Primary Myelofibrosis 

Updated: Jan 30, 2017
Author: Asheesh Lal, MBBS, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Primary myelofibrosis is a clonal disorder arising from the neoplastic transformation of early hematopoietic stem cells.[1, 2, 3, 4] Older terms for this disorder include agnogenic myeloid metaplasia with myelofibrosis and chronic idiopathic myelofibrosis.[5] Primary myelofibrosis is categorized as a chronic myeloproliferative disorder, along with chronic myelogenous leukemia (CML), polycythemia vera, and essential thrombocytosis. (See Etiology.)[6]

The disorder is characterized by the following (see Workup):

  • Anemia

  • Bone marrow fibrosis (myelofibrosis)

  • Extramedullary hematopoiesis

  • Leukoerythroblastosis and teardrop-shaped red blood cells (RBCs) in peripheral blood (see the image below)

  • Hepatosplenomegaly

    Peripheral smear from a patient with agnogenic mye Peripheral smear from a patient with agnogenic myeloid metaplasia. This image shows the presence of teardrop red blood cells (RBCs) and a leukoerythroblastic picture with the presence of nucleated RBC precursors and immature myeloid cells. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.

Treatment for primary myelofibrosis is tailored to disease severity. Observation alone may be appropriate for low-risk, asymptomatic disease. Mild cases may require only supportive therapy. Higher-risk disease may respond to ruxolitinib. Splenomegaly may be an indication for splenectomy. Finally, allogeneic stem cell transplantation is a potentially curative. See Treatment and Medication.

Complications

Portal hypertension occurs in approximately 7% of patients with primary myelofibrosis and may be related to increased portal flow resulting from marked splenomegaly and to intrahepatic obstruction resulting from thrombotic obliteration of small portal veins. This may result in variceal bleeding or ascites. Hepatic or portal vein thrombosis may occur. Symptomatic portal hypertension is managed by splenectomy, with or without the creation of a portosystemic shunt. (See Presentation, Workup, and Treatment.)

Splenic infarction may occur and results in an acute or subacute onset of severe pain in the left upper quadrant that may be associated with nausea, fever, and referred left shoulder discomfort. The episode is usually self-limited and may last several days. Treat patients with hydration and opiate analgesics. Individuals with refractory cases of primary myelofibrosis may require splenectomy or splenic irradiation. (See Presentation and Treatment.)

Extramedullary hematopoiesis may involve any organ, and symptoms depend on the organ or site of involvement. It may result in gastrointestinal (GI) tract bleeding, spinal cord compression, seizures, hemoptysis, and/or effusions. These are easily controlled with low-dose radiation. (See Treatment.)

Patients with primary myelofibrosis are also prone to developing infectious complications because of defects in humoral immunity.

Osteosclerosis, hypertrophic osteoarthropathy, and periostitis may occur, resulting in significant pain and discomfort. This may require the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics. Gout or urate stones may develop as a result of uric acid overproduction. Allopurinol should be used to keep uric acid in the reference range.

For discussion of myelofibrosis in children, see Pediatric Myelofibrosis. For patient education information, see the Cancer Center, as well as Anemia.

Pathophysiology

In patients with primary myelofibrosis, the hematopoietic system is most affected. Other organ systems may be involved via extramedullary hematopoiesis. (See the image below.)

Extramedullary hematopoiesis in the spleen of a pa Extramedullary hematopoiesis in the spleen of a patient with agnogenic myeloid metaplasia. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.

Clonality studies in patients with primary myelofibrosis demonstrate that myeloid cells arise from clonal stem cells; however, bone marrow fibroblasts and, sometimes, T cells are polyclonal. The cause of the excessive marrow fibrosis observed in primary myelofibrosis remains unclear.

Platelets, megakaryocytes, and monocytes are thought to secrete several cytokines, such as transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), interleukin 1 (IL-1), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), which may result in fibroblast formation and extracellular matrix proliferation. In addition, endothelial proliferation and growth of capillary blood vessels in the bone marrow are observed and may be a result of TGF-β and bFGF production.

Neoangiogenesis is a hallmark feature of chronic myeloproliferative disorders. Approximately 70% of patients with primary myelofibrosis have substantial increases in bone marrow microvessel density. Neoangiogenesis in primary myelofibrosis is noted in medullary and extramedullary hematopoiesis. Increased serum vascular endothelial growth factor levels have been postulated as the underlying mechanism for increased angiogenesis.

Etiology

Approximately 50-60% of patients with primary myelofibrosis have a gain-of-function mutation in the Janus kinase 2 (JAK2) gene, the JAK2 V617F mutation, which leads to increased cytokine responsiveness of myeloid cells. Another 5-10% of patients somatic mutations of JAK2 exon 12 or activating mutations of the thrombopoietin receptor gene MPL. In two separate studies, Klampfl et al and Nangalia et al found that mutations in the gene encoding calreticulin (CALR) were present in the majority of patients who lacked mutations in JAK2 or MPL.[7, 8]  Mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 have been found in <5% of patients.[9]

No specific risk factors can be identified in most patients with primary myelofibrosis. However, exposure to radiation, Thorotrast contrast agents, and industrial solvents (eg, benzene, toluene) have been associated with an increased risk.[10, 11, 12, 13]

Epidemiology

Primary myelofibrosis is an uncommon disease, with an annual incidence of approximately 0.5-1.5 cases per 100,000 individuals in the United States. The worldwide incidence of the disorder is unknown.

Race-, sex-, and age-related demographics

Primary myelofibrosis appears to be more common in white people than in individuals of other races. In addition, an increased prevalence rate of the disorder has been noted in Ashkenazi Jews.

A slight male preponderance appears to exist for primary myelofibrosis; however, in younger children, girls are affected twice as frequently as boys.

Primary myelofibrosis characteristically occurs in individuals over age 50 years, with the median age at diagnosis being approximately 65 years. However, the disease has been reported in persons in all phases of life, from neonates to octogenarians.

Approximately 22% of affected patients are younger than 56 years. Primary myelofibrosis in children usually occurs in the first 3 years of life.

Prognosis

The median length of survival for patients with primary myelofibrosis is 3.5-5.5 years. The 5-year survival rate is about half of that expected for age- and sex-matched controls. Fewer than 20% of patients are expected to be alive at 10 years.[14] The common causes of death in patients with primary myelofibrosis are infections, hemorrhage, cardiac failure, postsplenectomy mortality, and transformation into acute leukemia. Leukemic transformation occurs in approximately 20% of patients with primary myelofibrosis within the first 10 years.

Advanced age and anemia are associated with shorter survival. Renal failure, hepatic failure, and thrombosis have also been reported as causes of death.

Other poor prognostic factors include the following:

  • Hypercatabolic symptoms

  • Leukocytosis (leukocyte count of 10,000-30,000/μL)

  • Leukopenia

  • Circulating blasts

  • Increased numbers of granulocyte precursors

  • Thrombocytopenia (platelet count of <100,000/μL)

  • Karyotype abnormalities

Bone marrow vascularity is significantly increased in patients with primary myelofibrosis. Increased bone marrow microvascular density has also been reported in approximately 70% of patients with primary myelofibrosis, and it is an independent poor prognostic factor for survival.

A study of 570 patients with primary myelofibrosis found that prognostic significance exists for carriage of mutations in CALR (favorable) and ASXL1 (unfavorable). Patients who were CALR + ASXL1 - had the longest survival (median 10.4 years), whereas those who were CALR -ASXL1 + the shortest survival (median 2.3 years). Patients who were either CALR + ASXL1 + or CALR -ASXL1 - had similar rates of survival (median 5.8 years). The prognostic model was independent of the dynamic international prognostic scoring system (DIPSS; see below).[15]

Rozovski and colleagues developed a prognostic model for primary myelofibrosis consisting of four elements: age and mutations in the Janus kinase 2 (JAK2), CALR, and myeloproliferative leukemia virus (MPL) genes. By itself, the JAK2V617F allele burden proved to have prognostic significance: median overall survival (OS) was 80 months in patients with a JAK2V617F allele burden of 50% or over, versus 50 months in those with a JAK2V617F allele burden of less than 50% (P=0.01).[16]

The best prognosis, with a median survival of 126 months, was seen in patients aged 65 years or under who had a low JAK2V617F allele burden and CALR and MPL mutations. The worst was in patients older than 65 years with a low JAK2V617F allele burden or no JAK2, CALR, or MPL mutations (“triple negative”) who had a median survival of only 35 months. Intermediate survival duration occurred in patients with one risk factor.[16]

Scoring systems

A simple scoring system to determine the prognosis in primary myelofibrosis has been proposed.[17] This system uses two adverse prognostic factors: a hemoglobin value of less than 10 g/dL and a total white blood cell (WBC) count of less than 4000/μL or greater than 30,000/μL. Patients with no risk factors are at low risk, those with both the risk factors are at high risk, and those with a single risk factor are at intermediate risk. Median survival times for low-risk groups are 93 months; intermediate-risk groups, 26 months; and high-risk groups, 13 months.

Low-risk patients with an abnormal karyotype have a worse outcome than do those with a normal karyotype (median survival, 50 mo vs 112 mo). Leukocytosis (>30,000/μL) and abnormal karyotype have reportedly been associated with increased risk of transformation to acute myelogenous leukemia (AML).

The Dynamic International Prognostic Scoring System–plus (DIPSS-plus) for primary myelofibrosis uses the following eight adverse factors to predict survival[18] :

  • Age older than 65 years

  • Hemoglobin level lower than 10 g/dL

  • Leukocyte count higher than 25 × 109/L

  • Platelet count lower than 100 × 109 /L

  • Circulating blasts of 1% or more

  • Constitutional symptoms

  • Red cell transfusion dependency

  • Unfavorable karyotype (ie, complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), 5/5q-, 12p-, or 11q23 rearrangement)

DIPSS plus classifications and median survival times are as follows:

  • Low risk (0 adverse points): 15.4 years
  • Intermediate-1 risk (1 adverse point): 6.5 years
  • Intermediate-2 risk (2-3 adverse points): 2.9 years
  • High risk (4-6 adverse points): 1.3 years
 

Presentation

History

One fourth of patients with primary myelofibrosis are asymptomatic, and the diagnosis is made as a result of detecting splenomegaly or checking blood cell counts for an unrelated cause. Symptoms may occur as a result of anemia, splenomegaly, hypermetabolic states, extramedullary hematopoiesis, bleeding, bone changes, portal hypertension, and immune abnormalities.

Anemia may occur as a result of ineffective erythropoiesis, erythroid hypoplasia, and hypersplenism. Anemia may cause easy fatigability, weakness, dyspnea, and palpitations.

Splenomegaly may result in early satiety and left upper quadrant discomfort. Splenic infarcts, perisplenitis, or subcapsular hematoma may occur, causing severe left upper quadrant or left shoulder pain. Occasionally, patients may have diarrhea related to pressure on the colon.

A hypermetabolic state occurs and can result in weight loss, night sweats, and low-grade fever. Gout and urate kidney stones may develop.

Bleeding is observed in one fourth of patients with primary myelofibrosis and varies in severity from insignificant cutaneous petechiae to severe, life-threatening GI tract bleeding. Platelet dysfunction, acquired factor V deficiency, thrombocytopenia, disseminated intravascular coagulation (DIC), esophageal varices, and peptic ulcer disease may occur, contributing to bleeding.

Extramedullary hematopoiesis may cause symptoms, depending on the organ or site of involvement (see the image below). The condition may result in GI tract hemorrhage, spinal cord compression, focal seizures, symptoms related to brain tumors, ascites, hematuria, pericardial effusion, pleural effusion, hemoptysis, and respiratory failure.

Extramedullary hematopoiesis in the spleen of a pa Extramedullary hematopoiesis in the spleen of a patient with agnogenic myeloid metaplasia. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.

Portal hypertension may occur as a result of markedly increased splenoportal blood flow and decreased hepatic vascular compliance. Ascites, esophageal and gastric varices, GI tract bleeding, and hepatic encephalopathy may occur. Hepatic or portal vein thrombosis may also arise as complications.

Patients with primary myelofibrosis develop osteosclerosis. This may cause severe joint and bone pain.

One half of patients with primary myelofibrosis have abnormalities of humoral immunity. A variety of autoantibodies and circulating immune complexes may be detected, and amyloidosis may develop. Infections, commonly pneumonia, may occur as a result of immune deficiency.

Physical Examination

Splenomegaly is the most common finding in patients with primary myelofibrosis, and it is present in approximately 90% of patients. Spleen size may vary from barely palpable to massive (observed in 35% of patients).

Hepatomegaly is found in 60-70% of patients with primary myelofibrosis, and pallor is observed in 60% of patients. Other physical findings include :

  • Petechiae and ecchymosis (20%)
  • Lymphadenopathy (10-20%)
  • Signs of portal hypertension (10-18%)
  • Gout (6%)
 

DDx

Diagnostic Considerations

Diagnose primary myelofibrosis with caution in patients with another malignancy. The bone marrow involvement in carcinomas or lymphomas may be associated with marrow fibrosis. In these situations, the fibrosis reverses after effective treatment of the underlying disease. Similarly, marrow fibrosis may result in cases of granulomatous involvement of the bone marrow, as in histoplasmosis and tuberculosis.

Performing testing for bcr:abl gene rearrangements is important to exclude chronic myelogenous leukemia. JAK2V617F mutation can be detected in approximately 50–60% of patients with primary myelofibrosis.[19, 20, 21]

Differential Diagnoses

 

Workup

Complete Blood Count

A complete blood count (CBC) panel with careful examination of the peripheral smear is essential in patients thought to have primary myelofibrosis. Peripheral blood reveals leukoerythroblastosis with teardrop poikilocytosis, as depicted in the image below. Large platelets and megakaryocyte fragments may be observed.

Peripheral smear from a patient with agnogenic mye Peripheral smear from a patient with agnogenic myeloid metaplasia. This image shows the presence of teardrop red blood cells (RBCs) and a leukoerythroblastic picture with the presence of nucleated RBC precursors and immature myeloid cells. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.

Anemia

Anemia is present in most patients with primary myelofibrosis, with more than 60% having a hemoglobin concentration of less than 10 g/dL. Causes of anemia include hemodilution, ineffective erythropoiesis, and shortened red blood cell (RBC) survival. Approximately 15% of patients also experience a major hemolytic episode during the course of the illness. This may result from an erythrocyte defect similar to that observed in paroxysmal nocturnal hemoglobinuria or from antibodies to RBCs. Anemia resulting from blood loss or folate deficiency (because of increased consumption) may also occur.

Leukopenia and leukocytosis

Leukopenia is observed in up to one fourth of patients with primary myelofibrosis, whereas leukocytosis may be observed in one third. A small number of blasts and Pelger-Huet cells are observed.

Thrombocytosis and DIC

Thrombocytosis is more common than thrombocytopenia. Disseminated intravascular coagulation (DIC) is observed in 15% of patients. The condition is usually clinically silent, but changes in the form of decreased platelets, decreased clotting factors, and increased fibrin degradation products may be observed. Such changes may result in excessive bleeding at the time of surgery. Obtaining a preoperative DIC panel may therefore be prudent.

Imaging Studies

Skeletal radiographs show increased bone density and a prominence of bony trabeculae in persons with primary myelofibrosis. Increased bone density may be patchy, resulting in a mottled appearance.

Magnetic resonance imaging (MRI) may help the clinician to assess the severity and progression primary myelofibrosis. Marrow patterns observed on an MRI examination of the proximal femur appear to correlate with clinical severity. Liver and splenic enlargement is observed on ultrasonograms and computed tomography (CT) scans.

Genetic Testing

Cytogenetic studies of bone marrow are helpful in excluding chronic myelogenous leukemia (CML), myelodysplastic syndrome, or other chronic myeloid disorders. However, these studies may be difficult to obtain due to "dry tap" on bone marrow aspirates in over 50% of patients with primary myelofibrosis. Fluorescent in situ hybridization (FISH) studies or polymerase chain reaction (PCR) assay testing for bcr:abl may be helpful in excluding CML (this may also be performed on peripheral blood). FISH studies for abnormalities associated with myelodysplastic syndromes, such as del 7, 7q-, and 5q-, may also be helpful.

Procedures and Histologic Findings

Obtaining bone marrow aspirate and biopsy specimens is important to help establish the diagnosis of primary myelofibrosis. This is usually performed over the posterior iliac crest, using specialized needles. Biopsy specimens should not be obtained from the sternum; sternal aspirates are typically not useful because of the high frequency of dry taps and the inability to obtain a biopsy from this site.

Histology

Bone marrow aspirates are dry in up to 50% of patients with primary myelofibrosis. Performing a bone marrow biopsy is essential for confirming the diagnosis. Biopsy specimens reveal hypercellular marrow with increased megakaryocytes.

Characteristic features of primary myelofibrosis include patchy hematopoietic cellularity and reticular fibrosis. The amount of reticulin deposition varies from field to field. Megakaryocytes may be present in clusters and may show dysplasia. Distended marrow sinusoids, frequently containing intravascular hematopoiesis, are also observed. (See the images below.)

Bone marrow biopsy from a patient with agnogenic m Bone marrow biopsy from a patient with agnogenic myeloid metaplasia. This image shows extensive fibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.
Reticulin stain on a bone marrow biopsy from a pat Reticulin stain on a bone marrow biopsy from a patient with agnogenic myeloid metaplasia. This image shows extensive fibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.

Cytogenetic studies reveal chromosomal abnormalities in 50-60% of patients. The presence of an abnormal karyotype is associated with a poorer prognosis.

Liver biopsy specimens usually reveal normal histology or minimal portal fibrosis. Thrombotic lesions may occur in portal veins. Hepatic vein thrombosis may occur.

 

Treatment

Approach Considerations

Historically, therapy for primary myelofibrosis was mainly supportive. Patients received transfusions as needed. Thrombocytosis could be managed with hydroxyurea and other palliative agents. Low-risk, asymptomatic patients may be observed without intervention. Patients with milder disease may still be treated with supportive therapies. Ruxolitinib (Jakafi), a JAK1/JAK2 inhibitor, is the first chemotherapeutic agent to be approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis.

Patients with refractory splenomegaly may be candidates for splenectomy. Involved-field radiotherapy is most useful for patients with the following[1] :

  • Post-splenectomy hepatomegaly
  • Non-hepatosplenic extramedullary hematopoiesis
  • Primary myelofibrosis–associated pulmonary hypertension
  • Extremity bone pain

Patients with high or intermediate-2 risk disease, according to the Dynamic International Prognostic Scoring System–plus (DIPSS-plus; see Overview/Prognosis), or those with high-risk mutations such as ASXL1 or SRSF2, should be considered for hematopoietic stem cell transplantation (HSCT). An international working group has published consensus recommendations on the use of HSCT in primary myelofibrosis.[22]

Ruxolitinib

Ruxolitinib (Jakafi), a JAK1/JAK2 inhibitor, is the first chemotherapeutic agent to be approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis. The November 2011 approval was based on the results of the COMFORT-I and COMFORT-II trials. A gain-of-function mutation (VG17F) in JAK2 is present in approximately 50% of all patients with myelofibrosis and contributes to the pathophysiology of the disease. Thus, inhibition of this target is a potential therapeutic option.

In the COMFORT-1 trial, patients with intermediate-2 or high-risk myelofibrosis were randomized to either ruxolitinib (either 15 mg or 20 mg PO bid) or placebo. The primary endpoint was the proportion of patients with 35% or higher reduction in spleen volume at week 24 of therapy, assessed by MRI or CT. The primary endpoint response rate was 41.9% for ruxolitinib compared with 0.7% for placebo. The most common adverse events of any grade were abdominal pain (10.3% vs 41.1%), thrombocytopenia (34.2% vs 9.3%), fatigue (25.2% vs 33.8%), anemia (31% vs 13.9%), diarrhea (23.2% vs 21.2%), and peripheral edema (18.7% vs 22.5%).

The COMFORT-II trial was a randomized phase III study that compared the efficacy and safety of ruxolitinib with best available therapy in patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera-myelofibrosis, or post-essential thrombocythemia–myelofibrosis, and palpable splenomegaly. The primary endpoint was the proportion of patients achieving at least 35% reduction in spleen volume at week 48 as determined by MRI. The response rate was 28% for ruxolitinib compared with 0% for the control arm. The most common adverse events were thrombocytopenia, anemia, diarrhea, and edema.

A double-blind placebo-controlled trial by Verstovsek et al randomized patients with intermediate-2 or high-risk primary myelofibrosis to twice-daily oral ruxolitinib (n=155) or placebo (n=154). The primary endpoint was the proportion of patients achieving at least 35% reduction in spleen volume at week 24 as determined by MRI, which was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group. This reduction in spleen volume was maintained for 48 weeks in 67% of the patients. Anemia and thrombocytopenia were the most common adverse events, with 2 patients in ruxolitinib group having transformation to acute myeloid leukemia.[23]

A clinical trial by Harrison et al also found reductions in splenomegaly and other disease-related symptoms, improvements in quality of life, and modest toxic effects with oral ruxolitinib versus the best available therapy.[24]

Other Chemotherapeutics

Older chemotherapeutics have mainly been used as cytoreductive therapy to control leukocytosis, thrombocytosis, or organomegaly. Hydroxyurea is the preferred agent, but other drugs (eg, interferon, cladribine) have also been used. Busulfan has been used, but it is not a preferred agent in view of the lesser toxicity of hydroxyurea. Patients with primary myelofibrosis are especially prone to developing myelotoxicity with these agents, which should therefore be used with caution.

Interferon alfa is a viable alternative to hydroxyurea therapy, especially in young patients (25</ref>

Aggressive chemotherapy to induce remissions has been used; however, despite aggressive chemotherapy, hematologic remissions are rare and do not change the overall course of the disease.

Androgens and corticosteroids

These agents have been used to treat patients with severe anemia and are administered to improve symptoms and to decrease transfusional requirements. Approximately 30% of patients respond to therapy.

Thalidomide with prednisone

Studies using low-dose thalidomide (50 mg) and prednisone showed reduced side effects in comparison with higher doses of thalidomide. Some patients develop a significant increase in WBC or platelet counts, usually in the first 4-8 weeks, and may require additional cytoreductive therapy.[26, 27, 28, 29, 30, 31, 32, 33]

In a study in which low-dose thalidomide and prednisone were administered to 21 symptomatic patients suffering from myelofibrosis with myeloid metaplasia, an objective clinical response was demonstrated in 13 (62%) patients, all improvements in anemia.[26] Among 10 patients who were dependent on erythrocyte transfusions, seven (70%) improved and four (40%) became transfusion independent. Among 8 patients with thrombocytopenia (platelet count < 100 × 109/L), 6 (75%) experienced a 50% or higher increase in their platelet count. In four of 21 patients (19%), spleen size decreased by more than 50%.

Lenalidomide is a thalidomide analogue that is much more potent than thalidomide. It is approved for treatment of multiple myeloma and for patients with 5q- syndrome myelodysplastic syndrome. A study of 68 patients with symptomatic myelofibrosis and myeloid metaplasia revealed overall response rates of 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia.[34]

High-dose chemotherapy

This modality, combined with autologous transplantation, has been shown to slow disease progression. In a small study, evidence of improvement in fibrosis was noted.

Investigational drugs

Several new investigational drugs are being studied, including farnesyl transferase inhibitors,[35, 36] tyrosine kinase inhibitors,[20] vascular endothelial growth factor inhibitors,[37, 38] , Janus kinase 2 (JAK2) inhibitors, and telomerase inhibitors.[39]

Although thalidomide and lenalidomide can alleviate anemia in myelofibrosis, their use is limited by their respective potential to cause peripheral neuropathy and myelosuppression. Pomalidomide is a second-generation thalidomide analogue with reduced toxicity and enhanced anticancer and immunological activity.

A study by Tefferi et al found pomalidomide to be effective against myelofibrosis-associated anemia. The investigators conducted a phase II, randomized, multicenter, double-blind, adaptive study of 4 treatment arms of pomalidomide, including pomalidomide at a dose of 2 mg/day plus placebo, pomalidomide at a dose of 2 mg/day plus prednisone, pomalidomide at a dose of 0.5 mg/day plus prednisone, and prednisone plus placebo.[40] Pomalidomide was administered for as many as 12 treatment cycles lasting 28 days. During the first 3 cycles, prednisone (30 mg/d) was administered via a tapering dose schedule. Of 84 patients with myelofibrosis-associated anemia who were randomized, response in anemia was documented in 20 patients, including 15 who became transfusion independent.

The response rates were 23%, 16%, 36%, and 19%, respectively. With or without pomalidomide, the response was durable (range, 3.2-16.9+ mo) and was significantly better in patients without leukocytosis (37% vs 8%; P =.01). The presence of JAK2 V617F and the cytogenetic status did not affect the response. Toxicities of grade 3 or higher were infrequent and included neutropenia (9%, 16%, 5%, and 5%, respectively), thrombocytopenia (14%, 16%, 9%, and 5%, respectively), and thrombosis (9%, 5%, 0%, and 0%, respectively).

In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis. Guglielmelli et al conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high-risk or intermediate-risk subjects with primary or postpolycythemia vera/post-essential thrombocythemia myelofibrosis.[41] Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in doses of as much as 10 mg/d. The most common toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of more than 50% and more than 30% was observed in 20% and 44% of subjects, respectively.

A total of 69% and 80% of patients experienced complete resolution of systemic symptoms and pruritus, respecitvely. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25% of patients. Clinical responses were not associated with reduced JAK2 V617F burden, circulating CD34+ cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response.

Splenectomy

Splenectomy may be considered for patients with overt portal hypertension, progressive anemia requiring transfusions, or symptomatic splenomegaly refractory to hydroxyurea. Splenectomy has also been used in patients with severe thrombocytopenia; however, one review reported a lack of a sustained benefit in this situation.

Patients with primary myelofibrosis who require surgery are best treated under the supervision of an experienced hematologist, because splenectomy in these patients has been associated with a significant risk of operative mortality and morbidity from infections, hemorrhage, and thrombosis. Mortality rates in splenectomized patients of up to 38% have been reported, although other reports estimate the operative mortality rate to be approximately 9%. No clear data are available for optimal preoperative management.

Obtain CBC and platelet counts, and order studies to assess for subclinical DIC. Consider patients with significant thrombocytosis for cytoreductive therapy to decrease platelet counts to the reference range. Patients with primary myelofibrosis who experience problems with bleeding may require platelet transfusions and infusions of cryoprecipitate, based on coagulation parameters.

Patients with primary myelofibrosis may develop marked hepatomegaly and thrombocytosis after splenectomy, which may be minimized by close monitoring and the appropriate use of cytoreductive therapy. Aplastic crises do not occur following splenectomy, because bone marrow continues to be the predominant site of hematopoiesis.

Splenectomy is reportedly associated with a higher rate of transformation to AML. A study reported a cumulative transformation rate of 55% in splenectomized patients, compared with 27% in nonsplenectomized patients. Splenectomy was considered to be an independent risk factor for transformation to AML.

Radiation Therapy

Radiation may be used to treat symptomatic extramedullary hematopoiesis. This therapy is also beneficial for bone pain resulting from tumors or periostitis.

Splenic radiation is beneficial to patients with symptomatic splenomegaly or splenic infarction, although the effects are usually temporary (median duration, 6 mo).[42]

After splenic irradiation, prolonged pancytopenia may occur (25% of patients). In addition, splenectomy after splenic irradiation is associated with a very high risk of intra-abdominal hemorrhage. Accordingly, reserve splenic irradiation only for patients in whom surgery is contraindicated.

Stem Cell Transplantation

Allogeneic stem cell transplantation (SCT) is a potentially curative therapy in patients with primary myelofibrosis. Long-lasting, complete remissions have been reported. Regression of marrow fibrosis occurs following successful allogeneic transplantation.

Patients with hemoglobin values below 10 g/dL, karyotypic abnormalities, osteomyelosclerosis, and older age appear to have poorer outcomes. The 1-year mortality rate for persons receiving human leukocyte antigen (HLA)-identical sibling transplants is approximately 30%.

An analysis of the outcomes of 438 patients 43</ref>

A panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group developed a consensus recommendation that patients with intermediate-2 risk or high-risk disease and age 22 </ref>The panel recommended that patients with intermediate-1 risk disease and age <65 years be considered as candidates if they present any of the following:

  • Refractory, transfusion-dependent anemia
  • Greater than 2% of blasts in peripheral blood
  • Adverse cytogenetics

Newer, nonmyeloablative transplantations may improve the overall outcome by decreasing the early mortality observed after conventional high-dose chemotherapy–based transplantation regimens.

 

Medication

Medication Summary

Chemotherapeutics have mainly been used as cytoreductive therapy to control leukocytosis, thrombocytosis, or organomegaly. Hydroxyurea is the preferred agent, but other drugs (eg, interferon, cladribine) have also been used. Busulfan has been used, but it is not a preferred agent in view of the lesser toxicity of hydroxyurea. Ruxolitinib is indicated for myelofibrosis and is an effective agent to reduce splenomegaly. Patients with primary myelofibrosis are especially prone to developing myelotoxicity with these agents, which should therefore be used with caution.

Antineoplastic Agents

Class Summary

Antineoplastic agents are predominantly used as cytoreductive therapy to control leukocytosis, thrombocytosis, and organomegaly. Patients with primary myelofibrosis are especially prone to developing myelotoxicity with these agents; therefore, use them with caution.

Hydroxyurea (Droxia, Hydrea)

Hydroxyurea is an inhibitor of deoxynucleotide synthesis. It is less leukemogenic than alkylating agents (busulfan) are. Hydroxyurea's myelosuppressive effects last a few days to a week and are easier to control than those associated with alkylating agents. It is lethal to cells in the S phase and is cell-cycle specific.

This agent is used mainly to control counts and alleviate constitutional symptoms or symptoms resulting from hepatic enlargement. It can be administered at higher doses in patients with extremely high WBC counts (>300,000/µL) and adjusted accordingly as WBC and platelet counts fall. Hydroxyurea can be administered as a single daily dose or divided into 2-3 doses at a higher dose range.

Busulfan (Myleran, Busulfex)

Hydroxyurea is an inhibitor of deoxynucleotide synthesis. It is less leukemogenic than alkylating agents (busulfan) are. Hydroxyurea's myelosuppressive effects last a few days to a week and are easier to control than those associated with alkylating agents. It is lethal to cells in the S phase and is cell-cycle specific.

This agent is used mainly to control counts and alleviate constitutional symptoms or symptoms resulting from hepatic enlargement. It can be administered at higher doses in patients with extremely high WBC counts (>300,000/µL) and adjusted accordingly as WBC and platelet counts fall. Hydroxyurea can be administered as a single daily dose or divided into 2-3 doses at a higher dose range.

Cladribine (Leustatin)

Cladribine is a synthetic antineoplastic agent for continuous intravenous (IV) infusion. The enzyme deoxycytidine kinase phosphorylates this compound into active 5'-triphosphate derivative, which then breaks DNA strands and inhibits DNA synthesis. Cladribine disrupts cell metabolism, causing death to resting and dividing cells.

Ruxolitinib (Jakafi)

JAK1/JAK2 kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Janus-associated kinases (JAKs) JAK1 and JAK2 mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.

Biological Response Modulators

Class Summary

Immunotherapy (biotherapy) currently used to treat patients with melanoma includes IFN and IL-2.

Interferon alfa-2b (Intron A)

This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.

Peginterferon alfa-2b (Pegintron, Pegintron Redipen, Sylatron)

This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood, but direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Androgens

Class Summary

Androgens improve symptoms of anemia and decrease transfusion requirements in patients with primary myelofibrosis.

Oxymetholone (Anadrol-50)

Oxymetholone is used to manage anemias resulting from deficient RBC production.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

Prednisone

Prednisone inhibits phagocytosis of platelets and may improve RBC survival.

Prednisolone (Orapred ODT, Prelone, Millipred)

Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system. This agent does not need to undergo hepatic metabolism.

Immunomodulators

Class Summary

Agents in this category may have antiangiogenesis and immunomodulatory effects.

Thalidomide (Thalomid)

Thalidomide's mechanism of action not clearly known, but the drug is thought to work by immunomodulatory effects and antiangiogenesis.

Lenalidomide (Revlimid)

A thalidomide analogue, lenalidomide is an immunomodulatory agent with antiangiogenic and antineoplastic properties.