Evolving Roles of JAK Inhibitors in Cytopenic Myelofibrosis

TARGETED ONCOLOGY: How did JAK (Janus kinase) inhibitors come to be used in myelofibrosis (MF)?

NAVEEN PEMMARAJU, MD: The field was blown wide open when my colleague Srdan Verstovsek, MD, PhD, at The University of Texas MD Anderson Cancer Center and our colleague in the United Kingdom Claire Harrison, MD, published the COMFORT-I [NCT00952289] and COMFORT-II [NCT00934544] studies in the New England Journal of Medicine 11 years ago.^1,2 This put ruxolitinib [Jakafi], the first-in-class JAK1/JAK2 inhibitor on the map. It was initially FDA approved for intermediate- to high-risk primary or secondary MF,³ but also...is now FDA approved for polycythemia vera intolerant or failure to hydroxyurea, [based on the] RESPONSE study [NCT01243944]. It is also FDA approved for graft-vs-host disease for patients aged 12 and older.⁴ It’s a very fascinating anticytokine antineoplastic drug. It’s now being actively tested in HLH [hemophagocytic lymphohistiocytosis] and other inflammatory conditions.

What guidelines are there to using ruxolitinib in MF?

It has a cap at platelet count of 50 × 10⁹/L.⁴ That led to the drug development of pacritinib [Vonjo]. I personally watch the blood counts very closely when I prescribe drugs, as some patients’ counts can drop quickly. There is a known permissive anemia, although it can result in transfusion dependency. You want to watch the complete blood counts every couple of weeks when you first prescribe it. Usually patients feel amazing in the first week to first month, it levels off by 2 or 3 months…and if the patient starts to develop anemia/thrombocytopenia, you may have to make dose reductions and/or repeat the marrow [biopsy] to make sure there’s not disease progression.

A major thing to watch out for with the ruxolitinib are viral infections; you can get opportunistic infections, sometimes serious. They’ve been published as reports [including] tuberculosis and other but more common is [varicella zoster virus] shingles. It’s so common for me to see shingles that now…I offer some form of shingles protection [such as] the new Shingrix shot. It is a 2-shot series indicated for ages 50 and over in the United States. I try to offer that for everyone. If not, consider valaciclovir [Valtrex]. You don’t have to do it but shingles…is common enough where I do try to address it before I start ruxolitinib.

The second issue has been non-melanoma skin cancers. MF is not necessarily causing it, but it does exacerbate or increase the risk. A lot of my patients end up seeing a dermatologist; I’ve never stopped anyone because of it [since] it’s not life threatening. A third signal is weight gain with ruxolitinib. It’s because we started prescribing it in polycythemia vera and earlier MF, but the weight gain can be treacherous. For some patients, we’re talking about…gaining 20 to 30 pounds in a short order. It’s something I try to mention. There is some mechanistic reasoning behind it [related to] adipose tissue modulation leptin.

What is the role of pacritinib in this setting?

Pacritinib is the third-in-class, approved in February 2022 for platelets less than 50 × 10⁹/L.5 The most interesting part of it is this 200 mg twice daily dosing you can give. [Whether patients have] low platelets or anemia, that’s the dose.6 It does have a GI signal in the first 4 to 6 weeks, so watch out for diarrhea. The FDA had concerns about a cardiac bleeding signal that hasn’t panned out in real life, but you need to watch out for that, particularly in and around the time of bleeding, surgery procedures, [and with] anticoagulation.

What is the significance of the pathways involved in myelofibrosis?

The JAK/STAT pathway’s [role has been established]…for 11 to 12 years. My own research and what I’m leading is looking at what’s called disease modification. Can we look for the first time now beyond the JAK pathway to either combine drugs, or to understand the pathways in the JAK inhibitors that are approved that are also being modulated? For example, pacritinib doesn’t just hit the JAK/STAT pathway.7 It also hits another pathway called IRAK1 which is likely very important in inflammation and immune signaling. It also inhibits ACVR1, which is important in the anemia of myelofibrosis.8 Momelotinib [Ojjaara] also targets ACVR1.⁹ Both pacritinib and momelotinib in the studies show that not only they can be delivered in the setting of anemia, but also improve it.^8,10 Some of the novel agents that we’re working with have signals for anemia improvement, [such as] navitoclax and the bromodomain inhibitors.^11,12 The telomerase inhibitor imetelstat is showing anemia improvement in myelodysplastic syndrome.¹² Can you deliver one of the newer JAK inhibitors, or 1 of the novel agents, or the combination, and improve on the previous era’s problems of anemia and thrombocytopenia? That’s the era that we’re living in, that’s why I’m so excited.

ACVR1 is a pathway that’s important in anemia of chronic disease, chronic inflammation, this Smad-signaling pathway that functions through hepcidin. You have distributions of iron, hepcidin, and inflammation. It’s aberrant in MF, and [ACVR1 inhibition] leads to restoration that thereby leads to anemia improvement. What is amazing is that momelotinib has known ACVR1 activity, that’s why likely it’s improving the anemia, but pacritinib also has it.^8,10 In vitro data…show that pacritinib may be 4 times more potent at doing that in vitro.¹⁴ We have a JAK inhibitor class that may improve anemia rather than worsen it.

How effective is pacritinib in improving transfusion dependence?

Transfusion dependence vs independence is everything for a lot of our patients. It not only means that symptomatically you may feel better, but it means less time in the [infusion] chair. Particularly during the pandemic that was very important. [It means] fewer visits to the hospital, less shortness of breath, fewer issues with anemia and bleeding. The concept that you can take a patient from transfusion dependency to transfusion independence was not possible with the previous JAK inhibitors, but we do see that with pacritinib, so much so that transfusion independence was seen to be better with pacritinib as compared with the best available therapy [BAT] arms.⁸ This is probably a better strategy than giving exogenous erythropoietin and other artificial agents. Furthermore, the rate of 50% or more transfusion reduction with pacritinib…in the PERSIST-2 trial [NCT02055781]…vs BAT had a significant improvement over multiple weeks and months.⁸

_References:

_{1. 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}

_{2. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556}

_{3. Deisseroth A, Kaminskas E, Grillo J, et al. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res. 2012;18(12):3212-3217. doi:10.1158/1078-0432.CCR-12-0653}

_{4. Jakafi. Prescribing information. Incyte; 2023. Accessed August 29, 2023. https://tinyurl.com/ua3rzhwr}

_{5. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed August 29, 2023. https://tinyurl.com/4jcus8km}

_{6. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed August 29, 2023. https://tinyurl.com/yxjnn7yu}

_{7. Singer JW, Al-Fayoumi S, Ma H, Komrokji RS, Mesa R, Verstovsek S. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol. 2016;8:11-19. Published 2016 Aug 16. doi:10.2147/JEP.S110702}

_{8. Oh ST, Mesa RA, Harrison CN, et al. Pacritinib Is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood. 2022;140(suppl_1):1518-1521. doi:10.1182/blood-2022-156936}

_{9. Asshoff M, Petzer V, Warr MR, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood. 2017;129(13):1823-1830. doi:10.1182/blood-2016-09-740092}

_{10. Verstovsek S, Gerds AT, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0}

_{11. Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: Phase II safety and efficacy. J Clin Oncol. 2022;40(15):1671-1680. doi:10.1200/JCO.21.02188}

_{12. Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a phase 2 study of CPI-0610, a bromodomain and extraterminal domain inhibitor (BETi), As monotherapy or “add-on” to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Blood. 2019;134(suppl_1):670. doi:10.1182/blood-2019-127119}

_{13. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/JCO.2023.41.16_suppl.7004}

_{14. Oh S, Mesa R, Harrison C, et al. MPN-145 Retrospective analysis of anemia benefit of pacritinib from the PERSIST-2 trial. Clin Lymphoma Myeloma Leuk. 2022;22 Suppl 2:S327. doi:10.1016/S2152-2650(22)01439-2}