JAK2 and IRAK1 in Myelofibrosis - Episode 5
Expert hematologist/oncologists comment on the value of reducing fibrosis as a potential goal of therapy when treating patients with myelofibrosis.
Ruben Mesa, MD: Interestingly, both you and I are involved with multiple phase 3 studies now that are looking at some additional potential end points for studies for reversal of fibrosis or improvement in survival. Why don't we tackle each of those in turn before we start talking about some of the other targets such as JAK2 and IRAK? But first,what do you think about reversing fibrosis as a goal of a therapy?
John Mascarenhas, MD: Fibrosis, of course, is an integral part of the disease process. I still would argue that it is not fully understood in terms of its pathophysiology. There's a lot of data that would suggest that it's mediated by factors like TGF-beta [transforming growth factor beta] and those cytokines that are often produced by megakaryocytes and other MPN [myeloproliferative neoplasm]-related cells. There is data that would suggest that the fibroblasts themselves may be a part of the clonal process, so some of the aspects that revolve around fibrosis remain somewhat elusive. We know that it is a function of advanced disease and typically gets worse over time, and with that, you see more extramedullary hematopoiesis and often a more cytopenic disease state. We've always been interested in ameliorating or reducing the fibrosis in the bone marrow as at least an exploratory biomarker in most trials. I'm excited to say in 2021, you could look at a number of different trials that have demonstrated efficacy and outcome measures such as reduction in fibrosis. Whether it's navitoclax or pelabresib which is a BET inhibitor, bomedemstat which is a LSD1 inhibitor, or multiple other drugs such as imetelstat, a telomerase inhibitor, all have data that suggests 30% to 40% of patients can have reduction of at least 1 grade of bone marrow fibrosis. I think what we need to look at very closely and importantly—and I should mention PRM-151, the anti-fibrotic immunomodulator, of course, has also demonstrated that—is what is the clinical consequence or outcome and benefit of reduction in fibrosis? Although it would suggest with any of these therapies, the ability to have disease modification within the bone marrow, it's not always clear to me that there's an actual clinical outcome measure of benefit, such as alleviation of anemia or thrombocytopenia, or something tangible and meaningful to a patient. Even though a patient may have a reduction in bone fibrosis, if they can't really enjoy that in some form, I'm not sure how much of a success or how much value that has. The only data that I've seen that is encouraging across the board, in terms of reduction in fibrosis, is the data from imetelstat showing that a grade 1 reduction in fibrosis with treatment with the telomerase inhibitor had a statistically significant association with survival outcomes. So perhaps for the first time, this is linking the benefit of an exploratory biomarker such as bone marrow fibrosis reduction with a clinical outcome measure that's important to all of us like survival. I think what’s going to be paramount for any of the studies that you and I or anyone is involved in is to make sure that we conduct the studies in such a way to empower them so that we can at least be able to start to associate and correlate these biomarkers so that we know that they're actually meaningful to patients. But nevertheless, it is exciting. I will admit that I get excited every time I have a patient who has reduction in fibrosis. I feel like it is a sign that we are targeting the disease in a more meaningful way.
Ruben Mesa, MD: It's interesting what you mentioned about fibrosis. I take a subtle view of it that I try to share with patients. I don't think that it's the reticulin fibers themselves that are tied to worse outcomes in the disease. But all of that said, I do think that some of the medications that we're using that target the underlying drivers of fibrosis might be impactful by decreasing inflammation, by impacting stem cells so that there may be a correlation with improvement of the fibrosis. I don't think the fibrosis itself is choking the bone marrow, but it is a helpful marker.
Transcript edited for clarity.