Roundtable Discussion: Pettit Reviews Use of JAK Inhibitors for High-risk Myelofibrosis

Kristen M. Pettit, MD (Moderator)

Clinical Associate Professor

Rogel Cancer Center

University of Michigan Health

Ann Arbor, MI

PETTIT: I think we all struggle with managing cytopenias in our patients with MF. Not only are they a struggle to manage, but they are very common. In terms of platelet counts, in a survey of physicians who treat patients with MF, they reported that about one-third of their patients had normal platelet counts, about one-third had mild thrombocytopenia with platelet counts in the range of 50 to 100 × 10⁹/L, and about one-third had severe thrombocytopenia with platelet counts of less than 50 × 10⁹/L.¹ This is something very common that we need to wrestle with. Anemia is also common among patients with MF and often necessitates referral to an academic center because of the complexity of management of anemia with myelofibrosis.²

LIU: Most of my patients present with proliferative symptoms. Eventually, they progress into cytopenia, and a few of them become transfusion dependent.

BARAI: In my experience, thrombocytopenia is generally moderate at presentation, with platelet counts between 50 × 10⁹/L and 80 × 10⁹/L. Anemia is also moderate, with hemoglobin levels between 8 g/dL and 10 g/dL.

PETTIT: What has been your typical approach toward therapy? Let’s start with anemia. Do you have a particular way in which you approach anemia with MF? And does that impact your decision about whether to start treatment with a JAK [Janus kinase] inhibitor?

BARAI: I try to check patients’ iron studies, endogenous erythropoietin level, and JAK2 and MPL mutations, and then [I consider] the severity of the symptoms and [possible use of a] JAK2 inhibitor. And at that point, I might treat with erythropoietin if the patient’s endogenous level was less than 500 mU/mL and their hemoglobin level was less than 10 g/dL.

MARINELLA: Most of my patients have secondary MF subsequent to either essential thrombocythemia or polycythemia vera, and for them I use an erythropoiesis-stimulating agent [ESA]. I’ve used danazol to treat the anemia because, of course, if a patient is thrombocytopenic, ruxolitinib [Jakafi] can be a problem. But if a patient is relatively low risk and they mainly have anemia, I’ll use an ESA first, maybe danazol, and not jump [to using] ruxolitinib immediately because there are [adverse] events. I reserve danazol for situations when patients have some B symptoms: a big spleen, drenching night sweats, fatigue, weight loss, and so on. That’s how I’ve been doing it.

PETTIT: All of that sounds great. Has anyone had any experience, thoughts, or concerns about thrombocytopenia in these patients?

BEED: I used to put all patients on ruxolitinib because that’s all there was. But when the spleen is so big, you need to ask what the next step should be…with the variety of [available] drugs.

PETTIT: To summarize, this patient has high-risk MF with what appears to be a cytopenic phenotype with thrombocytopenia and anemia. He also has some leukocytosis and quite a bit of splenomegaly, so he does have proliferative features as well. What would your goals of therapy be? What would be the best-case scenario?

ISLAS-OHLMAYER: His biggest symptoms are splenomegaly and abdominal discomfort and also weakness and fatigue. Treating with a JAK inhibitor would be my priority. The platelet count is 43 × 10⁹/L, and so ruxolitinib is not ideal. I usually still use ruxolitinib, but I [may] reduce the dose, and most of the patients tolerate it.

PETTIT: Sounds good. When do you consider referral for a clinical trial? If you saw a patient like this, with a low platelet count or bothersome symptoms, would you consider sending them for a clinical trial, or would you try standard-of-care treatment first?

ISLAS-OHLMAYER: The right answer is a clinical trial no matter what.

PETTIT: I agree.

ISLAS-OHLMAYER: The problem is that we’ve had a few MF trials here, and in the last couple, the patients’ platelet counts needed to be above 50 × 10⁹/L. So we couldn’t enroll a single patient. That’s the biggest problem that we run into.

PETTIT: I think many of our agents that treat MF, both approved agents and investigational agents, unfortunately, have major dose-limiting thrombocytopenia as an adverse event [AE], so I completely agree with you.

SIDDIQUI: There was a trial of ruxolitinib plus a BCL2 inhibitor, but the trial excluded patients with platelets below 75 × 10⁹/L. My patient’s platelet count was in the low 60 × 10⁹/L range, [so she could not participate].

BEED: The problem I have is that my practice…is 2 and a half hours away from a major medical center that can enroll these patients in clinical trials. We don’t do them here. Since the cost of gas is up, the patients can’t afford to keep driving back and forth.

PETTIT: That’s a good point. We’ve definitely seen that factor into our clinical trial enrollments and decisions for patients too. I totally agree with that. Some centers are trying to give gas cards or other assistance to patients, but it’s a real limitation.

PETTIT: I’m curious to see your reactions to the data from the PERSIST-2 study of pacritinib, including the AEs, the overall toxicity profile, and the possible anemia improvements associated with pacritinib. What are your initial impressions?

ISLAS-OHLMAYER: I think the data look good, but it’s too early for me, so it would be my second- or third-line option for now, unless the platelets are a limiting factor. But it’s a little too soon [after FDA approval] for me to use it early in the course of treatment.

SIDDIQUI: I have a patient who has had MF for at least 10 years and has been on ruxolitinib for 7 or 8 years, a very noncompliant patient. She’s 68 years of age, with a spleen size of approximately 20 cm by ultrasound. I hadn’t seen her for a few months, and now she has come in with a hemoglobin level of 7 g/dL. I think we did a bone marrow biopsy a few months ago and found no transformation to leukemia. Slowly, the anemia is getting worse. We tried erythropoietin, but she did not respond. Her platelet count is 44 × 10⁹/L. Would this be a patient for whom pacritinib might work?

PETTIT: Yes, that patient would have been included in the PERSIST-2 trial. Those patients either had previously untreated thrombocytopenia or had long-standing MF treated with JAK inhibitors and subsequent thrombocytopenia.³ I think pacritinib is an option for your patient.

I do worry about compliance, monitoring, and those kinds of things, especially if a drug is going to cause gastrointestinal AEs early in treatment. If the patient is not willing or motivated to push through that and work with you on prophylactic measures, that could be an uphill battle. But I think it’s reasonable to consider pacritinib treatment in that clinical scenario.

KNAPP: [PERSIST-1] didn’t have a limitation on platelet count,⁴ and [PERSIST-2] had a limitation of no more than 100 × 10⁹/L.³ Is there a reason why the drug was approved for patients with a platelet count of less than 50 × 10⁹/L?⁵

PETTIT: That’s a good question. I think others were a little surprised by that, too. The approval was based on the subgroup analysis. The investigators did see responses in patients with all platelet counts that were normal, those with less than 100 × 10⁹/L, and those with less than 50 × 10⁹/L. But the most remarkable symptom improvements and spleen improvements were seen in the subset of patients with a platelet count of less than 50 × 10⁹/L [From the Data³]. Additionally, that’s the clinical scenario [for which] no other treatment option exists, so that’s where the FDA focused its initial approval of pacritinib. There is also an ongoing study [PACIFICA; NCT03165734] that is looking at patients with a platelet count of less than 50 × 10⁹/L. [The number of patients who are represented in the data] will definitely increase over time with this study. But it’s going to take a little time to get all the data from that study.

KNAPP: So from an AE standpoint, would there be any reason to choose pacritinib over ruxolitinib for a patient with a platelet count between 50 × 10⁹/L and 100 × 10⁹/L?

PETTIT: I think for the patients with platelet counts of less than 50 × 10⁹/L, physicians are starting to adopt pacritinib. [That’s where it is recommended in] the National Comprehensive Cancer Network guidelines⁶ and [the setting for which] it’s been approved,⁵ since those patients don’t have other options. And we can hopefully get a better dose of JAK inhibition into those patients with pacritinib than with the other agents. But for situations when the platelet count is between 50 × 10⁹/L and 100 × 10⁹/L, there is quite a bit of supportive data, but the drug hasn’t gotten label approval for that setting—and we do have some other treatment options— so that’s a real gray zone. That’s been brought up a lot in meetings and in the literature. I think insurance companies might somewhat dictate our options in that situation, but I think that question is up for debate.

BEED: I have a hard time deciding which one is best. We had a patient with active hepatitis. He needed treatment, and his spleen kept growing. We fixed that problem and put him on ruxolitinib. His spleen shrank a little bit but remained large. I was hoping that some of these new drugs would help his splenic size and his fatigue because his platelet counts are OK. At first his platelet counts went down with ruxolitinib, and I gradually increased the dose and they’ve come up nicely. But it’s mainly the spleen size and the pain that are causing [trouble]. The drugs all seem to be about the same.

PETTIT: That’s a good point. For the majority of people, all of these drugs initially reduce spleen volume by at least a small amount but then [do not work] as long as we want them to. I think there’s definitely a role for switching between these JAK inhibitors. They all work a little differently. They all inhibit JAK2, but we see that when ruxolitinib, for example, stops working, fedratinib [Inrebic] still has a reasonable chance of reducing spleen volume. And the same thing likely is true for pacritinib, due to some of the different kinases that are inhibited in addition to JAK2. I think some other intracellular pathways detect long-term JAK2 inhibition and drive the development of resistance. So I think there is a real role for switching between agents, but these different agents are all a little different in terms of monitoring requirements, toxicities, and dose reductions, and those things have to be considered when switching from one to another.

BEED: So if ruxolitinib isn’t working, maybe putting my patient on a different JAK2 inhibitor would be something to consider.

PETTIT: Yes, I think that is something to consider if the patient is otherwise a good candidate for it.

BEED: In the meantime, we’re sending him to [The Ohio State University] for a possible transplant.

PETTIT: Yes, there are lots of clinical trials, too. I think the big direction in clinical trials and in research is going to be combinations of JAK inhibitors plus other agents with slightly different mechanisms of action. These include BCL2, BCL-XL, BET, [and] PIM inhibitors or other kinase inhibitors that might be able to help overcome resistance to JAK inhibitors.

PETTIT: Obviously, blood counts are going to have some role in this. Are there any other factors that you consider now that we have 3 options? [Or is your choice based on] overall comfort level and experience?

LIU: I think that, based on all the data, it’s hard to know which drug is better. The only obvious difference is that 1 of them is approved for patients with platelet counts of less than 50 × 10⁹/L.⁵ As far as everything else, I don’t see any [data showing that] one is better than another.

_REFERENCES

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_{2. Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the Mayo Clinic experience. Mayo Clin Proc. 2012;87(1):25-33. doi:10.1016/j. mayocp.2011.11.001}

_{3. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818}

_{4. Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4(5):e225-e236. doi:10.1016/S2352-3026(17)30027-3}

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