. I’m curious: What did you end up doing for Mrs. M?

Lindsey Lyle

When considering switching her, we really looked at her individual perspective, like you stated. We know the potential for withdrawal symptoms when stopping ruxolitinib is real.⁵ Given the fact that we have the time to safely taper in our patient, decreasing the dose over a couple of weeks is something that we discussed and did plan to do.

We got the prescription going for fedratinib and tapered the ruxolitinib down to 5 mg twice daily for a week while waiting this approval. And then we pretty much just had her start fedratinib upon receipt the next day after taking ruxolitinib. She did well and there were no withdrawal symptoms. But providers should be aware that this could potentially happen.

Having options and the ability to sequence therapies is very exciting. We do know that in patients who discontinue ruxolitinib, overall survival is worse in those who are not able to be treated with another line of therapy.⁶ Patients who discontinue front-line ruxolitinib generally do so due to a loss of response or advancing disease. When we talk to these patients, it's important to reframe how we're going to be monitoring them. Maybe this is a time where we have to increase the frequency of monitoring  and watch really closely to just be sure that we don't have any further evidence of disease progression. Hopefully, we’ll see a response to the second-line agent.

Lindsey Kalhagen

What laboratory findings would make you worried about disease progression?

Lindsey Lyle

The big things for me from this perspective are really progressive leukocytosis and an increase in blasts. This is on the one side of things, more of a proliferative situation. On the other side of things, pancytopenia can be a huge problem, making utilizing the current treatment options really difficult. I imagine the same is for you. Do you find these patients with low counts particularly hard to treat?

Lindsey Kalhagen

Yes, I think that significant pancytopenia makes treatment difficult and unfortunately limits treatment options. This again brings up the discussion between patient and provider about goals of care and consideration of supportive or palliative care if there are no longer safe therapy options available for patients on cytopenias.

Lindsey Lyle

These are two really difficult patient populations, and it's interesting that they are on opposite sides of the spectrum, but more of a bone marrow failure–type picture versus a very proliferative disease progression. Outside of the two JAK inhibitors and transplant as options for patients with progressive disease, what research is being done at your institution

Lindsey Kalhagen

We are constantly looking for patients who could potentially be clinical trial candidates. The factors to consider, of course, are whether or not the patient is eligible for clinical trials that are opening, as well as whether or not the patient is interested in participating in them. Clinical trials that are expanding for MF in general include additional JAK inhibitors and other therapies targeting anemia and other approaches to MF in general, including combination therapies, which is a trial that we have available right now.^7-9 What else have you been seeing on the horizon?

Lindsey Lyle

Yes, in addition to other single-agent JAK inhibitors, combination therapies are becoming more and more popular, as in other types of blood cancer that we treat. This is exciting from the perspective of not only being able to possibly improve symptoms, but also perhaps change the disease biology. One of the tasks at hand is trying to make changes at a bone marrow microenvironmental level. Certainly, this is an exciting time as we move forward to offer our patients more options.