Dr. John Mascarenhas:
Welcome to The ASCO Post Roundtable Series on Addressing Unmet Needs in Myelofibrosis. I'm Dr. John Mascarenhas from the Icahn School of Medicine at Mount Sinai in New York. I'm really happy to be joined by two of my colleagues and friends, Dr. Gabriela Hobbs and Dr. Abe Yacoub. Gaby, maybe you could introduce yourself?
Dr. Gabriela Hobbs:
Hi, everyone. Thank you for having me today. I'm Gaby Hobbs. I'm the Clinical Director of the leukemia service at Mass General Hospital in Boston, and I specialize in the care of patients with myeloproliferative neoplasms.
Dr. Mascarenhas:
Abe?
Dr. Abdulraheem Yacoub:
Hello, my name is Dr. Abdulraheem Yacoub. I go by Abe. I'm a Professor of Medicine at the University of Kansas Cancer Center and I specialize in MPN and myeloid cancers.
Dr. Mascarenhas:
Fantastic. Today we have a great roundtable of experts that are focused on myeloid malignancies and specifically myelofibrosis. We're going to be discussing the treatment and management of myelofibrosis with three patient case studies and vignettes. This is our first installment with a focus on managing emergent anemia on ruxolitinib.
Case 1 is a patient, Mr. RH. He's 77 with a history of polycythemia vera diagnosed 10 years ago and treated with hydroxyurea. Now he's developed anemia, progressive splenomegaly, and drenching night sweats. On exam, he's got temporal wasting and a spleen that's easily palpated 10 cm below the left costal margin and tender with deep palpation.
His white count is 29,000, his hemoglobin is 9.8, platelets are 500,000, 2% blast on manual review of the smear, and the LDH is 800. A bone marrow biopsy is obtained and shows that it's hypercellular, with maturation of all three lineages, atypical megakaryocytes in loose and tight clusters, and less than 5% blast by immunohistochemical staining. The bone marrow fibrosis grade is 3 out of 3, so dense fibrosis, and the karyotype is normal. On sequencing he has a JAK2 V617F mutation with a VAF of 75%, a TET2 mutation with a VAF of 25%, and an ASXL1 mutation with a VAF of 10%.
By prognostic scoring systems, no matter which one you use, whether it's the DIPSS-plus, the MIPSS-70, or the MYSEC, he would be considered on the higher risk end of that score, either intermediate-2 or high risk based on certain clinical variables, and also now increasingly integrating genomic data as well.
This gentleman with high-risk myelofibrosis that's both symptomatic with a large spleen is started on ruxolitinib 20 mg twice daily and has immediate resolution of symptoms, as many patients do. After 6 months of therapy, the spleen is no longer palpable, but the anemia progressively worsens down to 7.2 g/dL and the patient does note more dyspnea on exertion at 9 months of therapy.
The question for the group that we're going to discuss is how do we address anemia and what are the treatment options to address anemia in an MF patient receiving ruxolitinib, but also achieving goal-directed success in terms of spleen and symptom burden and maybe what additional data points would assist in decision making. I'll start with that and maybe I'll ask Gaby to jump in and give me a sense of what would she do with this gentleman? Older gentleman, higher-risk disease, doing well from a perspective of spleen and symptom burden response with ruxolitinib, but hasn't really enjoyed any anemia benefit. I guess the first question is would you expect it with ruxolitinib? Is this characteristic and how would you approach a patient where anemia is becoming a problem?
Dr. Hobbs:
Lots of great clinical points to discuss. I think from an anemia perspective, unfortunately with ruxolitinib we generally don't expect to see an anemia improvement. Sometimes we would expect, if you shrink the spleen significantly, perhaps you're going to see less splenic sequestration and anemia improvement. But I can't say that I see that ever with ruxolitinib, so I wouldn't have expected an anemia benefit.
Oftentimes we do see a dip that occurs in the hemoglobin when ruxolitinib is first initiated. It's probably most pronounced in the first month and then tends to kind of plateau. For some patients, it doesn't really plateau like we see in this patient. It just kind of continues to go down. And although we know that the prognostic significance of having anemia that occurs in the context of ruxolitinib is not as detrimental to prognosis as anemia that occurs just de novo, it's still pretty clinically meaningful in a patient like this one where they used to have a hemoglobin in the 9s and didn't need transfusions and now they have a hemoglobin in the 7s and maybe need transfusions, especially an older gentlemen. So I think that's a pretty significant issue.
One thing I wanted to address before we talked about the anemia improvement is with this new diagnosis of myelofibrosis and discussing the risk scores, it's just reminding us that patients that have intermediate-2 or greater disease by DIPSS or higher-risk disease by the other scores, the MIPSS, warrant a consideration of a bone marrow transplant at diagnosis of myelofibrosis. And of course in this case, this gentleman is older, but I think it's worth at least addressing even if that person is not going to go to transplant to say, would this be a very functional person that would merit a consideration for transplant at all, or should we just assume that based on his age he's not a candidate? And of course in the higher 70s, most people wouldn't offer a transplant, but it's worth at least mentioning.
Dr. Mascarenhas:
Excellent. Abe, you're seeing this guy who is benefiting from the classic response assessment aspects of spleen and symptom with ruxolitinib, but continues to have anemia. I totally agree with Gaby, we don't expect an anemia response with ruxolitinib, and in fact, there's usually this characteristic dip. Sometimes it gets better, sometimes it doesn't. I look at anemia that's emergent right after starting ruxolitinib differently than anemia that emerges like 6 months after starting ruxolitinib. That's probably more disease-related anemia. So this guy, I would say, is not optimally controlled from a disease perspective if he's got anemia that's causing symptomatology. The question for you is what other data points would be helpful in deciding what to do next?
Dr. Yacoub:
Thank you very much, John. I think this is such a common and a true challenge that we will actually almost universally have to cross with every patient with myelofibrosis, especially with ruxolitinib therapy, that it's very helpful for us providers and for patients and for everybody who takes care of these patients to have a set of scales or a standardized approach to try to tackle anemia and myelofibrosis. This will keep coming and will keep happening and it's very common, and even though it is not necessarily prognostically adverse, having anemia from therapy, it is definitely a quality-of-life challenge. Transfusions become significantly resource consuming and just not necessarily favorable by any aspects of patient care. So it's very important that we have a general approach to this.
It is expected from with ruxolitinib that anemia is going to happen and it is dose-dependent. One approach would be to tailor the ruxolitinib dose to mitigate the anemia. Unfortunately, that could also be associated with less effectiveness in depth of response. So that remains always a maneuvering scale that we can use in these patients.
But anemia in myelofibrosis is multifactorial. Some of it is part of the disease and the therapy, but also we have to have a global approach to this. So any reversible risk factors that can be identified, whether patients have nutritional deficiency or any ongoing blood loss, any of the other common causes for anemia can and could happen and could be manageable in these patients. So that becomes the low-hanging fruit approach to reverse any reversible factors just like any other patients.
And then, since we've had ruxolitinib for the last 10 years, and there are a set of standard-of-care options that have been tested and tried. One approach to this is to try to add anemia active agents, and there are a few of those agents that we have found true activity for and they're listed on our guidelines like ESAs and danazol and thalidomide. We can go over some of those options in a little more depth and in more details. We also have more promising agents in clinical trials that may become more approved as combination with ruxolitinib like luspatercept, and there are also novel JAK inhibitors that might have effective cancer control approach with immunotherapy. So we do have a few tools that we can explore today in how we can tackle this disease and how can we help these patients.
Dr. Mascarenhas:
Okay, excellent. I'll give you some more data and then we can decide amongst the three of us what we would actually do here. So this individual has an EPO level of 100, the iron studies are normal, the ferritin is 200, the reticulocyte count is 2.3%, and as you pointed out, you've got to make sure that the things that are easy to address like B12 and folic acid are normal, haptoglobin is normal, and importantly a guaiac is negative, and he had a recent colonoscopy. That's negative. So there's no GI bleeding, there's no nutritional deficiencies that we can address, there's not hemolysis, and there's a sense that the EPO level may not be adequate enough in a patient like this in order to maximize erythropoiesis. I'll go back to Gaby. With this information, does it help you make a decision at this point what to do?
Dr. Hobbs:
Yeah, I think we have enough information to think about a different approach in treatment, and a little bit is what Abe was talking about. Do you consider lowering the dose of ruxolitinib initially, seeing if you get a little bit of a recovery of blood counts? I would say just anecdotally, I rarely see huge improvements in the cytopenias when you reduce the dose of ruxolitinib. It's not as responsive as, for example, when you stop the hydroxyurea and sometimes you see improvements in the PV patients. So that's, I think, an easy initial approach that is probably most practical in clinical practice.
But then really the difficult question is to decide do we add on therapy to ruxolitinib? Because this person has had a really fantastic response. They were really symptomatic the way the patient is described initially with temporal wasting, systemic symptoms, a really enlarged spleen. Ruxolitinib is an excellent JAK inhibitor to control all those things that you really don't want to lose that while you switch to, for example, another JAK inhibitor. So I think I would really have a conversation with the patient about, "Do we keep you on ruxolitinib and try to add, for example, a erythropoietin-stimulating agent." That's a pretty easy maneuver. It's not associated with more toxicity. I think the hardest part of having the ESA is just that the patient requires maybe more frequent visits to clinic or sometimes it's difficult to administer this at home or get it approved to be given at home. So the conversation that I would have would be between adding an ESA or considering switching to a newer agent such as momelotinib.
Dr. Mascarenhas:
Excellent and I agree with you. I think the challenge often is, if you are trying to reduce the anemia by reducing the dose of ruxolitinib, I often find that that doesn't really correct the anemia in a meaningful way. And often then what you start doing is compromising the spleen and symptom benefit. So it really becomes a defeating approach. And if someone is enjoying spleen and symptom benefit as this person is, and to me often the first line of therapy would be trying to add something that's been used and doesn't interfere with a spleen symptom benefit in the face of ruxolitinib like an ESA, and if that doesn't work, maybe moving on. In this individual, Abe, let's say an ESA is used, and after 3 months of therapy it's not really improving the hemoglobin, what would you consider in this patient?
Dr. Yacoub:
Obviously every agent we have for anemia will have a percentage or likelihood of working in the proportion of patients. There isn't really one drug that will be the ubiquitous active agent for anemia in most patients. And that really stems from the pathophysiology of anemia is different in different patients. So in the setting of EPO and not being effective, I think that also opens up a list of other anemia-specific agents that we can use.
Danazol has been an agent that consistently showed activity for anemia in patients with myelofibrosis even on prospective studies. So that's something that I offer to patients often. There has been data for IMiDs with prednisone in this setting also that could also be offered to patients. And then luspatercept has been truly a good companion agent for patients with myelofibrosis and anemia with the limitations of insurance and coverage and the ability to actually deliver the drug and acquire it for patients, and also with the caveats that the patients also need to come in for injectables to the office. It also has shown activity in myelofibrosis and particularly in patients with anemia while on ruxolitinib therapy. So some of these options in sequence can be offered to those patients and each one of them might have a 20% to 40% chance of activity, but hopefully at one point we'll find the right fit for each patient.
Dr. Mascarenhas:
Really well said and I agree. Collectively, whether it's ESAs, danazol, IMiDs, and there's data for all of these that collectively it's somewhere between 20% and 40% response rates. The durability response can really vary. And that can be sometimes disappointing. So sometimes you get that response, but it might only be for 6 months and then you're back to worsening anemia and even transfusion dependence. I love the luspatercept option, too. I have to just reinforce that that would be off label and the study is ongoing, but the data from the phase II study does provide us a glimpse of what to expect with a nearly 30% transfusion independence rate and 50% of the patients obtained at least a 50% reduction in transfusion burden or improvement in hemoglobin. So that clearly has another opportunity to maximize on anemia responses.
Let me change the case just slightly and go back to Gaby and see if this would affect your decision making. Let's say the patient’s on 15 mg twice a day of ruxolitinib and the spleen is not well controlled in this case, maybe the spleen is still 5 cm and a little bit tender, and maybe the night sweats are not totally gone, and there's a degree of fatigue and shortness of breath related to anemia. What would you do in a patient like that? Would that change your decision making?
Dr. Hobbs:
Yeah, I think that that makes it a little bit easier to think about switching to another JAK inhibitor, if you feel like with ruxolitinib you've gotten the max dose that you can, you're limited by cytopenias, you're limited by transfusion dependence, then I would favor switching to another JAK inhibitor. I guess it also depends on what you've been doing so far. One thing to think about in a case like this one, if we assume that this is a person that is ineligible for transplant, it's likely that all of the agents that have been discussed so far are going to be tried at some point to help with the anemia. So maximizing each of those options and giving each of those a good try is really important since none of these are going to cure the patient or permanently fix the problem.
Dr. Mascarenhas:
To that point, either Gaby or Abe, let's say you're at the point where you feel like you've optimized the patient as much as you can, you've maximized ruxolitinib's efficacy, and you're really looking to move on to the next line of therapy. Give me a sense of how one would choose between the other three approved JAK inhibitors. We've got fedratinib, a selective JAK2 inhibitor, it spares JAK1 to the most extent. It's also a FLT3 inhibitor. And then we have momelotinib, which is an equipotent JAK1/2 inhibitor, but also an ACVR1 inhibitor. And then pacritinib, which is a super selective JAK2 inhibitor, but also a IRAK1 inhibitor, ACVR1 inhibitor, and FLT3 inhibitor.
So these drugs are not all totally clean. They do have some other kinase activity that may or may not affect efficacy and toxicity. So what would be the optimal treatment or the best decision for the next line of therapy considering those other JAK inhibitors? And let me know why. So maybe, Gaby, what would you pick?
Dr. Hobbs:
In this case I think I would pick momelotinib next because what this person needs is two things. One is important control of spleen and symptoms because this was a person who was very symptomatic from both, but they also need improvement in anemia. So momelotinib, like you said, is equipotent to ruxolitinib with spleen and symptom response, but also has the ACVR1 inhibition, which can help with anemia. So for this person, I really like that.
If hemoglobin weren't the main problem with this patient in terms of cytopenias and it was just a proliferative patient that had a lot of symptomatology, a lot of splenomegaly that hadn't been controlled on max doses of ruxolitinib, then I think second-line fedratinib would be a reasonable choice, as that's not an agent that's expected to help with cytopenias and can also help with patients that have splenomegaly and symptoms.
Now, if this were a person that were more cytopenic, where cytopenias are really the limiting thing and not so much the symptoms of spleen and systemic symptoms, especially those patients that have platelets of less than 50, then pacritinib is a great option for those patients, as it's the least myelosuppressive. That's generally my approach to thinking about the different JAK inhibitors.
Dr. Mascarenhas:
Excellent. Abe, any take on that?
Dr. Yacoub:
No, I fully agree. I think it's inevitable that patients with ruxolitinib will eventually progress and to be familiar with the other JAK inhibitors and how they distinguish from each other and what are their strengths, I think that is very important. Many patients in this time in age are actually going to receive multiple JAK inhibitors during their journey with myelofibrosis. It's a very important point. Thank you.
Dr. Mascarenhas:
All right, fantastic discussion. I just want to summarize the key clinical takeaways from this case, which is, one, anemia is frequent at diagnosis. It's often progressive and prevalent through the course of disease. It's a well-recognized independent prognostic factor for outcome in most studies. In fact, it ends up in almost every risk scoring prognostic tool that we have.
Two, the etiology of anemia is multifactorial and complex. It could be poor production from bone marrow failure, splenic sequestration, hemolysis, blood loss from esophageal varices, for example, autoimmune-mediated, and then increasingly we're aware of the role of hepcidin and impaired iron access. So drugs that have ACVR1 inhibition such as momelotinib and pacritinib become of interest.
Number three, we can use data to help make our decisions. For example, if the EPO level is less than 200, by some guidelines less than 500, would consider an ESA. And that's pretty low-hanging fruit. But of course there's other drugs like danazol and IMiDs, like Abe pointed out, collectively with 20-40% response rates. But often the durability could be limited. And then I think the new emerging therapy that's exciting is luspatercept, an erythropoiesis maturation agent. That's now in phase III testing in the independent study. So we look forward to that data.
Lastly, we have three other JAK inhibitors that are approved, but specifically if we're talking about patients where cytopenias and anemia is significant, we have JAK inhibitors that do inhibit ACVR1 and downregulate hepcidin expression, and that includes momelotinib and pacritinib that can be dosed at the full dose, particularly in the second line. I will point out that although pacritinib is approved for less than 50,000 by label, it is NCCN-endorsed second line irrespective of platelet count, which is nice because I do think it gives patients and physicians who are prescribing these drugs different options and enables for sequencing of these drugs, as Abe pointed out, to try to optimize and maximize the options that we have to address the unmet needs in MF with anemia specifically.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in myelofibrosis or visit ascopost.com. Thanks very much.
