November 21, 2023

By Pearl Steinzor

Momelotinib has been added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for the treatment of patients with high- and low-risk myelofibrosis (MF) and myelofibrosis with anemia.

MF is part of a group of heterogeneous disorders of the hematopoietic system collectively knowns as Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs). MPNs are considered a rare disease, with the prevalence of MF in the United States estimated to be approximately 13,000, respectively.

Furthermore, MPNs are associated with symptom burdens that result in worse quality of life, functional status, and activities of daily living. Patients with MF are more likely to report symptoms such as fever, night sweats, and weight loss compared with patients with polycythemia vera (PV) or essential thrombocythemia (ET).

Momelotinib is an oral Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with a recommended dosage of 200 mg orally once daily with or without food. Special considerations for the use of momelotinib also includes risk of major adverse cardiovascular events, thrombosis, and development of malignancies, especially in patients who currently smoke or previously smoked.

The treatment approach for MF is currently identical for primary MF (PMF), post-PV MF, or post-ET MF.

Treatment for lower-risk MF includes momelotinib as a category 2B drug in symptomatic patients. Symptomatic patients may be treated with category 2A drugs, including ruxolitinib, peginterferon alfa-2a, or hydroxyurea, or category 2B momelotinib.

The treatment pathway requires monitoring the response and signs/symptoms of disease progression every 3 to 6 months. For those who respond to the treatment, the guidelines recommend continuing treatment and monitoring. For those with no response or loss of response, the guidelines recommend an alternative option not used for initial treatment, such as momelotinib. The guidelines recommend that patients with disease progression are moved to a higher-risk and accelerated/blast phase MF status.

In patients with high-risk MF, momelotinib was given category 2A status for those with higher platelets (≥50 x 10⁹/L) who were not a transplant candidate; other drugs include ruxolitinib (category 1), fedratinib (category 1), or pacritinib (category 2B). Similarly, the guidelines recommend monitoring patients every 3 to 6 months, continuing treatment for those with a response, recommending a clinical trial or alternative JAK inhibitor not used before for those with no response or loss of response, and accelerated/blast phase MF status for those with disease progression.

For the management of MF-associated anemia, the guideline recommends ruling out coexisting causes, such as bleeding; iron, vitamin B₁₂, or folate deficiency; and hemolysis. After treating coexisting causes, preferred regimens in patients with higher serum erythropoietin (≤500 mU/mL) include clinical trials or momelotinib. Other drugs that may be useful in certain circumstances include danazol, lenalidomide with or without prednisone, thalidomide with or without prednisone, or luspatercept (category 3). Those with a response are recommended to continue treatment, and those with no response or loss of response are recommended to select a treatment other than the one they initially began.

Reference

NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2023. Accessed November 21, 2023. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf\

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November 20, 2023

Targeted Oncology Staff

At a live virtual event, Jeanne Palmer, MD, provided commentary on the development of myeloproliferative neoplasms in patients, particularly those with newly diagnosed aggressive myelofibrosis. She highlighted the importance of the Janus kinase (JAK)-STAT pathways and how mutations in genes such as JAK2 can change a prognosis and a physician’s approach to treatment. Furthermore, she discussed the data behind the use of JAK inhibitors in this patient population and how they benefit patients in multiple ways but present a challenge in certain subsets of patients.

DEVELOPMENT AND INHIBITION TARGETS OF MYELOPROLIFERATIVE NEOPLASMS

The pathogenesis of the myeloproliferative neoplasms [MPNs], particularly the ones that are BCR-ABL1 negative, [occurs] primarily through the JAK-STAT pathway.¹ This is where we find what we call the driver mutations, which are the mutations that are critical in making the disease progress. There are 3 different mutations that we more commonly see, with the first being JAK2 V617F.² So JAK1 and JAK2…are right below the cell membrane, [and with this mutation], JAK2 is the one that is mutated, and when it is mutated, it keeps the 2 receptors it’s attached to on, which keeps it constitutively activated. Therefore, it goes on and continues to signal throughout the cell to make the cell grow disproportionally to what it should be.

In polycythemia vera [PV], most mutations are JAK2 V617F; however, there is a small percentage [of mutations in patients with PV] that are JAK2 exon 12, which is a mutation in another part of the JAK2 gene.² The [other 2] driver mutations, which are less common, are MPL and calreticulin.¹

The MPL mutation is in the thrombo-poietin receptor…and the CALR mutation is in calreticulin, and what happens is the calreticulin sits outside of the cell membrane.¹ The CALR mutation is interesting because it is extracellular. There are currently different therapeutics that target that because it is outside of the cell. The calreticulin is divided into type 1 or type 2. The type 1 is associated with a good prognosis, [whereas] type 2 isn’t necessarily [tied to a good prognosis].²

There are many factors that influence the production of MPNs, and this is an area of a lot of research, but there are a couple of [factors] that are prominent. First, the JAK2 mutant clone provides a survival advantage, and any of the mutations that are present in these myeloproliferative cells make them grow a lot.³ They’re extremely tough, they’re difficult to kill, and they try to predominate. There’s also evidence that some of the inflammation can drive these so that you have the cells that create inflammation because of the mutations and then that further drives for the replication and reproduction of the cells.³

There are also higher incidences of prior autoimmune conditions in patients with MPNs, and there’s a genetic predisposition to some of the MPNs as well as to the JAK2 mutation. Disruption of the JAK-STAT pathway can also affect NF-κB signaling, and there’s defective negative feedback regulation, hence what I talked about before about the signal being constitutively on.³

PATHWAYS INVOLVED IN MYELOFIBROSIS

One of the things that we’re learning with myelofibrosis is that there are a number of different pathways involved. We all know about the JAK-STAT pathway, but there are a couple of other pathways that we think are probably important and help us differentiate the [use] of different JAK inhibitors. One of them is IRAK1 and the other one is ACVR1.⁴ IRAK1 primarily involves a lot of the inflammatory cytokines…whereas ACVR1 [affects] the hepcidin pathway. We all remember hepcidin…from medical school when we learned about that iron metabolism pathway that you thought you’d never have to learn again. Well, hepcidin has made a resurgence not only in anemia of chronic disease but also in myelofibrosis and PV. However, one of the problems in myelofibrosis is that patients’ hepcidin [levels] can be too high, so if you can suppress it, they may benefit [from that kind of treatment]. The ACVR1 pathway reduces hepcidin transcription, which is thought to help anemia…and [researchers] found that this also appears to be a target of pacritinib [Vonjo].⁴

PERSIST-2 FINDINGS DEMONSTRATE PACRITINIB’S ROLE IN TREATMENT

[The baseline characteristics of the PERSIST-2 (NCT02055781) study] showed that there were fairly equivalent patient populations [between the study arms].⁵ One thing to note about the baseline demographics…is that in the control arm, almost half the patients had ruxolitinib [Jakafi] as their best available therapy and were allowed to continue it at the dosing level appropriate [for them]… depending on their platelet level. Again, [for those with] 50 × 10⁹/L to less than 100 × 10⁹/L platelet count, the dose recommended was 5 mg twice a day, which is what most patients were on [in the control arm].⁵

When we look at the spleen volume reduction rate in PERSIST-2 [findings]…it is a 35% decrease, and this spleen volume reduction is not as impressive in this [study]. The [spleen volume reduction] percentage is less [with] pacritinib as we would see [with] ruxolitinib.⁵ I also want to point out that these patients [in this study] have lower platelet [count], have a lower JAK2 allele burden, and maybe are less likely to respond well to JAK inhibitors. However, it is important to note that in PERSIST-2 [findings], the spleen volume reduction was greater in the patients who received treatment compared with those who did not.⁵

People have looked at JAK2 burden and response to JAK inhibitors, but they were more compiled data rather than split. You need a lot more patients to be able to note that difference. I would not use JAK2 allele burden as a decision point of whether to give somebody a JAK inhibitor or not. But there are some circumstantial data that [suggest] if somebody has a higher JAK2 allele burden then they’re more likely to respond to treatment.⁶

But that’s more likely because [the patient] probably has a proliferative variant, they have the hyperproliferative disease rather than cytopenic disease, and those patients tend to be more likely to respond to therapy because you can dose them adequately because their counts are high enough.

When using pacritinib, it’s important to remember that we don’t expect to see platelet [count] improvement, but sometimes we [see it] because the spleen shrinks, and when the spleen shrinks, you have less sequestration. But in general, I’ve seen platelet [count] go down a lot, so it’s very important not to give this drug [while] thinking, “Oh, my patients’ platelet [levels] are going to go up.” And then [you see the platelet levels go down and think] the drugs [are] not working, because what you hope for is that this will flatline.

When we look at the hematologic response [to pacritinib in the PERSIST-2 study findings], you do see that change in platelet count.⁵ Although 400 mg daily is not the prescribing dose, [their platelet counts went up]. Although those 400-mg data are not included in a lot of analyses because the dosing that’s found to be the best is 200 mg twice a day, you’ll see that the platelet [count] for those who were on 200 mg of pacritinib twice a day is flat. I don’t have a good explanation why the platelet [count] went up in the 400-mg once-a-day [group], because the responses weren’t that great, so [it] wasn’t the dose that was chosen to move forward. In terms of the red blood cell transfusions over time, they went down in patients, so the lower the red blood cell transfusion, the better it is in patients who are on 200 mg of pacritinib twice a day.⁵

When you look at patients with low platelet [count], the impressive thing about pacritinib is that you can maximize the dose and maximize the spleen volume reduction. If you took patients [with low platelet count] who got ruxolitinib at 5 mg twice a day, about 10% of them will have a spleen volume reduction of greater than 35%, so this is an extremely low rate of spleen volume reduction.⁵ One of the things that’s important to remember about this is pacritinib allows maximal JAK inhibition for patients with low platelet [count]. If you have somebody with normal platelet [count] and give them pacritinib, you’re not going to see the same benefit as you would with ruxolitinib, but a big part of that is [due to] the limitations with the cytopenias. For patients who have thrombocytopenia, pacritinib provides a significant advantage because you can maximize the dose.

TOXICITIES TO CONSIDER WITH JAK INHIBITION

[In the PERSIST-2 trial findings], all the adverse events [AEs] were expected, but I want to point out diarrhea is a major AE with pacritinib [Figure⁵]. Whenever using pacritinib, it’s extremely important to give [the patient] antidiarrhea and antinausea [medicine] when you start this medication. The majority of patients will have diarrhea, and it can be a significant AE.⁵

[Researchers in this study also looked at]…viral infections [and saw that] zoster can be activated in these patients through fungal infection.⁷ That’s something of interest to me, especially because I live in Arizona, where we have a lot of valley fever, which is a fungal infection.

What they had found…was that [in] these infections, especially if you look at pacritinib vs best available therapy or when best available therapy is ruxolitinib, we don’t see as [many cases], and in…[other] secondary [malignant tumors], it was even [fewer with] pacritinib compared with best available therapy with ruxolitinib.⁷

Frankly, there’s a lot of focus on these numbers that…when you look at the absolute numbers of these events, [they] are extremely low, but this is one area that they are trying to highlight where there is less of an infection risk [with pacritinib].⁷

_References

_{1. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390. doi:10.1056/NEJMoa1311347}

_{2. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405. doi:10.1056/NEJMoa1312542}

_{3. Mendez Luque LF, Blackmon AL, Ramanathan G, Fleischman AG. Key role of inflammation in myeloproliferative neoplasms: instigator of disease initiation, progression. and symptoms. Curr Hematol Malig Rep. 2019;14(3):145-153. doi:10.1007/s11899-019-00508-w}

_{4. Chifotides HT, Verstovsek S, Bose P. Association of myelofibrosis phenotypes with clinical manifestations, molecular profiles, and treatments. Cancers (Basel). 2023;15(13):3331. doi:10.3390/cancers15133331}

_{5. 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}

_{6. Vannucchi A, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment. Ther Adv Hematol. 2011;2(1):21-32. doi:10.1177/2040620710394474}

_{7. Pemmaraju N, Harrison C, Gupta V, et al. Risk-adjusted safety analysis of the oral JAK2/IRAK1 inhibitor pacritinib in patients with myelofibrosis. EJHaem. 2022;3(4):1346-1351. doi:10.1002/jha2.591}

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November 16, 2023

By Ryan Scott

Research providing a growing understanding of the molecular mechanisms of myelofibrosis has helped facilitate the development of new treatments for this patient population, and novel agents are poised to continue emerging in this space, according to Gaby Hobbs, MD.

In February 2022, the FDA approved pacritinib (Vonjo)for the treatment of patients with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10⁹/L.¹ Additionally, the regulatory agency approved momelotinib (Ojjaara) for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia in September 2023.² Both agents inhibit ACVR1, and their approvals are examples of how the growing understanding of the biology of myelofibrosis is informing drug development.

“We have a better understanding of several mechanisms that are involved in the development and the pathophysiology of myelofibrosis,” Hobbs said in an interview with OncLive^® following a State of the Science Summit™ (SOSS) on hematology, which she chaired.

In the interview, Hobbs discussed how further research into the biology of myelofibrosis has propelled the development of novel therapies for this patient population, expanded on ongoing and upcoming investigations of various agents, and highlighted the role that biomarkers play in the diagnosis, prognosis, and treatment response evaluation for these patients. Hobbs is a hematology-oncology physician, the clinical director of Leukemia Service, and an assistant in medicine at the Massachusetts General Hospital in Boston.

OncLive: Your presentations at the SOSS centered around the evolving treatment landscape of myelofibrosis and current standards of care. What were the key points you aimed to highlight during these discussions?

Hobbs: There have been a lot of changes in the therapies available for [patients with myelofibrosis] over the last couple of years. The first presentation focused on providing a brief overview of the current standard of care and new therapies that are available for [treating patients with] myelofibrosis.

The second talk [focused] an area where there’s still a lot of unmet need, which is anemia, [and I wanted to] give the audience an idea or approach on how to manage anemia for these patients, especially [after] the approval momelotinib.

What is the current understanding of the molecular mechanisms of myelofibrosis? How has this influenced the development of personalized treatment strategies for this patient population?

[The increased understanding of the mechanisms of myelofibrosis] has helped with some of the new drug approvals, including pacritinib and momelotinib. We were [previously] focused mostly on the JAK/STAT signaling pathway; now we appreciate that there are other signaling pathways that may also be involved in the pathophysiology of this disease.

For example, momelotinib and pacritinib also inhibit the ACVR1 pathway, which leads to an improvement in anemia. That’s a very clear way in which we’ve had improvement in therapies based on better understanding of the biology of [myelofibrosis].

Beyond momelotinib and pacritinib, are there any other agents currently under investigation in myelofibrosis that are intriguing?

There are many different agents that are currently being studied. The one that is most likely closest to being available to patients is luspatercept-aamt [Reblozyl], as that is already approved for patients with myelodysplastic syndrome, and that specifically will help patients with anemia. With regards to other novel therapeutics, there are many agents that are currently under development, including drugs like the telomerase inhibitor imetelstat, the BCL-2/BCL-XL inhibitor navitoclax, the BET inhibitor pelabresib [CPI-0610], the MDM2 inhibitor navtemadlin [formerly KRT-232], and the XPO1 inhibitor selinexor [Xpovio].

There are many agents under development now that [could] change the field of myelofibrosis from just having single-agent JAK inhibitors to having combination therapies that could hopefully help our patients live with less symptoms and also live longer.

What role do biomarkers play in the diagnosis, prognosis, and treatment response evaluation for patients with myelofibrosis?

When you say biomarkers in myelofibrosis, we rely significantly on genetic mutations and a variety of different risk scores to prognosticate for our patients. We know that patients with JAK2 mutations have different outcomes than those with CALR mutations. More specifically, we know that having additional mutations outside of JAK/STAT mutations also contribute to a negative prognosis, and those include mutations such as ASXL1, IDH, SRSF2, and EZH1. Those genetic mutations help us to understand prognosis with these patients, when taken into conjunction with other clinical variables that are included in [risk] scores.

References

1. CTI BioPharma announces FDA accelerated approval of VONJO™ (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. CTI BioPharma Corp. News release. February 28, 2022. Accessed November 8, 2023. https://www.prnewswire.com/news-releases/cti-biopharma-announces-fda-accelerated-approval-of-vonjo-pacritinib-for-the-treatment-of-adult-patients-with-myelofibrosis-and-thrombocytopenia
2. Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed November 8, 2023. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia

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November 16, 2023

By Patrick Daly

Dr. Masarova of The University of Texas MD Anderson Cancer Center in Houston, spoke with HemeToday on findings from a matched indirect treatment comparison of pacritinib and momelotinib in patients with mild myelofibrosis.

“I think it’s fantastic that we have a fourth inhibitor. It’s really good that [momelotinib] has a very broad indication for patients with myelofibrosis and anemia, where we haven’t had actually any drug,” Dr. Masarova said.

She detailed the mechanism of action of momelotinib and highlighted the relative benefits in safety and anemia response compared with pacritinib.

“The anemia responses that we have seen all seem to be little higher than those we’ve seen before although the mechanism of these agents is reported to be very similar. So that’s something that we’ll have to learn in clinical practice how to best sequence these patients and these agents in terms of patients responses,” Dr. Masarova said.

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The Janus kinase (JAK) 1 and 2 inhibitor ruxolitinib and the JAK2 inhibitor fedratinib, both approved by the U.S. Food and Drug Administration (FDA), are effective at reducing constitutional symptoms and spleen size in patients with myelofibrosis (MF) but often worsen anemia and increase transfusion needs. A study published in Blood Advances highlights a potential role for pacritinib among patients with MF and anemia.¹

Aaron Gerds, MD, MS, associate professor at Cleveland Clinic Taussig Cancer Institute, editor-in-chief of ASH Clinical News, and a coauthor of the recent paper, pointed out that the myeloproliferative neoplasm community has become increasingly interested in the hepcidin pathway in the treatment of anemia. Anemia in MF is multifactorial but seems to be partially driven by inflammatory cytokines and disease-related inflammation. This leads to increased production of the acute phase reactant hepcidin, which reduces iron transport out of cells and decreases serum iron levels, impairing erythropoiesis.

Momelotinib is a JAK1/JAK2 inhibitor that also inhibits activin A receptor, type 1 (ACVR1), which works upstream of the hepcidin gene. On September 15, the FDA approved momelotinib for the treatment of intermediate- or high-risk MF with anemia, regardless of prior therapy, making it the first therapy specifically for MF with anemia.

Researchers wanted to explore the potential role of pacritinib in patients with MF and anemia. Pacritinib is a JAK1 sparing inhibitor of JAK2 and IRAK1 (part of the toll-like receptor signaling pathway), as well as ACVR1; it is currently FDA-approved for patients with intermediate- or high-risk MF with a platelet count below 50,000/mcL. “Pacritinib works in a very similar manner to treat anemia as momelotinib, a drug specifically developed to ameliorate anemia in MF,” Dr. Gerds said.

In the phase III PERSIST-2 study of more than 300 patients with MF and thrombocytopenia, pacritinib demonstrated benefits for anemia. Patients on pacritinib experienced higher rates of clinical improvement in hemoglobin at week 24 compared to those treated with current best available therapy (which included ruxolitinib in some patients).²

The recent study retrospectively analyzed additional data from the PERSIST-2 trial. The researchers found that of patients who still required transfusion at baseline, a significantly greater proportion of those who received pacritinib (200 mg BID) became transfusion independent compared to those on best available therapy (37% vs. 7%, respectively; p=0.001). Moreover, significantly more patients on pacritinib had a greater than 50% reduction in transfusion burden (49% vs. 9%, respectively; p<0.0001).¹

The authors also performed additional in vitro data to assess the ACVR1 pathway and compare potency of other JAK2 inhibitors. They found the half-maximal inhibitory concentration (IC₅₀) using serial dilutions and used the maximum plasma concentration at the clinically recommended dose (C_max) to calculate inhibitory potency (C_max:IC₅₀). Pacritinib displayed the greater potency compared to momelotinib, fedratinib, or ruxolitinib (12.7 vs. 3.2, 1, and <0.01, respectively). Moreover, they demonstrated in further assays that pacritinib and momelotinib most potently reduced the expression of hepcidin in liver culture cells.¹

Partly based on these data, the most recent National Comprehensive Cancer Network guideline recommends pacritinib as a frontline agent for patients below 100,000 platelets/mcL and as a second-line agent regardless of platelet count.³

Dr. Gerds said the retrospective nature of the study is a key limitation. He also noted that differences between baseline characteristics of patients in this and other trials with JAK inhibitors make it difficult to compare agents, and in an ideal world, a prospective trial could assess the best approach to anemia in patients with MF.

“Pacritinib led to significant numbers of patients having improvement in their hemoglobin levels in a manner that’s like the way momelotinib works,” Dr. Gerds said. “To me, the take-home point is that in patients who have MF and anemia, you want to think about pacritinib as a possible treatment for their anemia.”

Any conflicts of interest declared by the authors can be found in the original article.

References

1. Oh ST, Mesa RA, Harrison CN, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv. 2023;7(19):5835-5842.
2. 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.
3. Gerds AT, Gotlib J, Abdelmessieh P, et al. Myeloproliferative neoplasms. Version 2.2023. NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/guidelines/recently-published-guidelines.

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Madeline Caduc and Steffen Koschmieder

Nov 2023