Hypereosinophilic Syndrome

Background

Hypereosinophilic syndrome (HES) is a myeloproliferative disorder (MPD) characterized by persistent eosinophilia that is associated with damage to multiple organs.^{[1, 2, 3, 4, 5, 6, 7]} Peripheral eosinophilia with tissue damage has been noted for approximately 80 years, but Hardy and Anderson first described the specific syndrome in 1968.^[8] In 1975, Chusid et al defined the three features required for a diagnosis of hypereosinophilic syndrome^[4] :

• A sustained absolute eosinophil count (AEC) greater than >1500/µl, which persists for longer than 6 months
• No identifiable etiology for eosinophilia
• Signs and symptoms of organ involvement

However, due to advances in the diagnostic techniques, secondary causes of eosinophilia can be identified in a proportion of cases that would have otherwise been classified as idiopathic hypereosinophilic syndrome.

The differential diagnosis (see DDx) of hypereosinophilic syndrome includes other causes of eosinophilia,^{[1, 9, 10, 11]} which may be classified as familial or acquired. Familial eosinophilia is an autosomal dominant disorder with a stable eosinophil count and a benign clinical course. Acquired eosinophilia is further divided into secondary, clonal, and idiopathic eosinophilia.^[12]

Secondary eosinophilia

Secondary eosinophilia is a cytokine-derived (interleukin-5 [IL-5]) reactive phenomenon. Worldwide, parasitic diseases are the most common cause, whereas in developed countries, allergic diseases are the most common cause.^[1] Other causes include the following:

• Malignancies – Metastatic cancer, T-cell lymphoma,^[13] colon cancer
• Pulmonary eosinophilia – Loffler syndrome,^[14] Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis
• Connective tissue disorders – Scleroderma, polyarteritis nodosa
• Skin diseases – Dermatitis herpetiformis
• Inflammatory bowel disease
• Sarcoidosis
• Addison disease

Clonal eosinophilia

Clonal eosinophilia is diagnosed by bone marrow histology, cytogenetics, and molecular genetics. Causes include the following:

• Acute leukemia – Pre-B acute lymphoblastic leukemia (ALL), acute myeloid leukemia M4 with bone marrow eosinophilia (AML-M4Eo)
• Chronic myeloid disorders

Molecularly defined disorders include the following:

• BCR-ABL chronic myeloid leukemia
• PDGFRA (platelet-derived growth factor receptor, alpha polypeptide)–rearranged eosinophilia – Systemic mastocytosis–chronic eosinophilic leukemia (SM-CEL)
• PDGFRβ-rearranged eosinophilia
• KIT-mutated systemic mastocytosis

Clinicopathologically assigned disorders include the following:

• Myelodysplastic syndrome (MDS)
• Myeloproliferative disorders (MPDs) – Classic MPD (polycythemia) and atypical MPD (chronic eosinophilic leukemia, systemic mastocytosis, chronic myelomonocytic leukemia)

Idiopathic eosinophilia

Idiopathic eosinophilia is a diagnosis of exclusion when secondary and clonal causes of eosinophilia are excluded. Hypereosinophilic syndrome is a subset of idiopathic eosinophilia characterized by persistent eosinophilia (AEC >1500/µL) of longer than 6 months' duration associated with organ damage. However, long-term follow-up and X-linked clonality studies indicate that at least some patients with hypereosinophilic syndrome have an underlying clonal myeloid malignancy or a clonal or phenotypically abnormal T-cell population, suggesting a true secondary process.

The literature now favors the view that cases of idiopathic hypereosinophilic syndrome with FIP1L1 indeed represent chronic eosinophilic leukemia, because these patients have a molecular genetic abnormality, specifically an FIP1L1–PDGFRA fusion gene.^[15] In addition, there are documented cases of acute transformation to either AML or granulocytic sarcoma in some cases of hypereosinophilic syndrome after an interval as long as 24 years. In such cases, a diagnosis of chronic eosinophilic leukemia is made in retrospect when acute transformation provides indirect evidence that the condition was likely to have been a clonal, neoplastic, MPD from the beginning.

In addition, some patients with hypereosinophilic syndrome present with features typical of MPDs, such as hepatosplenomegaly, the presence of leukocyte precursors in the peripheral blood, increased alkaline phosphatase level, chromosomal abnormalities, and reticulin fibrosis. Cytogenetic studies in such cases may be normal, but molecular genetic studies may show aberrations.

The best-described aberration is the interstitial deletion on chromosome 4q12, resulting in fusion of the 5’ portion of the FIP1L1 gene to the 3’ portion of the PDGFRA gene. This fusion gene encodes for the FIP1L1–PDGFR alpha protein, the constitutively activated tyrosine kinase activity that induces eosinophilia. The prevalence of such a mutation is 0.4% in unselected cases of eosinophilia, but it can be as high as 12–88% in cohorts that meet the World Health Organization (WHO) criteria for idiopathic hypereosinophilic syndrome, particularly those with features of MPD (increased levels of tryptase and mast cells in the bone marrow).

Patients with hypereosinophilic syndrome with the PDGFRA mutation have a very high incidence of cardiac involvement and carry a poor prognosis without therapy. Fortunately, the results of imatinib therapy in such cases of hypereosinophilic syndrome are very encouraging.

The other subset of idiopathic eosinophilia, hypereosinophilic syndrome with clonal or immunophenotypically aberrant T-cells, is associated with increased secretion of IL-5 and cutaneous manifestations. Simon et al reported immunophenotypic abnormality in 16 of 60 patients with hypereosinophilic syndrome.^[16] Moreover, nine patients had CD3+CD4+CD8- T cells, three had CD3+CD4-CD8+ cells, three had CD3+CD4-CD8- cells, and two had CD3-CD4+ cells (one patient had two distinct populations). Progression to T-cell lymphoma was observed in this subset of patients with hypereosinophilic syndrome, particularly those with the CD3-CD4+ phenotypes.^{[16, 17]}

Chronic eosinophilic leukemia

Chronic eosinophilic leukemia is caused by autonomous proliferation of clonal eosinophilic precursors. Simplified criteria for the diagnosis of chronic eosinophilic leukemia include the following:

• Eosinophil count of at least 1500/µL
• Peripheral blood blast count of >2% and a bone marrow blast cell count that is >5% but < 19% of all nucleated cells
• Criteria for atypical chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia, and chronic granulocytic leukemia (BCR-ABL–positive CML) are not met
• Myeloid cells are demonstrated to be clonal (eg, by detection of clonal cytogenetic abnormality or by demonstration of a very skewed expression of X chromosome genes)

Some of the cytogenetic abnormalities that have been described in chronic eosinophilic leukemia include t(5:12) and t(8:13), and molecular genetic abnormalities include the FIP1L1-PDGFRA fusion gene and ETV6-PDGFRβ.

Other resources

Other sources of information are as follows:

• For discussion of cases in children, see Pediatric Hypereosinophilic Syndrome
• For discussion of skin findings, see Dermatologic Manifestations of Hypereosinophilic Syndrome
• For patient education information, see the Cancer Center, as well as Leukemia

• References

Pathophysiology

Eosinophil production is governed by several cytokines, including IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-5 appears to be the most important cytokine that is responsible for differentiation of the eosinophil line.^{[2, 9]}

Unlike neutrophils, eosinophils can survive in the tissues for weeks. Their survival in tissues depends on the sustained presence of cytokines. Only eosinophils and basophils and their precursors have receptors for IL-3, IL-5, and GM-CSF. In vitro, eosinophils survive less than 48 hours in the absence of cytokines.

Eosinophil granules contain toxic cationic proteins, which are the primary mediators of tissue damage. These toxins include major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and eosinophil cationic protein. The latter two are ribonucleases. Free radicals produced by the eosinophilic peroxidase and the respiratory burst oxidative pathway of the infiltrating eosinophils further enhance the damage.

Eosinophils amplify the inflammatory cascade by secreting chemoattractants that recruit more eosinophils. Such chemoattractants include the following:

• Eotaxin
• Platelet-activating factor
• The cytokine RANTES (regulated upon activation, normal T cell expressed, and secreted).

Several mechanisms have been proposed for the pathogenesis of hypereosinophilic syndrome, including overproduction of eosinophilopoietic cytokines, their enhanced activity, and defects in the normal suppressive regulation of eosinophilopoiesis. Organ damage induced by hypereosinophilic syndrome is due to the eosinophilic infiltration of the tissues accompanied by the mediator release from the eosinophil granules. Hence, the level of eosinophilia is not a true reflection of organ damage.

The most serious complication of hypereosinophilic syndrome is cardiac involvement, which can result in myocardial fibrosis, chronic heart failure (CHF), and death. The mechanisms of cardiac damage are not entirely understood, but the damage is marked by severe endocardial fibrotic thickening of either or both ventricles, resulting in restrictive cardiomyopathy due to inflow obstruction.

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Epidemiology

Frequency

Various sources indicate that true hypereosinophilic syndrome is rare. The most common cause of eosinophilia in the United States is an allergic reaction or allergic disease. Worldwide, the most common cause of eosinophilia is parasitosis.^[18]

Mortality/Morbidity

Hypereosinophilic syndrome is a chronic and progressive disorder that is potentially fatal. Blast transformation could occur after many years. True idiopathic hypereosinophilic syndrome is generally indolent, but patients with characteristics suggestive of a myeloproliferative/neoplastic disorder and those who develop chronic heart failure have a worse prognosis.

An older review of 57 patients with advanced hypereosinophilic syndrome reported a mean survival of 9 months and a 3-year survival rate of 12%.^[4] A later analysis from France noted an 80% survival at 5 years and a 42% survival at 15 years among 40 patients with hypereosinophilic syndrome.^[19]

Race-, Sex- and Age-related Demographics

No racial predilection is reported for hypereosinophilic syndrome. There is a male predominance in hypereosinophilic syndrome, with a male-to-female ratio of 9:1.

Hypereosinophilic syndrome is most commonly diagnosed in patients aged 20-50 years, with a peak incidence in the fourth decade. Hypereosinophilic syndrome is rare in children. The incidence of hypereosinophilic syndrome seems to decrease in the elderly population.

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History

Hypereosinophilic syndrome is a heterogeneous disease process; thus, it has multiple manifestations, which may occur simultaneously or individually. The presentation can be sudden and dramatic, with cardiac, neurologic, or thrombotic complications, but, more often, the onset is insidious.^[20] In one case series, hypereosinophilic syndrome was discovered as an incidental finding in 12% of patients.

Virtually any organ system may be involved in hypereosinophilic syndrome, but the heart, central nervous system (CNS), skin, and respiratory tract are commonly involved. Thromboembolic disease is not infrequent. Major symptoms of hypereosinophilic syndrome include the following:

The cardiac system is one of the most frequently involved systems, and cardiac complications are a leading cause of mortality. Damage typically occurs in three stages: (1) initial acute necrosis early in the disease process that typically has no clinical manifestations but may occasionally be severe enough to cause symptoms; (2) thrombotic phase; and (3) endomyocardial fibrosis. Common symptoms in these phases include chest pain, dyspnea, or orthopnea.

Hematologic manifestations are largely nonspecific and may include fatigue, which may be due to the anemia that is occasionally observed with hypereosinophilic syndrome. Left upper quadrant pain may indicate splenomegaly, which occurs in about 40% of patients. Thrombotic episodes occur frequently and often present as neurologic symptoms. The thrombotic events may occur solely due to cardiac disease, or they may be caused by hypercoagulability. The mechanism of hypercoagulability is unknown.

Neurologic symptoms are as follows:

• Embolic or thrombotic strokes or transient ischemic episodes may occur and are often the initial manifestations of hypereosinophilic syndrome
• Some patients with hypereosinophilic syndrome experience an encephalopathy caused by CNS dysfunction
• Blurred vision and slurred speech have been reported
• Peripheral neuropathies account for about 50% of all neurologic symptoms in hypereosinophilic syndrome; their etiology is poorly understood, but they may present as symmetric or asymmetric sensory changes, pure motor deficits, or mixed sensory and motor complaints

Respiratory manifestations are as follows:

• The most benign variant of hypereosinophilic syndrome involves eosinophilic infiltrates in the bases and periphery of the lungs, according to one source.
• Patients often have recurrent angioedema
• A chronic, persistent cough, usually nonproductive, is the most common respiratory symptom reported in hypereosinophilic syndrome
• Dyspnea may occur due to CHF or pleural effusions (which are not always secondary to CHF)
• Less frequently, pulmonary fibrosis occurs after prolonged disease and often accompanies cardiac fibrosis
• Bronchospasm and asthmatic symptoms are infrequent
• Rhinitis is sometimes a presenting symptom

Rheumatologic manifestations are as follows:

• Arthralgias and myalgias are frequent complaints
• Raynaud phenomenon occurs but is infrequent

Dermatologic manifestations are as follows:

• Skin involvement is common and nonspecific
• The most common symptom is pruritus^[21]
• Dermatographism and angioedema are also frequently present

Gastrointestinal manifestations are as follows^[22] :

• Diarrhea is a relatively common complaint, occurring in approximately 20% of patients with hypereosinophilic syndrome
• Nausea and abdominal pain are also common complaints
• Occasionally, small bowel necrosis due to microthrombi can occur
• Some patients present with sclerosing cholangitis

Constitutional signs and symptoms are as follows:

• Many patients experience fever and night sweats
• Some sources identify anorexia and weight loss as common presenting symptoms; however, other sources report that these symptoms do not usually occur unless underlying cardiac disease is present

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Physical

The physical findings of hypereosinophilic syndrome are varied and parallel the clinical history.

Cardiac findings are as follows:

• Evidence of CHF becomes prominent with advanced hypereosinophilic syndrome and is an ominous sign
• Various murmurs may be heard, especially mitral or tricuspid regurgitation
• Splinter hemorrhages are often observed with cardiac involvement
• Physical findings typical of restrictive heart disease can be expected

Hematologic findings include splenomegaly in approximately 40% of patients.

Neurologic findings are as follows:

• Physical findings associated with stroke and transient ischemic attacks can be observed
• When peripheral neuropathy is present, findings may be purely sensory, entirely motor, or a combination of both
• Deficits are often symmetric
• Mononeuritis multiplex and muscle atrophy due to radiculopathy are sometimes encountered
• Generalized weakness is observed but is less specific

Pulmonary findings are as follows:

• Rales may accompany infiltrates and fibrosis
• Findings typical of CHF with effusion may also be encountered
• Angioedema is often a prominent feature associated with pulmonary involvement

Rheumatologic findings are as follows:

• Large joint effusions can occur
• Digital necrosis is rare but sometimes observed with associated Raynaud phenomenon

The skin is among the most common organ systems involved in hypereosinophilic syndrome; more than half of all patients have cutaneous involvement. In a minority of reports, skin involvement is the only manifestation of hypereosinophilic syndrome.

Most skin eruptions fall into two patterns. One pattern is angioedematous or urticarial and associated with a benign prognosis. The other pattern is erythematous, pruritic papules, plaques, and nodules, with or without ulceration. A special form of urticaria is dermatographism, which occurs in up to 75% of affected patients.

Less common cutaneous manifestations include the following:

• Erythroderma
• Erythema annulare centrifugum
• Erythema gyratum repens
• Mucosal ulcerations

Note the images below.

View Image

Indurated edematous plaques of hypereosinophilic syndrome on a patient's legs.

View Image

Erythroderma in a patient with hypereosinophilic syndrome.

Gastrointestinal findings are as follows:

• Hepatomegaly may occur with chronic active hepatitis due to hypereosinophilic syndrome
• Hepatomegaly may also occur with Budd-Chiari syndrome, which may infrequently be a thrombotic complication of hypereosinophilic syndrome

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Approach Considerations

After a thorough workup has excluded causes for secondary eosinophilia, a diagnosis of hypereosinophilic syndrome is suspected in cases of persistent eosinophilia. Any such patients with a documented absolute eosinophil count (AEC) greater than 1500/µL on at least two occasions should be evaluated for hypereosinophilic syndrome, regardless of the presence of symptoms.

A complete blood cell (CBC) count and peripheral smear is warranted.^[24]

Serum tryptase levels are elevated in FIP1LI-PDGFRA –positive hypereosinophilic syndrome, as well as systemic mastocytosis with chronic eosinophilic leukemia (SM-CEL). Hence, in such cases, the workup should include the following:

• Bone marrow tryptase levels
• Immunophenotyping of mast cells – Mast cells in systemic mastocytosis coexpress CD117 with CD2 and/or CD25
• Molecular genetic studies to detect FIP1L1-PDGFRA mutation (which is present in hypereosinophilic syndrome and systemic mastocytosis) and C-KIT mutation (which is present in systemic mastocytosis) are done to determine imatinib sensitivity

Bone marrow biopsy should be evaluated for the following :

• Morphologic examinations to look for features of myeloproliferative disorders (MPDs) and to look for dense aggregates of mast cells (greater than 15 cells) in systemic mastocytosis
• Special stains should include reticulin stain for myelofibrosis and tryptase staining for mast cells when serum tryptase levels are elevated
• Cytogenetics: Most patients with hypereosinophilic syndrome have normal karyotypes; in those who have cytogenetic changes, the changes may vary from aneuploidy to Philadelphia chromosome
• Molecular genetic studies: FIP1L1/PDGFRA should be evaluated in all patients with increased tryptase levels; this mutation is present in both hypereosinophilic syndrome and systemic mastocytosis; C-KIT mutation should also be evaluated in patients with increased tryptase levels

Human leukocyte antigen (HLA) typing should be done early in the course of hypereosinophilic syndrome for patients with aggressive disease, cytogenetic aberration, or the FIPL1/PDGFRA fusion gene.

Other studies include the following:

• T-cell immunophenotyping
• T-cell receptor gene rearrangement
• Interleukin-5 (IL-5) levels
• Computed tomography (CT) scanning of the chest, abdomen, and pelvis to look for lymphadenopathy and splenomegaly

Initial evaluation of suspected hypereosinophilic syndrome should include tests to look for any evidence of end-organ damage, as follows:

• Electrocardiography (ECG)
• Echocardiography
• Troponin levels: Increased levels indicate the presence of cardiomyopathy and predict the onset of cardiogenic shock due to imatinib therapy.
• Pulmonary function tests
• Tissue biopsy may be required in symptomatic patients, but is not always essential

Wang has proposed an algorithm for the workup of patients with hypereosinophilia.^[25]

• References

Imaging Studies

Echocardiography is helpful in the initial evaluation and monitoring of cardiac disease in patients suspected with hypereosinophilic syndrome.^[26] Intracardiac thrombi may be detected, as well as the fibrosis that appears not only as areas of increased echogenicity but often as posterior mitral valve leaflet thickening. Because the papillary muscles are often involved in hypereosinophilic syndrome, mitral and tricuspid dysfunction may also be detected by echocardiography.

CT scanning of the chest, abdomen, and pelvis is done to look for lymphadenopathy and splenomegaly.

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Histologic Findings

Eosinophil infiltrates are present in affected tissues in patients with hypereosinophilic syndrome. Cutaneous histologic features vary with the pattern of presentation. In patients with papular or nodular lesions, perivascular mixed cellular infiltrates (eosinophils and other cell types) are present. However, vasculitis is not present.

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Blood Studies

Results of hematologic studies in patients with hypereosinophilic syndrome are as follows:

• Eosinophilia is present (>1500 cells/µL)
• The overall neutrophil count may be normal, but it is often elevated in hypereosinophilic syndrome; many patients have absolute neutrophilia
• Approximately 50% of the patients with hypereosinophilic syndrome are anemic at presentation, often because of anemia of chronic disease
• Platelet counts are most often normal, but may be elevated
• Eosinophils in the peripheral blood are mostly mature forms; immature eosinophilic precursors are rare in the peripheral blood.
• Morphologic abnormalities that have been described include nuclear hypersegmentation, hypogranularity, and hypergranularity
• Cases of hypereosinophilic syndrome with features of myeloproliferative disorder (MPD) show circulating leukocyte precursor anemia and thrombocytopenia or thrombocytosis; teardrops and nucleated red blood cells may be seen
• A National Institute of Health series indicated that the presence of eosinophils with vacuolization and hypogranularity is more commonly associated with cardiac disease.^[27]
• Leukocytosis in excess of 90,000/µL carries a bad prognosis

Other blood study results are as follows:

• Increased serum tryptase level suggests a FIP1L1-PDGFRA mutation; always rule out C-KIT mutation, which is characteristic of systemic mastocytosis whenever serum tryptase is elevated, because disease from the most common form of C-KIT mutation in systemic mastocytosis, Asp 816 to Val, is not responsive to imatinib treatment
• Interleukin-5 (IL-5 ) levels are elevated in cases of hypereosinophilic syndrome that are associated with clonal T-cell disease; interferon alpha should be considered in such cases due to its down-regulating effects on IL-5 production by T-helper 2 (TH2) cells
• Immunoglobulin E (IgE) levels may be elevated, and hypergammaglobulinemia is common; increased IgE levels have prognostic significance, as these patients have a lower risk of developing hypereosinophilic syndrome–associated cardiovascular disease and respond well to steroid therapy
• Serum vitamin B-12 levels may be elevated in the presence of associated myeloproliferative features

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Biopsy

An endocardial biopsy may be performed via cardiac catheterization if any question about the diagnosis of hypereosinophilic syndrome exists.^[28]

Perform bone marrow aspiration and biopsy, and submit samples for cytogenetic studies. Occasionally, the findings may suggest an atypical presentation of chronic myelogenous leukemia. Cytogenetic abnormalities or the presence of a myeloproliferative picture in the bone marrow may be indicative of more aggressive disease.

If cutaneous involvement is present, skin biopsies may be performed to rule out other diagnoses that have similar skin presentations, such as the following:

• Drug eruptions
• Cutaneous T-cell lymphoma
• Wells syndrome
• Immunobullous diseases
• Vasculitis

• References

Approach Considerations

Whether and how to treat symptomatic hypereosinophilic syndrome depends on the clinical presentation, laboratory findings, and mutational analysis.^[29] Currently, there are no recommendations for treating asymptomatic patients with hypereosinophilic syndrome, as treatment itself is not without risks. Such patients are closely monitored with serum troponin level measurements every 3-6 months, and echocardiography and pulmonary function tests every 6-12 months.

In contrast, cases of hypereosinophilic syndrome with myeloproliferative features, particularly those with FIP1L1/PDGFRA mutation, should be treated aggressively. These patients carry a worse prognosis without treatment.

In all patients withoutFIP1L1/PDGFRA mutation, glucocorticoids are the first-line therapy.^[3] About one third of these cases do not respond to steroids. In such patients, interferon alpha and hydroxyurea are the second-line drugs of choice.^[30] For those individuals whose conditions do not respond to first- and second-line therapy, high-dose (400 mg/d) imatinib is the treatment of choice.

For patients withFIP1L1/PDGFRA mutation, imatinib is the drug of choice. The response rate in these cases approaches 100% in various studies.

For hypereosinophilic syndrome that is refractory to the usual treatments, chemotherapeutic agents that have been used with some success include chlorambucil, etoposide, vincristine, and 2-cda (2-chlorodeoxyadenosine) and cytarabine. However, alkylating agents are usually avoided in view of their potential to induce leukemias.

Alternatively, in refractory cases, particularly those resistant to imatinib therapy, hematopoietic stem cell transplantation (HSCT) has been shown to reverse the organ dysfunction. However, because of the limited experience and complications associated with HSCT, its routine use is not justified at the present time.

Recurrent thromboembolic complications occur despite anticoagulant therapy in hypereosinophilic syndrome. Currently, there are no recommendations for prophylactic use of aspirin or warfarin in the absence of documented thrombi in hypereosinophilic syndrome.

Leukapheresis is indicated as an emergency therapy in hypereosinophilic syndrome to control symptoms due to hyperleukocytosis.

Consult a hematologist to assist with the diagnosis, management, and follow-up care of patients with unexplained eosinophilia.

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Surgical Care

Management of cardiovascular disease

Valve replacement with bioprosthetic valves may be required in patients with hypereosinophilic syndrome and regurgitant lesions. Risk of thrombosis with mechanical valves is very high in patients with hypereosinophilic syndrome despite therapeutic anticoagulation.

Endocardiectomy may be required for patients with endomyocardial fibrosis, and thrombectomy may be required for individuals with thrombosis.

Splenectomy

Evidence of hypersplenism and pain due to splenic infarction are indications for splenectomy.

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Glucocorticoids

Due to the rapidity and reliability of its effect, a 5-day course of prednisone (1 mg/kg/d or 60 mg/d) is the initial treatment of choice for all FIP1L1/PGDFRA– negative patients. Eosinopenia occurs within hours of steroid administration. Subsequently, prednisone is tapered from a daily dose to the lowest dose required on alternate days to maintain disease control.

Glucocorticoids decrease eosinophilopoiesis by suppressing the transcription of genes for interleukin-3 (IL-3), IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF). These agents also inhibit cytokine-dependent survival of eosinophils, resulting in their increased apoptosis. Steroids are also believed to increase rapid sequestration of eosinophils.

Almost 70% of patients with hypereosinophilic syndrome respond well to steroid therapy, especially those who present with urticaria and high IgE levels. Response to steroid therapy indicates a better prognosis.

A course of steroid therapy is also given to asymptomatic patients to establish hypereosinophilic syndrome responsiveness to steroids, in case rapidly progressive organ involvement develops in the future.

Steroids are also used in the management of imatinib-induced cardiogenic shock. In such circumstances, elevation of the serum troponin level or an abnormal echocardiographic study is an indication for starting steroids.

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Imatinib

Imatinib mesylate (Gleevec) is the drug of choice for hypereosinophilic syndrome with FIP1L1/PDGFRA. A tyrosine kinase inhibitor, imatinib is also a potent inhibitor of other mutations, such as BCR-ABL, C-KIT, and PDGFRβ.

In patients with hypereosinophilic syndrome with FIP1L1/PDGFRA, imatinib induces clinical hematologic and molecular remission in the majority of cases. Resolution of symptoms and normalization of eosinophil count occur within 1-2 weeks. Bone marrow abnormalities, including myelofibrosis, resolve within 1–2 months.

In contrast, structural abnormalities in the cardiovascular system and fixed neurologic deficit may not improve with imatinib therapy. However, imatinib is shown to arrest progression of endomyocardial fibrosis if therapy is initiated before the onset of structural abnormalities.

However, in true idiopathic hypereosinophilic syndrome (FIP1L1/PDGFRA– negative), low-dose imatinib (100 mg/d) may not produce a durable remission. Response rates vary from 20% to 80%. This is thought to be due to alternate PDGFRA fusion partners. A higher dose (400 mg/d) is likely to produce partial to complete remission.

In addition, experience with imatinib in chronic myelogenous leukemia (CML) shows that it is not effective in eliminating the early progenitor cells in CML. Extrapolating these results to hypereosinophilic syndrome, lifelong therapy with imatinib would be required in majority of patients. Because FIP1L1/PDGFRA– positive hypereosinophilic syndrome is predominantly a disease of young men and oligospermia is a complication of imatinib, sperm banking before initiation of therapy should be considered.

Other complications of imatinib include the following:

• Neutropenia
• Life-threatening eosinophilic myocarditis
• Peripheral edema
• Nausea
• Muscle cramps
• Bone pains
• Rash

A few cases of hypereosinophilic syndrome with acquired resistance to imatinib have been reported in the literature. These cases have been associated with single-base (T6741) substitution. A newer agent, PKC-412 (N-benzoyl-staurosporine; midostaurin) has been shown to have efficacy against T6741 mutation in animal models and in vitro. It competes for binding to the adenosine triphosphate (ATP) site on the protein kinase C (PKC) family of serine-threonine kinases. Bone marrow transplantation is an alternative in imatinib-resistant cases.^[31]

Molecular responsiveness to imatinib is assessed by screening for the PDGFRA mutation in the peripheral blood by fluorescent in situ hybridization (FISH) or reverse transcriptase–polymerase chain reaction (RT-PCR) at 3-6 month intervals in the first year and at 6-12 months intervals thereafter.

Khoury et al reported on features that predict responsiveness to treatment with imatinib, as indicated by eosinophil count < 1.5 x 10⁹ L at 1 month and improvement in clinical symptoms.^[32] Patient groups and response rates in their study were as follows:

• FIP1L1-PDGFR myeloid neoplasm (FP) – 100%
• PDGFRA-negative hypereosinophilic syndrome with four or more criteria suggestive of a myeloid neoplasm (MHES) – 54%
• Steroid-refractory PDGFRA-negative hypereosinophilic syndrome with fewer than four myeloid criteria – 0%

After patients who responded had remained in complete remission for at least 18 months, imatinib was tapered and discontinued in eight of the 16 FP patients and in one of the 13 with MHES. Six of the eight FP patients   and the patient with MHES remained in remission off therapy for a median of 29 months (range 14-36 months).

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Second-line Agents

Interferon alpha is a second-line drug of choice for patients whose condition does not respond to glucocorticoids.^{[33, 34, 35]} Hydroxyurea has also demonstrated efficacy for steroid-refractory cases.^[31]

Alemtuzumab (CamPath), an anti-CD52 monoclonal antibody, has been shown to control symptoms as well as eosinophilia in patients with refractory hypereosinophilic syndrome.^{[36, 37]} Strati et al reported complete hematologic response (CHR) for a median duration of 66 weeks in 10 of 12 patients and for a median duration of 123 weeks in five of six patients retreated after relapse; time to progression was significantly longer in patients who received alemtuzumab maintenance therapy than in those who were only observed.^[38]

Mepolizumab, a humanized anti–interleukin-5 monoclonal antibody, demonstrated corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid-responsive subjects with hypereosinophilic syndrome. A study of long-term use (median exposure of 251 weeks) found that mepolizumab was well tolerated and effective for this purpose.^[39]

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications in patients with hypereosinophilic syndrome. Glucocorticoids are the first-line therapy in patients without the FIP1L1/PDGFRA mutation, while imatinib is the first-line choice in patients with the FIP1L1/PDGFRA mutation. A variety of second-line agents may be used for refractory cases.

• References

Prednisone (Deltasone, Rayos)

• Dosing, Interactions, etc.

Clinical Context:  Initial DOC. Once eosinophils are suppressed, the dose may be slowly tapered. Patients whose condition responds to steroids tend to have a better prognosis.

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Class Summary

Corticosteroids often cause a rapid reduction in level of the eosinophilia. The mechanisms for this are not entirely clear.

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Hydroxyurea (Hydrea, Droxia)

• Dosing, Interactions, etc.

Clinical Context:  Second line of treatment. Goal is to reduce total white blood cell (WBC) count to < 10,000 cells/µL. One week of therapy may be required before a reduction of the eosinophil count is observed. Anemia and thrombocytopenia are common complications associated with this drug.

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Vincristine (Vincasar PFS)

• Dosing, Interactions, etc.

Clinical Context:  May be instituted in patients whose condition fails or is only partially responsive to hydroxyurea. A response is often observed within 1-3 d. Marrow suppression is less common than with hydroxyurea, but occurrence of neurologic toxicity may limit treatment and closely resemble the neurologic symptoms of hypereosinophilic syndrome.

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Chlorambucil (Leukeran)

• Dosing, Interactions, etc.

Clinical Context:  Primary alkylating agent used in cases in which prednisone fails and in those patients who cannot tolerate hydroxyurea or vincristine. A reasonable alternative for long-term treatment. Bone marrow suppression may be a problem.

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Etoposide (Toposar)

• Dosing, Interactions, etc.

Clinical Context:  Etoposide is a glycosidic derivative of podophyllotoxin that exerts a cytotoxic effect by stabilizing the normally transient covalent intermediates formed between the DNA substrate and topoisomerase II. The drug leads to single-stranded and double-stranded DNA breaks that arrest cellular proliferation in the late S or early G2 phase of cell cycle.

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Cytarabine

• Dosing, Interactions, etc.

Clinical Context:  An antimetabolite antineoplastic agent, cytarabine is converted intracellularly to the active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. It is metabolized in the liver, with a half-life of 1-3 h. The agent is widely distributed, including in the central nervous system and tears, after IV administration.

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Imatinib (Gleevec)

• Dosing, Interactions, etc.

Clinical Context:  Imatinib is specifically designed to inhibit the tyrosine kinase activity of bcr-abl kinase in Ph1-positive leukemic CML cell lines. It is well absorbed after oral administration, with maximum concentrations achieved within 2-4 hours. Elimination is primarily in feces in the form of metabolites.

• References

Class Summary

Chemotherapeutic agents may be used in patients whose conditions are refractory to steroid treatment. As a group, antineoplastic agents interfere with the production of eosinophils, but they may also cause toxicity to normal tissues, especially the bone marrow.

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Peginterferon alfa 2a (Pegasys, Pegasys ProClick)

• Dosing, Interactions, etc.

Clinical Context:  Has been reported to effectively suppress eosinophilia in several different patients using several different doses. Some patients have had progression of disease despite therapy.

• References

Interferon alpha-2b (Intron A)

• Dosing, Interactions, etc.

Clinical Context:  Has been reported to effectively suppress eosinophilia in several different patients using several different doses. Some patients have had progression of disease despite therapy.

• References

Class Summary

Immunomodulators are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, and intralesionally. These agents have demonstrated efficacy in small trials.

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Complications

Hypereosinophilic syndrome has many and varied complications. Their development depends entirely on which organ systems are involved in the disease process (see Presentation and Pathophysiology). The most serious complication of hypereosinophilic syndrome is cardiac involvement, which can lead to myocardial fibrosis, chronic heart failure, and death (see Pathophysiology).

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Prognosis

Hypereosinophilic syndrome carries a variable prognosis. It is a chronic and progressive disorder that is potentially fatal if left untreated. Blast transformation may occur after many years.

Although initial studies of hypereosinophilic syndrome showed a very poor prognosis (a 3-y survival rate of 12%),^[4] management of cardiovascular disease by early echocardiographic monitoring and advances in medical and surgical therapies have improved the overall survival. A study of 40 cases by Lefebcve et al showed a 5-year survival of 80% and a 15-year survival of 42%.^[19]

The availability of tyrosine kinase inhibitors such as imatinib, which prevent progression of cardiac disease and other organ damage—particularly in FIP1L1/PGDFRA–positive cases—will likely further improve the prognosis of hypereosinophilic syndrome. However, FIP1L1/PGDFRA– negative cases of hypereosinophilic syndrome that are resistant to corticosteroids have not been shown to have a durable response to imatinib.

Lastly, additional insight into the molecular pathogenesis of such cases of hypereosinophilic syndrome is required to develop effective targeted therapies.

Features that indicate a favorable prognosis in hypereosinophilic syndrome include the following:

• Angioedema
• Urticaria
• Elevated serum IgE level
• Sustained response to corticosteroids
• Early diagnosis and intensive management

The presence of features that are suggestive of myeloproliferative disorder (MPD) and leukocytosis greater than 90,000/μ L carry a worse prognosis in hypereosinophilic syndrome.

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Long-term Monitoring

Periodically observe patients with hypereosinophilic syndrome to confirm that the eosinophilia is controlled and that no evidence of new or worsening organ involvement occurs. Patients should be advised to report any new or worsening symptoms.

Follow up patients with hypereosinophilic syndrome with serum troponin levels every 3 months, as well as with echocardiograms and pulmonary function tests every 6 months.

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