Primary Myelofibrosis (PMF)-The German ONKOPEDIA Guideline 2025

Myelofibrosis (MF) is a rare, clonal disorder of pluripotent hematopoietic stem and progenitor cells. It is characterized by abnormal proliferation of hematopoiesis, associated with pathologically increased fibrosis in the bone marrow, which is primarily caused by activation of the JAK2 signaling pathway. Myelofibrosis (MF) may occur de novo as primary myelofibrosis (PMF), or secondarily as a consequence of polycythemia vera (PV) or essential thrombocythemia (ET), termed post-PV-MF and post-ET-MF, respectively. The latter two are collectively referred to as secondary myelofibrosis. The most recent updates of the diagnostic criteria by the WHO and ICC were published in 2022. These revisions defined prefibrotic primary myelofibrosis (pre-PMF) as a distinct subentity alongside "classic" overtly fibrotic PMF and secondary myelofibrosis. A hallmark of pre-PMF is an initial isolated thrombocytosis, whereas in overt MF, anemia is frequently present already at diagnosis. Splenomegaly is also more commonly detected at diagnosis in overt fibrotic MF than in pre-PMF. The prognosis of MF is determined by patient age, the presence of constitutional symptoms, as well as hematologic and genetic parameters. Increasingly, cytogenetic and molecular genetic markers play a decisive role. The most common causes of death in MF include transformation to acute myeloid leukemia, infections, and cardiovascular complications. The only potentially curative treatment is allogeneic stem cell transplantation (alloSCT), which is generally indicated in transplant-eligible patients with unfavorable prognosis, that is, those classified as high- or very-high risk according to the MIPSS70+ v2.0. For symptomatic treatment of MF, a variety of therapeutic options are available. In recent years, oral therapy with the JAK1/2 inhibitor ruxolitinib has become the standard of care. Since 2021, the JAK2/FLT3 inhibitor fedratinib has also been approved in the EU (note: in Switzerland, fedratinib will no longer be available as of February 28, 2025, as Swissmedic did not extend its time-limited approval). Since 2024, the JAK1/2 and ACVR1/ALK2 inhibitor momelotinib has been approved for MF treatment in the EU (irrespective of risk category) and in Switzerland (restricted to intermediate- or high-risk disease) for patients with moderate or severe anemia and/or after prior treatment with ruxolitinib. Compared to the other two JAK inhibitors, momelotinib is particularly effective in patients with clinically symptomatic moderate to severe anemia. Results from studies investigating additional JAK inhibitors, combination therapies, and novel agents have also demonstrated significant efficacy and point toward future therapeutic developments, although these approaches are not yet available for routine clinical practice.