Primary Myelofibrosis

Updated: Sep 22, 2023

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

Primary myelofibrosis. Peripheral smear shows teardrop red blood cells (RBCs) and a leukoerythroblastic picture with 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, as follows:

Observation alone may be appropriate for low-risk, asymptomatic disease.
Mild cases may require only supportive therapy.
Higher-risk disease may respond to treatment with a JAK inhibitor.
Refractory splenomegaly may be an indication for splenectomy.
Allogeneic stem cell transplantation is potentially curative and should be considered for patients at high risk.

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 opioid analgesics. Individuals with refractory cases of primary myelofibrosis may require splenectomy or splenic irradiation. (See Presentation and Treatment.)

Extramedullary hematopoiesis may involve any organ; 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 the serum uric acid level in the reference range.

For discussion of myelofibrosis in children, see Pediatric Myelofibrosis. For patient education information, see the Blood Cancer Directory, 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 patient with primary myelofibrosis. 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 have 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 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. In a review of European data sources, the incidence rate of myelofibrosis ranged from 0.1 to 1 cases per 100,000 per year.[14]

Race-, sex-, and age-related demographics

Primary myelofibrosis appears to be more common in Whites 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.[15] 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 + and ASXL1- had the longest survival (median 10.4 years), whereas those who were CALR- and ASXL1+ had the shortest survival (median 2.3 years). Patients who were either CALR+ and ASXL1+ or CALR- and 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).[16]

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).[17]

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.[17]

Scoring systems

Several scoring systems to determine the prognosis in primary myelofibrosis have been developed.

DIPSS-plus

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 × 10 ⁹/L
Platelet count lower than 100 × 10 ⁹ /L
Circulating blasts of 1% or more
Constitutional symptoms
Red blood 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

MIPSS70

The MIPSS70 (mutation-enhanced international prognostic scoring system for transplant-age patients) includes clinical risk variables and mutations; subsequent versions include karyotype (MIPSS70+ and MIPSS70+ version 2.0). This system was developed for transplant decision-making in patients age 70 years or younger. An online score calculator is available for MIPSS70 and MIPSS70+ version 2.0.[19]

MIPSS70 is based on three genetic variables and six clinical risk factors. The genetic variables are as follows:

Absence of CALR type 1/like mutation
Presence of any high molecular risk [HMR] mutation, specifically ASXL1, SRSF2, EZH2, IDH1, or IDH2
Presence of ≥2 HMR mutations)

The clinical risk factors are as follows:

Hemoglobin < 10 g/dL
Leukocytes >25 × 10 ⁹/L
Platelets < 100 × 10 ⁹/L
Circulating blasts ≥2%
Bone marrow fibrosis grade ≥2
Constitutional symptoms

MIPSS70+ added “unfavorable” karyotype as a fourth genetic variable, and reduced the number of clinical risk factors to four (hemoglobin < 10 g/dL, leukocyte count >25 × 109/L, circulating blasts ≥2%, and constitutional symptoms). Those clinical and genetic risk factors were used to classify three risk categories for MIPSS70 (low, intermediate, and high) and four risk categories for MIPSS70+ (low, intermediate, high, and very high).

In the most recent version, MIPSS70+ 2.0, clinical risk variables and points are as follows:

Severe anemia (hemoglobin < 8 g/dL in women, < 9 g/dL in men): 2 points
Moderate anemia (hemoglobin 8–9.9 g/dL in women, 9–10.9 g/dL in men): 1 point
Circulating blasts ≥2%: 1 point
Constitutional symptoms: 2 points

Genetic variables and points are as follows::

Very high risk (VHR) karyotype (single/multiple abnormalities of −7, i(17q), inv(3)/3q21, 12p−/12p11.2, 11q−/11q23, +21, or other autosomal trisomies, not including +8/+9 [eg, +21, +19]): 4 points
Unfavorable karyotype (all other abnormalities): 3 points
≥2 HMR mutations: 3 points
One HMR mutation: 2 points
Absence of CALR type 1/like mutation: 2 points

Total score, risk factor level, and median survival, and estimated 10-year survival are as follows:

0 points - Very low ris; median not reached (92%)
1–2 points - Low risk; 16.4 years (56%)
3–4 points; Intermediate risk 7.7 years (37%)
5–8 points - High risk; 4.1 years (13%)
≥9 points - Very high risk; 1.8 years (< 5%)

Observation alone is advised for patiens whose MIPSS70+ version 2.0 scores are in the very low and low risk categories. Allogeneic stem cell transplant is the treatment of choice for high and very high risk disease. Patients with intermediate-risk disease are best served by participation in clinical trials.[19]

GIPSS

The GIPSS (genetically inspired prognostic scoring system) is based exclusively on genetic markers: mutations and karyotype.[20] Adverse factors and scores are as follows:

VHR karyotype – 2 points
Unfavorable karyotype – 1 point
Absence of type 1/like CALR mutation – 1 point
Presence of ASXL, SRSF2, and U2AF1Q157 mutations – 1 point

GIPSS risk categories and median survivals (5-year survival rate) are as follows:

Low (0 points): 26.4 years (94%)
Intermediate-1 risk (1 point): 8.0 years (73%)
intermediate-2 (2 points): 4.2 years (40%)
High (≥3 points): 2 years (14%)

Tefferi et al favor starting determination of prognosis with the GIPSS: patients with low-risk disease can receive long-term observation, while those with high-risk disease are candidates for allogeneic stem cell transplantation. MIPSS70+ version 2.0 can be considered for confirming the most appropriate treatment approach for an individual patient.[19]

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 gastrointestinal (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 patient with primary myelofibrosis. 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 the following:

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

DDx

Diagnostic Considerations

Primary myelofibrosis must be differentiated from conditions in which marrow fibrosis is a secondary development. For example, in patients with carcinoma or lymphoma, bone marrow involvement may be associated with marrow fibrosis, which reverses after effective treatment of the underlying disease. Similarly, in histoplasmosis and tuberculosis, marrow fibrosis may result in granulomatous involvement of the bone marrow.

Performing testing for bcr:abl gene rearrangements is important to exclude chronic myelogenous leukemia (CML). JAK2V617F mutation can be detected in approximately 50–60% of patients with primary myelofibrosis.[21, 22, 23]

World Health Organization diagnostic criteria for primary myelofibrosis include three major criteria and four minor criteria. Diagnosis requires meeting all three major criteria and at least two minor criteria.[6] The major criteria are as follows:

Megakaryocyte proliferation and atypia accompanied by reticulin and/or collagen fibrosis or, in the absence of reticulin fibrosis, the megakaryocyte changes accompanied by increased marrow cellularity, granulocytic proliferation and oftenndecreased erythropoiesis (ie, pre-fibrotic primary myelofibrosis)
Not meeting WHO criteria for chronic myeloid leukemioa, polycythemia vera, myelodysplastic syndrome, or other myeloid neoplasm
Demonstration of JAK2V617F or other clonal marker, or no evidence of reactive bone marrow fibrosis

Minor criteria are as follows:

Leukoerythroblastosis
Elevated serum lactate dehydrogenase level
Anemia
Palpable splenomegaly

The International Working Group for Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) has established diagnostic criteria for post–polycythemia vera myelofibrosis (PPV-MF) and post–essential thrombocythaemia myelofibrosis (PET-MF).[24] For both disorders, cases must meet the following two criteria:

Documentation of a previous diagnosis of PV or PET, as defined by the 2008 WHO criteria
Bone marrow fibrosis grade 2–3 (on a 0–3 scale) or grade 3–4 (on a 0–4 scale)

In addition, cases must meet at least two further criteria. For PVV-MF, the additional criteria are as follows:

Anemia or sustained loss of requirement for phlebotomy in the absence ofcytoreductive therapy
Leukoerythroblastic peripheral blood picture
Increasing splenomegaly - Either an increase in palpable splenomegaly of ≥5 cm from the left costal margin or the appearance of a newly palpable splenomegaly
Development of one or more constitutional symptoms (>10% weight loss in 6 months, night sweats, unexplained fever >37.5°C)

For PET-MF, the additional criteria are as follows:

Anemia and a decrease in hemoglobin level of 2 g/dL or more from baseline
Leukoerythroblastic peripheral blood picture
Increasing splenomegaly - Either an increase in palpable splenomegaly of ≥5 cm from the left costal margin or the appearance of a newly palpable splenomegaly
Development of more than one constitutional symptoms (>10% weight loss in 6 months, night sweats, unexplained fever >37.5°C)
Increased lactate dehydrogenase concentration

Differential Diagnoses

Workup

Approach Considerations

In addition to the history and physical examination, National Comprehensive Cancer Network (NCCN) guidelines recommend the following workup for patients with suspected myeloproliferative neoplasms[25] :

Complete blood cell count (CBC) with differential
Comprehensive metabolic panel with uric acid, lactate dehydrogenase (LDH), and liver function tests (LFTs)
Multiplex real time polymerase chain reaction (RT-PCR) (preferred) or fluorescence in situ hybridization (FISH) (if RT-PCR is not available) for BCR-ABL1to exclude the diagnosis of chronic myeloid leukemia
Examination of blood smear
Bone marrow aspirate and biopsy with trichrome and reticulin stain
Bone marrow cytogenetics (blood, if bone marrow is inaspirable) (karyotype ± FISH)
Molecular testing of blood for JAK2 V617F mutation; if negative, test for CALR and MPL mutations; or molecular testing using multigene next-generation sequencing (NGS) panel that includes JAK2, CALR, and MPL
Assessment of symptom burden using MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS; MPN-10; MPN-E 2 of 2)
Human leukocyte antigen (HLA) testing, if allogeneic hematopoietic cell transplant (HCT) is being considered
Serum erythropoietin (EPO) level
Serum iron studies
Coagulation tests to evaluate for acquired von Willebrand disease (VWD) and/or other coagulopathies in selected patients

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.

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 primary myelofibrosis 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 patient with primary myelofibrosis 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. Four Janus kinase (JAK) inhibitors are approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis. Other pharmacologic therapies have been used.

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.[26]

JAK Inhibitors

The following Janus-associated kinase (JAK) inhibitors are approved for the treatment of myelofibrosis:

Ruxolitinib (Jakafi)
Fedratinib (Inrebic)
Pacritinib (Vonjo)
Momelotinib (Ojjaara)

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 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.[27]

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.[28]

Fedratinib

Another JAK inhibitor, fedratinib (Inrebic), was approved in 2019 for adults with intermediate-2 or high-risk primary myelofibrosis (as well as for myelofibrosis secondary to polycythemia vera or essential thrombocythemia). The efficacy of fedratinib was investigated in JAKARTA (NCT01437787), a double-blind, randomized, placebo-controlled trial in 289 patients with intermediate-2 or high-risk myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis with splenomegaly. Patients were randomized to receive fedratinib 500 mg (N=97) or 400 mg (n=96) or placebo (n=96) once daily for at least 6 cycles.

Follow-up magnetic resonance imaging or computed tomography scanning showed that of the 96 patients treated with the recommended dose (400 mg) of fedratinib, 35 (37%) achieved a 35% or greater reduction in spleen volume, compared with 1 of 96 patients who received placebo (P < 0.0001). The median duration of spleen response was 18.2 months for the fedratinib 400 mg group. In addition, 40% of patients who received 400 mg experienced a 50% or greater reduction in myelofibrosis-related symptoms, compared with only 9% of patients receiving placebo.[29]

Pacritinib

In March 2022, the FDA approved pacritinib (Vonjo), the first treatment for adults with myelofibrosis and severe thrombocytopenia (platelet count < 50 × 109/L). Pacritinib is an oral JAK inhibitor that inhibits JAK2 and FLT3, as well as CSFIR and IRAK1.

Approval was based on the PERSIST-1 and PERSIST-2 phase III trials and the phase II PAC203 trial. The PERSIST-1 trial randomized 327 patients to receive pacritinib or the best available therapy (BAT) until disease progression or unacceptable toxicity. At week 24, 19% of the pacritinib-treated arm achieved the primary endpoint of spleen volume reduction (SVR) ≥35% compared with 5% in the BAT arm.[30]

PERSIST-1 led to PERSIST-2, which randomized 311 patients with myelofibrosis and platelet count ≤100 × 109/L to receive pacritinib 400 mg once daily, pacritinib 200 mg BID, or BAT (including ruxolitinib). Pacritinib at either dosage was more effective for SVR ≥35% compared with BAT (18% vs 3%, respectively) but twice-daily pacritinib was also significantly more effective for producing a ≥50% reduction in total symptom score (TSS), compared with BAT.[31]

A pacritinib dose of 200 mg twice daily also proved preferable in PAC203, a dose-finding study that enrolled 161 patients with primary myelofibrosis who had received prior ruxolitinib. Participants were randomized to receive 100 mg daily, 100 mg BID, or 200 mg BID. At Week 24, SVR ≥35% rates were highest with 200 BID (9.3%, versus 0% with 100 mg daily and 1.8% with 100 mg BID), particularly in patients with baseline platelet counts < 50 × 109/L (17%; 4 of 24). Reduction in the 7-component TSS by ≥50% through week 24 was similar across doses (100 mg daily, 7.7%; 100 mg BID, 7.3%; 200 mg BID, 7.4%).[32]

Momelotinib

In September 2023, the FDA approved momelotinib (Ojjaara) for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia. Momelotinib is a once-a-day, oral JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor.

Approval was based on the MOMENTUM study and a subpopulation of adult patients with anemia from the SIMPLIFY-1 phase III trial. The MOMENTUM trial randomized 195 patients to receive momelotinib or danazol for 24 weeks. The proportion of patients who reported a reduction in total symptom score of 50% or more was 25% in the momelotinib group versus 9% in the danazol group (P=0.0095).[33]

SIMPLIFY-1 was a multicenter, randomized, double-blind, phase III study that compared the safety and efficacy of momelotinib versus ruxolitinib in 432 patients with myelofibrosis who had not received prior treatment with a JAK inhibitor. Momelotinib met the primary end point of noninferiority for spleen response but not the key secondary end point of symptomatic improvement; however, more patients achieved transfusion independence with momelotinib than with ruxolitinib, and objective laboratory measures of anemia (eg, hemoglobin, serum iron, transferrin saturation) also favored momelotinib.[34]

FGFR Inhibitors

Pemigatinib

Pemigatinib (Pemazyre) is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3). It inhibits FGFR 1/2/3 phosphorylation and signaling, and decreases cell viability in cancer cell lines with activating FGFR amplifications and fusions. It is indicated for relapsed or refractory myeloid/lymphoid neoplasms (MLNs) in adults with FGFR1 rearrangement.

Approval was based on the phase 2 FIGHT-203 clinical trial. Study participants included patients with documented MLNs with an 8p11 translocation on conventional cytogenetics and/or an FGFR1 rearrangement on break-apart fluorescence in situ hybridization (FISH) testing.[35]

In patients with chronic phase in the marrow with or without extramedullary disease (EMD) (N = 18), the complete response (CR) rate was 78%. The median time to response of CR was 104 days (range, 44 to 435 days). The median duration of CR was not reached. In patients with blast phase in the marrow with or without EMD (N = 4), 2 patients achieved a CR. For all patients (N = 28, including 3 patients without evidence of morphologic disease) the complete cytogenetic response rate was 79% (22/28; 95% CI: 59, 92).[35]

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 (< 45 y), who have a long life expectancy. Response rates of 50% have been observed, with improvement in splenomegaly and blood cell counts. Results are best in patients with elevated counts.[36]

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 adverse 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.[37, 38, 39, 40, 41, 42, 43, 44]

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.[37] 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.[45]

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

Drugs being studied for myelofibrosis include the following:

Pomalidomide
Everolimus
Farnesyl transferase inhibitors ^{[46, 47]}
Tyrosine kinase inhibitors ^[22]
Vascular endothelial growth factor inhibitors ^{[48, 49]}
Telomerase inhibitors ^[50]

Pomalidomide

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.[51] 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).

Everolimus

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 post–polycythemia vera/post–essential thrombocythemia myelofibrosis.[52] 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 massive splenomegaly. Indications include abdominal pain and discomfort, symptomatic portal hypertension, severe thrombocytopenia, and need for frequent red blood cell transfusions.[53]

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 perioperative morbidity and mortality. Perioperative morbidity—principally infections, hemorrhage, and thrombosis—has been reported in approximately 30% of cases. Perioperative mortality—principally from infection and hemorrhage—averages approximately 8%.[53]

Tefferi et al created a prognostic model to help identify patients with myelofibrosis who are likely to benefit from splenectomy, using four risk factors found to be associated with shorter survival after splenectomy[54] :

Age > 65 years
Leukocyte count > 25 × 10 ⁹/L
Circulating blasts ≥ 5%
Need for red blood cell transfusion

Risk categories and 3-year and median postsplenectomy survival were as follows:

Low risk (0-1 risk factors): 47% and 2.9 years
Intermediate risk (2 risk factors): 11% and 1.3 years
High risk (3-4 risk factors): 0% and 0.3 years

Prior to splenectomy, 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 acute myeloid leukemia (AML). In one study, leukemic transformation occurred in 26.4% of splenectomized patients, conpared with 11.4% of nonsplenectomized patients.[53]

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).[55]

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%.

A study of long-term outcome of allogeneic SCT in patients with myelofibrosis, which included 837 patients with primary myelofibrosis, found that of patients who were disease-free 2 years after SCT, disease-free survival at 10 years was 64% (60-68%) and overall survival was 74% (71-78%). Older age, male sex, and no graft versus host disease (GVHD) in the the first 2 years after SCT were associated with a significantly higher risk of mortality; older age, reduced-intensity conditioning, male sex, donor other than an HLA-matched related donor, and no earlier GVHD were associated significantly with lower disease-free survival.[56]

An analysis of the outcomes of 438 patients < 65 years old at diagnosis of primary myelofibrosis who received allogeneic SCT (n = 190) or conventional therapies (n = 248) found that non–ruxolitinib-treated patients with intermediate-2 or high-risk disease were likely to benefit from allogeneic SCT, whereas patients with low-risk disease had a higher risk of death and nontransplant approaches should be considered. Individual counseling was suggested for intermediate-1 risk patients.[57]

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 < 70 years should be considered as candidates for allogeneic SCT.[26] 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. Salit et al reported that treatment with ruxolitinib prior to SCT is well tolerated and may improve outcome in transplanted patients.[58]

Guidelines

Guidelines Summary

The following organizations have published guidelines for the diagnosis and treatment of primary myelofibrosis:

National Comprehensive Cancer Network (NCCN)
European Society for Medical Oncology (ESMO)

Diagnosis

In addition to the history and physical examination, NCCN guidelines recommend the following workup for patients with suspected myeloproliferative neoplasms[25] :

Complete blood cell count (CBC) with differential
Comprehensive metabolic panel with uric acid, lactate dehydrogenase (LDH), and liver function tests (LFTs)
Multiplex real time polymerase chain reaction (RT-PCR) (preferred) or fluorescence in situ hybridization (FISH) (if RT-PCR is not available) for BCR-ABL1to exclude the diagnosis of chronic myeloid leukemia
Examination of blood smear
Bone marrow aspirate and biopsy with trichrome and reticulin stain
Bone marrow cytogenetics (blood, if bone marrow is inaspirable) (karyotype ± FISH)
Molecular testing of blood for JAK2 V617F mutation; if negative, test for CALR and MPL mutations; or molecular testing using multigene next-generation sequencing (NGS) panel that includes JAK2, CALR, and MPL
Assessment of symptom burden using MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS; MPN-10; MPN-E 2 of 2)
Human leukocyte antigen (HLA) testing, if allogeneic hematopoietic cell transplant (HCT) is being considered
Serum erythropoietin (EPO) level
Serum iron studies
Coagulation tests to evaluate for acquired von Willebrand disease (VWD) and/or other coagulopathies in selected patients

Both guidelines recommend use of the World Health Organization (WHO) diagnostic criteria for the most accurate diagnosis and grading of primary myelofibrosis.[25, 59]

Risk Stratification

The NCCN prefers use of the Mutation-Enhanced International Prognostic Scoring System (MIPSS) for the initial stratification of risk at diagnosis. The Dynamic International Prognostic Scoring System (DIPSS)-Plus is recommended if molecular testing is unavailable. The DIPSS is used if karyotyping is not available. The DIPSS-Plus is preferred for assessing risk during treatment.[25] The ESMO guidelines are in concurrence with NCCN.[59]

Treatment

All patients should be evaluated for allogeneic hematopoietic cell transplantation (HCT). Enrollment in clinical trials is also recommended for all patients with primary myelofibrosis.[25, 59]

The NCCN guidelines recommend administering the MPN-SAF Total Symptom Score (MPN-10) to assess symptom burden at baseline and during the course of treatment. Changes in symptom status can be an indication of disease progression and should trigger evaluation of current treatment efficacy and/or disease risk stratification.[25]

Lower-risk myelofibrosis

NCCN guidelines recommend monitoring asymptomatic patients for signs and symptoms of disease progression every 3-6 months. For symptomatic patients, NCCN recommends the following treatments in selected patients[25] :

Ruxolitinib
Peginterferon alfa-2A
Hydroxyurea, if cytoreduction would be beneficial

Higher-risk myelofibrosis

The NCCN and ESMO recommend allogeneic HCT.[25, 59] In patients who are not candidates, NCCN-recommended treatments include the following[25] :

Ruxolitinib
Fedratinib
Enrollment in clinical trials

Advanced myelofibrosis/acute myeloid leukemia

NCCN treatment recommendations include clinical trial enrollment or, for transplant candidates, inducement of remission with azacitidine or decitabine or intensive induction chemotherapy followed by HCT; for non-candidates for HCT, azacitidine or decitabine or low-intensity induction chemotherapy.[25]

Supportive Care

NCCN recommendations for supportive care include the following[25] :

Red blood cell (RBC) transfusions for symptomatic anemia
Platelet transfusions for thrombocytopenic bleeding or a platelet count < 10,000 m ³
Antifibrinolytic agents for bleeding that is refractory to transfusions
Iron chelation can be considered in patients receiving more than 20 transfusions, but NCCN cautions that the role of iron chelation is unclear ^[25]
Erythropoietin-stimulating agents (ESAs) for myelofibrosis-associated anemia ^{[25, 59]}
Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) for recurrent infections in patients with neutropenia; however, these agents are associated with splenic rupture and should be used with caution in patients with enlarged spleens ^[25]
Antibiotic prophylaxis for recurrent infections
Vaccinations
Hydroxyurea should be considered for treatment of thrombocytosis or leukocytosis
Tumor lysis syndrome (TLS) prophylaxis should be considered for patients undergoing induction therapy
Ruxolitinib may stabilize bone/muscle pain and improve pruritus

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. Another JAK inhibitor, fedratinib, is indicated for adults with intermediate-2 or high-risk primary myelofibrosis. 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)

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.

JAK Inhibitors

Class Summary

Myelofibrosis is a myeloproliferative neoplasm known to be associated with dysregulated Janus-associated kinase (JAK) signaling.

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.

Fedratinib (Inrebic)

Fedratinib inhibits Janus-associated kinase-2 (JAK2), which mediates signaling of cytokines and growth factors that are important for hematopoiesis and immune function. It is indicated for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.

Pacritinib (Vonjo)

Pacritinib is an oral kinase inhibitor with activity against wild type JAK2, mutant JAK2V617F form and FLT3, which contribute to signaling of several cytokines and growth factors that are important for hematopoiesis and immune function. It also inhibits additional cellular kinases (such as CSF1R and IRAK1), clinical relevance of which is unknown. It is indicated for the treatment for adults with myelofibrosis and severe thrombocytopenia (platelet count 9</sup>/L).

Momelotinib (Ojjaara)

Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anemia benefits in myelofibrosis. It is indicated for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post-polycythemia vera and post-essential thrombocythemia), in adults with anemia.

FGFR Inhibitors

Class Summary

Consider for relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

Pemigatinib (Pemazyre)

Orally bioavailable inhibitor of the FGFR types 1, 2, and 3 (FGFR1/2/3). Pemigatinib inhibits FGFR 1/2/3 phosphorylation and signaling, and decreases cell viability in cancer cell lines with activating FGFR amplifications and fusions. It is indicated for relapsed or refractory MLNs in adults with FGFR1 rearrangement.

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.

Author

Asheesh Lal, MBBS, MD Physician, Department of Internal Medicine, Lexington Medical Center

Asheesh Lal, MBBS, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Acknowledgements

Author: Asheesh Lal, MBBS, MD, Physician, Department of Internal Medicine, Lexington Medical Center.

Asheesh Lal is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology.

Editors: Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College; Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference; Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University.

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