Patient Scenario 2: A 68-Year-Old Woman With Anemic MF


Nearing the end of their program, panelists consider a patient with anemic myelofibrosis and optimal treatment strategies in that setting.


John O. Mascarenhas, MD: We’re going to move on to segment 3, which is myelofibrosis treatment in anemic MF [myelofibrosis]. This is patient case number 2, a 68-year-old woman who presents with fatigue and bone pain over the last several months; on exam, [she] has a spleen that’s 4 cm below the left costal margin and slightly tender on blood counts, has a blood count of 42,000, and hemoglobin of 8.1; bone marrow biopsy is done and confirms primary myelofibrosis. This is a different kind of a clinical presentation from our gentleman previously who presented with big spleen, a lot of symptoms, but robust blood counts. This patient has more of a bone marrow failure state, maybe not as [many] symptoms or maybe certain types of symptoms like fatigue. So, a little bit different considerations perhaps when meeting a patient like this. I guess, the first question is, what are you going to treat this patient with? JAK inhibitor [Janus kinase] naive, low platelets, low hemoglobin? [Dr Kuykendall], what would you treat this patient with?

Andrew T. Kuykendall, MD: Prior to the approval of pacritinib, which is going to be my answer, I think that we would’ve considered potential combinations with low-dose ruxolitinib plus an agent to support platelets and anemia. Danazol’s certainly an agent that could help with platelets and anemia, but it’s not going to do much for the spleen or the constitutional symptoms. You’d want to add some sort of JAK inhibitor approach here, but you’re not going to be well served with ruxolitinib or fedratinib. Pacritinib’s data in the low platelet group, as well as the emerging data with ACVR1 [activin A receptor type I] and potential anemia improvement, make it look like the appropriate choice for this patient.

John O. Mascarenhas, MD: You touched on this previously. If you had to guess, I don’t know that we know this exactly, but what mechanistically about pacritinib may help in terms of delivering a low platelets full dose and even seeing this 25% clinical improvement in anemia response rate?

Andrew T. Kuykendall, MD: I think with pacritinib, in addition, it being more of a selective JAK2 inhibitor. We also have the benefit of it being an ACVR1 inhibitor as well as this IRAK1 [interleukin-1 receptor-associated kinase 1] inhibition. Acting on a couple different pathways, which we know are certainly relevant targets within myeloid diseases as a whole as well as myelofibrosis. With these additional targets and what we’ve seen in the PERSIST studies [two phase III trials, PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781)], but also retrospectively with a more focused analysis. We can see that we do see improvements generally speaking with anemia, with pacritinib and certainly safely can be provided in the setting of markedly low platelets.

John O. Mascarenhas, MD: Excellent. I think the data that [Stephen T. Oh, MD, PhD] has presented are quite compelling in the sense that it is a potent ACVR1 inhibitor. The pharmacokinetics of the drug are such that a 200 mg twice daily, you’re continuously inhibiting ACVR1, which may provide that anemia benefit that’s in some cases quite substantial and not always immediate. I think that’s the other message to the practitioner, is that, for the anemia benefits, you often treat patients through that initial period where they may even have some worsening or seemingly worsening treatment emergent anemia before you can appreciate the benefits in hemoglobin level. So, persisting through the initial period is an important consideration, [with] [gastrointestinal] toxicity, even initially some low blood counts before you see better days. [With] anemia and myelofibrosis, obviously there’s a lot of interest in momelotinib. The PDUFA [Prescription Drug User Fee Act] date was August 17th, 2023 and has been pushed off for the next three months by the FDA, but the assumption is that that drug will be approved based on the MOMENTUM study [NCT04173494]. Gabby, maybe you could give us a background on what the MOMENTUM study was. Who were the patients who were being targeted in that study and what were some of the key outcome measures?

Gabriela S. Hobbs, MD: Sure. The MOMENTUM study was a phase III study that compared momelotinib to danazol. These were second-line patients, patients who had been either previously on ruxolitinib or were able to be off of a JAK inhibitor in order to enroll in the study. The main outcome was to look at symptom improvement. The most important one, if you ask me, would be the anemia improvement. They demonstrated that about 30% of patients treated on the momelotinib arm had an improvement in hemoglobin. Interestingly, about 20% of patients on danazol also had an improvement. [It is] probably the largest prospective study done on danazol showing that it does have some efficacy. The other thing that this study demonstrated was continued safety as well as tolerability of this agent. It is a JAK1/2 inhibitor, so there were some cytopenias seen, but the hemoglobin improvement was very encouraging.

John O. Mascarenhas, MD: Excellent. It’s an interesting study because they took patients who were on ruxolitinib, who had some degree of symptom burden and anemia, and randomized them to danazol. Some people might say, well, that wouldn’t be a drug that I would normally think of as an all-encompassing drug to treat symptoms in spleen. So, it wasn’t surprising that the primary endpoint was quite positive in favor of momelotinib in terms of symptom improvement, SBR improvement, in favor of momelotinib, and then that statistically significant noninferiority between the two arms in terms of anemia response. The data did look good; it looked like a safe agent. It wasn’t a specific toxicity concern, whether it’s overwhelming GI warranties [or] cardiovascular events necessarily. I think there’s durability both in the response and safety profile that provides some confidence in taking that drug forward. Even some of the more recent data from [a recent American Society of Hematology (ASH) meeting] demonstrating the ability to switch from ruxolitinib to momelotinib directly without incurring cytokine rebound or dramatic changes in spleen symptom or anemia, worsening anemia, provide some sense that there is ability to transition these patients in the future. [Dr Pettit], in the future, let’s say we have momelotinib approved, and let’s say you’ve got your cadre patients who are on ruxolitinib and one of them comes in and has great spleen symptom benefit but has some degree of anemia, maybe is receiving transfusions a unit every month and this is becoming a toll on the patient, what do you do with a patient like that? Is that the kind of patient who you would transition to momelotinib, or is that the kind of patient you would add luspatercept to? New thoughts because we have new emerging drugs?

Kristen M. Pettit, MD: Such a good question. I think it’s really [to be determined]. We’re going to have a lot of different options; hopefully one more option once momelotinib is available. I think momelotinib has some competition here in the anemic myelofibrosis space from a couple different things; pacritinib is one option for those patients based on some of the ACVR1 inhibition and anemia improvements that we saw. Between those two agents, I think there are some differences in terms of the kinase inhibition profile. Like we said, momelotinib inhibits JAK1 and JAK2 and there might be a little bit more cytopenias there, although the studies with momelotinib did go down to allow platelet count as low as 25. So, there’s still an option there, but fewer GI toxicities with momelotinib, which is nice. We’ve seen it, so far in studies, be a very well-tolerated agent in the short term and in the long term as far as the data out that we have. I think both of those two agents are good to have on the table for folks. I think some of the tolerability profile might play a role in that decision. And then, as you said, when do we use some of our other supportive care agents like luspatercept, for example, adding on to agents that people are already on. If someone was on ruxolitinib and otherwise doing well, their platelet count wasn’t too low, and it was just anemia with ruxolitinib that was the problem, then in that situation, I’ve tended to add on another agent. Whether it’s an ESA [erythropoiesis-stimulating agent] if the EPO [erythropoietin] level is low or luspatercept if I’m able to get it off label, then I haven’t necessarily changed the JAK inhibitor. But if the individual isn’t having a good enough response in terms of spleen and symptoms to the JAK inhibitor to ruxolitinib, or if their platelet count is getting on the low side and they’re anemic, then I think making a total switch over to either pacritinib or momelotinib once available, I think, makes sense.

John O. Mascarenhas, MD: Excellent. There have been data presented at meetings, last at ASH, demonstrating not just the simple obvious immediate benefit of getting a patient out of the transfusion suite and reducing health care resource utilization and improving quality of life, but also some of the data from the MOMENTUM and the simplified studies previously suggesting that there may be a survival benefit tied into attaining that transfusion independence. Much like the spleen volume reduction of 10% that Gabby reviewed with pacritinib correlating with improved survival, and data earlier on with ruxolitinib suggesting the deeper the spleen response, the better the survival. There are data with momelotinib suggesting that one of the benefits of anemia response could be a survival benefit tied into that as well.

Transcript edited for clarity.

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