All Eyes Are on Novel Combination Therapies and Molecular Targets in MPN at ASH 2025

As anticipation builds for the 2025 ASH Annual Meeting, several presentations are already generating significant buzz in the field of myeloproliferative neoplasms (MPN).

“Within the field of MPN, there are a number of developing stories we have our eyes on,” Aaron Gerds, MD, MS, shared in an interview with OncLive®. “At this year’s ASH Annual Meeting, one big focus is on developing therapies that are specific to the mutant calreticulin [CALR] protein. We [also] have our eyes intently set on are the follow-up results from the phase 3 MANIFEST-2 trial [NCT04603495].”

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

In the preview article below, Gerd’s insights are accompanied by exclusive perspectives from the following KOLs:

• John O. Mascarenhas, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai; as well as the director of the Center of Excellence for Blood Cancers and Myeloid Disorders, the director of the Adult Leukemia Program, and a member of The Tisch Cancer Institute in New York, New York.
• Naseema Gangat, MBBS, a professor of medicine and a consultant in hematology at Mayo Clinic in Rochester, Minnesota. Read on to learn which presentations warrant the most attention, and how such research could have meaningful implications for clinical practice going forward.

​​Editor’s note: This preview will continue to be updated with additional abstracts to watch in myeloproliferative neoplasms leading up to the 2025 ASH Annual Meeting.

Could long-term follow-up data from MANIFEST-2 provide the necessary justification for moving forward with pelabresib in combination with ruxolitinib over single-agent ruxolitinib in myelofibrosis?

Mascarenhas: For myelofibrosis, 96-week data from the phase 3 MANIFEST-2 trial confirm durable benefit in spleen [volume reduction (SVR)],symptom reduction, and anemia improvement with the combination of pelabresib [CPI-0610], the pan-BET inhibitor, with ruxolitinib [Jakofi] in JAK inhibitor–naive [patients with] myelofibrosis. The [agent’s] safety profile remains very reassuring and the imbalance in cases of blast phase disease has narrowed such that the overall survival is the same between the 2 arms. Biomarkers of disease modification all favor deeper biological activity with the combination arm compared to ruxolitinib monotherapy.

Gerds: The MANIFEST-2 trial, to date, is the largest trial ever done in myelofibrosis. What we saw with the initial 24-week data was that the combination was nearly twice as effective at shrinking spleens than the single agent.1 SVR [at week 35 (SVR35)] is a key primary end point in trials for myelofibrosis; it nearly doubled [in MANIFEST-2], but [the study] just missed statistical significance for a key secondary end point, symptom burden response at week 24. We are looking for additional data from this trial as we follow these patients long-term to justify moving this medication forward.

The major challenge is that a lot of the patients on this trial had intermediate-1 risk disease, so their predicted survival is going to be much longer. To see a survival advantage, we have to follow these patients for quite some time, but at least we can see treatment durability or maybe even composite end points become positive over time. The abstract [being presented at this year’s ASH Annual Meeting will highlight the] dual benefit [with this regimen] in terms of the number of patients who have both a spleen response and a symptom response. Again, there is that theme of anemia improvement in these patients, and the curve is starting to split now for SVR35 durability. That is an important early sign that there is a clear and distinct long-term advantage for the combination over single-agent [ruxolitinib].

This trial is an incredibly exciting story, and we will continue to follow along. This is definitely an effective, active combination that may have fallen short just because of trial design and picking the wrong measurements to adjudicate success. A lot of us who participated in this trial do think it is a very valid mechanism, and I have had patients on study do incredibly well, even better than expected. From both the data that exists in aggregate as well as anecdotal experience, I believe that it is a very valuable treatment. [However,] we need more footing and traction for this to continue to move forward.

Featured presentation:

• Abstract 910: Durable efficacy and long-term safety with pelabresib plus ruxolitinib in JAK Inhibitor-naive myelofibrosis: 96-week Results from the Phase III MANIFEST-2 study. Presentation time: Monday 12/8, 03:30 - 03:45 PM EST

Could nuvisertib serve as an equally effective, less toxic, addition to JAK inhibition for patients with relapsed/refractory myelofibrosis?

Mascarenhas: The new combination therapy approach to debut is that of nuvisertib [TP-3654], a selective PIM1 kinase inhibitor, and momelotinib [Ojjaara] in patients with myelofibrosis who have failed a prior JAK inhibitor [other than momelotinib] and have anemia, measurable symptom burden and splenomegaly. These phase 1/1b data [NCT04176198] are still early with 18 patients, but build on [prior] nuvisertib monotherapy data documenting spleen, symptom and anemia benefit with an acceptable toxicity profile. [The regimen’s safety profile is] most notable for low-grade gastrointestinal toxicity and the absence of significant cytopenias, making this rational approach attractive in patients with cytopenias. The changes in pro-inflammatory cytokines also were shown to correlate with clinical outcome measures.

Featured presentation:

• Abstract 482: Preliminary data from the phase I/II study of nuvisertib, an oral investigational selective PIM1 inhibitor, in combination with momelotinib showed clinical responses in patients with relapsed/refractory myelofibrosis Presentation time: Sunday 12/7, 09:40 - 10:00 AM EST

Does INCA033989 provide proof-of-concept for the continued development of mutant CALR–targeted therapies in essential thrombocytopenia and myelofibrosis?

Mascarenhas: In myelofibrosis and essential thrombocytopenia harboring the CALR driver mutation, we are seeing updated data [with INCA0339889] from the phase 1 essential thrombocytopenia cohort [of INCA033989-102 (NCT06034002)] and new data from the myelofibrosis cohort [of the phase 1 INCA033989-101 trial (NCT05936359)]. This very well-tolerated, humanized antibody to mutant CALR is very clean without obvious off-target toxicity and rapidly normalizes platelet counts in essential thrombocytopenia and improves symptoms, spleen, and anemia in myelofibrosis while correlatives indicate anti-clonal activity in reducing the mutant CALR subpopulation and normalizing hematopoiesis in the marrow with reduction in mutant megakaryocytes while allowing for an increase in wild type megakaryocytes.

Gerds:The preliminary data for patients with essential thrombocytopenia were presented at the 2025 EHA Congress this summer.2 At this year’s ASH Annual Meeting, we will get a first look at the data from patients with myelofibrosis, and we are all eager to see these results in detail.

In essential thrombocytopenia, we are seeing a large number of platelet responses [with this therapy], which is fantastic. Historically, if we look at comparable agents such as hydroxyurea, CALR-mutant disease tends to be somewhat resistant to hydroxyurea. [INCA0339889 could] provide [use with] another valuable therapy.

The most impressive part of the development of this monoclonal antibody is just the sheer lack of toxicity compared with a lot of other therapies that we use [in this space]. We are not seeing the numbers and severity of adverse effects we would expect with a monoclonal antibody. The combination of efficacy, particularly in essential thrombocytopenia combined with a great safety profile makes this a very attractive option, not just as a single agent but [for use] in combination with other therapies down the road.

Of course, this monoclonal antibody is just a springboard for other therapies. Off of monoclonal antibodies, we can develop bispecific antibodies that engage not only the target, but the immune system to kill the cell of interest—in this case, a megakaryocyte. We [also] have an antibody structure to work off of for engineering cellular therapies like CAR T-cell therapies. The efficacy of this particular agent, and [hopefully that] of agents to come, is incredibly exciting.

Featured presentations:

• Abstract 484: 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 Presentation time: Sunday 10/7, 10:15 - 10:30 AM EST
• Abstract 1024: Safety and efficacy of INCA033989, a novel first in class mutant calreticulin-specific monoclonal antibody, in patients with essential thrombocythemia. Presentation time: Monday 10/8, 17:15 - 17:30 PM EST

How might the revised DIPSS model help improve patient selection in chronic-phase primary myelofibrosis?

Gangat: DIPSS-R is the first risk model in primary myelofibrosis that is specific to chronic-phase disease. It preserves global applicability and improves upon DIPSS by eliminating host-related (age) and subjective (constitutional symptoms) parameters, as risk factors, without compromising model performance. It also utilizes severity- and sex-based grading to optimize the prognostic contribution of anemia and leukocytosis, and recognizes the independent prognostic contribution of monocytosis and thrombocytopenia to both overall and leukemia-free survival. [Overall,] DIPSS-R-independent genetic risk factors facilitate patient selection for transplant or clinical trials, within specific DIPSS-R risk categories, and are stronger predictors of leukemic transformation.

Featured presentation:

• Abstract 84: DIPSS-R: A Revised Age-Agnostic Clinical Risk Model for Chronic Phase Primary Myelofibrosis Presentation time: Saturday 12/6, 10:45 - 11:00 AM EST

What are some additional presentations of interest in polycythemia vera and systemic mastocytosis?

Mascarenhas: In polycythemia vera, we see durable responses in hematocrit control with the hepcidin mimetic rusfertide from the phase 3 VERIFY trial [NCT05210790]. This subcutaneously administered agent is not associated with a concerning toxicity profile and improved fatigue associated with iron deficiency.

Featured presentation:

• Abstract 81: Rusfertide or placebo plus current standard-of-care therapy for polycythemia vera: Durability of response and safety results through week 52 from the randomized controlled phase 3 VERIFY study Presentation time: Saturday 12/6, 10:00 - 10:15 AM EST

Gerds: Although [systemic mastocytosis] is not a true MPN—it has its own category within the classification system—it is still akin to what we do in MPN, and there are some exciting new agents on the horizon. We will get a look at data for bezuclastinib, which we are all excited to see again, in detail, as well as some long-term data from studies with avapritinib [Ayvakit]. These [presentations will] highlight the important role that KIT inhibitors can play in not just aggressive systemic mastocytosis, but also symptomatic, indolent mastocytosis—a disease that has a pretty long survival, but that can make patients quite symptomatic.

Featured presentations:

• Abstract 80: Efficacy and safety results from the primary analysis of the pivotal summit trial: bezuclastinib in adults with non-advanced systemic mastocytosis Presentation time: Saturday 12/6, 09:45 - 10:00 AM EST
• Abstract 2024: Avapritinib achieves deep and durable symptom control with a well-tolerated safety profile in ism: Long-term outcomes from pioneer Presentation time: Saturday 12/6, 17:30 - 19:30 PM EST
• Abstract 1022: Avapritinib treatment of patients with advanced systemic mastocytosis: 4-year safety, effect on bone and first-line efficacy results of the pathfinder clinical study Presentation time: Monday 12/8, 16:45 - 17:00 PM EST
• Abstract 5582: Changes in long-term bone health in patients receiving avapritinib for the treatment of indolent systemic mastocytosis in the pioneer study Presentation time: Monday 12/8, 18:00 - 20:00 PM EST

References

1. Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. Nat Med. 2025;31(5):1531-1538. doi:10.1038/s41591-025-03572-3
2. Mascarenhas J, Ali H, Yacoub A, et al. INCA33989 is a novel, first in class, mutant calreticulin-specific monoclonal antibody that demonstrates safety and efficacy in patients with essential thrombocytopenia (ET). Presented at: European Hematology Association (EHA) Congress; June 12-15, 2025; Milan, Italy.