Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm (MPN) originating from hematopoietic stem cells. It is characterized by the presence of nucleated red blood cells, immature granulocytes, and teardrop-shaped red blood cells in the peripheral blood, as well as bone marrow fibrosis and extramedullary hematopoiesis, which often result in hepatomegaly and splenomegaly. The median age at diagnosis is 65–70 years.
Pathogenesis
The underlying mechanisms of PMF are not fully understood. Early research identified the proliferation of type I, III, IV, and V collagen in the bone marrow of patients with PMF, with type III collagen predominating. Activation of the JAK2-STAT5 signaling pathway represents the main molecular basis of the disease. Additionally, approximately 80% of patients exhibit mutations in other genes, particularly those involved in epigenetic regulation and splicing factor encoding. Recent studies have highlighted the roles of mesenchymal stem cells, endothelial cells, monocytes, and T lymphocytes, which contribute to disease development by secreting profibrotic and proinflammatory cytokines.
Clinical Manifestations
Approximately 30% of patients are asymptomatic at the time of onset or experience nonspecific symptoms such as fatigue, constitutional symptoms (fever, diaphoresis, weight loss), and abdominal fullness due to splenomegaly. Severe cases may present with bone pain (especially in the lower extremities), fever, anemia, and bleeding. Splenomegaly is present in approximately 90% of patients, with hepatomegaly observed in 40–80% of cases. Extramedullary hematopoietic foci, sometimes accompanied by extensive fibrosis forming fibrotic hematopoietic extramedullary tumors, may occur in the adrenal glands, subcapsular kidney regions, lymph nodes, or other sites.
Laboratory and Other Examinations
Peripheral Blood Findings
The majority of patients present with normocytic, normochromic anemia. Peripheral blood smears may show nucleated red blood cells, anisopoikilocytosis of mature red blood cells, and the presence of teardrop-shaped red blood cells, which are diagnostically valuable. Leukocytosis with immature granulocytes is common, and thrombocytosis is observed in 1/3 of patients. Approximately 10% of cases exhibit pancytopenia.
Bone Marrow Findings
Bone marrow aspiration frequently results in a "dry tap." Bone marrow biopsy often reveals significant granulocytic hyperplasia, pronounced megakaryocytic proliferation with morphological abnormalities, and reduced erythroid proliferation. Reticulin fiber proliferation is identified with silver staining, while collagen fiber proliferation is visualized using H&E staining. PMF can be classified into four grades based on biopsy results.
Table 1 Grading of bone marrow fibrosis
Genetic Testing
JAK2 V617F mutations are found in 50–60% of cases, CALR mutations in 20–35%, and MPL mutations in 5–8%. Cases without these three driver mutations are classified as triple-negative PMF. Most PMF patients harbor at least one non-driver mutation, including ASXL1, IDH1/2, SRSF2, U2AF1, EZH2, SF3B1, and TP53.
Cytogenetics
The Philadelphia chromosome (Ph) is absent. Approximately 40% of patients exhibit abnormal karyotypes.
Biochemical Indicators
Hyperuricemia and elevated lactate dehydrogenase (LDH) levels are common. Increased neutrophil alkaline phosphatase activity is observed. Serum erythropoietin (EPO) levels are assessed to determine the suitability of EPO treatment for anemic patients.
Imaging Studies
Ultrasonography, CT, and MRI are utilized to evaluate hepatomegaly, splenomegaly, and extramedullary hematopoiesis. The spleen volume can be measured using CT and MRI.
Diagnosis and Differential Diagnosis
Diagnosis (2022 WHO Diagnostic Criteria)
The 2022 WHO classification divides PMF into two subtypes: prefibrotic myelofibrosis (pre-PMF) and overt myelofibrosis (overt-PMF). The diagnostic criteria for each subtype are as follows:
Pre-PMF Diagnosis
The diagnosis of pre-PMF requires meeting all three major criteria and at least one minor criterion.
Major Criteria:
- Bone marrow biopsy showing megakaryocytic proliferation with atypical features, without significant reticulin fiber increase (≤MF-1), age-adjusted increases in bone marrow cellularity with granulocytic predominance, and reduced erythropoiesis.
- No fulfillment of the diagnostic criteria for polycythemia vera (PV), BCR::ABL1-positive chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), or other myeloid malignancies.
- Presence of mutations in JAK2 V617F, CALR, or MPL, or absence of these mutations but with other clonal markers (e.g., ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1), or no evidence of secondary bone marrow fibrosis.
Minor Criteria (to be detected on at least two occasions):
- Anemia not attributable to other causes.
- White blood cell count ≥11 × 109/L.
- Palpable splenomegaly.
- Elevated serum lactate dehydrogenase (LDH).
Overt-PMF Diagnosis
The diagnosis of overt-PMF requires meeting all three major criteria and at least one minor criterion.
Major Criteria:
- Megakaryocytic proliferation and atypia, accompanied by reticulin and/or collagen fibrosis (MF-2 or MF-3).
- No fulfillment of the diagnostic criteria for PV, BCR::ABL1-positive CML, MDS, or other myeloid malignancies.
- Presence of mutations in JAK2 V617F, CALR, or MPL, or absence of these mutations but with other clonal markers, or no evidence of secondary bone marrow fibrosis.
Minor Criteria (to be detected on at least two occasions):
- Criteria 1–4 same as pre-PMF.
- Presence of nucleated red blood cells and immature granulocytes in peripheral blood.
Differential Diagnosis
PMF should be distinguished from other causes of splenomegaly. The differentiation between pre-PMF and essential thrombocythemia (ET) also warrants careful attention. Additionally, diseases such as chronic myelogenous leukemia (CML), lymphoma, multiple myeloma, and metastatic bone marrow involvement by malignant tumors may result in secondary bone marrow fibrosis and should be differentiated from PMF.
Treatment
The treatment strategy is tailored based on the patient’s prognostic grouping. Current therapeutic approaches primarily focus on managing clinical manifestations such as anemia, splenomegaly, and constitutional symptoms.
Supportive Care
Anemia and thrombocytopenia often require red blood cell or platelet transfusions. Long-term red cell transfusions warrant monitoring for iron overload, along with iron chelation therapy.
Anemia Management
Treatments that may elevate hemoglobin levels include androgen therapy (danazol or stanozolol), glucocorticoids, immunomodulators (thalidomide or lenalidomide), and erythropoiesis-stimulating agents (effective when EPO levels are <100 IU/L). Combinations of these therapies can be employed, with androgens also benefiting platelet counts.
Splenomegaly Management
In patients with marked leukocytosis or thrombocytosis, significant splenomegaly, but without severe bone marrow suppression, hydroxyurea or interferon can be used, although their effect on splenomegaly is limited.
JAK2 Inhibitors
Ruxolitinib, a non-selective JAK inhibitor, demonstrates superior efficacy in reducing splenomegaly compared to hydroxyurea or interferon. It also reduces pro-inflammatory cytokine release and represents the first-line treatment for symptomatic splenomegaly or severe constitutional symptoms in intermediate- to high-risk PMF patients. Initial dosing of ruxolitinib is adjusted based on baseline platelet counts.
Splenectomy
Indications include:
- Symptomatic portal hypertension (e.g., variceal bleeding or ascites).
- Severe splenomegaly with refractory pain or associated with pronounced cachexia.
- Transfusion-dependent anemia.
Splenectomy may lead to rapid liver enlargement after procedure, necessitating careful assessment of its risks.
Radiotherapy
Low-dose radiotherapy can be considered for extramedullary hematopoiesis-related compressive symptoms.
Hematopoietic Stem Cell Transplantation (HSCT)
HSCT remains the only curative option for PMF but is associated with significant treatment-related mortality. It is generally considered for patients with an expected median survival of less than five years who meet transplantation criteria, after careful evaluation of HSCT-associated risks and complications.
Prognosis
Prognosis is evaluated using the International Prognostic Scoring System (IPSS) and the Dynamic International Prognostic Scoring System (DIPSS).