Ruxolitinib Combos Explored to Address MPN-Associated Symptoms

Laura Michaelis, MD

One of the biggest challenges in patients with myeloproliferative neoplasms (MPNs) is managing associated symptoms, but a myriad of ongoing studies evaluating ruxolitinib (Jakafi) in combination are hoping to address this, said Laura Michaelis, MD.

Anemia is a common presenting symptom of myelofibrosis, one that can worsen when treatment with ruxolitinib is started, said Michaelis, an associate professor of the Medical College of Wisconsin. In an effort to overcome this issue, ruxolitinib is being combined with agents such as erythropoietin and danazol.

“Sometimes we need to combine ruxolitinib with erythroid-stimulating agents like that in order to prevent some of the anemia,” she explained.

The FDA-approved JAK inhibitor is also being studied in combination with hypomethylating agents, such as azacytidine, as well as PI3K inhibitors, such as TGR-1202. Beyond these combinations, newer-generation JAK inhibitors momelotinib and fedratinib are also progressing through the pipeline.

All the while, the role of interferon in the treatment paradigm remains in place, she added.

“Where the MPN field in general is going, when we are looking at essential thrombocythemia and polycythemia vera (PV) in particular, there is growing information on how to use interferon in the frontline [setting],” said Michaelis. “The question of whether or not interferon should be used early on in the disease rather than when patients become high-risk is one that is being vigorously debated in the community.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Michaelis highlighted the many ruxolitinib combinations under investigation and provided insight into the role of interferon in the space.

OncLive: What recent developments have been made in MPNs?

Michaelis: It's been 6 years since ruxolitinib has been FDA approved in myelofibrosis, but there are additional nuances in MPNs and PV. One of the things I spoke about [in my presentation] was how to deal with patients with myelofibrosis who also have anemia. Anemia is a common presenting symptom of myelofibrosis, and it can sometimes worsen once patients start treatment with ruxolitinib.

I also spoke about some combination therapies developed to help overcome this. That includes ruxolitinib in combination with approved agents like erythropoietin, for example. We could also combine it with some of the older therapies, such as danazol. Some individuals who present with MPNs and anemia can see their hemoglobin dip and then it will come back up. One of the things we see is that if patients with myelofibrosis have a lot of hemolysis, we can see that when the spleen shrinks on the ruxolitinib, their anemia can improve despite the suppressive effects of the agent.

The second question is what to do with the patients who present with myelofibrosis with increased blasts. This is a more dire situation, and it's definitely one of those [factors] that speaks to a more accelerated phase of the disease. Another thing I discussed was how to safely combine ruxolitinib with hypomethylating agents. That [approach] is new and it's something that many of us have been doing off-label because we not only have evidence that it can increase the blast count, but it may also reverse the fibrosis.

I also spoke to the studies conducted by The University of Texas MD Anderson Cancer Center with ruxolitinib plus azacitidine. Most of the trials being performed in MPNs, and myelofibrosis in particular, are looking at what we can combine ruxolitinib with. Many of those trials are geared toward improving patient symptoms, either the spleen hasn't shrunk enough on ruxolitinib alone or pervasive fatigue is occurring. A wide variety of agents [are being] combined with ruxolitinib [to counter that]. I focused on a PI3K-delta inhibitor and a BET inhibitor in my talk, both of which are being used to augment the effectiveness of ruxolitinib as well as potentially provide additional symptom management.

There are also next-generation JAK inhibitors that are making it further along in clinical development; momelotinib is one of those. Fedratinib, which is now moving a little bit closer to registration, was initially put on hold due to some adverse events that are now being reexamined in the context of their clinical trials. We think that fedratinib may be available to patients before too long.

Could you expand on the data exploring the use of ruxolitinib in combination with hypomethylating agents?

One of the most interesting things about the study out of The University of Texas MD Anderson Cancer Center was the way that the investigators devised their treatment plan. People came into the study on ruxolitinib already, or they were started on it. They had individuals stay on ruxolitinib and then the azacitidine rolled in later; it was cycle 4 where they started to use azacitidine. They also dose-reduced the azacitidine from 75 mg to 50 mg. That could be adjusted up later. In practice, when I've had somebody with high blast counts, I've often used it without that ramp up of [more than] 50 mg. However, it's great to see that actually be spelled out when you go to patients and say, “These are published data and we can do it like this.”

We know that hypomethylating agents are good for low blast count acute myeloid leukemia, but they are not necessarily good for everyone. I'm feeling increasingly supported by the data in using that combination. There's a point where medicine moves from science to craft, but every time there are new data, you feel that you are on firmer ground in terms of that particular therapy. [I should note that] there was significant concern about cytopenia with this combination.

What other ruxolitinib combinations are under investigation?

There have been predominately phase I and some phase II results for using ruxolitinib in combination with PI3K inhibitors and with HDAC inhibitors, but none of these are close to registration. We've been involved in a study out of Vanderbilt University Medical Center that's combining ruxolitinib with TGR-1202, a PI3K-delta inhibitor. This has some extremely favorable and encouraging symptom responses that we found. TGR-1202 is being utilized in other hematologic malignancies, such as lymphoma. However, these [combinations] are still in the hypothesis-testing stage rather than the true move-to-registration stage.

How would you define the role of interferon today?

As you know, most of the randomized data for the past 3 decades in PV has utilized hydroxyurea as one of the primary arms. However, there is increasing use of interferon, especially in patients who are JAK2-positive. We have early hints that over time, patients' molecular mutation burden might decline with the use of interferon. One of the big landmarks in MPNs was the publication in the National Comprehensive Cancer Network guidelines of treatment recommendations for these diseases. They did indicate that interferon was an appropriate frontline choice for some individuals.

In my practice, I tend to use interferon in younger patients because it's a little bit better tolerated. I use it in individuals where fertility is a concern because it's less likely to cause significant concerns in either male or female patients. Also, if I'm contemplating treatment for decades, the skin toxicities for hydroxyurea can be a problem over time. I do prefer to start with interferon since it can be well tolerated, especially in pegylated form. A novel interferon- alpha has been introduced in Europe, and we hope that will be the kind of agent that American patients have access to in the future.