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Hypereosinophilic Syndrome

By

Jane Liesveld

, MD, James P. Wilmot Cancer Institute, University of Rochester Medical Center

Reviewed/Revised Jan 2024
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Topic Resources

Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the absence of parasitic, allergic, or other secondary causes of eosinophilia Important Disorders and Treatments Associated With Eosinophilia Important Disorders and Treatments Associated With Eosinophilia . Symptoms can be myriad, depending on which organs are dysfunctional. Diagnosis involves excluding other causes of eosinophilia plus bone marrow and cytogenetic tests. Treatment may include corticosteroids and sometimes imatinib but depends on the specific subtype of hypereosinophilic syndrome.

Hypereosinophilic syndrome is traditionally defined as peripheral blood eosinophilia > 1500/mcL (> 1.5 × 109/L) persisting 6 months with evidence of organ dysfunction. (See also Eosinophil Production and Function Eosinophil Production and Function Eosinophils are granulocytes (white blood cells that contain granules in their cytoplasm) derived from the same progenitor cells as monocytes-macrophages, neutrophils, and basophils. They are... read more .)

Hypereosinophilic syndrome was previously considered to be idiopathic, but molecular characterization has revealed that many cases have specific clonal disorders (1 General references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ). One limitation of the traditional definition is that it does not include those patients with some of the same abnormalities (eg, chromosomal defects) that are known causes of hypereosinophilic syndrome but who do not fulfill the traditional hypereosinophilic syndrome definition for degree or duration of eosinophilia. Another limitation is that some patients with eosinophilia and organ damage that characterize hypereosinophilic syndrome require treatment earlier than the 6 months necessary to confirm the traditional diagnostic criteria. Eosinophilia of any etiology can cause the same types of tissue damage.

Clonal hypereosinophilic syndromes

There are 2 broad subtypes of clonal hypereosinophilic syndrome (see table ):

  • Myeloproliferative variant

  • Lymphoproliferative variant

The myeloproliferative variant is often associated with a small interstitial deletion in chromosome 4 at the CHIC2 site that causes the FIP1L1/PDGFRA-associated fusion gene (which has tyrosine kinase activity that can transform hematopoietic cells). Patients often have

  • Anemia

  • Elevated serum tryptase levels

  • Elevated serum vitamin B12 levels

  • Hypogranular or vacuolated eosinophils

  • Myelofibrosis

  • Splenomegaly

  • Thrombocytopenia

A small proportion of patients with the myeloproliferative variant of hypereosinophilic syndrome have cytogenetic changes involving platelet-derived growth factor receptor beta (PDGFRB) and may also be responsive to tyrosine kinase inhibitors such as imatinib (2 General references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ). Other cytogenetic abnormalities include rearrangement of the gene for fibroblast growth factor receptor 1 (FGFR1) or Janus kinase 2 (PCM1-JAK2). Recently, ETV6-ABL1 and various FLT3 fusions have been added to the gene rearrangements associated with hypereosinophilia.

Some patients have chronic eosinophilic leukemia, in which blast cells are increased on bone marrow examination but not more than 20%.

The lymphoproliferative variant is associated with a clonal population of T cells with aberrant phenotype. Polymerase chain reaction (PCR) shows a clonal T-cell receptor rearrangement. Patients more often have

  • Angioedema, skin abnormalities, or both

  • Circulating immune complexes (sometimes with serum sickness)

  • Hypergammaglobulinemia (especially high IgE)

Patients with the lymphoproliferative variant also more often respond favorably to corticosteroids and occasionally develop T-cell lymphoma.

Other hypereosinophilic syndrome variants include Gleich syndrome (episodic angioedema with eosinophilia), familial hypereosinophilic syndrome mapped to 5q 31-33, and other organ-specific syndromes. In organ-specific eosinophilic syndromes, eosinophilic infiltration is confined to a single organ (eg, eosinophilic gastrointestinal disease, chronic eosinophilic pneumonia Chronic Eosinophilic Pneumonia Chronic eosinophilic pneumonia (CEP) is a disorder of unknown etiology characterized by an abnormal, chronic accumulation of eosinophils in the lung. (See also Overview of Eosinophilic Pulmonary... read more 3 General references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ).

Hyperleukocytosis may occur in patients with eosinophilic leukemia and very high eosinophil counts (eg, > 100,000 cells/mcL [> 100 × 109/L]). Eosinophils can form aggregates that occlude small blood vessels, causing tissue ischemia and microinfarctions. Common manifestations include brain or lung hypoxia (eg, encephalopathy, dyspnea or respiratory failure).

Table

Idiopathic hypereosinophilic syndrome

Idiopathic hypereosinophilic syndrome is rare, has an unknown prevalence, and most often affects people age 20 through 50 years. Only some patients with prolonged eosinophilia Eosinophilia Eosinophilia is defined as a peripheral blood eosinophil count > 500/mcL (> 0.5 × 109/L). Causes and associated disorders are myriad but often represent an allergic reaction or... read more Eosinophilia develop organ dysfunction that characterizes hypereosinophilic syndrome. Although any organ may be involved, the heart, lungs, spleen, skin, and nervous system are typically affected. Cardiac involvement can cause significant morbidity and mortality.

General references

  • 1. Wang SA, Orazi A, Gotlib J, et al: The international consensus classification of eosinophilic disorders and systemic mastocytosis. Am J Hematol 98(8):1286–1306, 2023. doi:10.1002/ajh.26966

  • 2. Apperley JF, Gardembas M, Melo JV, et al: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 347:481–487, 2002.

  • 3. Shomali W, Gotlib J : World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management. Am J Hematol 97:129–148, 2022.

Symptoms and Signs of Hypereosinophilic Syndrome

Symptoms are diverse and depend on which organs are dysfunctional (see table ).

Table

Occasionally, patients with very severe eosinophilia (eg, eosinophil counts of > 100,000/mcL [> 100 × 109/L]) develop complications of hyperleukocytosis, such as manifestations of brain or lung hypoxia (eg, encephalopathy, dyspnea, respiratory failure). Other thrombotic manifestations (eg, cardiac mural thrombi) may also occur.

Diagnosis of Hypereosinophilic Syndrome

  • Exclusion of secondary eosinophilia

  • Tests to identify organ damage

  • Bone marrow examination with cytogenetic testing if secondary causes of eosinophilia are not identified

Evaluation for hypereosinophilic syndrome should be considered in patients who have peripheral blood eosinophilia > 1500/mcL (> 1.5 × 109/L) present on more than one occasion that is unexplained, particularly when there are manifestations of organ damage.

Evaluation for organ damage should include blood chemistry tests (including liver enzymes, creatine kinase, renal function, and troponin); ECG; echocardiography; pulmonary function tests; and CT of the chest, abdomen, and pelvis. Bone marrow aspirate and biopsy with flow cytometry, cytogenetic testing, and reverse transcriptase-polymerase chain reaction (rtPCR) or fluorescence in situ hybridization (FISH) are done to identify the FIP1L1/PDGFRA-associated fusion gene or other common fusion transcripts and to evaluate for clonality of the T cell–receptor to exclude the lymphocytic variant of hypereosinophilic syndrome and other possible causes of eosinophilia (1 Diagnosis reference Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ).

Diagnosis reference

  • 1. Klion AD: Approach to the patient with suspected hypereosinophilic syndrome. Hematology Am Soc Hematol Educ Program 2022; 2022(1):47-54. doi: 10.1182/hematology.2022000367

Treatment of Hypereosinophilic Syndrome

  • Corticosteroids for hypereosinophilia and often for ongoing treatment of organ damage

  • Imatinib for patients with the FIP1L1/PDGFRA-associated fusion gene or other similar gene fusions

  • Sometimes medications to control eosinophil counts (eg, hydroxyurea, interferon alfa, etoposide, cladribine)

  • Supportive care

Treatments include immediate therapy, definitive therapies (treatments directed at the disorder itself), and supportive therapies (1 Treatment references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ). There is no set level of eosinophilia at which organ damage occurs or at which treatment must be started, but most experts recommend starting therapy at an absolute eosinophil count of 1500 to 2000 eosinophils/mcL (1.5 to 2 × 109/L).

Immediate therapy

For patients with very severe eosinophilia, complications of hyperleukocytosis such as dyspnea or mental status changes may occur (usually in patients with eosinophilic leukemia). In these cases, high-dose corticosteroids (eg, ranging from prednisone 1 mg/kg or equivalent to 1 gram of methylprednisolone) should be initiated as soon as possible. If the eosinophil count is lower (eg, by 50%) after 24 hours, the corticosteroid dose can be repeated daily; if not, an alternative treatment (eg, hydroxyurea) is begun. Once the eosinophil count begins to decline and is under better control, additional medications may be started.

It is important to consider possible Strongyloides infection prior to administration of high-dose corticosteroids, since corticosteroids can precipitate potentially fatal disseminated infection (hyperinfection syndrome Hyperinfection syndrome and disseminated strongyloidiasis Strongyloidiasis is infection with Strongyloides stercoralis. Findings include abdominal pain and diarrhea, rash, pulmonary symptoms (including cough and wheezing), and eosinophilia.... read more Hyperinfection syndrome and disseminated strongyloidiasis ).

Definitive therapy

Patients with the FIP1L1/PDGFRA-associated fusion gene (or similar fusion genes involving PDGFA/B) are usually treated with imatinib (2 Treatment references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ) and, particularly if heart damage is suspected, corticosteroids as well. Imatinib started at diagnosis may forestall organ damage. If imatinib is ineffective or poorly tolerated, another tyrosine kinase inhibitor (eg, dasatinib, nilotinib, sorafenib) can be used, or allogeneic hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more can be used. Case reports suggest ruxolitinib, a JAK2 inhibitor may be useful in the rare cases that are associated with the JAK2 mutation (3 Treatment references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ).

Patients without the FIP1L1/PDGFRA-associated fusion gene, even if asymptomatic, are often given one dose of prednisone 60 mg (or 1 mg/kg) orally to determine corticosteroid responsiveness (ie, a decrease in the eosinophil count). In patients with symptoms or organ damage, prednisone is continued at the same dose once a day for 2 weeks, then tapered. Patients without symptoms and organ damage are monitored for at least 6 months for these complications. If corticosteroids cannot be easily tapered, a corticosteroid-sparing drug (eg, hydroxyurea, interferon alfa) can be used.

Mepolizumab, a fully humanized monoclonal IgG antibody that inhibits binding of IL-5 to its receptor, may be used for the treatment of idiopathic hypereosinophilia (4, 5 Treatment references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ). Reslizumab (anti-IL-5), benralizumab (anti-IL-5 receptor), and dupilumab (anti-Il-4 receptor) are other biologics that have been used in hypereosinophilic syndrome. Clinical trials of many of these biologics are ongoing.

Supportive care

Investigational therapy

Novel inhibitors of FGFR1 are being evaluated in this rare population of patients with hypereosinophilia.

Treatment references

  • 1. Ogbogu PU, Bochener BS, Butterfield HJ, et al: Hypereosinophilic syndromes: A multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 124:1319–1325, 2009. doi:10.1016/j.jaci.2009.09.022

  • 2. Cortes J, Ault P, Koller C, et al: Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood 101:4714–4716, 2003. doi:10.1182/blood-2003-01-0081

  • 3. Klion AD: Approach to the patient with suspected hypereosinophilic syndrome. Hematology Am Soc Hematol Educ Program 2022; 2022(1):47-54. doi: 10.1182/hematology.2022000367

  • 4. Roufosse F, Kahn JE, Rothenberg FE, et al: Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol 146: 1397–1405, 2020. doi: 10.1016/j.jaci.2020.08.037

  • 5. Rothenberg ME, Klion AD, Roufosse FE, et al: Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 358:1215–28, 2008. doi:10.1056/NEJMoa070812

Prognosis for Hypereosinophilic Syndrome

Death usually results from organ, particularly cardiac, dysfunction. Cardiac involvement is not predicted by the degree or duration of eosinophilia. Prognosis varies depending on response to therapy. Response to imatinib improves the prognosis among patients with the FIP1L1/PDGFRA-associated fusion gene and other responsive gene fusions.

Key Points

  • Hypereosinophilic syndrome is peripheral blood eosinophilia (> 1500/mcL [> 1.5 × 109/L]) not caused by parasitic, allergic, or other secondary causes of eosinophilia, that has persisted 6 months and caused organ damage or dysfunction.

  • Hypereosinophilic syndrome appears to be a manifestation of a number of hematopoietic disorders, some of which have a genetic cause.

  • Any organ may be involved but the heart, lungs, spleen, skin, and nervous system are typically affected; cardiac involvement can cause significant morbidity and mortality.

  • Do tests for organ involvement, including liver enzymes; creatine kinase, creatinine, and troponin levels; ECG and echocardiography; pulmonary function tests; and CT of the chest, abdomen, and pelvis.

  • Do bone marrow examination with cytogenetic testing to identify a cause.

  • Give corticosteroids for severe eosinophilia and/or organ damage. Tyrosine kinase inhibitors such as low-dose imatinib may be of benefit in subtypes associated with distinct chromosomal abnormalities.

Drugs Mentioned In This Article

Drug Name Select Trade
Gleevec
DROXIA, HYDREA, Mylocel, Siklos
Etopophos, Toposar, VePesid
Leustatin, MAVENCLAD
Deltasone, Predone, RAYOS, Sterapred, Sterapred DS
A-Methapred, Depmedalone-40, Depmedalone-80 , Depo-Medrol, Medrol, Medrol Dosepak, Solu-Medrol
Sprycel
Tasigna
Nexavar
Jakafi, Opzelura
Nucala
CINQAIR
Fasenra
DUPIXENT
Anacin Adult Low Strength, Aspergum, Aspir-Low, Aspirtab , Aspir-Trin , Bayer Advanced Aspirin, Bayer Aspirin, Bayer Aspirin Extra Strength, Bayer Aspirin Plus, Bayer Aspirin Regimen, Bayer Children's Aspirin, Bayer Extra Strength, Bayer Extra Strength Plus, Bayer Genuine Aspirin, Bayer Low Dose Aspirin Regimen, Bayer Womens Aspirin , BeneHealth Aspirin, Bufferin, Bufferin Extra Strength, Bufferin Low Dose, DURLAZA, Easprin , Ecotrin, Ecotrin Low Strength, Genacote, Halfprin, MiniPrin, St. Joseph Adult Low Strength, St. Joseph Aspirin, VAZALORE, Zero Order Release Aspirin, ZORprin
Plavix
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