The Biology of Myelofibrosis and Emerging Ways to Manage it

Kristi Wiggins

Tajuana, in addition to disease management, I’d like to talk about what myelofibrosis is. What do you feel makes myelofibrosis different than other marrow dyscrasias?

Tajuana Bradley

That's a really good question, Kristi. I think as advanced practice providers, when we look at and think about myeloproliferative neoplasms as a whole, we need to recognize that these are blood cancers. We really need to make sure that we disclose this to our patients, as well as our other colleagues because often I see that patients don't even realize that they have a malignancy. Specifically when we look at myelofibrosis, this is a unique disease state because every patient with myelofibrosis presents differently. First, we have primary myelofibrosis where it just can happen on its own. There's no rhyme or reason. It's important to note that patients will sometimes think that these things can be hereditary or passed down genetically to their family members, and that's not the case. As you know, we’ve discovered that there are these driver mutations, JAK2, MPL, and calreticulin (CALR), which can make this disease a little bit more challenging because of the impact that it has on our patients' quality of life, specifically when there's anemia, thrombocytopenia, and then the splenomegaly that can be seen.

Kristi Wiggins

And then there’s secondary myelofibrosis. Let’s take a moment to talk about that.

Tajuana Bradley

Of course! Secondary myelofibrosis, or what we call post-ET/post-polycythemia or essential thrombocythemia, can occur after these patients have been dealing with these diseases for a long time and then they develop myelofibrosis. Essentially what happens in myelofibrosis is you have these driver mutations that result in the abnormal production of blood cells that results in scarring and fibrosis of the bone marrow. In myelofibrosis there is a grading system used, grading 0,1,2,3. The higher the number the more extensive the disease. But specifically, when we're thinking about the pathophysiology and breaking it down into what we're actually seeing in our patients, anemia specifically, we know that these patients can have anemia and they become transfusion-dependent.

This is all driven by the fact that you have the scarring in the bone marrow and this disruption in normal erythropoiesis. You have pro-inflammatory cytokines that can also lead to anemia. It's just a never-ending cycle of continuing and worsening progression of the fibrosis in the bone marrow, as well as increased red blood cell turnover. Then you have this extramedullary hematopoiesis, where you have splenic sequestration that can occur, so these patients become really dependent on red blood cell transfusions. To add an extra layer, we worry about secondary iron overload that necessitates adding iron chelation therapy for these patients. I think the data has shown that as these patients become more transfusion-dependent or as anemia worsens, it impacts their overall survival and their prognosis. The same goes for thrombocytopenia.

Looking at constitutional symptoms, like fevers, chills, night sweats, fatigue, early satiety, itching, and pruritus, we know these are directly caused by increased pro-inflammatory markers and cytokines like IL-8 and IL-15. Then splenomegaly, which is caused by the extramedullary hematopoiesis that can be seen in the liver and the spleen. As that spleen gets bigger, these patients have more and more symptoms. So, over time we've discovered that we have these driver mutations like JAK2, calreticulin, and MPL.

That's a little bit about the pathophysiology of it. But now that we're bringing up the idea of these targetable markers, Kristi, are you able to discuss a little bit more about some of these biomarkers that we're seeing in terms of myelofibrosis?

Kristi Wiggins

Sure. I think it's really exciting that we finally have myelofibrosis treatment based on molecular markers. We didn't have those in the past. We were limited to using hydroxyurea and interferons. Now we can actually look at certain pathways present in myelofibrosis and consider therapy based on these. What we currently believe happens in MF is that the JAK pathways stimulate myofibroblasts, which is where the word myelofibrosis comes from. You have fibroblasts that create scarring in the bone marrow. What we believe the primary mechanism for the scarring is happens in the marrow due to JAK pathway activity. JAK stands for Janus associated kinase, and there are several of these kinases that are associated with this. Among the many markers that we've looked at in myelofibrosis, JAK1 and 2 are the primary ones for which therapies have been developed and can be used for patient treatment.

Interestingly, there’s recent information regarding a new target: BCL-2. It's actually not new to science and to treatment in oncology, but it's new to myelofibrosis. BCL-2 stands for B-cell lymphoma 2. It was discovered in lymphoma but now of course we know that it's also a presenting marker in myelofibrosis and other diseases. This protein lives in the mitochondria of the membrane in the cells. It was the first identifiable apoptotic regulator in non-Hodgkin's lymphoma, which is really interesting to think about in myelofibrosis because in myelofibrosis cells don't go into apoptosis. They don't have normal programmed cell death. They just continue to make more of themselves and cause the scarring tissue to be laid down in the marrow. So, with BCL-2 overexpression, it leads to more fibrosis. This perpetual process is what leads to that scarring secondarily impacting the blood cell production, which over time causes the blood counts to get lower and lower.

As you mentioned, the thrombocytopenia, the anemias, the things that impact the patient's quality of life, can impact their overall survival rates. The marrow can become aplastic in some cases. Most patients have malignant transformation before aplasia happens. This situation occurs if the abnormal cell growth continues to go unchecked.

Tajuana Bradley

Kristi, we’ve been talking about driver mutations. Is that still a truly accurate term?

Kristi Wiggins

That's an interesting question, Tajuana. Recently, I heard some researchers talking about those, and they're saying that particular term may be going away. They said it implies that there's a cause and effect, that one factor affects the other one and affects the next one in a linear fashion. Because there's so much crosstalk between these particular proteins and the cytokines that happen in this disease, they're looking at the whole milieu of these things. Current treatments are aimed at JAK and other pathways to suppress them, but it doesn't really change the clone that causes the myelofibrosis. So, while looking at different ways of going about suppressing cytokines as well as these markers, they feel like the driver mutation title is insufficient because of the cellular crosstalk.

The future will be interesting, adding what we know about myelofibrosis to what we think we know about downstream factors. There are other cellular pathways, and you mentioned a few of those, such as mTOR, PI3K, and Raf, as well as many others. Researchers are looking at epigenetic changes, which I think is so hard to pin down. It's something that's less understood, but we're fortunate so far to have the JAK and BCL-2 pathways that have been identified, and therapies can be created.

Regarding current treatment, you mentioned the spleen size and other symptoms like the night sweats, itching, and additional things that affect the quality of life. Current treatment basically focuses on those things for most patients with MF. People will have symptom relief with JAK inhibitors because it decreases the size of the spleen and suppressed some of the cytokine proliferation. But it is known that over time the results from a JAK inhibitor can be short-lived in some patients. It's estimated that about 50% of patients who come off JAK inhibitor therapy usually come off within the first three years of treatment. Patients usually stop the treatment because they have a lack of response or they've plateaued in some way, so there are some shortcomings in the JAK pathway treatments.

So, Tajuana, what has been your experience with JAK inhibitors such as ruxolitinib? What are some of the toxicities that you commonly encounter in your practice with this JAK 1 and 2 inhibitor?

Tajuana Bradley

Diarrhea is the one that's been an issue for some of the patients. I had a patient that had some rash as well. These patients may even develop some cytopenias that necessitate holding treatment and/or making some dose modifications. There can be a little bit of nausea and some GI upset.

Kristi Wiggins

Do you have any experience with the new JAK2 inhibitor, pacritinib?

Tajuana Bradley

I do actually, with pacritinib. Diarrhea has been a major issue for these patients, a major issue. So what I find helps is holding the patient’s pacritinib therapy. We wait for the diarrhea to resolve and then start them back at a lower dose to see if that can just smooth them out and transition them back onto the medication, to see if it helps them tolerate it.

Kristi Wiggins

Have you noticed as much change in the blood counts with pacritinib? It doesn't inhibit JAK1 like ruxolitinib does, so I wondered what your experience was as far as blood count suppression with the newer medicine.

Tajuana Bradley

So quite interestingly, we just started a couple of patients on this, and we saw one recently. She hadn’t really been on it long enough for me to see a change in the counts, but I know the diarrhea was part of our discussion today and just trying to manage that. I’m really excited to see what happens with her counts and with her spleen because that's a major impact on her quality of life right now.

Kristi Wiggins

So, if we can control the GI symptoms, it sounds like the blood issues may not have as much of an impact for these folks. One of the drawbacks with most clinicians is they don't want to continue with ruxolitinib because of the count suppression. But with the newer agent, there are GI effects. That's difficult for these patients who already have early satiety because of the enlarged spleen. It’ll be interesting to see how that pans out.

Treating the side effects of myelofibrosis out in the community, I imagine you usually see a lot of these people pretty early on in their treatment. In my current work setting, I tend to see people close to transplant, so they are in later stages of MF. What are the biggest challenges in managing these patients when you're seeing them in the community? Is it difficult to keep them on treatment? Tell me about your experience with JAK inhibitors and medication adherence.

Tajuana Bradley

For the few patients that we have, what's really been a struggle is just the blood counts that require us to provide blood transfusion support. During the pandemic, we've had some blood shortages. We also had difficulty getting things scheduled and arranging transportation, as well as the logistics of chair time in our outpatient infusion center. We don’t transfuse blood but we're a part of a hospital system that does. Managing and navigating all the logistics for that can be quite challenging while we’re trying to manage the anemia, the thrombocytopenia, and the spleen.

We’ve done some splenic radiation on a couple of patients, but that only helps and relieves patients for a while. As you know in these patients, sometimes they may not have some of the best markers or they may have these mutations where the prognosis is a little bit worse. These patients will, despite the splenic radiation, end up developing even more splenomegaly and progressing in that aspect. That can be really uncomfortable, and there’s the weight loss, so it's just been a real challenge.

Kristi Wiggins

I'm curious about ruxolitinib in your practice. Do you usually provide transfusion support when the counts are low or do you back off, do a dosage adjustment, or give them a holiday off the medicine?

Tajuana Bradley

A combination. We may continue with the blood support depending on how low they are. Then we may do dose hold and then do a dose modification and do a dose reduction. But I really try to encourage patients, specifically depending on if the toxicity they're experiencing is GI-related, to try to work around that so they can get the best out of the medicine before we stop it due to the side effects, trying to get the best out of it to see what kind of an impact it can have on the spleen and so forth.

Kristi Wiggins

As far as the prognostics of thrombocytopenia, is thrombocytopenia something that you use to prognosticate with patients to explain to them what their survival rates might be? Do you use any particular tools like the DIPSS [Dynamic International Prognostic Scoring System] or any of the other symptom management scales to determine prognosis and talk to your patients about those?

Tajuana Bradley

Yes, I tailor my discussions based on who I have in front of me. If I have a patient who's a little bit more savvy, then I may use some of those tools. But MPN Connect is a really great resource that I've used when trying to help explain why they're feeling the way they're feeling and why their spleen is big, why they may be having itching and so forth. So I typically use those, and then I will also tailor my discussions in terms of their blood counts because patients can get really caught up on the numbers at times. I'll use that time to try to discuss the data and say, "We know that when patients have worse thrombocytopenia and some of these cytopenias, your prognosis may not be as great." But again, I just try to be very mindful that everyone may not understand some of the terminology that we use and I tailor my discussions based on their level of health literacy and understanding.

Kristi Wiggins

Very good. In my practice, we see patients before they come to transplant, when they're at that end stage. In patients beginning therapy, I find it interesting that if their platelets are over 100,000, they have a really good chance of overall survival. It's amazing that thrombocytopenia tends to be the one factor that really lends to the prognostication of what their overall survival might be and what their symptom burden could be. Once they're below 100,000, we know that the overall survival rates drop. Once platelets drop below 50,000, patients have a really short survival curve. I typically see patients at that point.

I find it interesting that the NCCN guidelines first consider the symptoms scale. It's not the DIPSS that we use to stage people, but it's the symptom assessment form score. NCCN specifically mentions the MPN-SAF TSS. This scoring tool lists just 10 quick questions you would ask any patient that we see with myelofibrosis, just to see what their quality of life and symptoms are. They're looking at starting therapy based on what the patient tells you. I think it’s pretty amazing that we have all this technology, but  decide on when to start therapy based on what patients with MF are telling us about their symptoms, what impacts their quality of life.  This is what's really wonderful about what we do in practice, connecting with our patients.

Tajuana Bradley

Kristi, I want to go back and make a comment about when you talked about looking at the impact of just the counts and the platelets and how in the NCCN guidelines they even talk about that. I think the data suggest that the median overall survival of patients when their platelets are less than 50,000 is only about, what, 15 months? I think it's important for us as clinicians to be aware of this so we can be truly transparent with our patients and realistic about what the goal is and what we're trying to do here.

Kristi Wiggins

Absolutely. I think it is really great that the NCCN factors quality of life questions into the guidelines for the patients with MF because it is a key factor in myelofibrosis. Treatment isn't just based on pathology. It's based on clinical presentation, as well as the dialogue and the long-term relationship we’ve established with patients that is so important. I think this point makes MF a little different than other diagnoses that we see. The NCCN guidelines for MF were updated in March 2022, version 3.2022, and it’s available online to anyone at any time.

Tajuana, I want to segue to the newer drugs, if that's okay with you.

Tajuana Bradley

I think that's a good way to segue on to the newer drugs.

Kristi Wiggins

All right, so we already know that there are medicines approved for JAK1 and JAK2 inhibition. Looking at the newer drugs that have JAK2-specific inhibition, they're avoiding JAK1 and JAK3, which we're hoping will avoid some of the immune suppression factors and maybe even lower the risk of infections. What we won’t know for a while are the long-term effects since these drugs are so new. One drug with which I have no experience is fedratinib. I know that it is a JAK2 inhibitor, specifically for the JAK2 V617F mutation, which is a special population. The interesting side effect reported with this drug is encephalitis. So, this has not been a very popular drug. Do you have any experience with that one?

Tajuana Bradley

No Kristi, I don’t have any experience with it, but in patients that I have recommended fedratinib to, encephalitis did bring some hesitation and caution. I definitely agree with you about fedratinib not being a very popular drug due to encephalitis. However when I review the data, it is impressive, specifically with spleen size reduction. In reviewing the PI, there are recommendations for monitoring, levels at baseline and not starting therapy if levels are low. If the patient develops encephalitis, recommendations are to discontinue it and begin parenteral thiamine. We had a patient that we recommended fedratinib to; however, she declined it once she saw the side effects, so we ended up prescribing her old-school danazol, and she's holding steady.

Kristi Wiggins

Sometimes the old ones work just as well for some people for a while. The other one that I know you have an experience with is pacritinib. It is a JAK2 inhibitor, but interestingly it also has some FLT3 inhibition, which I'm very interested in because I see a lot of patients with leukemia. There are fewer cytopenias with the drug so far. This drug could be promising with FLT3+ disease. It's yet to be seen. We don't really know what that role might be in the treatment of leukemia. As you mentioned previously, the GI side effects are going to be one of the limiting factors for that particular drug. Both drugs, the fedratinib and the pacritinib, in all the studies that I've reviewed seem to decrease disease burden. But again, they don't destroy the disease clone. Therefore, it doesn't cure myelofibrosis, only suppresses it. Are you familiar with any of the clinical trials that are going on with any of the newer drugs and newer agents?

Tajuana Bradley

There was one that I recently received an email about, Momelotinib, but it seems pretty interesting, pretty provocative, and exciting once the approval comes in June 2023.

Kristi Wiggins

When I heard about the BCL-2 inhibition, I got really interested in it because we've used venetoclax for our patients with leukemia and we're using it off-label for other things. Navitoclax, a cousin to venetoclax, is a BCL-2 inhibitor. It's actually an anti-apoptotic drug. In my mind, that's the one thing missing in treatment for myelofibrosis­– stopping these cells from going into the proliferation phase. So if researchers can find something that stops the BCL-2 proliferation, it might stop the laying down of fibrotic tissue in the marrow, which would be amazing. Current clinical trials are using navitoclax in combination with ruxolitinib, looking at intermediate-2 and high-risk myelofibrosis so far. They're looking at intermediate-2 and high-risk myelofibrosis so far. There might be some synergy between the JAK2 inhibitor and the BCL-2 inhibitor. Again, this is hypothesized, but they're hoping this combination might be able to induce apoptosis of the clone that causes MF, which would be phenomenal. If we could prevent the fibrosis, that would be the goal.

Tajuana Bradley

Definitely practice-changing.

Kristi Wiggins

So far in the clinical trials, preliminary data shows that the complications associated with the navitoclax are thrombocytopenia and pneumonia. With thrombocytopenia, it’s often difficult to know if the etiology is the drug or the disease. The occurrence of pneumonia could just be related dysregulation of the immune system as a result of MF. It'll be interesting to see how the data is interpreted when the data analysis is completed. It looks like they've met their accrual for the study, but the preliminary report may be released next spring around March or April [2023]. I think it’s called the TRANSFORM-1 study.

Tajuana Bradley

Right. Awesome.

Kristi Wiggins

I think it's going to be really exciting to see if these drug combinations can cure MF. What do you think some of the benefits will be from these new drugs and mixing and matching? Now that we have a few on the market, are you mixing and matching anything yet or do you have thoughts on that?

Tajuana Bradley

We haven't mixed and matched yet, but I'm excited about it. Spleens in these patients can be pretty large, so I'm excited about the possibility of the splenic volume reduction, and it seems the data looks really good for both the pacritinib and fedratinib. Just thinking about the mixing and matching, as you said with the new BCL-2 plus the ruxolitinib, that's going to be exciting as well.

I do have some caveats in terms of the cytopenias and the side effect profile and toxicities, but as APPs and nurses, we are really good at managing some of these GI toxicities. We do a really good job of educating and counseling our patients, as well as their care team, about what to report and the monitoring and managing. I think while it may be that we can have some concern, I do take comfort in knowing that we've been using ruxolitinib now for quite some time. I think we'll figure out the niche, and we'll figure out how to get it right and be able to help our patients get on therapy and hopefully, like you said, be able to transform myelofibrosis.

Kristi Wiggins

That’s so exciting. I think about how this may translate into other areas. We know that myelofibrosis can evolve and have that malignant transformation to leukemia. About 30% of people with leukemia have a FLT3 mutation. I'm thinking, well, would drugs like this be able to suppress the MF clone and prevent transformation into a FLT3-positive leukemia down the road? That would be earth-shattering. If these new drugs could help stop myelofibrosis and potentially prevent the FLT3 mutation from occurring, that that would be amazing. I'd love for these new treatments to put me out of a job. I'm excited to see what navitoclax and some of these other agents can do. I think it's going to be a very interesting future for myelofibrosis.