Savona Discusses First-Line JAK Inhibition for Patients With Myelofibrosis at Risk of Anemia

Michael R. Savona, MD (MODERATOR)

Director of Hematologic Malignancies Research and Early Therapy Program

Professor of Internal Medicine and Cancer Biology

Vanderbilt University Medical Center

Nashville, TN

EVENT REGION Kentucky, Michigan, and Ohio

PARTICIPANT LIST Melhem S. Jabbour, MD | Gowri Ramadas, MD | Karim Anwar, MD | Ed A. Faber, DO, MS | Tarek M. Sabagh, MD | Shyamal R. Bastola, MD

CASE SUMMARY

A 76-year-old woman presented to her physician with symptoms of mild fatigue, night sweats, and abdominal pain/fullness lasting 4 months; she also reported an unexplained loss of 12 lb. Her spleen was palpable 8 cm below the left costal margin. She had no known comorbidities.

Laboratory values included a red blood cell count of 3.40 × 10¹²/L, hemoglobin level of 9.8 g/dL, and platelet count of 181 × 10⁹ L. Next-generation sequencing showed a JAK2 V617F mutation. The karyotype was 46XY. A bone marrow biopsy showed megakaryocyte proliferation and atypia with MF-2 reticulin fibrosis.

The patient received a diagnosis of primary myelofibrosis with Dynamic International Prognostic Scoring System high risk, Mutation and Karyotype- Enhanced International Prognostic Scoring System for Primary Myelofibrosis in adults 70 years and younger (MIPSS70) intermediate risk, and MIPSS70+ version 2.0 high risk. The patient was not interested in a transplant; a decision was made to initiate momelotinib (Ojjaara) due to moderate anemia.

SAVONA: I think [ruxolitinib (Jakafi)] is the standard of care for a reason. It’s got a history; we’ve treated thousands of patients with this drug. I’ve treated or consulted on hundreds of patients through the years, and we have a good safety record. Momelotinib looks good, but…that drug is still getting its sea legs and we’ll see in the postmarket analysis if it’s as safe as it looked in the phase 3 study [SIMPLIFY-1 (NCT01969838)], but it looked pretty good.

JABBOUR: Does momelotinib work on the spleen like ruxolitinib in decreasing symptoms and shrinking the spleen?

SAVONA: Yes it does. It’s impressive and maybe not quite as good as ruxolitinib in treating the spleen dose for dose, although that remains to be determined. But it’s a JAK1/JAK2 inhibitor, and it leads to reduction of splenomegaly and reduction in symptom score. The difference is that there’s less anemia with that drug because of the ACVR1 inhibition [From the Data¹].

DISCUSSION QUESTION

• What are the treatment goals for a patient like this?

RAMADAS: The first thing is always quality of life with the fatigue and maintaining the blood cell counts. Typically, we’re able to see that fairly quickly. Sometimes it’s gratifying once you start these patients on some of these medications to see how [well] they’re feeling even just a few weeks out.

SAVONA: There’s 1 in 20 patients who you [give] ruxolitinib to…and they get a lot of adverse events…but more often than not, you put them on these drugs and…it’s very gratifying to see them feeling better. I’m with you; [I value] quality of life improvement.

In this case, we would like to see the hemoglobin stay up more in that safe zone than get down to the 6.8 g/dL to 7.5 g/dL range where for a 76-year-old you’re starting to worry and you’re stuck with transfusions.

ANWAR: [I look for] improvement in cytopenia and the symptoms.

SAVONA: The only reason you [give this patient] momelotinib instead of… is you’re hoping that this anemia [improvement seen in] the phase 3 [SIMPLIFY-1 trial] helps in your patient. ACVR1 inhibits hepcidin, which in turn inhibits late-stage erythropoiesis….² These drugs like pacritinib [Vonjo] and momelotinib have potency at that target. It can be gratifying because not only do you see spleen size reduction and symptom improvement, but in a select number of patients you can see improvement in erythropoiesis.

Some of these patients have such bad marrow dysfunction because they have such late-stage disease that if you [shrink] their spleen, which is where their blood is being made, they don’t have any capacity to make cells anywhere else. Your expectation is increasing the hemoglobin in a lot of cases, but especially in the previously treated patients, you have to be checking their [blood cell] counts frequently because you may be surprised there.

DISCUSSION QUESTION

• How do you monitor and manage anemia in patients with primary myelofibrosis who are receiving a JAK inhibitor?

JABBOUR: Normally, erythropoietin-stimulating agents [ESAs] will help with anemia symptoms if erythropoietin is at 500 IU/L.

SAVONA: There is a little bit more trepidation to push the dose [of ESAs] because of the clot risk and because the erythropoietin receptor exists on breast cancers, but in marrow failure syndromes, the darbepoetin alfa [Aranesp] starting dose is 150 μg every 3 weeks. I’ve had patients on 500 μg every week, and I will push the dose to that level before I give up on ESA if I see progression or improvement with each dose escalation. I like to use darbepoetin, if I can get it paid for, because it’s a little easier for patients, unless I have a reason for them to come every week or their insurance allows them to self-inject.

What about monitoring? What do you do when [they are receiving a] JAK inhibitor, and what do you usually tell them?

FABER: It depends on where their cytopenias start. [I may monitor them] once a week for the first cycle to get a sense of when the cytopenias may start and then if I look at a dozen patients, I probably monitor them 4 or 5 different ways trying to time when they may need ESA or…a blood transfusion if they’re not responding to ESA. I am a transplanter, so with some of my patients, I may be moving toward a stem cell transplant. I want to minimize transfusions and to try to avoid iron overload and other complications.

SAVONA: We know that iron overload is an independent risk factor for morbidity and mortality in stem cell transplant. We don’t do a lot of splenectomies anymore, except in rare cases in transplant. Our practice is to try to avoid them. But you’re right; you don’t want to load someone up with a lot of transfusions, but you do want to reduce clone size.

It’s a balance there. I ask, “How do you monitor?” of a lot of [physicians], and I get that answer of, “I [monitor] 10 patients in 10 different ways.”

If you’re starting with someone at 9.0 g/dL hemoglobin, you can’t let them come back into clinic 3 months later at 5.8 g/dL with inverted T waves. You have to follow those patients differently from someone who’s at 12.0 g/dL. I’ve seen patients’ [hemoglobin levels] drop like a rock, and…the nadir of hemoglobin on a steady dose of ruxolitinib is 12 to 16 weeks, and it’s dose dependent.³

FABER: From [data from] the COMFORT-I [NCT00952289] and COMFORT-II [NCT00934544] studies, we learned that those patients who were able to stay on 15 mg or 20 mg had better symptom management and better reduction in splenic volume.^4,5 But we didn’t have next-generation sequencing readily available. As time has gone on, we’ve learned that allelic frequency and dosing have a relationship, and we should try to move the dose to 20 mg or even 25 mg. What do you do in your practice? If you’re having a good response, do you tolerate the cytopenias more to get your dose to maximum?

SAVONA: We’re oncologists. We [often] push to the maximum tolerated dose. The answer depends, because I do have to take [multiple factors] into account when making this decision, but I don’t know the answer. I don’t think anyone does. But there’s very good reason to think that suppression over time does lead to improvement. We have patients we treated in phase 1 with ruxolitinib. Now, this is biased because they’re still on the drug, but if [they’re] on the drug 15 years later, we’ve got patients who have lost their JAK2 allele burden.⁶

SABAGH: [What] about the use of ruxolitinib in patients with myelofibrosis who don’t have splenomegaly but have anemia or thrombocytopenia? Is there an indication for ruxolitinib in the absence of splenomegaly?

SAVONA: With very low-risk patients, it’s hard to justify the nonmelanoma skin cancer risk, the shingles risk, and [other] potential risks that may come with these drugs. But I treat those patients with low to intermediate disease with JAK inhibitors because I think I change the natural history of their disease. If I put someone on ruxolitinib, and their hemoglobin goes from 12.0 g/dL…[to] 9.0 g/dL, I didn’t do them any favors, and I’ve got to mitigate that.

By the same token, I don’t take a [healthier] person and [give] them a drug that just came out and that doesn’t have any real postmarketing data, like momelotinib. I save that for my sicker patients who may have some significant anemia at the [start]. Everything is risk mitigation. What you’re describing is a very uncommon patient. Most patients have…spleen symptoms and nonspleen symptoms. There are cytopenias, there are the genetics that you’re dealing with, and there are the bone marrow changes.

DISCUSSION QUESTIONS

• How do the data discussed support/change your approach to treating this patient?
• How do the overall survival data influence your choice of therapy?

SAVONA: Do the survival data change how you might think about treating patients earlier on?

ANWAR: If there are signs that your patient has anemia, momelotinib might be a better drug. If they have thrombocytopenia, then pacritinib may be used. In other patients, ruxolitinib can be used. It does make sense to start them early on rather than later.

SAVONA: Yes, I like the idea of starting earlier. You can use ruxolitinib in patients with anemia or thrombocytopenia, but you have to be careful. There are patients who might do better with ruxolitinib and ESAs, and you might do OK with that, but if you’re dosing ruxolitinib down and you’re getting down to the 5-mg once-a-day dose, you’re below the effective dose, so it is worth trying a different approach, with momelotinib, for example.

We did the low-platelet study [NCT01348490] where we…titrated patients up [with ruxolitinib], and some patients got to 5 mg twice a day and had to stop, but in some patients, you were able to [ease] that dose up.⁷ It’s not a bad strategy, because now we have a program where you can give patients different doses of the drug throughout the month. But now that we have other drugs, and a lot of oncologists are very busy—you might have 1 patient with myelofibrosis and you’re seeing 120 patients a week—unless you have good nurse practitioner support, the idea of following someone closely [to] inch up and try to [squeeze] every benefit out of ruxolitinib may not appeal as well as a new JAK inhibitor like momelotinib or pacritinib…

BASTOLA: I have patients who are in their late 80s, where I feel like if I touch them, they’re going to do [poorly], but they still have symptoms. They can’t get to tertiary care to get an opinion…. If I want to try these new drugs, I can’t imagine being able to start at a full dose.

SAVONA: I want you to be comfortable enough that you do treat these patients, but I understand your trepidation and respect that. With ruxolitinib, there are a lot of different dose levels and we have a good feel for it, and that’s one of the benefits of ruxolitinib. Momelotinib [comes in] 100-mg, 150-mg, or 200-mg [tablets].⁸ [Dose adjustments are] not on the label. Nobody recommends 100 mg every other day. We haven’t experimented like that with momelotinib. It was 200 mg twice daily in the phase 1 studies, and we went down to 200 mg once daily. For patients with renal insufficiency or liver insufficiency, we start patients at 100 mg once a day.

With ruxolitinib, you could probably push a little more because you know more about what that drug does and [we studied] more drug doses. With pacritinib, patients are on anticoagulants, or they have a heart condition, and that obviates the use of that drug. With momelotinib, you only have 3 doses, and the drug has only been on the market for months.

So you have to be careful, but you have to talk to your patients and listen to them. Sometimes they’re 80 years old and have a lot of symptoms, but [they do not want treatment]. But some people say, “This [kind of] life’s not living, so I’ll do whatever I need to do.” Sometimes those patients take the gamble and try it. We all develop our tolerance for that in our field. The reality is patients in their 80s and 90s develop more comorbidities and make it more difficult for us, and sometimes we can’t get the medicines to them.

REFERENCES:

1. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor–naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. doi:10.1200/ JCO.2017.73.4418

2. Oh ST, Talpaz M, Gerds AT, et al. ACVR1/ JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4(18):4282-4291. doi:10.1182/ bloodadvances.2020002662

3. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799- 807. doi:10.1056/NEJMoa1110557

4. Palandri F, Palumbo GA, Bonifacio M, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017;8(45):79073- 79086. doi:10.18632/oncotarget.18674

5. Menghrajani K, Boonstra PS, Mercer JA, et al. Predictive models for splenic response to JAK-inhibitor therapy in patients with myelofibrosis. Leuk Lymphoma. 2019;60(4):1036- 1042. doi:10.1080/10428194.2018.1509315

6. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701-1707. doi:10.1038/leu.2016.148

7. Talpaz M, Prchal J, Afrin L, et al. Safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts (50 - 100 × 109/L): final analysis of an open-label phase 2 study. Clin Lymphoma Myeloma Leuk. 2022;22(5):336-346. doi:10.1016/j.clml.2021.10.016

8. Ojjaara. Prescribing information. GlaxoSmithKline; 2023. Accessed March 5, 2024. https://tinyurl.com/4wc5dmet