More Research and Development on JAK Inhibition May Improve Myelofibrosis Management

September 15, 2019

In an interview with&nbsp;<em>Targeted Oncology&nbsp;</em>during the 2019 SOHO Annual Meeting, <mark style="background-color:inherit; color:inherit; font-size:14px">Laura C. Michaelis, MD,&nbsp;</mark>discussed the currently approved JAK inhibitors and the future landscape for myelofibrosis, as well as treatment considerations for graft-versus-host disease.

Laura C. Michaelis, MD

Outcomes for patients with myelofibrosis have improved with the approvals of two JAK inhibitors, ruxolitinib (Jakafi) and fedratinib (Inrebic). Laura C. Michaelis, MD, explains, however, that the development of novel agents and additional research are needed to further shape the myelofibrosis paradigm.

“There are large categories of treatments that are coming down the pipeline and may be able to mitigate some of the toxicities or failure to respond in some of our higher-risk patients,” said Michaelis, an associate professor at the Medical College of Wisconsin.

In an interview withTargeted Oncologyduring the 2019 SOHO Annual Meeting, Michaelis discussed the currently approved JAK inhibitors and the future landscape for myelofibrosis, as well as treatment considerations for graft-versus-host disease (GVHD).

TARGETED ONCOLOGY: How are you using ruxolitinib (Jakafi) in light of the FDA approval of fedratinib?

Michaelis:I haven't switched over to using fedratinib in first-line therapy yet because I wasn't a member of the clinical trials that were testing it. [Using fedratinib] is something that a lot of physicians in our field are going to have to figure out. Who is the right patient to move to that?

I have 2 patients who have inadequate response who have progressed [on ruxolitinib]. Those are both patients who I'm now looking at fedratinib as second-line therapy or employing clinical trials in that setting. We don't know yet if there are groups of patients who would benefit from fedratinib versus ruxolitinib. We are going to need a lot more data on that.

TARGETED ONCOLOGY: What are the differences in terms of adverse events (AEs) between these 2 JAK inhibitors?

Michaelis:Properly managed, both of them are very tolerable drugs for most people. We forget, especially when talking to patients, how poor they really feel with advanced myelofibrosis. Many patients are willing to tolerate some of these AEs in order to feel better from their underlying disease.

TARGETED ONCOLOGY: What are the next steps in research in the myelofibrosis landscape?

Michaelis:We have clearly come a long way since [ruxolitinib] was brought on the market. Yet, we still haven't been able to eradicate the clone. The first question, is it necessary? We have better stratification systems now and some people can live with myelofibrosis for a long time, so maybe treatment isn't necessary. There is certainly a category of people who can be observed.

If we have somebody with higher-risk disease, how are we modifying the disease? How are we getting to the root of it? I don't think ruxolitinib alone or JAK inhibitors as a whole are going to be the answer, although they are quite good for splenic response and reduction symptom response. Should we be using more drugs earlier, even in patients who have lower risk of disease, to prevent that clone from expanding? Or, do we need drugs that can tackle the clone at a lot of different areas of vulnerability, not just the JAK-STAT pathway?

I also think we need to figure out how to make transplant safer and perform transplants earlier before patients have a kind of resistant, damaged marrow and other organs, such as liver or lungs, that can make transplant more dangerous.

TARGETED ONCOLOGY: What is your advice to community oncologists regarding myelofibrosis treatment?

Michaelis:There are safety data for combining therapies that are already approved. You don't always have to wait for clinical trials to say, “This is a patient with whom hypomethylating agents and ruxolitinib might be the right approach.” Those data are out there, even if it is not at stage III level.

TARGETED ONCOLOGY: How do you determine the best treatment options for each patient?

Michaelis:It's a combination of conversations with the patient. On the left side of a piece of paper, I often write what the patient’s goals are. Is it to feel better, live as long as possible, or get this cured? What are our options? Then, I go through treatment options and explain that, “This one might not cure you, but it might make you feel better. This one could cure you but might make you feel worse.” We make a debate that way. It's important to identify the patient's individual goals and then apply the toolbox that we have to address those goals.

TARGETED ONCOLOGY: Patients who undergo transplant face a risk of GVHD. When does GVHD occur and what is the difference between acute and chronic GVHD?

Michaelis:GVHD occurs in the follow-up after the donor graft has taken hold in the patient. There have classically been 2 phases of GVHD: acute GVHD, which is classically defined as occurring in the first 100 days, and chronic GVHD, which can last a lot longer. Those definitions [of using] 100 days [as a descriptor] are a falling to the wayside, but we think of acute GVHD as being much more rapidly occurring. It probably influences the development of chronic GVHD disease later on.

TARGETED ONCOLOGY:Before the approval of ruxolitinib for GVHD, what options were available for patients?

Michaelis:Most GVHD is treated with immune suppression; that come in the form of multiple agents, such as steroids, to get rid of some of the T cells that were plagued. That immune suppression not only suppresses the donor cells, but also exposes the patient to the risks of chronic immune suppression, including fevers, infections, and more.