Novel Updates in Frontline Myelofibrosis Treatment Research

Aaron Gerds, MD, Cleveland Clinic Taussig Cancer Institute, Cleveland, California, discusses data from the MANIFEST-2 and TRANSFORM-1 trials exploring first-line treatment options for patients with myelofibrosis, as well as makes the case for re-evaluating optimal clinical trial end points for future studies. 

Transcript:

Hi. My name is Aaron Gerds. I'm associate professor of medicine at the Cleveland Clinic Taussig Cancer Institute. I also serve as the Medical Director for the Case Comprehensive Cancer Center Clinical Research Office.

I spend most of my time, when I'm not doing administrative things, caring for patients with myelofibrosis as well as working on developing new treatments for those patients with myelofibrosis. There’s a lot going on in the field right now. The topline interest is in these 2, large, prospective randomized phase 3 trials done in the frontline setting. One looking at the combination of ruxolitinib plus pelabresib vs ruxolitinib alone. And the other, the TRANSFORM[-1] trial, looking at the combination of ruxolitinib plus navitoclax vs ruxolitinib alone. Again, both of these trials are for the frontline for the treatment of myelofibrosis—which itself is, I think, a big story—that we've come so far in this field where we're doing combination studies in the frontline setting.

The primary results for each of these trials, the MANIFEST-2, looking at pelabresib, and the TRANSFORM, looking at navitoclax, were presented at the ASH annual meeting back in December 2023. Then we had updates at the summer meetings, both ASCO and EHA. Both trials are positive trials. There were statistically significant and clinically significant improvements in the number of patients who had spleen volume responses with combination therapy vs single agent ruxolitinib alone. They were both positive trials. Yet, there is a lot of trepidation about these combinations moving forward.

Primarily because a secondary end point of total symptom score (TSS) reduction did not hit for either trial. There was a numerical improvement in the MANIFEST-2 trial, but it wasn't quite statistically significant. And in the TRANSFORM study, the 2 arms looked pretty close in terms of the number of patients who had at least a 50% reduction in their total symptom score.

There’s a couple of things to think about when we look at this. One, what is the value of spleen volume response? Well, certainly spleen volume responses can make people feel better, they can eat better, get better nutrition. And in studies with JAK inhibitors as single agents, spleen volume responses correlate with a better survival. So, the question is, is this a valid biomarker for improved survival? And I think we will need more time to sort that out.

But there is quite a bit of value in spleen volume responses. As a minor note too, for the patients who are transplant-eligible, there is a lot of data supporting reductions in spleen volume before going on to transplant. So I think this is a very valid finding. And it is the primary end point for both of these trials. The secondary end point of total symptom score I think is more challenging, because many of the symptoms are influenced by other things. We think about fatigue, for example. While fatigue is incredibly severe and prevalent in patients with myelofibrosis, it can be influenced by sleep apnea, blood pressure medications, depression, or other things. And so it may not fully represent the value of a therapy for myelofibrosis specifically.

Secondly, when we look at this, ruxolitinib is incredibly good at treating symptoms by itself. So expecting a combination to do even better may be intertwined with some folly. And lastly, getting back to my earlier point, people have symptoms that may be unrelated. And actually, it looked at a 50 % reduction, which may not be a true assessment of the total benefit.

Where would have these patients if they never had myelofibrosis at all. Where would their fatigue be? Where were their night sweats be? Where would all their symptoms be? And are we getting them back to their baseline? Or are we hoping to get them even lower? It may be unrealistic to get them better than what they would be if they never had myelofibrosis.

So, analyzing the TSS50 in this nature, in the setting of a comparator that is a JAK inhibitor, may be very difficult. When you're comparing just a JAK inhibitor alone vs say, a placebo or best available therapy, that may be different because you know getting them to their baseline will probably be a large improvement, but getting to someone vs a JAK inhibitor back to their baseline with a combination trial I think is a very valid end point. I think ultimately what these 2 trials are testing are not only these therapies, but are the end points that we choose for clinical trials.

And to me, it is a loud call for 1, critically evaluating the end points that we use in these trials right now, but 2, developing better end points. End points that do also correlate rigorously with other outcomes of interest, such as treatment durability, prevention of progression, as well as improvements in overall survival. So 1, these trials are positive and they're exciting and they will hopefully bring along new therapies for our patients, but 2, I think they're an opportunity to really critically evaluate how we conduct clinical trials and what end points we're looking at for our patients with myelofibrosis.