The American Society of Hematology (ASH) has published 2026 guidelines for managing adults with myelofibrosis. They contain 10 conditional recommendations. Several of them advise against reflexive treatment: JAK inhibitors are not recommended for asymptomatic higher-risk disease, and pegylated interferon, routine pre-transplant JAK inhibition and iron chelation are not recommended as routine care. Others advise earlier action, with extended molecular testing at diagnosis and early transplant consultation in higher-risk patients who are responding to JAK inhibitors.
Developed by Brady Stein and colleagues, the guidelines cover molecular testing, interferon, JAK inhibitor therapy, anemia management, allogeneic hematopoietic cell transplantation, aspirin and iron chelation. They apply to primary myelofibrosis, including prefibrotic disease where specified, and to myelofibrosis evolving from polycythemia vera or essential thrombocythemia. A multidisciplinary panel used the GRADE methodology and systematic evidence reviews of studies published through January 31, 2025.
Extended Molecular Testing
ASH suggests extended molecular testing for all patients, beyond the conventional JAK2, CALR and MPL driver mutations. The recommendation draws on 15 studies of 5,104 patients and has moderate certainty of evidence.
Mutations in ASXL1, EZH2, SRSF2, IDH1/2 and U2AF1 Q157 add prognostic information beyond clinical variables, and TP53 and RAS pathway mutations may mark particularly adverse biology. These findings underlie molecularly informed models such as MIPSS70 and MIPSS70-plus, which combine mutation profiles with clinical and cytogenetic features. In one analysis reviewed by the panel, 46% of patients classified as high risk by MIPSS70 had previously been assigned to lower-risk categories by IPSS.
That reclassification can change transplant evaluation, especially in patients whose presentation looks indolent. ASH recommends testing at diagnosis and suggests repeating it at major decision points: progression, treatment failure and pre-transplant evaluation.
Pegylated Interferon in Prefibrotic Disease
ASH suggests against routine pegylated interferon in prefibrotic myelofibrosis when there is no indication for cytoreduction. Interferon has attracted interest as a disease-modifying therapy in early myeloproliferative neoplasms, but studies have not established that treating asymptomatic prefibrotic disease prevents progression to overt myelofibrosis or improves survival. The recommendation does not exclude interferon in patients who need cytoreduction for significant leukocytosis, thrombocytosis, thrombotic risk or symptomatic splenomegaly.
Higher-Risk Disease Without Symptoms
ASH suggests against starting a JAK inhibitor solely because of higher-risk classification in patients with overt myelofibrosis without symptomatic splenomegaly or other disease-related symptoms. The evidence review identified two small, single-arm studies involving 19 patients without splenomegaly who received ruxolitinib. The phase 3 Re-THINK trial tested ruxolitinib in patients with high molecular risk but limited clinical manifestations. It enrolled 49 patients before being terminated because of poor accrual, and no progression-free or overall survival analysis was performed.
ASH emphasizes regular, structured symptom assessment during observation because treatment indications may develop over time. Higher-risk patients may also benefit from early transplant consultation, even when immediate JAK inhibition is unnecessary.
Symptomatic Lower-Risk Disease
For lower-risk overt myelofibrosis with symptomatic splenomegaly or disease-related symptoms, ASH suggests JAK inhibitor therapy. Seven observational studies, five retrospective and two prospective, evaluated ruxolitinib in lower-risk populations and reported improvements in spleen size and symptom burden. A reduction of at least 50% in symptom burden on the Myeloproliferative Neoplasm Symptom Assessment Form was reported in approximately 21% to 80% of patients.
The evidence primarily concerns ruxolitinib, with limited data for other JAK inhibitors in this population. Treatment selection should account for symptom burden, baseline blood counts and the potential for treatment-associated cytopenias.
Anemia and Initial Treatment
Anemia can result from the disease, treatment-associated myelosuppression or both, and may limit therapies that control spleen size and symptoms. When disease-related anemia is the main reason to start treatment, ASH suggests momelotinib or pacritinib, or non-JAK inhibitor anemia-directed treatment.
Momelotinib improved transfusion outcomes in randomized studies and is relevant when anemia coexists with a need for spleen or symptom control. Pacritinib is an option particularly for patients with concurrent thrombocytopenia, and its evidence base includes studies enrolling patients with low platelet counts. ASH considers both agents particularly relevant for transfusion-dependent patients because some achieve transfusion independence.
For patients who are not transfusion-dependent, anemia-directed options include erythropoiesis-stimulating agents in eligible patients, luspatercept and danazol. Treatment selection depends on anemia severity, transfusion requirements and the presence of other disease manifestations requiring control.
Anemia on a JAK Inhibitor
ASH separates two situations. When anemia prevents adequate dosing for spleen and symptom control, the panel suggests switching to momelotinib or pacritinib. When the current JAK inhibitor still provides adequate control, ASH favors continuing treatment while managing anemia with supportive or anemia-directed therapies.
Timing helps distinguish the cause. Ruxolitinib-associated anemia commonly reaches its nadir about 8-12 weeks after starting and may then stabilize or improve. Anemia that develops later, especially with worsening counts or other clinical changes, raises concern for disease progression. The guideline also notes that ruxolitinib-induced anemia does not carry the adverse prognostic significance of anemia due to myelofibrosis itself.
Early Transplant Referral
Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for myelofibrosis. ASH suggests early transplant consultation for higher-risk patients who are responding to a JAK inhibitor, instead of waiting for treatment failure.
Waiting for failure may leave patients with worse performance status, deeper cytopenias or progressive disease that complicates transplantation. ASH gives particular priority to patients with adverse molecular or cytogenetic features, even when symptoms and splenomegaly are well controlled.
Early referral provides time for donor identification, transplant risk assessment and discussion of patient preferences. It does not mean every higher-risk patient should proceed immediately to transplantation. The decision remains individualized.
JAK Inhibition Before Transplant
ASH suggests against routinely starting JAK inhibitors before transplantation in patients who have not previously received them, unless marked splenomegaly or disease-related symptoms justify treatment. Three non-randomized studies informed the recommendation. The evidence did not establish a consistent benefit from routine pre-transplant JAK inhibition for transplant-related mortality, engraftment or graft-versus-host disease.
Patients with marked splenomegaly or impaired functional status may benefit from treatment before conditioning. Retrospective European transplant data suggested better event-free survival in patients transplanted while maintaining a response to ruxolitinib than in those who never responded or had lost their response. The guideline therefore supports pre-transplant JAK inhibition when there is a clinical indication.
Aspirin for Thrombosis Prevention
ASH suggests low-dose aspirin for primary thrombosis prevention in JAK2 V617F-positive myelofibrosis without contraindications. For other patients, treatment should be individualized by subtype, age, cardiovascular risk factors, platelet count and bleeding history.
The recommendation draws on evidence from related myeloproliferative neoplasms and observational data, as direct aspirin studies in myelofibrosis were not available. Thrombocytopenia, acquired von Willebrand disease and previous bleeding are important considerations when assessing the balance.
Iron Chelation
ASH suggests against routine iron chelation in overt myelofibrosis with transfusional iron overload. Four non-randomized studies were reviewed, including reports of improved anemia or survival among patients receiving chelation. The available findings were insufficient to establish a clinical benefit that would support routine use.
Patients preparing for transplantation may need separate consideration because iron overload could affect transplant-related complications.
Unresolved Questions
Several questions remain open for future studies. These include whether treatment guided by specific mutation profiles improves outcomes, whether JAK inhibitors can delay progression in asymptomatic higher-risk patients and whether interferon can modify the course of prefibrotic disease.
The optimal sequence of JAK inhibitors after treatment failure remains an area for active research. For higher-risk patients responding to JAK inhibitors, further evidence is needed to determine the best timing of transplantation.
