JAK2 Therapies Show Promise, and a Catch, for MPN

Managing myeloproliferative neoplasms (MPN) increasingly means managing more than the JAK2 mutation itself, according to research presented at the European Hematology Association 2026 Congress focused on ruxolitinib (RUX), the standard-of-care Janus kinase (JAK) inhibitor for myelofibrosis (MF) and polycythemia vera (PV).^1,2 Patients currently on JAK inhibitor therapy derive real benefits but have to face real trade-offs as well.

One team of investigators found that ruxolitinib may raise cholesterol, especially in patients who have PV, adding a cardiovascular wrinkle to a drug already known for metabolic-related adverse effects.¹ Another group found that adding the investigational BET inhibitor pelabresib (PELA) to ruxolitinib in difficult-to-treat MF produced deep, durable spleen responses and anemia improvements, filling a gap for patients whose disease has outgrown JAK inhibition alone.²

Ruxolitinib’s Cholesterol Surprise in PV¹

A team from Guy’s and St Thomas’ NHS Foundation Trust and King’s College London School of Cancer and Pharmaceutical Sciences set out to answer a question buried in earlier studies: Does ruxolitinib’s known association with weight gain and metabolic change translate into clinically meaningful cholesterol elevation? Using a retrospective single-center analysis of 400 patients initiated on ruxolitinib between 2009 and 2024, the researchers narrowed in on 97 patients with paired pre- and posttreatment lipid measurements.

The results were hard to ignore. Over a median interval of 8 months, mean total cholesterol rose by 0.65 mmol/L (95% CI, 0.40-0.90; P <.001), with 72% of patients showing an increase. Cholesterol levels above 5 mmol/L, the clinically significant threshold per European Society of Cardiology and European Society of Hypertension guidelines, jumped from 13.4% of patients before treatment to 35.9% post treatment. The effect, however, wasn’t uniform across MPN subtypes: Patients living with PV showed significantly higher posttreatment cholesterol than patients living with MF, and a greater share crossed the 5 mmol/L threshold (46% vs 30%; P = .028). PV was also linked to 96% higher odds of elevated low-density lipoprotein cholesterol (OR, 1.96; 95% CI, 1.04-3.82; P = .042).

The authors tie this to biology already in the literature: JAK2 inhibition may impair macrophage cholesterol efflux, a mechanism that could drive rising lipids independent of weight change. Notably, the shift didn’t correlate with age or gender, suggesting it may be tied to the drug’s mechanism. As the team writes in their conclusion, “Ruxolitinib was associated with a significant increase in total cholesterol in MPN,” and “given the intrinsically elevated [cardiovascular risk] in MPN, proactive lipid monitoring and cardiovascular risk optimization should be systematically integrated into long-term management.”

Pelabresib Delivers Durable Spleen and Symptom Relief in MF²

What happens when ruxolitinib alone stops being enough? This is the question a global team of investigators sought to answer. Ruxolitinib remains first-line therapy for MF, a chronic, progressive blood cancer. However, spleen and symptom responses “may be suboptimal or short-lived,” and treatment options have primarily encompassed switching to another JAK inhibitor with a similar mechanism, the authors explained.

Pelabresib, an oral BET inhibitor, is designed to work with JAK inhibition by targeting different inflammatory pathways. This analysis, from arm 2 of the open-label phase 2 MANIFEST study (NCT02158858), evaluated 87 patients with suboptimal response to ruxolitinib. Fifty-nine patients were transfusion-dependent (TD) and 28 were not, and all added pelabresib to their existing regimen. Median prior ruxolitinib duration exceeded 30 months, and median baseline spleen volume was 1860.5 cm³.

Among the overall 83 evaluable patients, 18.1% achieved a 35% spleen volume reduction at week 24, including 16.4% of the TD cohort and 21.4% of the non-TD cohort. Responses proved durable, too, with a median spleen response duration of 180.9 weeks. Anemia responses were also notable: 37.6% of the TD patients achieved transfusion independence at any point during treatment, and hemoglobin response was sustained through week 48.

The researchers concluded, “PELA added to RUX led to deep and durable spleen responses” and that the combination showed “disease modification potential with improvements in anemia and bone marrow pathology,” all with a safety profile consistent with each individual drug.

Looking to Future Treatment

Read side by side, these posters make a unified case: JAK inhibition is foundational to MPN care, but it’s not a finish line. Whether the next step is watching cholesterol or adding a second targeted agent, both studies argue for moving past a “set it and forget it” approach to ruxolitinib therapy.

References

1. Torre E, Robertson H, Gill T, et al. Phenotype-specific cholesterol elevation following ruxolitinib in MPN: enrichment in polycythaemia vera. Presented at: EHA 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Poster PS2007.
2. Kremyanskaya M, Harrison C, Gupta V, et al. Evaluation of pelabresib (PELA) as add-on therapy to Janus kinase inhibitor (JAKi) ruxolitinib (RUX) in myelofibrosis (MF) patients: results from arm 2 of the open-label, phase 2 MANIFEST study. Presented at: EHA 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Poster PF894.