Primary Myelofibrosis (PMF)

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

• Primary (more common)

• Secondary to a number of hematologic, malignant, and nonmalignant conditions (see table Conditions Associated With Myelofibrosis)

Primary myelofibrosis results from neoplastic transformation of a pluripotent hematopoietic stem cell. The primary myelofibrosis progeny cells stimulate bone marrow fibroblasts (which are not part of the neoplastic transformation) to produce excessive collagen. The peak incidence of primary myelofibrosis is between 50 and 70 years, and it occurs 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 3 mutations are present (triple-negative primary myelofibrosis).

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 marrow fibrosis ). The serum lactate dehydrogenase level is often elevated. Bone marrow failure eventually occurs, with consequent anemia and thrombocytopenia. Rapidly progressive, chemotherapy-incurable acute leukemia develops in approximately 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.

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 any organ in which it occurs, including the brain.

• Complete blood count (CBC) and peripheral blood smear

• Bone marrow aspirate and biopsy

• Testing for JAK2, CALR, and MPL mutations

• Sometimes next generation sequencing with a myeloid-directed panel

Primary myelofibrosis should be suspected in patients with some combination of splenomegaly, splenic infarction, and unexplained anemia. If the disorder is suspected, a CBC should be performed and peripheral blood morphology and a bone marrow biopsy should be examined. If myelofibrosis is present on a bone marrow biopsy (as detected by reticulin staining or trichrome staining, indicating excess collagen), other disorders associated with myelofibrosis (see table 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 are 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 a characteristic morphologic feature. Nucleated RBCs and neutrophil precursors are typically present in peripheral blood. White blood cell counts are usually increased but can be 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.

• Symptomatic therapy

• Sometimes peginterferon

• Sometimes ruxolitinib, fedratinib, pacritinib, or momelotinib Sometimes ruxolitinib, fedratinib, pacritinib, or momelotinib

• Sometimes allogeneic stem cell transplantation

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

In early primary myelofibrosis, peginterferon alfa-2a 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 (In early primary myelofibrosis, peginterferon alfa-2a 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, 2).

For symptomatic primary myelofibrosis in need of treatment, the nonspecific JAK pathway inhibitor, ruxolitinib, is the therapy of choice in patients with a platelet count > 50,000 platelets/mcL (50 For symptomatic primary myelofibrosis in need of treatment, the nonspecific JAK pathway inhibitor, ruxolitinib, is the therapy of choice in patients with a platelet count > 50,000 platelets/mcL (50× 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 when administration is stopped abruptly a withdrawal syndrome may occur, with significant worsening of symptoms in part due to splenic enlargement and a rebound in inflammatory cytokines. Low-dose glucocorticoids may be used short term for disease symptom control. When splenomegaly is significant, ruxolitinib can precipitate tumor lysis syndrome, and allopurinol should be used to prevent this.mutation or splenomegaly is present. The main adverse effects of ruxolitinib are anemia and thrombocytopenia. Care must be taken when stopping ruxolitinib because when administration is stopped abruptly a withdrawal syndrome may occur, with significant worsening of symptoms in part due to splenic enlargement and a rebound in inflammatory cytokines. Low-dose glucocorticoids may be used short term for disease symptom control. When splenomegaly is significant, ruxolitinib can precipitate tumor lysis syndrome, and allopurinol should be used to prevent this.

Fedratinib, also a JAK 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 medication. Fedratinib is associated with rare incidence of Wernicke-like encephalopathy, so thiamine levels must be maintained during its use. Fedratinib, also a JAK 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 medication. Fedratinib is associated with rare incidence of Wernicke-like encephalopathy, so thiamine levels must be maintained during its use.

Another JAK2 inhibitor, pacritinib is available for patients whose platelet counts are too low to initiate ruxolitinib, generally < 50,000 platelets/mcL (< 50 Another JAK2 inhibitor, pacritinib is available for patients whose platelet counts are too low to initiate ruxolitinib, generally < 50,000 platelets/mcL (< 50× 10⁹/L).

Momelotinib is both a JAK2 inhibitor and an inhibitor of activin A receptor type 1 (ACVR1) which may be protective against anemia (Momelotinib is both a JAK2 inhibitor and an inhibitor of activin A receptor type 1 (ACVR1) which may be protective against anemia (3).

For patients with advanced disease, allogeneic stem cell transplantation may be beneficial and is the only potentially durable treatment (4). Nonmyeloablative allogeneic stem cell transplantation has been successfully used in older patients. In patients who are eligible for stem cell transplantation, treatment is directed toward survival prolongation and mitigation of the fibrosis. Some of these patients may benefit from JAK2 inhibitors prior to stem cell transplantation to reduce symptoms and spleen size.

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. Treatment of anemia is often challenging in myelofibrosis, and in addition to transfusions, erythropoietin and sometimes danazol can be helpful.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. Treatment of anemia is often challenging in myelofibrosis, and in addition to transfusions, erythropoietin and sometimes danazol can be helpful.

Among agents that are under investigation for treatment of myelofibrosis is luspatercept, an activin receptor ligand trap for treatment of anemia. Many other agents are being evaluated singly or in combination with JAK2 inhibitors such as anti-Bcl-xL compounds, phosphatidylinositol-3-kinase inhibitors, and BET (bromodomain and extraterminal motif protein) inhibitors such as pelabresib (Among agents that are under investigation for treatment of myelofibrosis is luspatercept, an activin receptor ligand trap for treatment of anemia. Many other agents are being evaluated singly or in combination with JAK2 inhibitors such as anti-Bcl-xL compounds, phosphatidylinositol-3-kinase inhibitors, and BET (bromodomain and extraterminal motif protein) inhibitors such as pelabresib (5). New JAK inhibitors are also being tested as first-line therapies or in patients who progress on or do not tolerate currently available JAK2 inhibitors.

The median survival in primary myelofibrosis is 5 years from onset, but variation is wide; some patients have a rapidly progressing disorder, including development of acute myeloid leukemia, with short survival, but most have a more indolent course. Only allogeneic stem cell transplantation is curative.

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

A number of useful risk stratification systems are available to aid prognosis and guide decisions to institute medical therapy or stem cell transplantation. The Dynamic International Prognostic Scoring System (DIPSS) for Primary Myelofibrosis can be used to predict progression or survival as the disease evolves (1). Some scoring systems, such as the GIPSS (genetically inspired prognostic scoring system [2]) or the MIPSS70+ (mutation and karyotype-enhanced international prognostic scoring system [3]), also incorporate cytogenetics and molecular markers. These can be accessed on line for calculation of risk in individual patients (4).

Clinical Calculators

Genetically Inspired International Prognostic Scoring System (GIPSS) for Primary Myelofibrosis in Adults

Validated symptom assessment tools (eg, Myelofibrosis Symptom Assessment Form) are also available for patients with myelofibrosis and can be useful to monitor therapeutic responses (5).

Patients with polycythemia vera or essential thrombocythemia with myelofibrosis usually have a much better prognosis than those with primary myelofibrosis, and their outcome can be predicted by using the MYelofibrosis SECondary to polycythemia vera and essential thrombocythemia Prognostic Model (MYSEC-PM) (6).