What Advanced Practitioners Need to Know about Myelofibrosis

Julie Huynh-Lu: Okay. Welcome to part 3 of our round table discussion on myelofibrosis. My name is Julie Huynh-Lu, and I'm back again with my colleagues, Lindsay Lyle and Maureen Thyne. Lindsey and Maureen, thank you again so much for joining me today. In our previous discussions, we talked about pathophysiology, how patients are diagnosed with this disease, with myelofibrosis, risk factors and how they present, and then we also talked about quality of life and what treatment options are there for these patients and how we personalize them. Now that we've already discussed treatments, a big component is also how we manage side effects of these drugs in our patients. Maureen, if you don't mind taking the helm on this one.

Maureen Thyne: Sure, yes, let's start off. Many of you are probably already familiar with ruxolitinib. As Julie mentioned in the previous video, it was the first of the approved JAK inhibitors. Many of you, again, have been using it and are familiar with it already. Some of the basic hematologic toxicities include the cytopenias, so thrombocytopenia, anemia, neutropenia. We certainly want to watch out just in case our patients might develop or start with an infection. We wouldn't want to initiate therapy if that were the case. Some of the non-heme toxicities are the most common, would be bruising, dizziness, headache, and even diarrhea. One of the other things we want to monitor for our patients are also lipid counts. We noticed this on some of the trials, comfort trials, that the lipids can become elevated. For your patients who might not be on a statin or another lipid lowering agent, this might need to be initiated. For those that are on one, it might need to be adjusted. 

For fedratinib, this is another JAK inhibitor, of course, and many of these potential AEs are the same. Potential for cytopenias, anemia from thrombocytopenia, potential for non-heme toxicities. Again, this is an oral agent, so a lot of these are GI, diarrhea, nausea, vomiting. We also watch here for pancreatic things like amylase and lipase elevation and hepatic toxicity. Fedratinib is unique in that it carries a black box warning for Wernicke's encephalopathy. Watching for things like ataxia, mental status changes, and ophthalmoplegia. In this case, of course, because of the Wernicke's, we want to make sure we're checking a thiamine level at baseline, and because that makes me sound smart, I just want to translate that thiamine is vitamin B1, so this is not actually anything fancy.

Pacritinib is our third JAK inhibitor approved. This one, again, I sound like a broken record. Heme toxicities that are possible include thrombocytopenia and anemia, some of the non-heme toxicities, again, oral agents, so GI stuff, diarrhea, nausea, and also possibly peripheral edema. This one should, if you remember, this one was a little bit less myelosuppressive, and so there should be less thrombocytopenia here. Remember that pacritinib was the agent that was approved for patients who had thrombocytopenia, so we should be seeing less of that in this agent, but just to be on the lookout. Pacritinib, which is our third JAK inhibitor, the heme toxicities, again, are going to sound very similar potential for thrombocytopenia or anemia, although if you remember, pacritinib was the agent that was approved for patients who already have thrombocytopenia or platelets that are < 50.

This agent should have less thrombocytopenia than the agents I've already talked about, ruxolitinib and fedratinib. Some of the non-heme toxicities that are possible to be seen, again, oral agents, so GI things are kind of front and center, possible for diarrhea or nausea. Also, we see a little bit of peripheral edema in this one, so we're watching for that. Some of the other things we want to look out for here is not using with a CYP3A4 inhibitors or inducers, so watching for the other medications that your patient's taking, and cardiac in this one as well, QTC prolongation. So patients who have any sort of cardiac background, you want to just be watching out.

For momelotinib, our most recent approved medication, we're watching, again, heme toxicities, so again, broken record, thrombocytopenia, anemia, neutropenia, and non-heme, the most prominent here is diarrhea. We're also checking just in case for nausea and it's possible to see elevated LFTs. I would say the most unique feature about both pacritinib and momelotinib is that there is just a little bit of an alert for patients who are smokers or previous smokers that we should watch out for using pacritinib or momelotinib in those patients.

I know I just ran through like a freight train and through some of that, but anybody have anything that they think I missed or that they're watching out for in their patients?

Lindsay Lyle: I think, Maureen, you did such a good job, and you're right, because of the mechanism which ties always back into the pathophysiology, we kind of are anticipating these cytopenias. I think that the biggest thing from an advanced practitioner perspective is to be aware of these potential AEs and how to manage them.

Because we want to be able to keep our patients on therapy so long as it's safe to do so, and so we just really need to be aware of how we can proceed safely and maybe there are dose adjustments needed, maybe there are pauses needed. We just kind of have to keep all this in mind so that we can give them the best shot at really having adequate exposure to whichever therapy they're on for the potential for them to have the biggest benefit. The other thing-

Maureen Thyne: Yeah, part art, part science, right?

Lindsay Lyle: Exactly. Exactly. Yeah, and there's pretty good guidance within each drug's prescribing information of how to do these things. I would recommend everybody check that out, especially prior to prescribing or initiating a therapy in a patient, because one of the things that may differ is dose modifications for renal or hepatic impairment. Some agents have data for use in patients with dialysis and some don't. But, of course, our patients are generally older, and so they're going to have these comorbidities. They're going to have potential drug interactions, as you mentioned, so just really needing to be astute and comprehensive as we're looking at therapies and potential AE profile.

Maureen Thyne: Yes, it's really easy to see them as one class. They're all JAK inhibitors, they all do the same thing, but as you can see, they're really unique. They all have a little bit of idiosyncrasy to them, so it's really important to know what makes them different even though they're all kind of getting at that same treatment goal that we talked about previously.

Lindsay Lyle: Exactly.

Julie Huynh-Lu: Lindsey, do you want to kick us off with our first case study?

Lindsay Lyle: Absolutely, yes. We have two case studies just to really try and bring this to life a little bit. The first case is a patient named Benjamin, not his real name, is a 67-year-old male who presents to his primary care with fatigue, weight loss, and abdominal fullness. He is a retired electrician, past medical history of type 2 diabetes and hypertension. On exam, he does have a palpable spleen, 10 centimeters below the left costal margin and otherwise has a benign exam. His blood work reveals leukocytosis with a white blood cell count of 14, hemoglobin of 8.2, and platelets of 100. He had a bone marrow biopsy performed, which showed a hypercellular marrow with increased atypical megakaryocytes and MF-2 grade fibrosis. On molecular panel analysis, he does have the JAK2 V617F mutation and has deployed cytogenetics. This is not an uncommon presentation that we see, especially for initial diagnosis.

If we're looking at this patient's diagnostic features, we really can be sure he does have primary myelofibrosis without a known antecedent MPN, like ET or PV. We're looking at his bone marrow biopsy, it's hypercellular. He's got grade 2 fibrosis and a JAK2 mutation, so there's clonal fibrosis going on, and he clearly has anemia related to his disease. He has a high white blood cell count, although it's not high enough to be a negative prognostic feature for him, and his platelets are low, they're 100,000. From a very objective perspective, these things add to his risk categorization, but also the patient has palpable spleen and symptoms. This patient is already a higher-risk patient with myelofibrosis, and so we need to consider treatment for this patient. Maureen or Julie, how would you approach identifying the need for treatment and how you would have these conversations with the patient?

Julie Huynh-Lu: One, like you mentioned, determining the patient's risk factors and doing their prognostic calculation, and that kind of gears what direction we go in terms of their treatment. Is he going to even qualify for a transplant because of his age or his past medical history or other things that we take a look at? Then aside from that, he has an enlarged spleen. He does have symptoms, fatigue, weight loss, this abdominal fullness probably related to the splenomegaly. If there is anything that we could treat him with that can help improve symptoms, which we know JAK inhibitors can do that and also reduce the spleen size, again, JAK inhibitors can do that, but the tricky part for me is that his hemoglobin is 8.2. We mentioned earlier that these different JAK inhibitors have specific idiosyncrasies, as you mentioned, Maureen, that might help with spleen and symptoms, but can affect other things such as the hemoglobin level or the platelet level. Some of them affect certain numbers more than others, so it's a bit tricky trying to determine what would be the best course of action for the patient.

Maureen Thyne: Yes. I would get him, just as Julie said, I would get him, at the very least, if he is in any way convenient to a transplant center, I'd be getting the ball rolling on at least transplant consult, get him matched, get him typed, see what his options are while you're figuring out what kind of treatment you want to be starting him on because you know at least that transplant is his only option for potential cure. He's certainly not going to transplant tomorrow, but you certainly want to see what kind of choices he has and that takes time. While you're sorting out his transplant potential, you can be starting his treatment today or tomorrow. From a treatment perspective, there's a couple of things that we don't know from the case. We don't know if he has peripheral blasts. For me, the way that I'm kind of spot-checking him real quick is that he's kind of right on the cusp of an intermediate 2 or high-grade disease or high risk disease.

We don't know if he has peripheral blasts. His platelets are low, but they're literally right on the threshold. He definitely has anemia, but by and large, he's a quasi-high risk guy. Like Julie said, I totally agree you want to be treating him tomorrow. What JAK inhibitor you choose, I don't think you can necessarily choose the wrong thing, but you need to be getting him some treatment with a goal of making the big three we've talked about, you want to make his spleen smaller, you want to make his anemia better, you want to make his quality of life better, and if at all possible, you want to get him into a transplant if he has matches.

Julie Huynh-Lu: Okay. Lindsay mentioned that we have two cases, so this is the second one. We have Laura, who's a 72-year-old female with myelofibrosis. She has previously been treated with ruxolitinib for the past 10 years with adequate control of her spleen and symptoms. However, over the last year, her hematologist has noted that she's developed worsening anemia and thrombocytopenia that did not improve with a reduction in the ruxolitinib dose. She still is transfusion independent. Her symptoms of abdominal fullness, early satiety, and drenching night sweats have now returned. Her blood work shows leukocytosis of 28,000, hemoglobin of 8.5, platelets are 45,000, and peripheral blasts are 2% while on ruxolitinib 5 milligrams twice a day. Her spleen is palpable at 18 centimeters from the left costal margin and her hematologist is considering switching her therapy to pacritinib but is concerned regarding the possibility of diarrhea. In looking at this patient, there's quite a number of things that's concerning about her. She was previously on a JAK inhibitor with great response and had good spleen and symptom control, but over the last year, now her counts are diminishing and decreasing.

If you're purely looking at her blood work, the fact that she has leukocytosis over 25,000, that should be a ding for you and hemoglobin of 8.5 even though she is transfusion independent, and of course her platelets are 45,000 while on ruxolitinib 5 milligrams twice a day, which we know, based off of studies, that this dose doesn't really do much in terms of spleen symptom control and controlling of the disease, and, of course, she has peripheral blasts, 2% on blood. Her spleen is huge, 18 centimeters. I think all of this is a good indication that perhaps ruxolitinib at 5 milligrams twice a day, which is all she can tolerate at this point because her platelets are so low, is no longer doing what we want it to do. Of course, switching to a different therapy, like her hematologist is considering, is probably recommended. Lindsay or Maureen, would you have considered switching this patient to pacritinib or would you have thought to do something else?

Lindsay Lyle: I certainly would. As we know, pacritinib is safe and indicated in patients with platelets > 50,000. One thing I certainly would consider in this patient is, depending on how quickly her white blood cells have increased, I may certainly repeat a marrow just to make sure she is not have more blasts in the marrow than the 2% in the peripheral blood, that we're not looking at an evolving disease given these severe cytopenias with a high white count, and prior to starting pacritinib, I would do that. Maybe you'd need a little bit of bridging while you're doing that marrow with one of these cytoreducers that we talked about before. But certainly diarrhea is something to consider. We know from the studies that it's generally curbed within the first 8 weeks. I think that, depending on the conversation you have with your patients, there's certainly mitigation strategies that you can come up with to try and either prevent this if they're prone to having diarrhea at baseline or ways to jump on this quickly if that were to happen.

Maureen Thyne: I totally agree with Lindsay, especially about the bone marrow, and really, the only thing that I have to add is that maybe in what we do, the hardest thing is simply to make a decision. It looks like this patient has kind of been in this position for about a year and sometimes not deciding to do something different is making a decision, except it's probably the wrong one. Just deciding to do something different is important. That's the only thing I guess I would emphasize, is that I think Lindsay's choices are correct, it turns out, but the hardest thing is simply to decide, to recognize that there's something that's not going and to actively decide to change that, and that's really important.

Lindsay Lyle: Maureen, I think you are exactly right. Number one, the fact that this patient has been on ruxolitinib for 10 years is pretty amazing.

Maureen Thyne: Yes.

Lindsay Lyle: As we've discussed, we are now seeing patients who have been on ruxolitinib for this long and are now kind of developing this sort of refractory disease after many years of disease control.

Prior to recently, we didn't have a lot of options for making a change outside of a trial. Now for advanced practitioners who work so closely with their physician colleagues to also really know the available treatments and when things are changing, that can help be an advocate for the patient to maybe have an earlier change in therapy now that we are not kind of just tied to ruxolitinib, which has done amazing things, but now we do have other options. I think that's a huge point and just wanted to emphasize that as well.

Julie Huynh-Lu: This brings us to the end of our Myelofibrosis Roundtable series. Lindsay and Maureen, again, thank you guys so much for sharing your expertise with us, me and the viewers. For more information and to view our other discussions on myelofibrosis, please visit JADPRO.com.