Myelofibrosis is a rare myeloproliferative neoplasm characterized by the buildup of scar tissue in the bone marrow, leading to decreased erythropoiesis, progressive bone marrow failure, and anemia. Currently, the discovery of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway's role in the pathogenesis of myelofibrosis is transforming the landscape with novel agents that improve patients' outcomes. However, correctly diagnosing and managing this disease using novel therapies and strategies remains challenging for clinicians.
Oncology Data Advisor: Welcome to Oncology Data Advisor, a digital resource for the multidisciplinary cancer team. Today I am joined by Dr. John Mascarenhas from the Icahn School of Medicine at Mount Sinai, New York. Recently, he recorded an educational continuing medical education/nursing continuing professional development (CME/NCPD)–approved activity, Managing Symptom Burden and Optimizing Treatment Outcomes in Myelofibrosis. Today he is here to share with us the importance of participating in this activity and further elaborate on the evolving landscape of treatment options for myelofibrosis.
Dr. Mascarenhas, would you like to introduce yourself and tell us a bit about your research interests?
John Mascarenhas, MD: Sure. So, my name is John Mascarenhas. I'm a Clinical Investigator in myeloid malignancies. I direct the Leukemia Program here at Mount Sinai in New York City. My interest has been particularly in myeloproliferative neoplasms (MPNs) and translational research, early clinical investigation, and late phase clinical studies in myelofibrosis, essential thrombocythemia, polycythemia vera and related acute leukemias.
Oncology Data Advisor: Why is it important that health care professionals participate in this activity and stay up to date regarding management of myelofibrosis?
Dr. Mascarenhas: I think it's important to stay up to date in the management of myelofibrosis because it really is quite dynamic and quickly evolving in terms of the understanding of the science that drives a lot of the clinical development, even the science that drives prognostication and risk stratification. And then, the advances that we're seeing in terms of translational research from mechanism-based strategies that exploit and leverage scientific findings in myelofibrosis really make it a fast-paced and changing area of hematology.
It would be very difficult, I think, for most people who don't do this for a living or stay immersed in it in the way some people do, to keep up to date and informed. It's quite exciting to see the field change like this because it obviously wasn't like this forever, and it's great. It's great for us that are involved. It is exciting to see this, but I think ultimately, it's great for the patients to have additional treatment options and a plan that might go beyond an initial therapy—so sequencing therapies and strategies and data that provide evidence for sequencing therapies.
Oncology Data Advisor: As you just started mentioning about the strategies and everything, could you describe some of the emerging strategies to reduce symptom burden and prolong overall survival of myelofibrosis?
Dr. Mascarenhas: We found out a long time ago from the COMFORT studies that JAK inhibitors, the first one being ruxolitinib, were significantly associated with a downregulation of inflammatory cytokine expression and that it was likely driving the symptom burden of these patients who were quite symptomatic. It was really rewarding as a physician to see patients feel significantly better, be able to get up and walk again, be able to get more engaged in family and work life, and simply feel better—reversal of cachexia, improvement in performance status. I think this is what drove the modest survival benefits that we have seen with ruxolitinib from the COMFORT studies.
There's a clear correlation or association between improvement in symptoms, which is a palliative effect, and how that palliative effect can actually have an impact on other meaningful outcome measures like survival. Although we were not inducing complete molecular remissions or pathologic remissions in the patients we were treating, we were clearly making them feel better, and patients who felt better and moved and ate were patients who were more likely to live longer.
Now that was a great first step, but obviously our interest now is in improving that by adding drugs to ruxolitinib, for example, that synergize with ruxolitinib from preclinical data that support it. That would hopefully have a more profound disease-modifying effect that would then extend survival even further.
Oncology Data Advisor: And could you just describe a little bit of what JAK inhibitors are and why they're so important to the treatment of myelofibrosis?
Dr. Mascarenhas: JAK inhibitors are a class of oral drugs. They actually started clinical development in myelofibrosis. Now there are a lot of indications for JAK inhibitors that go beyond myelofibrosis, including connective tissue disorders and dermatologic diseases and even within hematology, graft-versus-host-disease (GVHD). But it started in myelofibrosis.
They are small molecule inhibitors that briefly interrupt the JAK-STAT signaling pathway, which is integral to signaling through thrombopoietin and the MPL (myeloproliferative leukemia) receptor, granulocyte colony-stimulating factor (G-CSF and its receptor), erythropoietin and the erythropoietin receptor. So, these cytokine-driven signaling systems were overactive, either because of a JAK-2 V617F mutation, a calreticulin mutation, or a MPL mutation and were driving the phenotype of these diseases, the overproduction of blood cells, the inflammatory consequences, splenomegaly, etc. It was quite obvious that by giving them these small molecule JAK2 selective inhibitors, we were having a profound effect on certain aspects of the disease.
Oncology Data Advisor: In the activity, you mentioned some clinical trials; have there been any updates from those regarding treatment or anything that you would like to mention?
Dr. Mascarenhas: One of the exciting things about being a clinical investigator in MPNs these days is there's never a paucity of data that's emerging from clinical trials that are ongoing or completed. From the early days of the COMFORT studies all the way up to 2022, we now have three approved JAK inhibitors: ruxolitinib in 2011, fedratinib in 2019, and pacritinib in March of this year, 2022, and then likely a fourth JAK inhibitor approved, momelotinib, likely the first quarter of 2023.
And what you see are niches that are developing for these drugs. Although they're all JAK2 inhibitors, there are differences in their kinase profiles and selectivity for other important signaling molecules that likely explain differences in toxicity profiles, but potentially differences in efficacy that may provide advantages for certain niches. So, for example, pacritinib was approved for patients with severe thrombocytopenia but could be used for patients with platelet counts even up to 100,000.
This drug is associated with less myelosuppression. It is a JAK2 inhibitor. It is a FLT3 inhibitor like fedratinib. It does inhibit IRAK1, which is thought to also contribute to its activity, and you can get a 25% anemia response rate and stability, even improvement in some patients with low platelet counts, and deliver the full dose and obtain significant symptom and spleen benefits. So, that's a huge addition.
Fedratinib has excellent data that often needs to be reminded to the treating community as a second-line agent for patients who've had prior ruxolitinib in terms of spleen and symptom responses of 30%. One can see a world where you can pick niches and even sequentially have a plan for treatment with JAK inhibitors.
Then with momelotinib coming in, which also inhibits ACVR1, and a recent publication shows that pacritinib also inhibits ACVR1.This has been linked to the potential for anemia responses through hepcidin modulation. So, all of a sudden, we're looking at a world where there are different BCR-ABL inhibitors— it's almost like chronic myelogenous leukemia (CML) in a sense. We're not getting those CML-like responses in terms of four and a half full reductions in the driver lesion, but we are seeing areas where you can maybe tailor the treatment based on degree of thrombocytopenia and anemia and can have second- and even third-line options for patients in the commercial space.
And then, as I've alluded to, the other exciting aspect is the prospect of adding rational drugs to these JAK inhibitors. It's ruxolitinib mainly and mostly at this point, but they could be added to other JAK inhibitors, whether they're bromodomain and extra-terminal (BET) inhibitors like pelabresib, BCL2 inhibitors like venetoclax, 3-kinase inhibitors like parsaclisib, and a whole host of other drugs that are being developed.
There are even drugs that could have effect as monotherapy as a non–JAK inhibitor approach after JAK inhibitor, whether it's tagraxofusp, imetelstat, or Bomedemstat; there are a number of different drugs that have mounting data that are even non–JAK inhibitor options, either alone or in combination with a JAK inhibitor. I think one of the most exciting aspects—and it sort of makes sense for a disease that's both chronic and progressive, is the idea of moving combination therapies upfront, not even waiting for patients to fail the first-line JAK inhibitor. So, I think the best example of that is the MANIFEST study, combining pelabresib, the BET inhibitor, with ruxolitinib in Arm 3 of the MANIFEST study in patients who are JAK inhibitor–naive—not waiting for patients to fail, because we know once you fail ruxolitinib, with a median time to discontinuation of three years from the COMFORT studies, the outcomes are pretty poor with the median survival of 14 months.
And that's why imetelstat was very popular in the phase 2 study, because it looked like it was pushing the survival, almost doubling the survival of patients after they've discontinued. That's why studies like IMpactMF, evaluating imetelstat ina phase 3 setting of patients with ruxolitinib-refractory disease, are really paradigm shifting. So, it's not just trying to treat patients earlier on with disease with combinations of therapies that might have a more profound effect, but also trying to introduce non-JAK inhibitor options to improve survival. You'll see that, I think, progressing each five-year period. I think we will start to bring therapies that can work in concert with existing therapies earlier on in the disease that might have more profound effects than simply inhibiting the JAK-STAT signaling pathway, which is not unimportant, but is probably not sufficient alone.
Oncology Data Advisor: Since recording, have you learned anything, or would you like to add anything, that you feel the health care team should know regarding myelofibrosis?
Dr. Mascarenhas: Well, I think I'm most excited to see what happens at the American Society of Hematology (ASH) meeting in December, because that's really where the next big update in clinical development will be shared with the group. So, that's definitely where I learn the most and see what my colleagues are doing. One thing I think I is worth mentioning is if it weren't for the brave patients that sometimes go out of their way to participate in clinical trials, we wouldn't even be able to have this discussion. So, it's really a tribute to the groundbreaking work that is a combination of physicians and patients, and the trust that exists there to participate in these studies, because it can be quite frightening to have a disease like myelofibrosis.
It can be quite frightening to participate in clinical trials, particularly when there's an unknown, and that takes a lot of courage. So, that's sometimes not appreciated by everyone involved, but it is really a group effort on many people's parts: people in drug development, people in the physician community, and then obviously the patient community and the patient support groups for bringing all of these groups together.
And, ASH is a great place for us to see what kind of success we've had. We know that it won't be the end of it, but it will give us a sense of what we've accomplished, and maybe identify unmet needs and areas to move into. That is what I'm looking forward to, and hopefully after ASH I could get back with you and share some updates of what we've learned. One good thing too about the MPN research community, is it's quite collaborative in the sense that you will notice that a lot of the people who are really engaged and dedicated to this, work together in groups to accomplish advancing the field in a rare disease where you really need to pull resources and to work together.
I am proud to say that that does happen very successfully in this area—it's not a one-man show by far—it's really a lot of men and women across the world that are dedicated to this mission of improving the understanding and ultimately the outcome of patients with myelofibrosis and related MPNs. And for that, I think we're in a better place than we were probably 15 or 20 years ago.
Oncology Data Advisor: This is really great information, and definitely after ASH we'd like to follow up with you. So, we'll keep in touch about that. Thank you so much, Dr. Mascarenhas, for being here today and giving us such great information and passion about the topic. And we'll talk to you soon.
Dr. Mascarenhas: My pleasure. Nice to talk to you.
If you would like access to learn more about managing symptom burden and treatment outcomes in myelofibrosis, Dr. Mascarenhas' free CME/NCPD activity is available here until June 29, 2023.
About Dr. Mascarenhas
John Mascarenhas, MD, is a Professor of Medicine at the Icahn School of Medicine at Mount Sinai, New York, where he directs the Adult Leukemia Program and plays a key role as a clinical investigator in the Myeloproliferative Disorders Program. Dr. Mascarenhas is the Director of the Center of Excellence for Blood Cancers and Myeloid Disorders. His research interests revolve around myeloproliferative neoplasms, translational research, early clinical investigation, and late phase clinical studies in myelofibrosis.
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.
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