Factors for JAK Inhibitor Selection in Myelofibrosis in the First Line and Beyond

In an interview with OncLive^®, Anthony Hunter, MD, elaborated on factors that contribute to the selection of a JAK inhibitor for patients with newly diagnosed myelofibrosis and those who have experienced disease progression after treatment with ruxolitinib (Jakafi).

Hunter also detailed genetic alterations associated with higher-risk myelofibrosis and how these affect treatment decisions and patient outcomes, including a deep dive into how TP53 mutations are viewed in this patient population. In a previous article, Hunter expanded on novel targets that could help expand the treatment paradigm in myelofibrosis.

Hunter is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and the medical director of the Immediate Care Center at Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive: For a patient with newly diagnosed myelofibrosis presenting with moderate to severe anemia, what is the typical first-line treatment approach?

Hunter: Ruxolitinib [Jakafi] has been our standard for a long time and has some great efficacy in the frontline setting. There are some dosing strategies, perhaps starting at a little bit lower dose and trying to titrate up over time that can help patients who are more anemic. Momelotinib [Ojjaara] is emerging in this space now. [It is] approved specifically for patients with anemia and does have the potential for similar spleen and symptom reductions that we may see with ruxolitinib; however, it also has the potential to improve anemia over time and may even lead to transfusion independence for some patients who are transfusion dependent.

[Momelotinib] is an emerging agent in that [anemic] population. What still [needs to] be sorted out is the cutoff is for anemia. When should we use momelotinib over ruxolitinib? We have a longer safety and track record with ruxolitinib; however, [the anemia cutoff was not specified on the FDA label [for momelotinib]. A lot of people think about anemia in studies in various ways, and [a patient is generally considered anemic if they have a hemoglobin level] of less than 10 g/dL. That’s not an unreasonable place.

I often personally think about doing things differently for patients who are anemic, when they're starting to get to 9 g/dL and below. There's a little bit of room from patient to patient. Some patients tolerate anemia a lot better than others. [Treatment selection in the frontline setting] can still be tailored a bit to the patient. Ruxolitinib is still a reasonable option, but with more profound anemia, momelotinib is the emerging agent in this space. For patients who also have a lot of concurrent thrombocytopenia, pacritinib [Vonjo] is an option in this area as well.

For patients with myelofibrosis who experience disease progression after treatment with ruxolitinib, what factors guide the selection of the most appropriate subsequent JAK inhibitor?

Historically, the real-world data suggest that after ruxolitinib failure, survival is only a little over a year on average for most patients. This is a tough population to treat. Some older studies well before [the emergence of] additional JAK inhibitors did show that experimental therapies—mostly JAK inhibitors—were better than using older things like hydroxyurea, which didn't have a lot of activity in the [post-ruxolitinib] setting. [Through sequencing], JAK inhibitors will hopefully be able to improve outcomes a little bit here compared with [the time when] we only had ruxolitinib.

Much like the first-line setting, there's a little bit of room to pick [a subsequent JAK inhibitor] based on patient presentation. Some patients who still have fairly proliferative disease and big splenomegaly, fedratinib [Inrebic] perhaps has the best data in the second line as far as the most robust spleen responses from the [phase 2] JAKARTA2 study [NCT01523171]; however, a lot of patients, as they progress, we are going to see more cytopenias, anemia, and thrombocytopenia, and both pacritinib and momelotinib again are potentially more active [for patients with more underlying cytopenias, anemia, and thrombocytopenia]. These agents are a little bit easier to use, and in that setting, both do have second-line data from multiple studies at this point demonstrating activity.

Certainly, clinical trials [are something to consider] for patients [following progression on ruxolitinib] to be able to potentially combine some of these newer JAK inhibitors with emerging agents.

In myelofibrosis, what genetic alterations are associated with higher risk?

Risk stratification in myelofibrosis has evolved over time. There are several systems out there, but the Mutation-Enhanced International Prognostic Score System [MIPSS] is the most comprehensive and includes both clinical and genomic data. [There are] six mutations that have classically been called high–molecular risk mutations, including ASXL1, U2AF1, EZH2, SRSF2, IDH1, and IDH2. Those are the 6 that, at least in the MIPSS system, are most impactful on either survival, leukemic progression, or both. That's been shown in multiple studies for most of these. Those are the most impactful ones that we see.

However, RAS mutations are ones that have jumped out in other studies, including [potential association with] more resistance to JAK inhibitors, and these can be impactful. TP53 mutations are not all that common early on in the disease, but it is certainly not ideal to see those, and they do increase the risk of leukemic progression. We do see more TP53 mutations arising in patients who are progressing to more blast-phase disease as well. All of those mutations are ones [that are linked with] decreased survival. Some of them do seem to impact outcomes with JAK inhibitors as well, and they do increase the risk of disease for these patients.

When a TP53 mutation is detected, what is its significance and how does that influence treatment strategies in myelofibrosis?

TP53 mutations are recognized for anyone who treats any myeloid neoplasm, including myelodysplastic syndrome [MDS], acute myeloid leukemia [AML], and myelofibrosis, and it is the last mutation you want to see. They are significantly impactful in regard to inferior prognosis and outcomes for patients across the board. Thankfully, we don't see quite as many TP53 mutations early on in primary myelofibrosis as maybe we do with some diseases like MDS. However, we do see them [in myelofibrosis], and they are certainly high-risk mutations to see.

We do see [TP53 mutations] start to pop up more as patients progress to blast-phase disease or accelerated disease, and they do lead to a pretty dismal prognosis. They decrease survival after transplant. In patients who progress to blast-phase disease, [these mutations] do impair the efficacy of most of our available treatment options, such as intensive chemotherapy, which already is not as successful in these patients [compared with] patients with de novo AML. TP53 mutations only decrease [the efficacy of treatments] further, including with our newer ventoclax [Venclexta]-based approaches, which do not improve outcomes all that much in these patients with TP53 mutations anyway. [The presence of this mutation] signifies a fairly dismal prognosis, unfortunately, and there is still a lot of room to try to improve outcomes in this molecular subgroup.