Next-Generation JAK Inhibitors Signal the Future of Myelofibrosis Treatment Advances

Newer-generation JAK inhibitors are increasingly adept at controlling symptoms in patients with myelofibrosis and may recapture treatment response in patients who have progressed on prior ruxolitinib (Jakafi), according to Joseph G. Jurcic, MD.

“Using drugs that target all these particular abnormalities can result in symptom and spleen improvement, and in some, a reduction in cytokines and allelic burden,” Jurcic said in an interview with OncLive^®.

In the interview, Jurcic discussed the benefits and limitations of several JAK inhibitors for patients with myelofibrosis, highlighting the treatment advances that have been made since the introduction of ruxolitinib to the treatment paradigm, considerations for the use of fedratinib (Inrebic), and the potential advantages of pacritinib (Vonjo) for patients with anemia.

For instance, Jurcic explained the clinical implications of findings from the phase 2 JAKARTA-2 trial (NCT01523171), in which 31% of patients in the intent-to-treat population who received fedratinib (n = 97) achieved a spleen volume reduction (SVR) of at least 35%. In a cohort of patients who met more stringent definitions of prior progression on ruxolitinib (n = 79), 30% achieved a SVR of at least 35%.¹

Jurcic also noted key findings with pacritinib from the phase 3 PERSIST-1 trial (NCT01773187) that laid the groundwork for further use of this agent in patients with myelofibrosis. Pacritinib received FDA accelerated approval in 2022 for the treatment of patients with intermediate- or high-risk myelofibrosis with a platelet count below 50 × 10⁹/L based on findings from PERSIST-1, the pivotal phase 3 PERSIST-2 trial (NCT02055781), and the phase 2 PAC203 trial (NCT04884191), in which the agent generated a SVR of at least 35% in 29% of patients vs 3% of those who received best available therapy (BAT), including ruxolitinib.²

Jurcic is a professor of medicine at Columbia University Medical Center, as well as the director of the Hematologic Malignancies Section in the Division of Hematology/Oncology at the Columbia University Herbert Irving Comprehensive Cancer Center, both in New York, New York.

OncLive: How has the field of myelofibrosis treatment changed in recent years?

Jurcic: [Myelofibrosis] is a major field in malignant hematology. Myeloproliferative neoplasms [MPNs] are fairly common, [including] primary myelofibrosis and myelofibrosis arising from the other MPNs. It’s also an exciting time because several new therapeutics have been licensed in the past few years. Putting all these factors into perspective is important for oncologists.

What unmet needs exist for patients with myelofibrosis?

The major issue in treating myelofibrosis is symptom control. Patients will develop extreme fatigue due to cytokines. They’ll also develop significant splenomegaly, which can result in multiple symptoms, including anorexia. These are the major issues we’re dealing with on a day-to-day basis. However, we also have to think about the long term and how [to] improve survival of patients with myelofibrosis. Those are the major issues: symptom control, controlling splenomegaly, helping with anemia, and ultimately, prolonging survival.

How did findings from the phase 3 COMFORT-I trial (NCT00952289) of ruxolitinib in patients with myelofibrosis establish a foundation for further investigation of JAK inhibitors in this patient population?

Ruxolitinib was the first FDA-approved JAK inhibitor. [COMFORT-I] was a major study [that led to] a major breakthrough in the treatment of [patients with myelofibrosis], in that [it showed that ruxolitinib] could reduce spleen volume in a large number of patients and result in symptom control or improvement. However, one of the problems with [ruxolitinib] is that it causes significant myelosuppression, so it could worsen anemia, which is [a symptom] that many patients with myelofibrosis suffer from. It can also worsen thrombocytopenia. [Ruxolitinib] had some drawbacks, [and] there was a need for more agents.

What did the phase 3 JAKARTA (NCT01437787) and JAKARTA-2 trials elucidate about the use of fedratinib in patients with myelofibrosis?

[These trials evaluated] fedratinib [and had] similar findings [compared with COMFORT-I] in that [they found that this agent] could reduce spleen volume and symptoms. Where fedratinib fits best [into the myelofibrosis treatment paradigm] is for patients who have been on ruxolitinib and have lost their response, because fedratinib has also been shown to recapture those responses. Its major drawback [is its association with] myelosuppression. You need to be careful about this. I would be reluctant to use fedratinib in patients who have severe anemia and severe thrombocytopenia.

How does pacritinib fit into the myelofibrosis treatment paradigm, based on findings from the PERSIST-1 trial?

PERSIST-1 evaluated pacritinib vs BAT. [Similar to the other JAK inhibitors, pacritinib induced] SVR and improvement in symptoms. Pacritinib doesn’t seem to worsen thrombocytopenia, so for patients with significant thrombocytopenia, I reach for pacritinib. [Also, interestingly, pacritinib] inhibits the ACVR1 gene, which is involved in anemia, [indicating that pacritinib may] improve anemia. That may be a potential advantage of pacritinib as well.

References

1. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: an updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020;95(6):594-603. doi:10.1002/ajh.25777
2. 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 March 15, 2024. https://prn.to/33ZY8lU