Myeloproliferative Neoplasms

Overview

Myeloproliferative neoplasms (MPNs) are a group of clonal myeloid cell–derived disorders characterized by myeloproliferation without dysplasia, bone marrow hypercellularity, and predisposition to thrombosis, hemorrhage, and bone marrow fibrosis. This chapter is focused on the “classical” Philadelphia chromosome–negative MPNs, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).

The estimated incidence of PMF ranges from 0.8–2.1 per 100,000/year, PV 0.4–2.8 per 100,000/year, and ET 0.4–3.4 per 100,000/year.

Epidemiology

Gender

The overall incidence of myelofibrosis (MF) is approximately the same in men and women. The prevalence of PV is slightly higher in men than women (male-to-female ratio, 1.8:1), and ET is more prevalent in women than men (male-to-female ratio, 1:2).

Age

Most patients are diagnosed with MPNs after age 60; however, the diseases can occur at any age. Median age of diagnosis of PMF is 65 years; median age of diagnosis of ET is 56 years; and median age of diagnosis of PV is 61 years.

Etiology and Risk Factors

For most cases of MPN, the etiology is unknown.

Genetic Factors

MPNs are not thought to be inherited; however, some evidence suggests a genetic predisposition to developing MPN in general. A Swedish population-based study found that first-degree relatives of patients with MPN have a 5- to 7-fold increased risk of developing MPN. The 10-fold higher incidence of MPNs in Ashkenazi Jews also indicates a genetic predisposition. The JAK2 46/1 haplotype has been shown to predispose patients to developing JAK2^V617F-positive MPN, and an association has been reported between a single nucleotide polymorphism in the TERT gene and risk of developing an MPN.

Environmental Factors

Exposure to high levels of radiation is a risk factor for developing an MPN. In addition, exposure to petrochemicals, such as benzene and toluene, has been associated with the development of PMF.

Polycythemia Vera

Signs and Symptoms

Many of the signs and symptoms of PV are associated with an increased blood viscosity and reduced blood flow. Patients often present with constitutional symptoms, such as headache, fatigue, dizziness, and sweating. Aquagenic pruritus is a common complaint. On physical examination, patients may have a ruddy complexion, and mild splenomegaly is common. Ocular migraine or erythromelalgia associated with erythrocytosis and thrombocytosis can also occur. Transient visual disturbances can be seen. as well.

Pathology and Laboratory Features

Peripheral blood

The primary feature of PV is an elevated red blood cell mass, reflected in part by elevated hemoglobin levels (> 18.5 g/dL for men or > 16.5 for women). Leukocytosis and thrombocytosis are not uncommon. Red blood cells usually appear normal on peripheral blood smear. Erythroid colony growth in vitro in the absence of exogenous erythropoietin is characteristic of PV.

Bone marrow

Bone marrow is typically hypercellular due to myeloid hyperplasia and increased megakaryocytes. Megakaryocytes typically have normal morphology but are often found in clusters.

Some patients may have low-grade bone marrow fibrosis.

Other laboratory findings

Blood viscosity may be five to eight times greater than normal. Serum erythropoietin levels are low in most patients (> 85%). Hyperuricemia is often present. Iron deficiency may be present in some patients, causing low mean corpuscular volume.

Cytogenetic and Molecular Findings

Chromosomal abnormalities

The incidence of chromosomal abnormalities in patients with PV is less than 20%. The most common abnormalities include partial duplication of chromosome 1, trisomy 8 or 9, or deletion of 13q or 20q. While some evidence suggests that trisomy 1 and del(13q) may be correlated with transformation to MF, myelodysplastic syndromes, or acute myeloid leukemia, none of the abnormalities have been shown to be prognostic.

Molecular findings

Nearly all patients with PV harbor a JAK2 mutation (95% of patients are positive for JAK2^V617F and an additional 3% harbor mutations in JAK2 exon 12). Other mutations have also been identified in some patients (eg, TET2, ASXL2, LNK); however, their prognostic significance is unknown.

Diagnosis

TABLE 1: World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis

PV is diagnosed according to 2008 World Health Organization (WHO) criteria on the basis of clinical, histological, and molecular characteristics (Table 1). Major diagnostic criteria for PV include elevated hemoglobin and presence of a JAK2 mutation (either V617F or exon 12). The presence of a JAK2 mutation, along with elevated red blood cell mass (or abnormally high hemoglobin) and low erythropoietin levels, is strongly suggestive of PV.

Prognosis

Several studies have confirmed that age older than 60 and previous thrombosis are the main risk factors for thrombosis, the most common cause of death in patients with PV. The estimated 15-year cumulative risk of thrombosis is 27%, and the 15-year risks of transformation to either acute leukemia or MF are 7% and 6%, respectively.

Life expectancy for patients with PV is predicted to be slightly shorter than that of age- and gender-matched healthy individuals. The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) developed a prognostic model that includes age (≥ 67 years: 5 points; 57–66 years: 2 points), leukocyte count (≥ 15 × 10⁹/L: 1 point), and history of venous thrombosis (1 point) as independent predictors of poor prognosis. Patients with 0 points, defined as low risk, had a median survival of 28 years; patients with 1 to 2 points, defined as intermediate risk, had a median survival of 19 years; and patients with 3 or more points, defined as high risk, had median survival time of 11 years. Independent risk factors for shorter leukemia-free survival time are age > 61 years, abnormal karyotype, and leukocyte count ≥15 × 10⁹/L. Bone marrow fibrosis in patients with PV may increase the risk of transformation to post-PV MF. However, the usefulness of these prognostic models awaits further validation in additional patient populations.

Treatment

TABLE 2: Treatment approaches for patients with polycythemia vera or essential thrombocythemia

The current treatment approach for PV is focused on preventing thrombotic events and reducing constitutional symptoms (Table 2). In addition to treating the signs and symptoms of PV, cardiovascular risk factors should be aggressively managed when present.

Phlebotomy and low-dose aspirin

Phlebotomy to reduce the hematocrit to below 45% for men and below 42% for women is a safe and effective treatment indicated for all patients. Phlebotomy induces iron deficiency, which is thought to reduce hematopoiesis and has not been shown to be detrimental in the absence of anemia. Low-dose aspirin should also be administered to all patients to reduce the risk of thrombosis, unless aspirin is contraindicated.

Chemotherapy

Hydroxyurea. Hydroxyurea (HU) is the most widely used cytoreductive therapy for reducing blood counts in patients with PV and has not been proven to increase the risk of AML. However, up to 20% of patients can develop resistance to or be intolerant of HU.

Interferon-a. Interferon-a (IFN-a) is effective in suppressing erythrocytosis, reducing spleen size and alleviating pruritus in 80% to 90% of patients with PV. However, up to 50% of patients discontinue treatment due to side effects including flu-like symptoms, fatigue, and depression. More recently, pegylated forms of IFN-a have been shown to be equally as effective, but with fewer adverse effects. In some patients, pegylated IFN-a has been shown to significantly reduce the JAK2 allele burden, suggesting that it may suppress the malignant clone. A phase III randomized study comparing a longer-acting form of pegylated IFN-a (PEG-proline-IFN-a-2b) with HU in patients with PV is currently being conducted in Europe (Clinical.Trials.gov identifier: NCT01259856). IFN-a is currently recommended as a first-line therapy, as is HU, but is particularly useful in women of childbearing age.

Pipobroman, busulfan, and radioactive phosphorus. Pipobroman (Vercyte), busulfan (Busulfex), and radioactive phosphorus have been used as second-line agents for patients after failure of primary therapy with either HU or IFN-a. However, due to their potential leukemogenicity, they should generally be reserved for older patients with a short life expectancy.

JAK2 inhibitors. In December 2014, the oral JAK1/2 inhibitor ruxolitinib (Jakafi) was approved in the US by the Food and Drug Administration for treating patients with PV who have an inadequate response or cannot tolerate HU. In the pivotal phase III RESPONSE trial, which randomized patients to either ruxolitinib (at 10 mg bid) or best available therapy (BAT), 77% of patients in the ruxolitinib arm achieved hematocrit control without phlebotomy and/or ≥ 35% reduction in spleen volume at week 32, compared with only 1% of those in the BAT arm. Most patients had symptom improvement, and 49% had a ≥ 50% improvement in the MPN-Symptom Assessment Form (MPN-SAF) total symptom score, a validated measure of patient-reported symptoms. Anemia and thrombocytopenia were the main toxicities observed but these could be managed with dose reductions.

Treatment recommendations

The main goal of treatment is to reduce symptoms and prevent thrombotic complications. A prospective randomized trial in 365 patients with PV (the CYTO-PV study) found that strict control of hematocrit levels significantly reduced the risk of death caused by cardiovascular risk factors or thrombotic events. Current guidelines ask treating physicians to aim to reduce and maintain the hematocrit at < 45% for men and 42% for women.

All patients should receive phlebotomy and low-dose ASA, unless contraindicated. Patients at high risk for thrombosis (those over 60 years of age or with a history of thrombosis) should receive cytoreductive therapy. Hydroxyurea is the currently preferred agent, although IFN-a can be considered, especially for younger patients or those who are pregnant. Patients who are resistant to or intolerant of HU should be treated with ruxolitinib. Patients who do not respond to treatment, experience toxicity, or relapse after receiving standard therapies should be considered for inclusion in clinical trials of novel targeted agents.

Essential Thrombocythemia

Signs and Symptoms

Some patients with essential thrombocythemia (ET) are asymptomatic and are diagnosed after abnormal findings on a routine blood count screening. In symptomatic patients, vasomotor symptoms can be seen in 30% to 40% of patients and often manifest as headache, lightheadedness, syncope, erythromelalgia, acral paresthesia, livedo reticularis, atypical chest pain, and transient visual disturbance. Up to 40% of patients have mild splenomegaly (< 5 cm), 30% to 40% have leukocytosis, and 10% to 20% have mild anemia. Thrombosis and hemorrhage are common complications that have been reported in 18% to 26% and 4% to 11% of patients, respectively. The risk of hemorrhage increases in patients with platelet counts > 1.5 × 10⁹/L, due to acquired Von Willebrand factor deficiency. Constitutional symptoms are uncommon. Transformation to acute leukemia or MF is the most serious complication of ET. The estimated 15-year cumulative risk of transformation to acute leukemia is about 2%, while the 15-year cumulative risk of transformation to MF is about 9%.

Pathology and Laboratory Features

Peripheral blood

A primary feature of ET is elevated platelet counts (> 450 × 10⁹/L). A markedly increased number of platelets are also seen on peripheral blood smear. Leukocytosis or, rarely, mild anemia may also be present.

Bone marrow

Bone marrow biopsy typically shows slight hypercellularity, myeloid hyperplasia, and an increased number of large mature megakaryocytes with hyperlobulated nuclei. Fibrosis should not be present.

Cytogenetic and Molecular Findings

Chromosomal abnormalities

Karyotypic abnormalities in ET are uncommon (< 5% to 10% of cases). Trisomy 8 or 9, del(13q), and del(20q) are most common abnormalities.

Molecular findings

Nearly 90% of patients with ET have mutations in one of three genes that drive the disease process. Approximately 50% to 60% of patients harbor the JAK2^V617F mutation, while an additional 3% to 5% harbor a mutation in the gene for the thrombopoietin receptor (MPL^W151L/K). Mutations in the CALR gene have been identified in 67% to 71% of ET cases that are both JAK2- and MPL-negative (25% of all ET cases).

Diagnosis

ET is diagnosed according to 2008 WHO criteria on the basis of clinical, histological, and molecular characteristics (Table 1). The diagnosis of ET is one of exclusion. While major criteria include elevated platelets (≥ 450 × 10⁹/L), exclusion of chronic myelogenous leukemia, PV, PMF, or myelodysplastic syndrome is required for proper diagnosis.

Prognosis

The survival duration of patients with ET overall is not significantly shorter than that of the healthy population. Thrombosis and hemorrhage are the most common disease-related complications. The main risk factors for thrombosis are age older than 60 years and a history of thrombosis. Platelet count has not been shown to correlate with risk of thrombosis.

Studies of a series of 891 patients published by the IWG-MRT reported a 6% incidence of major bleeding (0.79% of patients per year) and a 25% incidence of thrombosis (1.9% of patients per year). Arterial thrombosis (1.9% of patients per year) was more common than venous thrombosis (0.6% of patients per year). The International Prognostic Score of thrombosis in ET (IPSET-thrombosis) was recently proposed (Table 2). The prognostic score includes four risk factors: age ≥ 60 years, previous thrombosis, cardiovascular risk factors (diabetes, hypertension, smoking), and presence of the JAK2V617F mutation. Patients could be stratified into three risk categories with an annual risk of thrombosis ranging from 1.03% of patients per year to 3.56% of patients per year. A prognostic score predicting overall survival at diagnosis (IPSET) included age ≥ 60 years, leukocyte count ≥ 11 × 10⁹/L, and prior thrombosis as independent risk factors for survival. Patients could be stratified into three risk groups with median survival ranging from 14.7 years (high risk) to > 25 years (low risk) (Table 2). While prognostic scoring systems need to be tested in prospective studies to determine their usefulness in clinical practice, the data suggest that patients with these risk factors should be monitored more closely.

Treatment

Most patients with ET have a normal life expectancy and, therefore, the main goal of treatment is to prevent thromboembolic events. Antiplatelet therapy and cytoreductive therapy are the two major classes of drugs currently used to treat ET. A recommended treatment algorithm is summarized in Table 3.

Antiplatelet agents

Low-dose aspirin: Low-dose aspirin is safe and effective for reducing microvascular symptoms in most patients, but its role in reducing or preventing thrombotic events is unclear. The use of aspirin in patients with very high platelet counts (> 1,500 × 10⁹/L) should be avoided due to an increased risk of bleeding caused by von Willebrand disease. Therefore, patients with very high platelet counts should be screened for von Willebrand disease and possibly considered for cytoreductive therapy to decrease bleeding risk.

Chemotherapy

Hydroxyurea. HU is the currently recommended first-line treatment for patients with high-risk ET (age > 60 years or history of thrombosis). It can also be considered for patients with platelet counts above 1,500 × 10⁹/L, to reduce the risk of bleeding. HU has been shown to reduce platelet counts and significantly reduce the incidence of thrombosis compared with placebo.

Anagrelide. Recommended as a second-line treatment for patients with high-risk ET, anagrelide blocks megakaryocyte differentiation and proliferation. In a large, randomized study comparing anagrelide plus aspirin to HU plus aspirin (UK MRC PT-1), anagrelide plus aspirin was associated with increased rates of arterial thrombosis, serious hemorrhage, and transformation to MF. However, a more recent randomized study of anagrelide monotherapy vs HU monotherapy (ANAHYDRET) showed noninferiority of anagrelide to HU.

Interferon-alpha. Studies of conventional IFN-a in patients with ET have shown hematologic responses rates > 75%; however, up to 50% of patients discontinued treatment due to intolerable side effects. Pegylated IFN-a-2a has been shown to have a better toxicity profile than standard IFN-a, with neutropenia being the main adverse event in patients with ET. In a phase II study of pegylated IFN-a-2a in patients with ET, 76% of patients achieved a complete hematologic response (normalization of platelet counts in the absence of thromboembolic events), and 38% had reductions in JAK2 allele burden.

Treatment recommendations

The main goal of therapy for patients with ET is prevention of thromboembolic events. However, because overall survival in ET is similar to that of the general population, overtreatment should be avoided. Low-dose aspirin can be safely used to treat microvascular symptoms in all patients unless contraindicated. HU is recommended as a frontline therapy to treat patients with high-risk ET (ie, those over 60 years of age or with a history of thrombosis), though recent data suggest that anagrelide may also be a good first-line treatment option. Pegylated IFN-a-2a should be reserved as a second-line therapy for those who are intolerant of or resistant to HU or for women who are pregnant or of childbearing potential.

Myelofibrosis

Signs and Symptoms

MF has the most heterogeneous clinical presentation of the three MPNs; patients can present with no or few symptoms in the early stages of the disease or with severe signs and symptoms, such as fatigue, transfusion-dependent anemia, and symptomatic splenomegaly as the disease progresses. Although leukopenia and thrombocytopenia are most common as the disease progresses, some patients may present with leukocytosis or thrombocytosis. These patients are at greater risk of developing thrombohemorrhagic complications. Nearly half of patients present with anemia.

Extramedullary hematopoiesis can lead to marked hepatosplenomegaly. Up to 85% of patients present with palpable splenomegaly and 50% have hepatomegaly. Splenomegaly can cause abdominal discomfort, early satiety, and pain under the left ribs. Complications associated with splenohepatomegaly include portal hypertension, variceal bleeding, and splenic infarcts. Extramedullary hematopoiesis can also lead to pulmonary hypertension, ascites, pericardial tamponade, cord compression, and paralysis.

Debilitating constitutional symptoms are common and can lead to very poor quality of life. Fatigue is the most common of these: 84% of patients reported having fatigue in an internet-based survey. Other common symptoms include night sweats (56% of patients), pruritus (50% of patients), bone pain (47%), unintentional weight loss (20% of patients), and fevers (18% of patients).

Pathology and Laboratory Features

Peripheral blood

The peripheral blood smear typically shows leukoerythroblastosis (nucleated red blood cells and left-shifted granulopoiesis), with teardrop-shaped red blood cells, large platelets, and rare myeloblasts. Circulating CD34+ cells are also elevated.

Bone marrow

Bone marrow biopsy shows clustering of variably sized megakaryocytes with hyperchromatic and hyperlobulated nuclei. In the prefibrotic stage, bone marrow may be hypercellular. In the fibrotic stage, there is marked expansion of bone marrow sinusoids and increased interstitial reticulin fibrosis, as well as collagen fibrosis.

Other laboratory findings

Serum lactate dehydrogenase is often elevated; vitamin B12 levels can be elevated; and some patients experience hyperuricemia.

Cytogenetic and Molecular Findings

Chromosomal abnormalities

The incidence of chromosomal abnormalities in MF has been reported to range from 32% to 48%. The most common abnormalities are del(13q), del(20q), trisomy 8 or 9, and abnormalities of chromosome 1 [partial trisomy and der(6)t(1;6)]. Sole deletions of 13q or 20q, or trisomy 9 alone or with one other abnormality, are considered “favorable” abnormalities, as they associated with survival times that are similar to those of patients with the diploid karyotype. Abnormalities of chromosomes 5 or 7, or the presence of more than three chromosomal abnormalities (complex karyotype) define an “unfavorable” karyotype and are associated with shorter overall survival time. Abnormalities in chromosome 17 are associated with the poorest survival.

Somatic mutations

Mutations in genes that activate JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling are thought to drive the disease process in most patients with primary MF. Approximately 50% to 60% of patients carry the JAK2^V617F mutation, and an additional 5% carry a mutation in MPL (MPL^W151L/K). Mutations in CALR, another gene involved in dysregulated JAK-STAT signaling, have been found in 25% to 35% of PMF cases, and appear to be mutually exclusive with JAK2 and MPL mutations. Other described mutations found in approximately 3% to 20% of patients include those in ASXL1, SRSF2, EZH2, TET2, DNMT3, CBL, and IDH1/IDH2. These mutations often co-occur with the three driver mutations and are not exclusive of each other. While the prognostic relevance of these mutations has not been definitively shown, studies evaluating their prognostic relevance in patients with primary MF suggest that mutations of CALR (favorable) and ASXL1, EZH2, and SRSF2 (unfavorable) have prognostic significance that is independent of the Dynamic International Prognostic Scoring System (D-IPSS).

Diagnosis

Primary MF is diagnosed according to 2008 WHO criteria on the basis of clinical, histological, and molecular characteristics (Table 1). Secondary MF (post-PV or post-ET MF) is diagnosed according to criteria developed in 2007 by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) (Table 4).

TABLE 3: International Working Group for Myelofibrosis Research and Treatment recommended criteria for diagnosis of post–polycythemia vera and post–essential thrombocythemia myelofibrosis

TABLE 4: International prognostic score for essential thrombocythemia (IPSET) and IPSET-thrombosis

Primary MF is diagnosed based on assessment of clinical and laboratory findings as well as careful pathological examination of the bone marrow. The differential diagnosis should include bone marrow fibrosis associated with other neoplastic and non-neoplastic conditions. Post-PV and post-ET MF should be diagnosed based on criteria defined by the IWG-MRT, which include the following: previous diagnosis of PV or ET by WHO criteria; bone marrow fibrosis grade 2–3 (on a 0–3 scale) or grade 3–4 (on a 0–4 scale); and presence of two additional criteria (anemia, leukoerythroblastic peripheral blood picture, increasing splenomegaly, increased lactate dehydrogenase level [for ET], or development of one or more constitutional symptoms (> 10% weight loss in 6 months, night sweats, unexplained fever).

Prognosis

The most common fatal complications of MF are thrombohemorrhagic complications, infections, and transformation to acute leukemia. The International Prognostic Scoring System (IPSS) constructed by the IWG-MRT in 2009, which is designed to be used at diagnosis to guide treatment decisions, is the most widely used prognostic scoring system (Table 5). The risk factors included in the model are age > 65 years, presence of constitutional symptoms, hemoglobin < 10 g/dL, leukocyte counts > 25 × 10⁹/L, and circulating blasts > 1%. The prognostic model stratifies patients into four risk categories with estimated median survival times ranging from 2.3 years (high risk) to 11.3 years (low risk).

TABLE 5: Prognostic scoring systems for primary myelofibrosis

An updated version of the IPSS, the D-IPPS, which treats the risk factors as time-dependent covariates in the multivariate model, can be used to define prognosis at any point in the course of a patient’s treatment. The only difference in scoring between the IPSS and D-IPSS is that in the D-IPSS, anemia is given 2 points instead of 1 (see Table 5). Patients stratified by the D-IPSS have survival times ranging from 1.5 years (high risk) to “not reached” for those categorized as low-risk. A third prognostic model, DIPSS-plus, which includes red blood cell–transfusion dependence, platelet count < 100 × 10⁹/L, and unfavorable karyotype as additional risk factors, has also been developed. This model also stratifies patients into four risk categories, with survival ranging from 1.3 years (high risk) to 15.4 years (low risk).

A summary of the three prognostic scoring systems is shown in Table 5. All of these prognostic risk-stratification systems can be useful for identifying high-risk patients who may benefit most from intensive treatment strategies, such as allogeneic stem cell transplantation (ASCT). Recent studies have suggested an association between mutations and prognosis. CALR has been associated with longer survival, while survival duration is predicted to be shorter for patients who do not have any of the known driver mutations (JAK2, CALR, MPL), so-called “triple-negative” disease. In addition, mutations in epigenetic modulator genes have been associated with worse survival (ASXL1, SRSF2, EZH2) and risk of transformation to acute leukemia (ASXL1, SRSF2, EZH2, IDH1/IDH2). How best to implement this molecular information in clinical practice has not yet been determined.

Treatment

Risk stratification should be performed at diagnosis to guide treatment decisions. While younger patients in the intermediate-2 and high-risk groups should be considered for allogeneic stem cell transplantation (ASCT), treatment planning for patients not eligible for ASCT and for those in the lower-risk categories is usually based on the presence of disease-related symptoms and signs. A recommended treatment algorithm is shown in Table 6.

Treatments for anemia

TABLE 6: Treatment approach for patients with myelofibrosis

Progressive anemia with transfusion dependency remains a significant problem in managing patients with MF. Options for managing MF-related anemia include the use of erythroid-stimulating agents, steroids, androgens, or immunomodulatory drugs (thalidomide [Thalomid] or lenalidomide [Revlimid]). Subcutaneous erythropoietin (EPO) injections (40,000 U/wk) can be given to patients with low serum EPO (< 125 U/L). Corticosteroids, such as prednisone (0.5–1 mg/kg/d), or androgens, such as testosterone enanthate injections (400–600 mg/wk) and oral fluoxymesterone (10 mg tid) have also been shown to be useful. Immunomodulatory drugs such as thalidomide and lenalidomide have also been shown to improve MF-related anemia. Thalidomide can be given at low doses (50 mg/day) in combination with tapering doses of prednisone (for first 3 months only). A phase II study combining lenalidomide and prednisone for the first 3 months reported a 30% hemoglobin response, but only in patients without baseline thrombocytopenia or neutropenia.

Treatments for splenomegaly and constitutional symptoms

The majority of patients with symptomatic MF report significant splenomegaly and constitutional symptoms that severely reduce quality of life. Options for managing these symptoms include HU, alkylating agents (melphalan, busulfan, or cladribine), IFN-a, immunomodulatory agents, JAK2 inhibitors, splenectomy, and splenic radiation. The pros and cons of each are discussed below.

Conventional drug therapy. Before the approval of ruxolitinib, HU was considered the first-line treatment for splenomegaly. However, the response rate is less than 50% and HU rarely induces complete spleen regression. In addition, high dosbides are often necessary to elicit a significant response and can result in intolerable cytopenias. Oral alkylating agents have also been used, but their use often results in severe and prolonged cytopenias. Immunomodulatory agents, such as low-dose thalidomide or lenalidomide, have been shown to be useful in reducing splenomegaly, in addition to improving anemia. Lenalidomide, given in combination with prednisone for the first 3 months, has been shown to reduce splenomegaly in up to 40% of patients and anemia in up to 30%. In addition, evidence suggests that the combination may occasionally reduce JAK2 allele burden and improve bone marrow fibrosis.

Interferon-a. IFN-a has been evaluated as a therapy for MF, but response rates have been low and the significant toxicity of this agent prevents its use in many patients. However, it has been suggested that IFN-a may alter the natural history of disease and reverse bone marrow fibrosis if used in early-stage MF and in patients with proliferative features (high blood count) but without splenomegaly. Thus, pegylated IFN-a, which has been reported to have fewer side effects, may be worth studying in this setting. We at MD Anderson recommend using IFN-a for women of childbearing age contemplating pregnancy.

JAK inhibitors. Before the discovery of the essential role of dysregulated JAK-STAT signaling in MF, treatments for MF were mainly palliative, had limited efficacy in reducing clinical manifestations, and were often poorly tolerated. The development of JAK2 inhibitors and the approval of ruxolitinib in the US, Europe, and Canada represent a significant milestone in the development of therapies for MF. In addition to ruxolitinib, several other JAK inhibitors are being evaluated in clinical trials.

Regulatory approval of ruxolitinib for use in patients with MF was based on the results of two pivotal phase III trials, one comparing ruxolitinib against placebo (COMFORT-I) and the other comparing it against best available therapy (COMFORT-II). Both studies showed that significantly more patients in the ruxolitinib arms had a ≥ 35% reduction in spleen volume from baseline (as measured by MRI or CT; approximately 50% reduction by palpation) at week 24 (COMFORT-I) or week 48 (COMFORT-II). Ruxolitinib also improved MF-related symptoms and quality of life significantly more than either placebo or best available therapy. More importantly, long-term follow-up analyses have shown that these effects are durable and that ruxolitinib may even improve survival and possibly delay or reverse bone-marrow fibrosis in the long term.

The most common toxicities associated with ruxolitinib are thrombocytopenia and anemia. However, most patients with symptomatic splenomegaly or systemic MF-related symptoms, even those with transfusion-dependent anemia, can be successfully treated with ruxolitinib. Current recommendations are to use a starting dose of 20 mg twice per day (bid) in patients with platelet levels above 200 × 10⁹/L, 15 mg bid in patients with platelet levels between 100 and 200 × 10⁹/L, and 5 mg bid for patients with platelet counts between 50 × 10⁹/L and 100 × 10⁹/L. The dose can then be modified as tolerated to a maximum dose of 25 mg bid.

Splenectomy and radiation. Splenectomy is only indicated in patients with symptomatic portal hypertension, severe splenomegaly associated with pain or severe cachexia that is refractory to drug therapy, or frequent red blood cell transfusions and cytopenia. The procedure is associated with significant morbidity and mortality: up to 50% of patients have complications after splenectomy, and perioperative mortality is 5% to 10%.

For cases of painful hepatosplenomegaly, radiation can provide transient symptomatic relief (median duration of response, 3–6 months); however, it is associated with a > 10% mortality rate due to complications. Therefore, splenic radiation is only recommended as a last resort for palliation in patients who have not responded to other therapy.

Allogeneic stem cell transplantation

ASCT is the only curative treatment for MF; however, less than 10% of patients undergo the procedure owing to advanced age, severe comorbidities, or not having a donor. Patients with intermediate-2 or high-risk disease should be considered for ASCT if they have good performance status and no comorbidities. Reduced-intensity conditioning may be used in older patients and those with comorbidities. The role of splenectomy before ASCT is controversial and this procedure is not routinely recommended. More recently, it has been suggested that therapy with ruxolitinib may be used as a bridge to ASCT. Prospective studies are underway to evaluate whether pretreatment with ruxolitinib may be an effective strategy to improve outcomes after ASCT and potentially increase the number of patients who are eligible for this procedure.

Suggested Reading

Barbui T, Barosi G, Biregard G, et al: Philadelphia-negative classical myeloproliferative neoplasms: Critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 29:761–770, 2011.

Barbui T, Thiele J, Passamonti F, et al: Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: An international study. J Clin Oncol 29:3179–3184, 2011.

Barbui T, Thiele J, Passamonti F, et al: Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. Blood 119:2239–2241, 2012.

Cervantes F, Dupriez B, Pereira A, et al: New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 113:2895–2901, 2009.

Finazzi G, Carobbio A, Thiele J, et al. Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia 26:716–719, 2012.

Harrison C, Kiladjian JJ, Al-Ali HK, et al: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366:787–798, 2012.

Jones AV, Chase A, Silver RT, et al: JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genetics 41:446–449, 2009.

Jones AV, Cross NC: Inherited predisposition to myeloproliferative neoplasms. Ther Adv Hematol 4:237–253, 2013.

Mehta J, Wang H, Iqbal SU, et al: Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 2013:1–6, 2013.

Mesa RA, Niblack J, Wadleigh M, et al: The burden of fatigue and quality of life in myeloproliferative disorders: An international internet-based survey of 1179 MPD patients. Cancer 109:68–76, 2007.

Moulard O, Mehta J, Fryzek J, et al: Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol 92:289–297, 2014.

Mughal TI, Vaddi K, Sarlis NJ, et al: Myelofibrosis-associated complications: Pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med 7:89–101, 2014.

Passamonti F, Rumi E, Pungolino E, et al: Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med 117:755–761, 2004.

Passamonti F, Cervantes F, Vannucchi AM, et al: A dynamic prognostic model to predict survival in primary myelofibrosis: A study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 115:1703–1708, 2010.

Passamonti F, Maffioli M, Merli M, et al: Clinical predictors of outcome in MPN. Hemtol Oncol Clin North Am 26:1101–1116, 2012.

Passamonti F, Thiele J, Girodon F, et al: A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood 120:1197–1201, 2012.

Quintas-Cardama A, Kantarjian H, Cortes J, et al: Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov 10:127–140, 2011.

Rosenthal A, Mesa RA: Janus kinase inhibitors for the treatment of myeloproliferative neoplasms. Expert Opin Pharmacother 15:1265–1276, 2014.

Stein BL, Tiu RV: Biological rationale and clinical use of interferon in the classical BCR-ABL-negative myeloproliferative neoplasms. J Interferon Cytokine Res 33:145–153, 2013.

Stubig T, Alchalby H, Ditschkowski M, et al: JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis. Leukemia 28:1736–1738, 2014.

Tefferi A, Rumi E, Finazzi G, et al: Survival and prognosis among 1545 patients with contemporary polycythemia vera: An international study. Leukemia 27:1874-1881, 2013.

Vannucchi AM, Lasho TL, Guglielmelli P, et al: Mutations and prognosis in PMF. Am J Hematol 88:141–150, 2013.

Vannucchi AM, Hagop K, Kiladjian J-J, et al: A pooled overall survival analysis of the COMFORT studies: 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. Blood 122: abstract 2820, 2013.

Vannucchi AM, Kiladjian JJ, Griesshammer M, et al: Ruxolitinib vs standard therapy for the treatment of polycythemia vera. N Engl J Med 372:426–435, 2015.

Vardiman JW, Thiele J, Arber DA, et al: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important change. Blood 114:937–951, 2009.

Verstovsek S, Mesa RA, Gotlib J, et al: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799–807, 2012.

Verstovsek S, Mesa RA, Gotlib J, et al: Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: Results of a median 2-year follow-up of COMFORT-I. Haematologica 98:1865–1871, 2013.