Encouraging Early Results for Nuvisertib Combination in Myelofibrosis

A key highlight was the first clinical update on the investigational PIM1 inhibitor nuvisertib used alongside momelotinib, a JAK/ACVR1 inhibitor, in patients with relapsed or refractory MF complicated by anemia. The ongoing Phase 1/2 trial enrolled 26 heavily pretreated patients, all of whom had prior exposure to JAK inhibitors, with a significant proportion carrying high-risk mutations.

The combination demonstrated a manageable safety profile, with no dose-limiting toxicities reported. The most common treatment-related side effects included gastrointestinal symptoms and thrombocytopenia, generally consistent with expectations in this population. Importantly, hemoglobin levels and platelet counts remained stable over a 24-week period, suggesting limited hematologic compromise.

Clinical activity signals were notable. Among patients evaluable after at least 12 weeks of therapy, nearly three-quarters achieved meaningful spleen reduction, and more than half experienced substantial symptom improvement. By 24 weeks, all evaluable patients showed spleen volume reductions, while symptom and anemia responses deepened. A combined “triple response”—improvement in spleen size, symptoms, and anemia—was observed in a majority of patients at that time point.

These early outcomes are particularly meaningful given the limited treatment options and biological complexity of advanced MF.

Targeting Complementary Disease Pathways

The rationale for this combination reflects growing recognition that MF progression is driven not only by JAK signaling but also by alternative pathways that can sustain disease activity despite JAK inhibition. PIM1 kinase, frequently upregulated in MF, is influenced by signaling routes such as NF-κB and ERG, which may enable treatment resistance.

By pairing nuvisertib with momelotinib, investigators aim to inhibit both primary and compensatory pathways simultaneously. This dual targeting approach could potentially produce deeper and more durable disease control compared with single-pathway therapies.

Translational Insights: Explaining Hemoglobin Improvements

Additional translational research offered insight into how nuvisertib may contribute to improvements in anemia—a key unmet need in MF. Laboratory and early clinical findings suggest that beyond inhibiting PIM1, nuvisertib also interacts with ACVR1, a regulator linked to iron metabolism.

This interaction appears to reduce levels of hepcidin, a hormone that controls iron availability. Lower hepcidin levels may improve iron utilization and support red blood cell production, providing a plausible explanation for the stable or rising hemoglobin levels observed in treated patients.

Resistance Patterns Identified in Acute Leukemia

SMPA also shared findings related to enzomenib, a menin inhibitor under investigation for acute leukemia. Researchers identified specific genetic alterations associated with acquired resistance following initial treatment response.

Serial molecular analyses revealed that a mutation known as E368K emerged as the dominant resistance mechanism in more than half of relapsing patients. Preclinical models had predicted this mutation, and importantly, data suggest it may not confer resistance to all drugs in the same class.

These observations support the concept of sequential menin inhibitor therapy, where switching agents could help overcome resistance and extend clinical benefit.

Implications for Future Treatment Strategies

Collectively, the data presented at EHA 2026 highlight two important trends in hematologic malignancy research:

• Combination strategies designed to overcome pathway redundancy in diseases like MF
• Precision approaches that identify and adapt to resistance mechanisms in leukemia

While results remain preliminary, they contribute to a growing body of evidence supporting multi-targeted and adaptive treatment paradigms. Ongoing studies will be critical in confirming whether these early findings translate into durable clinical benefits for patients.