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Key Clinical Updates in Primary Myelofibrosis
The newer JAK2 inhibitor pacritinib is an option for patients with a platelet count less than 50,000/mcL (50 × 109/L).
RAS/CBL mutations predict resistance to ruxolitinib therapy.
Tefferi A. Am J Hematol. [PMID: 36680511]
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ESSENTIALS OF DIAGNOSIS
Striking splenomegaly.
Teardrop poikilocytosis on peripheral smear.
Leukoerythroblastic blood picture; giant abnormal platelets.
Initially hypercellular, then hypocellular bone marrow with reticulin or collagen fibrosis.
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GENERAL CONSIDERATIONS
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Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by clonal hematopoiesis that is often but not always accompanied by pathogenic variants of JAK2, CALR, or MPL genes; bone marrow fibrosis; anemia; splenomegaly; and a leukoerythroblastic peripheral blood picture with teardrop poikilocytosis. In response to bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes. According to the WHO and ICC classifications, “prefibrotic” primary myelofibrosis is distinguished from “overtly fibrotic” primary myelofibrosis; the former might mimic essential thrombocytosis in its presentation, and it is prognostically relevant to distinguish the two. The latter also can occur as a secondary process following the other myeloproliferative disorders (eg, polycythemia vera, essential thrombocytosis).
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A. Symptoms and Signs
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Primary myelofibrosis develops in adults over age 50 years and is usually insidious in onset. Patients most commonly present with fatigue due to anemia or with abdominal fullness related to splenomegaly. Uncommon presentations include bleeding and bone pain. On examination, splenomegaly is almost invariably present and is commonly massive. The liver is enlarged in more than 50% of cases.
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Later in the course of the disease, progressive bone marrow failure takes place as it becomes increasingly more fibrotic. Progressive thrombocytopenia leads to bleeding. The spleen continues to enlarge, which leads to early satiety. Painful episodes of splenic infarction may occur. The patient becomes cachectic and may experience severe bone pain, especially in the upper legs. Hematopoiesis in the liver leads to portal hypertension with ascites and esophageal varices, and occasionally myelopoiesis in the epidural space causes transverse myelitis.
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B. Laboratory Findings
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Patients are almost invariably anemic at presentation. The WBC is variable—either low, normal, or elevated—and may be increased to 50,000/mcL (50 × 109/L). The platelet count is variable. The peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the RBC line (eFigure 15–21). Nucleated RBCs are present, and the myeloid series is shifted, with immature forms including a small percentage of promyelocytes or myeloblasts. Platelet morphology may be bizarre, and giant degranulated platelet forms (megakaryocyte fragments) may be seen. The triad of teardrop poikilocytosis, leukoerythroblastic blood, and giant abnormal platelets is highly suggestive of myelofibrosis.
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