Expert Discusses Methods for Treating Progression in Myelofibrosis

In an interview with <em>Targeted Oncology</em>,<em> </em>Prithviraj Bose, MD, reviewed his thoughts on identifying and treating progression in myelofibrosis, which he recently presented on during the 2019 SOHO Annual Meeting.&nbsp;&nbsp;

Prithviraj Bose, MD

In the treatment of patients with myelofibrosis who have progressed on ruxolitinib (Jakafi), there is no established standard of care, said Prithviraj Bose, MD. In the case of progression to AML, the only chance of long-term survival is to get patients to remission so that they can undergo allogeneic hematopoietic cell transplantation. New therapeutic approaches are needed to achieve better outcomes in patients with advanced myelofibrosis when they progress on ruxolitinib.

Ruxolitinib is the standard first-line drug for this patient population. Until recently, there was no second-line agent available following progression on ruxolitinib.

Recently, theFDA approval of fedratinib(Inrebic) for the treatment of patients with intermediate-2 or high-risk primary or secondary myelofibrosis filled an unmet need for a Janus kinase inhibitor (JAK) in the second-line setting. The approval was based on data from the JAKARTA trials.

In a recent re-analysis of the JAKARTA-2 trial using revised and much more stringent criteria for resistance/intolerance to ruxolitinib, the spleen response rate after 6 months of fedratinib was 30%, and the symptom response rate 27%

In an interview withTargeted Oncology,Bose, associate professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, reviewed his thoughts on identifying and treating progression in myelofibrosis, which he recently presented on during the 2019 SOHO Annual Meeting.

TARGETED ONCOLOGY:Can you provide an overview of your SOHO presentation?

Bose:I was tasked this year with talking about progression in myelofibrosis, which is a bit of a challenge because it's not a well-defined entity. Various definitions have been used in different clinical trials, and it's something that there's not been a lot of consensus on.

My topic was identifying and treating progression. Essentially, there are the International Working Group (IWG) 2013 criteria that are formal criteria for progression. But, those are for spleen progression and leukemia transformation, that's it. However, in practice, a patient can progress in many ways. You can have the spleen grow. You can have symptoms worsen. You can have blood counts worsen, and by that, I mean the development of anemia, or thrombocytopenia. You can have the white blood cell count go up. You can also have the blasts go, and end up in accelerated or blastic phase, which is the same as leukemic transformation. It can be any of these things or a combination of these because patients don't always progress in just one dimension.

Currently, there's not a whole lot that is available for these patients. Ruxolitinib is our standard first-line drug for most patients with myelofibrosis. Progression, to me, generally means progression on ruxolitinib.

We just had the FDA approval of fedratinib. That is a new option now, which certainly would be a valid option in a good number of patients who progress on ruxolitinib. There are data from the JAKARTA-2 study supporting fedratinib's use in the post-ruxolitinib setting.

Where things get interesting is when you look at the definitions used in various trials that have studied agents in the post-ruxolitinib setting. JAKARTA-2, for example, originally had a loose definition and then the data were re-analyzed using a stringent definition. The recent trial of pacritinib (PAC203), another JAK2 inhibitor, used the same definitions as they used in the revised analysis of JAKARTA-2. Hopefully, [this means that] some sort of a consensus is emerging in the field. What was interesting was that, when they used the revised definition, the response rates dramatically changed. The originally reported spleen response rate was 55% and with the new definition, it was 30%. The symptom response rate was virtually identical though, it was 26% and 27% in the original and the re-analysis.

Beyond fedratinib, there are many investigational agents that have been studied in the post-ruxolitinib setting. A few that come to mind are, the anti-fibrotic drug, PRM-151, the telomerase inhibitor, imetelstat, the JAK2 inhibitor, NS-018, and there's quite a few more.

Something I pointed out during my presentation was imetelstat. There was a lot of interest in the data that we saw at the ASH 2018 Annual Meeting because there seems to be a good survival rate in this post-ruxolitinib setting. It was reported to be almost 30 months for these patients at the higher dose of imetelstat. That took people by surprise because it has been reported that the survival in this setting is only 13 to 14 months. Both the MD Anderson Cancer Center and Moffitt Cancer Center have shown that. That was certainly interesting, but then that takes you back to the definition of what is ruxolitinib failure and how was it defined in the imetelstat trial.

There are a lot of nuances to this that could potentially make a difference and give you a markedly different number from what you would have expected. For example, the Italians have recently reported a 27-month median survival in the chronic-phase patients after ruxolitinib. It makes you wonder, are some people stopping ruxolitinib earlier than others. Is that why you're getting a longer survival in some studies and shorter survival in others?

I think the imetelstat data have to be taken in the context of the various definitions. Although, I will say that the Moffitt group looked at the imetelstat data in comparison with their own historical controls, and found that it did hold up.

The other thing I covered beyond this second-line setting is suboptimal response to ruxolitinib. Again, various definitions have been used and some trials have used no definition and left it to the investigator's discretion. Other have tried to define it. One that I particularly like is the parsaclisib trial that's a PI3K-delta inhibitor. I thought they had a nice definition of suboptimal response. After 6 months of ruxolitinib with 8 weeks or more of a stable dose, if the patient's spleen was more 10 cm, or 5 to 10 cm with symptoms, that was considered a suboptimal response and I thought that was a reasonable definition.

There are quite a few agents that have been tested in this setting. [The data] are preliminary at this point. We don't have a lot of data to go by. One interesting agent is the bromodomain inhibitor, CPI-0610, and there are others that we are waiting for data on, [which we will hopefully see at the next ASH meeting].

The last thing I touched on is progression to acute myeloid leukemia, which is called blast transformation. Unfortunately, there's been very little progress in this area therapeutically. We and others have tried ruxolitinib plus decitabine with fairly disappointing results. Although it's easy to deliver a regimen that patients can get in the outpatient setting, [the survival benefit] is not great. The [routine is still to] get them in a complete remission and take them to transplant and, unfortunately, that bar hasn't moved at all.

TARGETED ONCOLOGY:What are the differences seen as far as adverse events between fedratinib and ruxolitinib?

Bose:In my view, the 2 drugs are very similar in terms of efficacy and toxicity, but not entirely. For example, if you look at the spleen response rates and the symptom responses rates in the COMFORT trials of ruxolitinib and in the JAKARTA trials of fedratinib, you'll notice that the rates of spleen volume reduction, total symptom score reduction, as well as anemia and thrombocytopenia—the major [adverse] effects—are comparable. But, what I will point out is that fedratinib is also an inhibitor of FLT3 and this is why it is thought to cause a significant amount of gastrointestinal (GI) toxicity, which we do not see with ruxolitinib.

We now have 8 years of post-marketing approval and experience with ruxolitinib and it's a very well-tolerated drug. Having used it in many patients, [I know that patients] can get headaches, dizziness, and bruising, but those are more annoying than anything else. Most patients don't report any [adverse] effects.

With fedratinib, we have less experience but because of the FLT3 inhibitory action, there is the GI aspect of it. As is well known, initially, there was a concern about Wernicke's encephalopathy with fedratinib, and that led to the drug originally being discontinued by Sanofi, the original developer. That concern has been mitigated to a certain extent. The cases were re-analyzed and only one was found to be a genuine case of Wernicke's encephalopathy. I don't think that's a major concern. There is a black box warning about it on the label, I believe. I would be very careful in someone who's malnourished, for example, because they're already set up for things like that. Those are the main differences that come to mind.

TARGETED ONCOLOGY:What are your thoughts on the special considerations included in the NCCN guidelines for the use of JAK inhibitors?

Bose:For the use of ruxolitinib, we've had these special consideration listed in the guidelines and new ones just came out for fedratinib. One issue that I'd like to touch on is that there was a controversial report from Europe a year or so ago talking about the possibility of JAK inhibition therapy leading to an increased risk of non-Hodgkin lymphoma. While it was a general JAK inhibitor—related phenomenon, as the author put it, the vast majority of their patients had ruxolitinib, because that was the approved drug. That has been mentioned in the special considerations. The reason I bring it up is that we already know that lymphoma is more common in patients with myeloproliferative neoplasms. Several groups, including ours, have shown that. Specifically, after this report got published, we looked at our experience at MD Anderson and published inBloodthat this is not the case. We did not see an increase in non-Hodgkin lymphoma in our ruxolitinib-treated patients, as opposed to those who did not receive ruxolitinib. We don't think this is a real phenomenon, and I think it's important for the NCCN guidelines to include both of those pieces of data. Also, the original study refers to JAK inhibitors as a whole, so if this was an effect at all, it would be a class effect. But, I don't feel that there is a risk there at all.

TARGETED ONCOLOGY:What advice would you give to community oncologists using these 2 JAK inhibitors?

Bose:What I would do in my own practice is start with ruxolitinib. Again, this is a drug with 8 years of experience since its approval. It's a very well-tolerated drug and has an overall survival benefit. It makes people feel dramatically better very quickly, for the most part. Of course, there are some patients who are refractory, or who become resistant.

Given the fact that the 2 drugs are similar in efficacy and the main toxicities (anemia and thrombocytopenia), to me, there is no reason to begin with fedratinib. I would begin with ruxolitinib. Then, in the post-ruxolitinib setting, when I see signs of failure, I would absolutely use fedratinib. Again, [the signs of failure are not clearly defined]. But, with clinical experience, I think you have a good sense of when [ruxolitinib] is not working as well. The 30% spleen volume reduction rate that they showed in the more stringently done re-analysis of JAKARTA-2 is decent and so is the 27% symptom response rate. I think it's a good second-line drug and we are happy that we now have a second-line drug after ruxolitinib.

TARGETED ONCOLOGY:Are there any other emerging agents that you think are important for the treatment landscape?

Bose:There is one agent of interest called momelotinib. It's going into a pivotal trial called the MOMENTUM trial. This is a drug that has been in phase III trials before and had mixed results. This drug was also acquired from the original developer, Gilead Sciences, by Sierra Oncology, who is now resurrecting it. They are now going into a phase III pivotal trial against danazol and looking at symptoms and anemia as the primary and key secondary endpoint, not spleen response. This is informed by the results of the prior studies that were done with this drug. I think this is a drug that people are looking forward to because it improves anemia. That will be something nice to have.

Otherwise, there is a whole slew of investigational agents that it's too early to talk about.