Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis, leading to ineffective hematopoiesis, splenomegaly, and extramedullary hematopoiesis. Primary myelofibrosis (PMF) arises de novo, while secondary myelofibrosis can develop from polycythemia vera (PV) or essential thrombocythemia (ET). The disease course varies widely, from indolent to rapidly progressive, with some patients remaining asymptomatic for years and others experiencing debilitating symptoms. Pathogenesis is strongly associated with mutations in the JAK2, CALR, and MPL genes, which drive abnormal signaling in hematopoietic stem cells. The resulting clonal proliferation and cytokine release contribute to the hallmark features of MF, including fibrosis, anemia, and constitutional symptoms such as fatigue, weight loss, and night sweats. The disease has a poor prognosis in its advanced stages, with a median survival ranging from 2 to 11 years, depending on risk stratification.

The diagnosis of myelofibrosis requires a comprehensive approach, combining clinical, hematologic, cytogenetic, and histopathological assessments. Initial suspicion often arises from abnormal blood counts, with most patients presenting with normocytic anemia, and varying degrees of leukocytosis and thrombocytosis. Peripheral blood smears typically show leukoerythroblastosis, tear-drop-shaped red cells (dacrocytes), and circulating immature granulocytes. A bone marrow biopsy is essential for diagnosis, revealing characteristic features such as dense reticulin or collagen fibrosis, atypical megakaryocyte proliferation, and a reduction in hematopoietic cells. Genetic testing is crucial, as approximately 60% of PMF patients harbor a JAK2 mutation, 20-30% have CALR mutations, and 5-10% have MPL mutations. These mutations, along with cytogenetic abnormalities like del(13q) or del(20q), aid in diagnosis and prognostication. Additional tests may include serum lactate dehydrogenase (LDH), often elevated due to increased cell turnover, and splenic imaging (e.g., ultrasound or MRI) to assess splenomegaly, a common finding in MF.

Prognostication in MF is complex, requiring the integration of clinical, hematologic, and molecular factors. The International Prognostic Scoring System (IPSS) and its dynamic version (DIPSS) are widely used to stratify patients into risk categories based on five variables: age >65 years, hemoglobin <10 g/dL, leukocyte count >25 × 10^9/L, circulating blasts ≥1%, and presence of constitutional symptoms. The DIPSS-plus further incorporates transfusion dependency, platelet count <100 × 10^9/L, and unfavorable karyotype (e.g., complex karyotype, monosomy 7). Mutational analysis has refined risk assessment, with mutations in ASXL1, SRSF2, and EZH2 linked to poor outcomes. High-risk patients have a median survival of less than 3 years, while low-risk patients may live over a decade. Assessment of these factors is crucial for guiding treatment decisions, including the timing of more aggressive interventions like allogeneic stem cell transplantation.

The assessment of myelofibrosis extends beyond initial diagnosis to ongoing evaluation of disease progression and treatment response. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a validated tool for quantifying symptom burden, including fatigue, pain, and pruritus, which significantly impact quality of life. Regular monitoring of complete blood counts (CBC), along with LDH and other markers of cell turnover, is critical for tracking disease progression. Bone marrow biopsies may be repeated in certain clinical scenarios to assess fibrosis and clonal evolution, particularly when considering a change in therapeutic approach. Imaging studies, such as spleen ultrasound or MRI, are used to monitor splenomegaly and extramedullary hematopoiesis, both of which are key indicators of disease burden. The introduction of molecular monitoring, particularly for JAK2, CALR, and MPL mutations, offers additional insights into disease activity and treatment response, guiding the adjustment of therapeutic strategies.

Treatment of myelofibrosis is tailored to the patient’s risk category, symptom burden, and overall health status. Low-risk, asymptomatic patients may be managed with observation and supportive care, while those with significant symptoms or high-risk disease require more aggressive interventions. Ruxolitinib, a JAK1/2 inhibitor, is the first-line therapy for symptomatic splenomegaly and constitutional symptoms, improving quality of life and potentially extending survival. For anemia, treatments include erythropoiesis-stimulating agents, corticosteroids, androgens, or danazol, though their efficacy is often limited in advanced disease. Allogeneic stem cell transplantation remains the only curative option for myelofibrosis, recommended for younger patients with high-risk features, though it carries substantial risks of morbidity and mortality. For those ineligible for transplantation, investigational therapies, including other JAK inhibitors (e.g., fedratinib, momelotinib) and antifibrotic agents, are being explored in clinical trials. Symptomatic management, including transfusions, splenectomy, or radiation for refractory splenomegaly, may be considered on a case-by-case basis. Regular reassessment is essential to adapt treatment strategies as the disease evolves.