Treatment Options Beyond JAK Inhibitors for Myelofibrosis

Over the past decade, the myelofibrosis space has seen an explosion in the development and approvals of JAK inhibitors, going from 0 to 4 options. Beyond JAK inhibition, a number of new agents and targets are in development for the treatment of patients with myelofibrosis.

​Currently, the standard-of-care for patients with intermediate- or high-risk myelofibrosis is ruxolitinib (Jakafi). Other agents with the potential for improvement in quality of life and survival, including the JAK inhibitor fedratinib (Inrebic) are considered if individual symptoms plague patients, which may include anemia or cytopenia.

In February 2022, the FDA approved pacritinib (Vonjo) for patients with myelofibrosis based off of the results of the phase 3 PERSIST-1 (NCT01773187), the phase 3 PERSIST-2 (NCT02055781), and phase2 dose-finding PAC203 trials.

According to John Mascarenhas, MD, the future of myelofibrosis will most likely include several JAK inhibitor treatment niches and combination regimens with JAK inhibition in both the upfront and second-line setting, as well as agents that may offer benefit in overall survival (OS).

In an interview with Targeted Oncology, John Mascarenhas, MD, professor of medicine at Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of The Tisch Cancer Institute, discusses his presentation during the 26th Annual International Congress on Hematologic Malignancies, hosted by Physicians Education Resource®, on the emerging therapies in treating myelofibrosis in the frontline setting as well as for those who have received prior ruxolitinib treatment.

What are the new and emerging modalities for myelofibrosis treatment?

Some of the more advanced in clinical testing that were reviewed were therapies like parsaclisib, the PI3 kinase inhibitor, and the phase 2 data that is driving the limber studies which are PI3 kinase inhibitor, parsaclisib plus ruxolitinib, the JAK inhibitor in naive patients, or the PI3 kinase inhibitor, of parsaclisib plus ruxolitinib in those patients already on ruxolitinib with suboptimal response. Looking at 2 different patient populations, the phase 2 data has shown that there is clinical activity with this selective P13 Delta inhibitor at 5mg daily in reducing spleen and symptom burden. It may be a nice option to try to regain disease control in patients particularly who are on ruxolitinib and who have lost response or had a suboptimal response. This is predicated on preclinical data showing the utility of dampening the PI3 kinase pathway and the relevance in MF biology.

A second approach that's been also exciting to watch is the BET inhibitor, pelabresib [CPI-0610] from the MANIFEST study [NCT02158858] to now the MANIFEST-2 [NCT04603495] randomized, phase 3 study, which is ongoing. This is an old drug that is given at 125 milligrams daily, 2 weeks on, 1 week off, so a 3-week cycle. In the MANIFEST study, it was given as a monotherapy to patients who failed ruxolitinib and have been discontinued in arm 2 as a combination similarly to the PI3 kinase inhibitor that have suboptimal response, and in arm 3 as a combination in JAK inhibitor naive patients.

It was arm 3 that looked the most impressive. The response rate was 67% for spleen volume reduction and nearly 57% for symptom burden improvement, which compares very favorably to the prospective monotherapy JAK inhibitor, ruxolitinib, specifically. It is a treatment that likely affords deeper spleen symptom benefit, as well as bone marrow fibrosis progression and does not really have additive cytopenias as a treatment for emergent adverse events. In fact, there were some patients who had improvements in anemia and reduction in fibrosis.

The idea is that this BET inhibitor that downregulates and targets gene expression, as well as TGFb and BCL-2, likely has effects within the diseased cells in the bone marrow that translates to improvements in other disease aspects like fibrosis, reduction JAK2 allele burden, and cytopenia. I look forward to the ongoing MANIFEST-2 study as it's the first study that has predicated on moving the treatment paradigm upfront and not waiting for patients to fail ruxolitinib.

Can discuss the recent studies in the myelofibrosis space?

The third study that we highlighted was the navitoclax, BCL-2 inhibitor study. They have ongoing studies, the TRANSFORM studies, in upfront and the second-line combining their agent which inhibits BCL-2 and BCL-XL, which has substantial rationale. The inhibition of that in the initial phase 2 study in combination with ruxolitinib did lead to some spleen and symptom benefit. A third of the patients had bone marrow fibrosis reduction and on target, cytopenia was seen. This is clearly an active drug, and I look forward to seeing the results of the TRANSFORM studies as well.

The last study I highlighted was imetelstat, a timeless inhibitor that is sort of different from the other drugs. It's an infusional drug that has shown early on in its development, complete responses, both pathologic responses in the bone marrow, as well as molecular responses in pilot study. It's predicated on the idea that telomerase, an enzyme that is expressed in MMC-34 cells and only transiently in normalcy 34 cells, add to telomerase to the ends of chromosomes and therefore provides a signal of immortality and avoidance of apoptosis and cell arrest. Poisoning this with imetelstat would selectively target the MPN CD34 cell population, which has been shown in preclinical modeling.

In a randomized phase 2 study called the EMBARK study [NCT02319837], we treated patients at 2 dose levels, 9.4 mg/kg and 4.7 mg/kg. What we saw was spleen and symptom benefit, but most importantly, overall survival benefit. This was a ruxolitinib, refractory population and if you fail ruxolitinib, the median survival by 5 independent studies are somewhere between 12 and 15 months, and the median survival in the 9.4 mg/kg arm of the imetelstat delivered every 3 weeks by infusion was close to 30 months. It is a drug that appears to have the potential to prolong survival, event-free survival, and other parameters of outcome. It also reduced fibrosis and JAK2 allele burden.

We have studies that have shown a correlation between these biomarkers and clinical responses, including survival outcome. That really inspired the current IMpactMF study, which is a randomized phase 3 study for patients who are refractory to ruxolitinib and are randomized imetelstat or the best available therapy, excluding JAK inhibitor therapy. The primary end point was overall survival, so a different sort of study with a different end point, and a different patient population compared to the other studies mentioned.

In what ways has the treatment landscape for this patient population changed in recent years?

The treatment landscape has definitely changed. I started in this field a little over 15 years ago, and there were no approved drugs. Then, in 2005 with the revelation of a JAK2 mutation driving a substantial proportion of disease in myelofibrosis, a number of companies set out to develop JAK2 inhibitors. Ruxolitinib really was the first drug, from the preclinical stage, to demonstrate spleen and symptom benefit to the clinic recapitulating that in patients with myelofibrosis.

The COMFORT studies were the pivotal randomized phase 3 studies that led to the first approval of ruxolitinib in which it was very clear that that drug improved quality of life symptom burden, reduction spleen, and there was a survival benefit that was tied into treating patients with this JAK inhibitor, as opposed to delaying treatment with a JAK inhibitor.

Generally, the drug is not effective, particularly by itself, in modifying the disease further in terms of responses in the bone marrow, histopathologic responses, molecular responses, bone marrow fibrosis reduction, and does incur treatment of emergent on-target cytopenias. The field has moved more recently into combination therapy approaches to try to build upon that initial success. Along the way, other JAK inhibitors have been approved, like fedratinib, which provides a commercial access to second-line agents to try to rescue spleen symptoms symptom burden in those patients who've previously seen ruxolitinib in which a third of the patients can have substantial benefit from fedratinib. That's an important drug that still remains accessible to community oncologists.

Then, the approval of pacritinib expands the ability to give a JAK inhibitor to those patients who have thrombocytopenia, which has been the unmet need. These patients are particularly poor and the current JAK inhibitors are not indicated for patients with less than 50,000. It kind of rounds out the ability to provide treatment options and gives the ability to treat patients with these drugs. It's important to point out that momelotinib has also provided frontline data and will be presented at upcoming meetings showing that it is a drug in the ruxolitinib treated patient population with anemia that can afford spleen and symptom benefit. Also importantly, to maintain transfusion independence in patients with significant anemia, transfusion dependence, and maybe an option that may become commercially available in the future to address and to have additional treatment options for patients with significant anemia and in need of JAK inhibition.

It is exciting to see it go from 0 to 4 JAK inhibitors and to see the explosion of combination treatment approaches and other approaches like an imetelstat that are aiming to modify the history of this disease. It is a very exciting period for clinical investigators and practitioners to be treating myelofibrosis.

How do you feel the recent FDA approval of pacritinib will impact the future of this space?

I'm thrilled about the approval, and I think it was a long time in the making. I personally think it probably could have been approved a long time ago as the data has been available, particularly from the phase 3 study demonstrating the safety profile and efficacy of pacritinib in those patients with low platelets that don't have other options. These patients do very poorly. The ability to deliver some relief from symptoms is crucial to this subset of patients, so I'm excited to see that.

The reality is, with these approvals, we move the field forward. It is incremental, but pacritinib potentially has other applications as well. It's an IRAK inhibitor, so inhibiting the IO1 pathway and down regulating nuclear factor kappa B also has other important effects in this disease and related diseases. The potential to combine equipment with other drugs also exists, and I think there's a lot of possibilities to look forward to.