CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management

Although JAK inhibitors have become mainstays across myeloproliferative neoplasm (MPN) treatment paradigms, the integration of targeted therapies for these patient populations could drive further progress in disease modification and help improve long-term outcomes, according to Aaron Gerds, MD, MS.

“There’s a ceiling effect with JAK inhibitors. We need to break through that ceiling and fundamentally alter the course of disease,” Gerds said in an interview with OncLive^®. “JAK inhibitors do lead to better survival of patients, but they’re not fundamentally changing the disease like what we traditionally think about in cancer medicine, where we’re clearing out a bunch of malignant cells and extending survival because of remissions.”

Gerds provided an overview of the rationale driving research of agents targeting CALR mutations;¹ explained how these agents could be integrated into MPN treatment paradigms; and spoke about the potential use of combination therapies utilizing these agents.

Gerds is a physician in the Department of Hematology and Medical Oncology at Cleveland Clinic, as well as an assistant professor in the Department of Medicine of the School of Medicine, deputy associate director for Clinical Research, and member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center of Case Western Reserve University in Ohio.

OncLive: What is the importance of ongoing research exploring novel targeted therapies in the treatment of patients with MPNs?

Gerds: JAK inhibitors have been so instrumental at moving forward the care of patients with MPNs. I don’t want to ignore that fact. If you think about the time before JAK inhibitors, there was limited effective therapy outside of transplant, and [with the introduction of JAK inhibitors], there was a sea change of, ‘Wow, we can make patients feel better, and patients are living longer on JAK inhibitors.’ [JAK inhibitors] are so important, and they brought attention to these disorders, [drove] funding for other research, and moved [the field] forward in a tremendous way.

That being said, there is a certain ceiling to what JAK inhibitors can do. They can shrink spleens and improve symptoms, and patients are living longer because, primarily, they’re living better. There may be other benefits as well in certain instances, but there’s a ceiling effect with JAK inhibitors.

Looking at CALR mutations specifically, what is the prevalence of these alterations within MPN populations and the rationale for using them as a potential therapeutic target?

I dare to use the term ‘precision medicine’ because it’s such a buzz term, but that’s what this is. We’re looking at individual driver mutations within one disease. For example, if you take myelofibrosis as a whole, not every patient has the same mutational profile. Some patients have CALR [mutations], some have JAK2 mutations, some have MPL mutations, and some have other mutations. [The development of targeted therapies] is a big step forward into asking: What are the genetic underpinnings of an individual disease, and can we tailor therapy to meet that? That’s the importance of targeting CALR.

The unique aspect of the CALR-mutant protein is that it’s different than the proteins that come out of, say, a JAK2 mutation or MPL mutation. It’s external to the cell, and it almost acts like a fake thrombopoietin in that receptor. It sits in the thrombopoietin receptor and activates that whole pathway, so it lends itself to disruption in that manner. Mutant JAK2 is inside the cell and protected; it’s hard to get to. [However, if a] protein is sitting outside the cell, it’s ripe as a target, and that’s what we're seeing [with CALR mutations]. For example, a monoclonal antibody can get there, get stuck on [mutant CALR], and disrupt that signaling pathway, starving the megakaryocytes of that critical, positive force that causes their growth and expansion.

Secondly, if [a target] is external to the cell in such a significant way, we can start to target it with immunotherapy, such as bispecific antibodies or even cellular therapies, like engineered T cells. If the protein is inside the cell, like JAK2, for example, you can’t get to it with those types of therapy. [Targeting an external mutation] opens the opportunity to use all these amazing technologies that have made such great advances in other disease [settings].

With JAK inhibitors engrained within MPN treatment paradigms, are there avenues for combination regimens utilizing both JAK inhibition and targeted therapy?

We’re oncologists by training, so if we get one drug that works and another drug that works, we’re going to [try to] put them together. In combination therapy, that’s the strength of a lot of these targeted agents. Using monoclonal antibodies as an example, the fully humanized [agents are associated with] few adverse effects [AEs]. The safety profile is such where there’s almost no overlap with JAK inhibitors, or other therapies, for that matter.

I would not limit our creativity to combining a JAK inhibitor with a monoclonal antibody. We’re already [thinking about potential] triplets. You can envision a future for a patient with high-risk myelofibrosis where you [combine] a JAK inhibitor primarily to lower cytokine levels and treat spleen symptoms, with something like a BET inhibitor to deeply dislodge the disease, and a monoclonal antibody [targeting] mutant CALR; putting those 3 together in a triplet [might induce] a deeper and better response.

How might therapies like CALR-targeted agents continue to evolve and eventually affect the MPN treatment paradigm?

[Agents] specifically targeting CALR mutations are [likely] not going to work [against] these other driver mutations, although there are trials launching [that are using these agents in] that [JAK-STAT] pathway in [subsets of] polycythemia vera and myelofibrosis that don’t have a CALR mutation. It will be interesting to see if targeting that [pathway] in a similar way is going to have a similar outcome.

The other big thing that’s starting to turn now in early-phase trials are JAK2-specific agents. These are JAK inhibitors that are specific to JAK2 V617F mutations or type II JAK inhibitors, which work on the inactive conformation of JAK2 relative to the active conformation. Are they going to be different than the JAK inhibitors we have available right now? I don’t know. We have to do the studies. Theoretically, they would be more specific or [elicit] a deeper response, whether we’re talking a JAK2 V617F–specific inhibitor or a type II inhibitor. However, if we get better JAK inhibitor backbones, and then we circle back to these alternative pathways, perhaps we can make even bigger inroads there.

We’re still looking at combinations in the larger trials. In phase 3 trials, we’re still evaluating pelabresib [CPI-0610], for example, in terms of BET inhibition. There’s the [phase 3] MANIFEST-3 study [(NCT07357727) of pelabresib plus ruxolitinib [Jakafi] in JAK inhibitor–naive myelofibrosis] that’s launching right now. We’re waiting for the imetelstat [Rytelo] data from the [phase 3] IMpactMF trial [(NCT04576156) in patients with high-risk myelofibrosis who have not responded to JAK inhibition]. Then, of course, the selinexor [(Xpovio) plus rituximab (Rituxan)] data [from a March 2026] press release [from the phase 3 SENTRY trial (NCT04562389) in first-line myelofibrosis] are intriguing.²

[In SENTRY,] spleen responses were no big surprise, and symptom [score improvements] weren’t better [vs placebo plus ruxolitinib]—no surprise there. The surprise for me, at least, was seeing that survival advantage even as early as week 24. That caught my attention, and that’s a story that needs to be followed up.

In [the phase 3] MANIFEST-2 trial [NCT04603495] and the trials that were done with navitoclax [(ABT-263), a survival advantage] is the one thing that they have not been able to show. We all know that these drugs work and that they’re valuable for patients, and we’re trying to use these antiquated end points of a spleen volume reduction of 35% and a total symptom score reduction of at least 50% to measure something that’s different; [those end points] didn’t have the power to detect a survival benefit. However, in [SENTRY], we’re seeing [signs of a survival benefit]. That’s going to be huge.

References

1. Mascarenhas J, Al-Ali HK, Gupta V, et al. Safety and efficacy of the mutant calreticulin-specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib in patients (pts) with myelofibrosis (MF): preliminary results from dose escalation of two global phase 1 studies. Blood. 2025;146(suppl 1):484. doi:10.1182/blood-2025-484
2. Karyopharm’s phase 3 SENTRY trial in myelofibrosis met first co-primary endpoint, demonstrating statistically significant improvement in spleen volume reduction. News release. Karyopharm Therapeutics. March 24, 2026. Accessed April 14, 2026. https://investors.karyopharm.com/2026-03-24-Karyopharms-Phase-3-SENTRY-Trial-in-Myelofibrosis-Met-First-Co-Primary-Endpoint,-Demonstrating-Statistically-Significant-Improvement-in-Spleen-Volume-Reduction

This article was supported in part by Incyte. Content independently developed and published by OncLive.