Research Swells in Myelofibrosis With JAK Inhibitors, Novel Agents

Historically, patients with myelofibrosis who progressed on ruxolitinib (Jakafi) had limited treatment options. However, the JAK inhibitors fedratinib (Inrebic), which received regulatory approval in August 2019, momelotinib, and pacritinib have shown promising activity as single agents. Meanwhile, the novel agents CPI-0610 and navitoclax have also demonstrated efficacy when in combination with ruxolitinib, according to Prithviraj Bose, MD.

“We don’t know that ruxolitinib really has an anticlonal effect. We don’t know that it’s a truly disease-modifying drug,” said Bose. “Yes, it improves survival, but there’s still a quest for something that really impacts the disease biology, rids the bone marrow of fibrosis, and reduces the mutant allele burden.”

In an interview with OncLive, Bose, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the current role of ruxolitinib in myelofibrosis, the potential advantages of next-generation JAK inhibitors, and the novel agents that are being explored as single agents and in combination with ruxolitinib.

OncLive: What are some of the advantages and disadvantages of ruxolitinib?

Bose: Ruxolitinib is a cornerstone of treatment in myelofibrosis. The drug has been around for almost 9 years. It’s a very good drug for shrinking the spleen and improving symptoms. Patients feel dramatically better on ruxolitinib. It’s a game changer for their quality of life. From long-term follow-up from the COMFORT trials, we know that there is a survival benefit with ruxolitinib. [We believe the reason why] is because patients feel better. They are more energetic, they eat better, they gain weight, etc. [Ruxolitinib provides] an indirect but important benefit. Those are the big plusses of the drug.

The negatives are that it does drop patients’ hemoglobin and platelets, particularly early on. It gets better later on, but ruxolitinib can lead to a significant drop in hemoglobin in the first 12 to 24 weeks of treatment. Unfortunately, that can be the reason for discontinuation. It actually happens quite a lot. That is a limitation of the drug.

What are the management strategies for patients who progress on ruxolitinib?

Historically, it has been very difficult. We haven’t had an approved drug, and people have used whatever makes sense from a clinical standpoint. There has been a lot of continuation of ruxolitinib because we didn’t have any other approved drug. People have also used hydroxyurea to control counts, maybe danazol to improve hemoglobin. Perhaps, thalidomide (Thalomid) or lenalidomide (Revlimid) [is appropriate to use]. The immunomodulatory drugs used to be very popular before ruxolitinib have been used [in this setting].

Those were the main agents [we used] prior to the fedratinib approval. Fedratinib has a broad approval in myelofibrosis, so it’s an option we can use after ruxolitinib.

Another approach we have some evidence to support is to stop ruxolitinib for a while and bring it back. Rechallenging patients with ruxolitinib was another approach we used prior to the approval of fedratinib.

How has the approval of fedratinib helped fill an unmet need in the second-line setting?

The FDA approval of fedratinib is a very broad one; it’s not specific for ruxolitinib failure in the second-line setting. It’s a broad approval in myelofibrosis. The JAKARTA trial was conducted in the frontline setting. It was a placebo-controlled trial in patients who were JAK inhibitor–naïve. The FDA mainly based their decision on those data, which is why the approval is not a specific second-line approval.

There was also the JAKARTA-2 study, which was a truncated study. The drug’s development got shelved back in the day because of the concern for Wernicke encephalopathy. The trial couldn’t be completed. It was a much smaller trial than the investigators would have liked, and they couldn’t really get all the response assessments they would have liked. Regardless, it provided some data for fedratinib in the post-ruxolitinib setting.

Those data have been reanalyzed with more stringent criteria for what defines ruxolitinib failure. [The JAKARTA-2 trial] was conducted much earlier when people were still learning about ruxolitinib and there were no clear criteria for ruxolitinib failure. Therefore, in 2019, the investigators reanalyzed the data with more of a modern consensus for ruxolitinib failure. The definition included a 30% spleen response rate and a 27% symptom response rate, both of which are decent. The data set [from the JAKARTA-2 trial] consisted of about 97 patients overall, and 79 of them met these stringent criteria for ruxolitinib failure. With this data set, we have some data to support its use. Because it’s the only approved drug [apart from ruxolitinib], it’s definitely a valuable option.

How do you determine whether to add on a drug to ruxolitinib or switch to another drug class if the patient has a suboptimal response with ruxolitinib?

This is a tough question, and there is really no right answer to this. Right now, add-on therapies to ruxolitinib are being investigated in clinical trials. None of them are approved for add-on therapy. However, it’s a very popular approach in clinical trials.

If I have a patient that is getting some benefit from ruxolitinib, I am more inclined, given that it’s such a proven drug, to not stop treatment and add something in the hopes of resurrecting that lost benefit or that insufficient response. I would look for clinical trials with agents that include CPI-0610, navitoclax, and parsaclisib. There are quite a few agents in development.

However, in some situations, it’s clear that patients are refractory to ruxolitinib. Either they never got any benefit from ruxolitinib or they completely lost it. There are no clear criteria and a lot of the decision comes down to judgement.

[It is good that we have the] ruxolitinib failure criteria that were embraced by the FDA and used in the pacritinib and fedratinib trials. It’s the same criteria that were used in the JAKARTA-2 reanalysis. Those guidelines provide a framework regarding what ruxolitinib failure is. I’m not saying those guidelines are absolute or ideal, but they are helpful. [It is helpful for] when you think [the patients are not having] a benefit with ruxolitinib, and you probably want to go to a different agent altogether or to a different class. There are quite a few novel drug classes that are being investigated.

There are some agents in clinical trials that are not JAK inhibitors, which you can pursue. However, in practice, you don’t have access to those agents, but you have fedratinib. Now that there is another agent, there is less of a reason to persist with ruxolitinib when you are seeing loss of response. The criteria that were used in the reanalysis in JAKARTA-2—such as spleen regrowth or lack of shrinkage by certain parameters after a certain amount of time, or an excessive transfusion burden while on ruxolitinib—[help us determine whether to continue on or abandon ruxolitinib]. In the absence of clinical trials, fedratinib is reasonable because a 30% spleen response rate and 27% symptom response rate are fairly decent. We haven’t seen that [level of activity] with anything else.

Momelotinib and pacritinib are also under investigation. How do these agents differ from fedratinib?

Momelotinib and fedratinib are not interchangeable. There are significant differences. Fedratinib is a JAK2 inhibitor. People think JAK1 inhibition may be important for symptom control. That being said, fedratinib has a decent symptom response rate. We don’t fully understand [the mechanisms of the disease]. Momelotinib is a JAK1/2 inhibitor. It’s more like ruxolitinib in that respect, but it has another important distinction from both ruxolitinib and fedratinib, and even pacritinib in that it improves anemia.

That will be a very important benefit, if proven, in the upcoming phase 3 trial. Momelotinib appears to improve anemia by blocking ACVR1, also known as ALK-2. By doing this, it suppresses the production of hepcidin, which is a hormone from the liver that controls iron metabolism. Momelotinib is able to improve anemia by this mechanism.

Pacritinib is a JAK2 inhibitor like fedratinib; it doesn’t have JAK1 activity. At the 2019 ASH Annual Meeting, we saw data from the PAC203 trial, which established the safety of pacritinib. The trial looked at various doses of pacritinib because there had been some concern of cardiovascular mortality, bleeding, etc. The investigators proved the safety and proceeded with a dose of 200 mg twice daily. The PACIFICA trial, which has opened in certain centers, will only enroll patients with platelets less than [50,000]. That’s important because none of these JAK inhibitors are safe to use [in patients with a platelet count less than 50,000].

Pacritinib may be an exception because it’s not as myelosuppressive [as the other JAK inhibitors]. Ruxolitinib and fedratinib are not easy to use [in patients with low platelet counts]. I won’t say they cannot be used, but they’re not easy to use [in that setting]. There’s no guidance on dosing. [Pacritinib] could help fill an unmet need [for these patients]. [The PACIFICA trial will enroll] patients who have not had more than 3 months of ruxolitinib, so it won’t be a heavily pretreated population. It’ll be a fairly treatment naïve and minimally treated population with low platelets.

What novel agents are you excited about?

The novel agents are being studied as add-ons to ruxolitinib and on their own after ruxolitinib failure or JAK inhibitor failure. Many of these drugs are being studied in both settings. CPI-0610 is interesting. That agent is a bromodomain inhibitor. Navitoclax is interesting. These 2, from what we have seen so far, are the big ones as far as add-ons go. Navitoclax is a cousin of venetoclax (Venclexta); it’s a BH3 mimetic or BCL-2/BCXL antagonist.

In terms of drugs that are being studied as single agents post-ruxolitinib, imetelstat continues to be intriguing because of its apparent survival advantage. Of course, it wasn’t really compared to anything, so it’s hard to say that it has a real survival advantage; in comparison to historical controls, it looks like it does. I am looking forward to more data on that agent.

There’s PRM-151, which is an anti-fibrotic drug. There is an LSD1 inhibitor called bomedemstat, [which we have] very preliminary [evidence for]. These are all active drugs. We have a lot to watch in the field. At the 2020 European Hematology Association Congress, which is going to be virtual, we hope to see some abstracts and new data [with these agents].

Is there any insight into whether these up-front combination approaches are better than sequential single-agent therapy?

I don’t think we know that yet. At the 2019 ASH Annual Meeting, we saw data with the up-front combination of CPI-0610 and ruxolitinib. It was a small group of patients. Of about 15 evaluable patients, 12 had a 35% spleen volume reduction at 12 weeks, so 80% at an early time point. That’s certainly very exciting. They have announced that they’re taking this into a phase 3 trial and will compare the combination with ruxolitinib alone.

In terms of the results we have today, all we have is the early data from the 2019 ASH Annual Meeting. It’s very early, but is certainly promising. It’s the long-term results that really matter. Survival is always the gold standard, and then things like bone marrow fibrosis and mutant allele burden [have to be taken into consideration]. We have to consider whether we are making a difference in the biology of the disease, or whether we’re just getting responses quicker. We have to see, and only time will tell.