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Primary Myelofibrosis

By

Jane Liesveld

, MD, James P. Wilmot Cancer Institute, University of Rochester Medical Center

Medically Reviewed Jul 2022 | Modified Sep 2022
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Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis requires bone marrow aspirate and biopsy and exclusion of other conditions that can cause myelofibrosis (secondary myelofibrosis). Treatment is often supportive, but Janus kinase 2 (JAK2) inhibitors, such as ruxolitinib, fedratinib, or pacritnib, may decrease symptoms and stem cell transplantation may be curative.

Pathophysiology of Primary Myelofibrosis

Myelofibrosis is a reactive, reversible increase in bone marrow collagen often with extramedullary hematopoiesis (primarily in the spleen). Myelofibrosis may be

Primary myelofibrosis results from neoplastic transformation of a multipotent bone marrow stem cell. These primary myelofibrosis progeny cells stimulate bone marrow fibroblasts (which are not part of the neoplastic transformation) to secrete excessive collagen. The peak incidence of primary myelofibrosis is between 50 and 70 years and predominantly in males.

Mutations of the Janus kinase 2 (JAK2) gene are present in a high proportion of cases of primary myelofibrosis. JAK2 is a member of the class I type tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) receptors among other entities. Mutations of the thrombopoietin receptor gene (MPL) or the calreticulin (CALR) gene also may be the cause of primary myelofibrosis. However, there are rare cases of primary myelofibrosis in which none of these three mutations are present (triple negative primary myelofibrosis). Some of these patients have other uncommon MPL mutations, which can only be detected by next generation sequencing.

In primary myelofibrosis, nucleated red blood cells (normoblasts) and myelocytes are released into the circulation (leukoerythroblastosis) when there is extramedullary hematopoiesis (ie, non-marrow organs have taken over blood cell production because of the fibrosed marrow). The serum lactate dehydrogenase level is often elevated. Bone marrow failure eventually occurs, with consequent anemia and thrombocytopenia. Rapidly progressive, chemotherapy-incurable acute leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more develops in about 30% of patients.

Malignant myelofibrosis (sometimes called acute myelofibrosis), is a rare variant of myelofibrosis characterized by pancytopenia, myeloblastosis, and marrow fibrosis that has a more rapidly progressive downhill course and is generally due to a type of acute leukemia called acute megakaryoblastic leukemia.

Table

Symptoms and Signs of Primary Myelofibrosis

In many patients, myelofibrosis is asymptomatic. Other patients have anemia, splenomegaly, or, in later stages, general malaise, weight loss, fever, or splenic infarction. Hepatomegaly occurs in some patients. Lymphadenopathy is rare. Severe extramedullary hematopoiesis can disturb the function of organs in which it occurs, including the brain.

Diagnosis of Primary Myelofibrosis

  • Complete blood count (CBC) and peripheral blood smear

  • Bone marrow aspirate and biopsy

  • Testing for JAK2, CALR, and MPL mutations

Primary myelofibrosis should be suspected in patients with splenomegaly, splenic infarction, and anemia. If the disorder is suspected, CBC should be done and peripheral blood morphology and a bone marrow biopsy should be examined. If myelofibrosis is present on bone marrow aspirate and biopsy (as detected by reticulin staining or trichrome staining, indicating excess collagen and osteosclerosis), other disorders associated with myelofibrosis (see table Conditions Associated With Myelofibrosis Conditions Associated With Myelofibrosis Conditions Associated With Myelofibrosis ) should be excluded by appropriate clinical and laboratory evaluation.

The diagnosis of primary myelofibrosis is confirmed by detecting a mutation in JAK2, CALR, or MPL. In some cases, none of these mutations is expressed (triple-negative myelofibrosis). A broader next-generation sequencing panel may detect gene mutations associated with increased risk of leukemic transformation and may therefore be useful for prognosis.

Anemia is typically present and usually increases over time. Blood cell morphology is variable. Red blood cells (RBCs) are poikilocytic. Reticulocytosis and polychromatophilia may be present; teardrop-shaped RBCs (dacryocytes) are characteristic morphologic features. Nucleated RBCs and neutrophil precursors are typically present in peripheral blood. White blood cell counts are usually increased but are highly variable. In advanced stages, myeloblasts may be present, even in the absence of acute leukemia. Platelet counts initially may be high, normal, or decreased; however, thrombocytopenia tends to supervene as the disorder progresses.

Prognosis for Primary Myelofibrosis

Unfavorable prognostic markers include hemoglobin < 10 g/dL (< 100 g/L), a history of transfusions, leukocytosis, and a platelet count < 100,000/mcL (< 100,000 × 109/L). Patients in the least favorable risk group usually survive < 1 year, but those with low-risk disease have a median survival of 10 years. Several prognostic scoring systems are available to predict survival.

A number of useful risk stratification systems are available to aid prognosis and guide decisions to institute medical therapy or stem cell transplantation. The The Dynamic International Prognostic Scoring System (DIPSS) for Myelodysplastic Syndromes can be used to predict progression or survival as the disease evolves (1 Prognosis references Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis... read more ). Some scoring systems also incorporate cytogenetics and molecular markers (eg, DIPSS-Plus).

Validated symptom assessment tools (eg, Myelofibrosis Symptom Assessment Form) are also available for patients with myelofibrosis and can be useful to monitor therapeutic responses.

Patients with polycythemia vera or essential thrombocythemia with myelofibrosis have a better prognosis than those with primary myelofibrosis, and their outcome can be predicted by using the MYelofibrosis SECondary to PV and ET Prognostic Model (MYSEC-PM— 2 Prognosis references Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis... read more ).

Prognosis references

  • 1. Passamonti F, Cervantes F, Vannuchi AM, et al: Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood 115:1703–1709, 2010.

  • 2. Passamonti F, Giorgino T, Mora B, et al: A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia 31(12):2726–2731, 2017. doi: 10.1038/leu.2017.169

Treatment of Primary Myelofibrosis

  • Symptomatic therapy

  • Sometimes interferon

  • Sometimes ruxolitinib, fedratinib, or pacritinib

  • Sometimes allogeneic stem cell transplantation

Treatment is directed at symptoms and complications. Some patients can be observed without treatment.

In early primary myelofibrosis, pegylated interferon has been shown to reduce marrow fibrosis and spleen size and can be used for low-risk patients as defined by various prognostic scoring systems (1 Treatment reference Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis... read more ).

Currently, for advanced primary myelofibrosis, the nonspecific JAK pathway inhibitor ruxolitinib is the therapy of choice in patients with a platelet count > 50,000/mcL (50,000 × 109/L). Ruxolitinib is effective whether or not a JAK2 mutation or splenomegaly is present. The main adverse effects of ruxolitinib are anemia and thrombocytopenia. Care must be taken when stopping ruxolitinib because a withdrawal syndrome may occur, with significant worsening of symptoms in part due to splenic enlargement and a rebound in inflammatory cytokines. Low-dose corticosteroids may be used short term for symptom control. When splenomegaly is significant, ruxolitinib can precipitate tumor lysis syndrome.

Fedratinib, also a JAK-2 inhibitor, can be used when there is resistance or intolerance to ruxolitinib. Some patients who develop intolerance to ruxolitinib may be able to tolerate it again after a period off the drug.

A third JAK-2 inhibitor, pacritinib is available for patients whose platelets counts are too low to initiate ruxolitinib.

Androgens, erythropoietin, splenectomy, chemotherapy, thalidomide, lenalidomide, splenic embolization, and radiation therapy have been tried for palliation. Of these, low-dose thalidomide and prednisone can be effective in controlling splenomegaly, anemia, thrombocytopenia, and circulating blast cells. However, the other modalities are of limited effectiveness or have significant adverse effects. Splenectomy should be avoided if possible; splenic irradiation has only a temporary effect and can cause severe neutropenia and infection.

Among agents that are under investigation for treatment of myelofibrosis is luspatercept, an activin receptor ligand trap.

Treatment reference

Key Points

  • Myelofibrosis is excessive bone marrow fibrosis, often with loss of hematopoietic cells and consequent extramedullary hematopoiesis.

  • Myelofibrosis is often primary but may occur secondary to a number of hematologic, malignant, and nonmalignant disorders, including polycythemia vera and essential thrombocytosis.

  • Primary myelofibrosis is a clonal hematopoietic disorder and often involves JAK2, CALR, or MPL mutations.

  • Diagnose with blood count, examination of peripheral blood smear and bone marrow, and molecular testing for JAK2, MPL, and/or CALR mutations.

  • Some patients have an indolent course and do not require therapy immediately, but some patients have a rapidly progressive downhill course with short survival.

  • Ruxolitinib is the therapy of choice for control of symptoms; allogeneic stem cell transplantation is of benefit in selected cases.

Drugs Mentioned In This Article

Drug Name Select Trade
Jakafi, Opzelura
INREBIC
VONJO
Thalomid
Revlimid
Deltasone, Predone, RAYOS, Sterapred, Sterapred DS
REBLOZYL
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