JAK Inhibitor–Based Combinations Could Represent the Next Frontier in Myelofibrosis

In an interview with OncLive^® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium, Ashwin Kishtagari, MD, discussed advancements in the treatment of patients with intermediate-risk to high-risk myelofibrosis and highlighted recent data from the 2023 ASH Annual Meeting for combination therapies using JAK inhibitors.

Studies presented at the meeting included the phase 3 TRANSFORM-1 clinical trial (NCT04472598) evaluating navitoclax plus ruxolitinib (Jakafi), as well as the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib.^1,2

Kishtagari, who serves as an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee, provided further updates on JAK inhibitors for the treatment of patients with myelofibrosis in another interview with OncLive.

OncLive: How do you see the treatment paradigm for myelofibrosis evolving in the future?

Kishtagari: We have 4 JAK inhibitors which are FDA approved for the treatment of [patients with] myelofibrosis, with the first being ruxolitinib. Fedratinib [Inrebic] was the second agent approved in 2019. Pacritinib [Vonjo] was approved by the FDA in 2022, and momelotinib [Ojjaara] was approved in 2023.

We are moving toward combination therapies because our goal is to have a more significant improvement in splenomegaly response and symptom improvement. The whole field of myelofibrosis is moving toward combination therapy, especially for patients with higher- or intermediate-risk myelofibrosis.

What trials caught your eye in the realm of myelofibrosis at the 2023 ASH Annual Meeting?

Navitoclax which was studied in the phase 3 TRANSFORM-1 trial, where [patients were randomly assigned to receive] navitoclax plus ruxolitinib vs ruxolitinib [plus placebo]. [Data showed that] in [patients with] intermediate- or higher-risk myelofibrosis, [the combination reduced spleen volume by at least 35% (SVR35) at week 24] in 63.2% [of patients] vs 31.5% [of patients given ruxolitinib plus placebo].

SVR35 is the end point that is used for all clinical trials in myelofibrosis. In that randomized arm, one of the primary end points was SVR35, which was met in [TRANSFORM-1]. However, the second primary end point was improvement in total symptom score [TSS]. At week 24, there was a not a statistically significant difference between the 2 groups. It was a little bit discouraging to see that only one of the end points was met by the combination arm, but not the other end point.

Most importantly, cytopenias were challenging with the combination of navitoclax plus ruxolitinib. [Fifty-one percent] of patients developed [grade 3 or higher] thrombocytopenia in the combination arm. That is the huge barrier of this combination, and we're still waiting on the FDA to know if they would be willing to approve [a combination] like this. This level of cytopenias is very concerning.

Another clinical trial presented at the 2023 ASH Annual Meeting is MANIFEST-2. This was a randomized trial [that enrolled patients with] treatment-naive primary myelofibrosis, as well as post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Investigators included both patients with intermediate-1– and higher-risk [disease]. Comparatively, TRANSFORM-1 only included patients with intermediate-2– and higher-risk [disease].

In MANIFEST-2, [patients] were randomly assigned to pelabresib plus ruxolitinib vs ruxolitinib [plus placebo]. The [primary] end point was SVR35 at week 24. A secondary end point included TSS at week 24.

The results showed that SVR35 at week 24 [was achieved by] 65.9% of patients in the combination arm vs 35.2% in the placebo arm. The combination has shown a significant improvement in SVR35 at week 24.

TSS improvement at week 24 was numerically better with pelabresib plus ruxolitinib [–15.99] vs ruxolitinib plus placebo [–14.05], but [the difference] was not statistically significant. Once again, we have an improvement in SVR35, but TSS was similar to [single-agent] ruxolitinib.

Coming to the safety profile, [the combination] was very well tolerated, and there has been an improvement in hemoglobin with this combination, which is encouraging. The company has submitted [the data] to the FDA, and we are eagerly waiting for [potential approval of] the combination, especially for higher-risk myelofibrosis, which could change the practice of how we treat myelofibrosis [in the frontline setting].

How could ongoing data for JAK inhibitor–based therapies and combinations affect the treatment of myelofibrosis for community oncologists?

Although community colleagues are well experienced with the use of ruxolitinib, there are other JAK inhibitors that are approved by the FDA and can be utilized in a specific setting.

For example, pacritinib can be used in patients who have low platelet count [below 50 x 109/L]; we could use pacritinib in that particular setting. If the patient presents with anemia, we can use momelotinib, which clearly has shown improvement in hemoglobin [levels].

If a patient has a particular cytopenia, JAK inhibitor [selection] can be guided based on that rather than giving everyone up-front ruxolitinib. My approach has been based on the blood counts; if the blood counts are preserved, go with ruxolitinib. However, if they have thrombocytopenia, [go with] pacritinib; if they have anemia, go with momelotinib.

If the patient is fit or [younger than] 35 [years of age], these patients need to be referred for bone marrow transplant. Even today, patients with myelofibrosis can be cured only by bone marrow transplant. Whenever it is feasible for the right patient, we always need to consider transplant.

References

1. Pemmaraju N, Mead AJ, Somervaille T, et al. Transform-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood. 2023;142(suppl 1):620.doi:10.1182/blood-2023-173509
2. Rampal R, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus Kinase Inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141