Emerging Therapeutic Strategies Transforming Myelofibrosis Care in 2026

Myelofibrosis (MF) management has historically centered on reducing splenomegaly and debilitating constitutional symptoms, with JAK inhibition forming the backbone of therapy. As the field moves into 2026, the treatment conversation is expanding beyond “How do we control symptoms?” toward “How do we individualize therapy by phenotype and biology—and potentially improve long-term outcomes?”

This shift is being fueled by a more intentional selection among available JAK-pathway options—particularly for patients with anemia—and a maturing pipeline of add-on and novel-mechanism agents that aim to deepen responses, address cytopenias, and, in some cases, test disease-modifying hypotheses.

Reframing First-Line Decisions: Phenotype-Driven Use of Approved Options

Even as investigational agents generate excitement, the day-to-day reality in MF remains that many patients start with a JAK2 inhibitor to reduce spleen size and symptom burden. What is changing is the precision with which clinicians and pharmacists are approaching that first decision—especially when anemia is a defining problem.

Momelotinib (Ojjaara; GSK) is specifically indicated for patients with either intermediate- or high-risk MF with anemia, because it is increasingly recognized that “anemia” should not be relegated to the fine print but is an important, central determinant of function and treatment response.¹ This is more of an approach by phenotype: patients whose clinical picture is heavily shaped by anemia may prompt earlier consideration of therapies positioned to address both inflammatory symptoms and hemoglobin-related outcomes, rather than cycling through options that primarily target splenomegaly.

In this evolution, for pharmacists, the importance of baseline and longitudinal monitoring (CBC trends, transfusion history, symptom trajectory) and medication-access coordination is accentuated. The "right drug for the right MF phenotype" approach can also reduce downstream treatment disruptions, particularly when anemia is the primary driver of dose reductions, interruptions, or early discontinuation.

Mutation-Directed Therapy Moves Closer to Reality: Targeting Mutant CALR

One of the important trends going into 2026 is the emergence of mutation-directed therapy in MF, which is still in its infancy compared to other hematological malignancies. Mutant calreticulin (CALR) is an important player in about half of cases of myeloproliferative neoplasms, and early clinical signals suggest it may be targetable.

INCA033989, a first-in-class monoclonal antibody targeting mutant CALR, recently announced early positive data from the early phases of the study, including marked reduction in spleen volume and symptom response, and hints of anemia response in mutant CALR-related disease.² While these data are still in the early phases of evaluation and should be supported in larger cohorts, the takeaway is broad—the MF therapeutic arena may soon stratify not only on risk and cytopenias but also on molecular subgroup.

Combination “Add-On” Strategies: Deepening Response After Suboptimal JAK Benefit

Another major theme for 2026 is the push toward rational combination therapy. Real-world experience has underscored a common clinical problem: many patients initiate ruxolitinib (or another JAK inhibitor) and experience partial or waning benefit over time. Rather than immediately switching therapies, multiple programs are testing whether adding a second mechanism can enhance the depth and durability of the response.

One prominent example is navtemadlin (KRT-232; Kartos Therapeutics), which is being evaluated as an add-on to ruxolitinib (Jakafi; Incyte) in the phase 3 POIESIS trial (NCT06479135).³ The study is designed to test whether combination therapy can outperform ruxolitinib alone in patients who have a suboptimal response—an approach aligned with how clinicians already manage many chronic malignancies: optimize the anchor therapy, then intensify with a complementary mechanism.

From a pharmacy practice standpoint, combination strategies raise the bar for proactive adverse-effect prevention and medication management. Overlapping toxicities, drug–drug interaction screening, and clear patient counseling on what to report (eg, bleeding symptoms, infections, severe GI effects, new or worsening fatigue) become even more important when therapies are layered.

Late-Stage Readouts on the Horizon: Selinexor in MF

In 2026, MF clinicians will also be watching for pivotal readouts that could reshape later-line strategies. Karyopharm has reported that top-line data from the phase 3 SENTRY trial (NCT04562389) evaluating Selinexor (XPOVIO; Karyopharm Therapeutics) in MF is expected in March 2026.⁴ A positive phase 3 outcome would be meaningful not only because it adds another option for a difficult-to-treat population, but also because it would validate a non-JAK, non–“symptom-only” mechanism in MF treatment sequencing.

For pharmacists, late-stage readouts matter because they translate quickly into real-world needs: formulary review, pathway updates, prior authorization planning, and rapid staff education on dosing, contraindications, and supportive care. Having a ready-to-deploy framework for onboarding a new MF agent—especially one used in combination or after prior therapies—can shorten the time between FDA action and safe, effective use.

Testing Disease Modification: Imetelstat and Survival-Focused Endpoints

The MF pipeline is increasingly willing to test survival-focused endpoints and disease-modifying hypotheses—an important evolution in a field where symptom improvement has often been the most pragmatic near-term goal.

Geron has highlighted the ongoing development of imetelstat (Rytelo; Geron) in relapsed/refractory MF through the phase 3 IMpactMF program, including expectations for an interim overall survival analysis in the second half of 2026.⁵ While MF remains biologically complex and heterogeneous, a credible signal that therapy can extend survival (not just reduce spleen volume) would meaningfully alter clinical discussions and patient expectations.

Where Pharmacists Fit as MF Care Accelerates

As MF care transforms in 2026, pharmacists are positioned to be the connective tissue between cutting-edge evidence and consistent real-world implementation. That includes aligning therapy choice with phenotype (especially anemia), ensuring molecular testing informs treatment opportunities, managing complex combination regimens, preventing and triaging adverse effects, and helping patients navigate access barriers. The pipeline is pushing MF toward a more personalized, mechanism-driven era—and pharmacists will be essential to making that era practical, safe, and scalable.

REFERENCES

1. OJJAARA (momelotinib) tablets, for oral use. Prescribing information. U.S. Food and Drug Administration. Accessed via FDA label. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216873s000lbl.pdf

2. Incyte Announces New Positive Data for INCA033989, its First-In-Class mutCALR-Targeted Monoclonal Antibody, in Patients with Myelofibrosis Presented at ASH 2025. Incytecorp. Published December 7, 2025. Accessed January 20, 2026. https://incytecorp.gcs-web.com/news-releases/news-release-details/incyte-announces-new-positive-data-inca033989-its-first-class

3. 3.Study of Navtemadlin add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib (POIESIS). Clinicaltrials.gov. Updated September 25, 2025. Accessed January 20, 2026. https://www.clinicaltrials.gov/study/NCT06479135

4. Karyopharm Announces Preliminary Unaudited 2025 Revenue and Reiterates Expectation of Delivering Potentially Transformative Phase 3 Data in 2026. Karyopharm. Accessed January 20, 2026. https://investors.karyopharm.com/2026-01-12-Karyopharm-Announces-Preliminary-Unaudited-2025-Revenue-and-Reiterates-Expectation-of-Delivering-Potentially-Transformative-Phase-3-Data-in-2026

5. Geron Corporation Reports Third Quarter 2025 Financial Results and Recent Business Highlights. Geron. Published November 5, 2025. Accessed January 20, 2026. https://ir.geron.com/investors/press-releases/press-release-details/2025/Geron-Corporation-Reports-Third-Quarter-2025-Financial-Results-and-Recent-Business-Highlights/default.aspx