JAK-STAT Pathway–Targeting Approaches in Myelofibrosis Are Evolving

Raajit K. Rampal, MD, PhD

Director, Center for Hematologic Malignancies

Director, Myeloproliferative Neoplasms Program

Memorial Sloan Kettering Cancer Center

New York, NY

Targeted Oncology: What is the latest understanding of the classification and pathogenesis of myeloproliferative neoplasms (MPNs)?

RAAJIT K. RAMPAL, MD, PHD: Nothing has changed in terms of the 2022 [World Health Organization] classification, unlike what has happened with myelodysplastic syndrome.¹ JAK-STAT signaling is a hallmark of MPN pathogenesis, and all of the mutations that we're aware of at the moment—JAK2, CALR [calreticulin], and MPL—function in the JAK-STAT pathway. MPL is the thrombopoietin receptor which complexes with JAK [Janus kinase].

CALR is interesting, because CALR was discovered in 2013 but we think at the moment CALR complexes with MPL and results in the aberrant activation of MPL, but CALR does traffic to the cell surface.^2,3 That makes it a target for immunotherapy. That is the target of a couple of clinical trials; one is open [LIMBER (NCT06034002)] and the other is about to open, which is really interesting [and] could change everything in MPNs.

All that being said, there are still at least 8% to 15% of myelofibrosis cases that are "triple negative."^2,3 If you look at those cases by gene expression profiling, they have the JAK-STAT signature. The issue with those cases is that we haven't identified the particular lesion that occurs there, but it is a JAK-STAT–activated lesion, regardless of what the actual driver is. Those are the important things to think about with regards to how the disease is driven.

What are the therapeutic targets of JAK inhibitors in this patient population?

When it comes to the JAK inhibitors, there are a couple of things to keep in mind. One is that all of them hit JAK2, but fedratinib [Inrebic], ruxolitinib [Jakafi], [and momelotinib (Ojjaara)] also inhibit JAK1.⁴ Is that a good thing or a bad thing? I don't know.

We have to have some different perspective on this in the sense that JAK1 inhibitors by themselves have been in clinical trials for MPNs and have shown some degree of spleen reduction and some degree of symptom improvement. It’s not to the same extent that JAK2 inhibitors have, but that would at least [show] inhibiting JAK1 may be of some benefit. On the other hand, the infectious complications that we see with JAK inhibitors, namely reactivation of zoster and, in some cases tuberculosis reactivation, we think are at least partly mediated by JAK1 inhibition.⁵ JAK1 inhibits natural killer cell function, which has been known for some time.⁶ The thinking is that maybe some of the adverse events [AEs] we see from JAK inhibitors, infection wise…may be mediating them.

Aside from JAK-STAT inhibition, there are other pathways that are hit. One that is important for our discussion is ACVR1, which seems to play a role in hepcidin regulation. [Targeting this] is hypothesized to potentially have a beneficial effect in terms of anemia, which we see with both momelotinib and pacritinib.⁷ Both of those do inhibit ACVR1, and both of those…have shown some degree of anemia benefit in patients in clinical trials. These are some of the important targets of the inhibitors that we have.

How does risk assessment of primary myelofibrosis relate to treatment selection?

The approach to treatment of myelofibrosis is becoming more complicated, but I think that's ultimately a good thing. There isn't one particular algorithm; it depends on what the problem is.

There is risk assessment and then there is the treatment of the patient, and…the patient's risk stratification doesn't dictate their treatment in any way. The only thing it should dictate is whether or not [allogeneic stem cell] transplant may be considered. If we think about patients with low-risk disease, these are patients who are not likely going to benefit from transplant given transplant-related mortality and the other AEs from transplant. Once they cross intermediate-risk disease and higher, they are the patients who are more likely to benefit from transplant, and this has been evaluated in Center for International Blood and Marrow Transplant Research studies.

Risk stratification tools are evolving. There are things like the Dynamic International Prognostic Scoring System, which is used at the time of diagnosis, and now more recently, things like the Mutation-Enhanced International Prognostic Score System-70, which incorporates mutation profile as well. Risk stratification is an issue to try to understand if transplant is something that should be considered.

What characteristics have the most influence on choice of therapy for myelofibrosis?

Breaking down what you do for the patient on an individual level depends on what the issue is. There are patients who have anemia as their major disease modification without having massive splenomegaly or even constitutional symptoms. These are not common patients, but they exist. For those patients, there are a number of different options, and those include a lot of older drugs like danazol, thalidomide, prednisone, erythropoietin stimulating agents, and potentially momelotinib.⁸

For those patients who have splenomegaly or elevated [blood cell] counts without anemia or symptoms, sometimes there is still a role for hydroxyurea, but randomized studies have shown ruxolitinib to be superior for controlling spleen size vs hydroxyurea. For patients with anemia with splenomegaly or symptoms, momelotinib and pacritinib [Vonjo] both have anemia signals and can be used. Ruxolitinib can also be used but one of the major AEs of ruxolitinib is anemia, so one has to keep that in mind.

For patients with profound thrombocytopenia, pacritinib is often the drug of choice. For patients who have been on a JAK inhibitor, most commonly ruxolitinib, [and the disease failed to respond]…per the National Comprehensive Cancer Network, you can use one of the other JAK inhibitors. The question is, what are the data to support that? The data that we have are mostly from switching from ruxolitinib to another agent. In other words, we don't have any data regarding what happens if you take a patient who starts on fedratinib and switch them to pacritinib or momelotinib. There are not any robust data there, which doesn't mean you can't do it, but it’s something to be aware of. Whereas we do have a number of studies in which patients have been on ruxolitinib and switched to momelotinib, pacritinib, or fedratinib. That is something to keep in mind.

_References:

_{1. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850}

_{2. 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}

_{3. 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}

_{4. Duminuco A, Torre E, Palumbo GA, Harrison C. A journey through JAK inhibitors for the treatment of myeloproliferative diseases. Curr Hematol Malig Rep. 2023;18(5):176-189. doi:10.1007/s11899-023-00702-x}

_{5. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122(7):1192-1202. doi:10.1182/blood-2013-03-484642}

_{6. Schonberg K, Rudolph J, Cornez I, Brossart P, Wolf D. The JAK1/JAK2 inhibitor ruxolitinib substantially affects NK cell biology. Blood. 2013;122(21):16. doi:10.1182/blood.V122.21.16.16}

_{7. Duminuco A, Chifotides HT, Giallongo S, Giallongo C, Tibullo D, Palumbo GA. ACVR1: a novel therapeutic target to treat anemia in myelofibrosis. Cancers (Basel). 2023;16(1):154. doi:10.3390/cancers16010154}

_{8. Tefferi A, Pardanani A, Gangat N. Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis. Haematologica. 2023;108(11):2919-2932. doi:10.3324/haematol.2022.282612}