eMedicine Specialties > Hematology > Immune System and Disorders
Hypereosinophilic Syndrome: Treatment & Medication
Updated: Oct 4, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Overview of the management of hypereosinophilic syndrome
- 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 every 3-6 months, and ECHO 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, as they carry worse prognosis without treatment.
- A decision to treat hypereosinophilic syndrome, therefore, depends on the clinical presentation, laboratory findings, and mutational analysis.
- Glucocorticoids are the first-line therapy in all patients without FIP1L1/PDGFRA mutation.3 About one third of patients conditions do not respond to steroids. In such patients, interferon alpha and hydroxyurea are the second-line drugs of choice.25 For those individuals whose conditions do not respond to first- and second-line therapy, a high dose (400 mg) of imatinib is the treatment of choice.
- For those with FIP1L1/PDGFRA mutation, imatinib is the drug of choice with a very good response rate that approaches 100% in various studies.
- For those patients whose condition is refractory to the usual treatment of hypereosinophilic syndrome, 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.
- In patients whose condition is refractory to treatment, particularly those resistant to imatinib therapy, hematopoietic stem cell transplantation has been shown to reverse the organ dysfunction. However, because of the limited experience and complications associated with hematopoietic stem cell transplantation, 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 Coumadin 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.
- 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.
Glucocorticoids
- Due to 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. Then, the daily dose of prednisone is tapered to the lowest dose required on alternate days to maintain disease control.
- Glucocorticoids decrease eosinophilopoiesis by suppressing the transcription of genes for IL-3, IL-5 and GM-CSF. These agents also inhibit cytokine-dependent survival of eosinophils, resulting in their increased apoptosis. It is also believed that steroids increase rapid sequestration of eosinophils.
- Almost 70% of the cases of hypereosinophilic syndrome respond well to steroid therapy, especially those that present with urticaria and high IgE levels. Cases of hypereosinophilic syndrome that respond to steroids have 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 future.
- Steroids are also used in the management of imatinib-induced cardiogenic shock. In such circumstances, steroids are started when there is an elevation of the serum troponin level or an abnormal ECHO study.
- A tyrosine kinase inhibitor, imatinib mesylate (Gleevac) is the drug of choice for hypereosinophilic syndrome with FIP1L1/PDGFRA. It’s also a potent inhibitor of other mutations like 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 the patients. 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 shows that it is not effective in eliminating the early progenitor cells in chronic myelogenous leukemia. Extrapolating these results to hypereosinophilic syndrome, a lifelong therapy with imatinib is required in majority of the 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 neutropenia, life-threatening eosinophilic myocarditis, peripheral edema, nausea, muscle cramps, bone pains, and 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) 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.
- 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.
- As mentioned above interferon alpha is a second-line drug of choice for patients whose conditions do not respond to glucocorticoids. Patients with hypereosinophilic syndrome with associated abnormal T-cell clones should also receive some other agent in addition to interferon alpha. It’s believed that interferon alpha inhibits eosinophil differentiation, proliferation, and degranulation.
- A humanized anti–IL-5 monoclonal antibody (eg, mepolizumab [Bosatria]) and an anti-CD52 antibody (alemtuzumab [Campath]) have been shown to control symptoms as well as eosinophilia.29 However, durable remission was seen with maintenance therapy with alemtuzumab (30 mg q3wk) compared with single-dose therapy (1 mg/kg) with mepolizumab.
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.
Endocardectomy may be required for patients with endomyocardial fibrosis, and thrombectomy may be required for individuals with thrombosis.
Splenectomy
Evidence of hypersplenism or pain due to splenic infarction are indications for splenectomy.
Consultations
Consult a hematologist to assist with the diagnosis, management, and follow-up care of patients with unexplained eosinophilia.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications in patients with hypereosinophilic syndrome.
Corticosteroids
Corticosteroids often cause a rapid reduction in level of the eosinophilia. The mechanisms for this are not entirely clear.
Prednisone (Deltasone, Meticorten, Orasone)
Initial DOC. Once eosinophils are suppressed, the dose may be slowly tapered. Patients whose condition responds to steroids tend to have a better prognosis.
Adult
Initially: 1 mg/kg/d PO or 60 mg/d PO
With response, may taper the dose and may ultimately be administered qod for long-term suppression
Pediatric
Not established
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with the coadministration of diuretics.
Documented hypersensitivity; viral/fungal infections & tuberculosis; peptic ulcer disease; hepatic dysfunction.
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
The dose should be lowered by tapering; may have increased adverse effects in the presence of hypertension, diabetes, hypothyroidism, cirrhosis, and CHF and in patients at high risk for peptic ulcer disease
Antineoplastic Agents
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.
Hydroxyurea (Hydrea)
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.
Adult
1-2 g PO qd; adjust dose as WBC count decreases
Pediatric
Not established
Coadministration with fluorouracil or cytarabine can increase neurotoxicity.
Documented hypersensitivity; severe anemia or bone marrow suppression
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in the presence of renal failure or in patients with a history of radiation therapy; monitor blood counts in patients on chemotherapeutic agents
Vincristine (Oncovin, Vincasar)
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.
Adult
1-2 mg IV q2wk
Pediatric
Not established
Acute pulmonary reaction may occur when taken concurrently with mitomycin-C.
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Dose adjustments may be required in patients with preexisting neuromuscular disease or hepatic impairment; caution in patients with severe cardiopulmonary or hepatic impairment and in patients with preexisting neuromuscular disease; monitor blood counts in patients who are taking chemotherapeutic agents
Chlorambucil (Leukeran)
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.
Adult
A pulse of 4-10 mg/m2/d PO for 4 d every other mo
Pediatric
Not established
Increases the toxicity of barbiturates
Documented hypersensitivity; previous resistance; bone marrow suppression
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Monitor blood counts; there is a risk for secondary leukemia in patients on long-term treatment with alkylating agents.
Immunomodulators
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.
Interferon alpha-2a (Roferon-A)
Has been reported to effectively suppress eosinophilia in several different patients using several different doses. Some patients have had progression of disease despite therapy.
Adult
Initial doses as high as 8 million U/d IM/SC followed by maintenance doses of 2 million U/d used successfully
Lower doses, such as 3 million U 3 times/wk, also used with success
Pediatric
Not established
Theophylline may increase the toxicity of interferon alpha by reducing clearance; cimetidine may increase the antitumor effects of interferon alpha; zidovudine and vinblastine may increase toxicity of interferon alpha.
Documented hypersensitivity; uncontrolled thyroid disease; autoimmune hepatitis; patients who are diabetic and prone to DKA
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage has been reported in association with alpha interferon therapy; in bone marrow suppression, before the initiation of therapy, perform tests to quantitate the peripheral blood hemoglobin, platelets, granulocytes, hairy cell, and bone marrow hairy cells; monitor the patient periodically (eg, monthly) during the treatment to determine the response to treatment; if the patient's condition does not respond within 6 mo, discontinue treatment; if a response occurs, continue treatment until no further improvement is observed (it is not known whether continued treatment after that time is beneficial).
Interferon alpha-2b (Intron A)
Has been reported to effectively suppress eosinophilia in several different patients using several different doses. Some patients have had progression of disease despite therapy.
Adult
Initial doses as high as 8 million U/d IM/SC followed by maintenance doses of 2 million U/d have been used successfully.
Lower doses, such as 3 million U 3 times/wk, have also been used with success.
Pediatric
Not established
Theophylline may increase the toxicity of interferon alpha by reducing clearance; cimetidine may increase the antitumor effects of interferon alpha; zidovudine and vinblastine may increase the toxicity of interferon alpha.
Documented hypersensitivity; uncontrolled thyroid disease; autoimmune hepatitis; patients who are diabetic and prone to DKA
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage has been reported in association with alpha interferon therapy; before the initiation of therapy, perform tests to quantitate the peripheral blood hemoglobin, platelets, granulocytes, hairy cell, and bone marrow hairy cells; monitor the patient periodically (eg, monthly) during treatment to determine the condition's response to treatment; if the patient's condition does not respond within 6 mo, discontinue treatment; if a response occurs, continue the treatment until no further improvement is observed; it is not known whether continued treatment after that time is beneficial.
More on Hypereosinophilic Syndrome |
| Overview: Hypereosinophilic Syndrome |
| Differential Diagnoses & Workup: Hypereosinophilic Syndrome |
 Treatment & Medication: Hypereosinophilic Syndrome |
| Follow-up: Hypereosinophilic Syndrome |
| Multimedia: Hypereosinophilic Syndrome |
| References |
| Further Reading |
| « Previous Page | Next Page » |
References
Seifert M, Gerth J, Gajda M, et al. [Eosinophilia - a challenging differential diagnosis] [German]. Med Klin (Munich). Aug 15 2008;103(8):591-7. [Medline].
Galli SJ, Goetzl EJ. Eosinophils, basophils, and mast cells. In: Handin RI, Stossel TP, Lux SE, Stossel TP, eds. Blood: Principles and Practice of Hematology. Baltimore, Md: Lippincott Williams & Wilkins; 1995:621-40.
Klion AD, Bochner BS, Gleich GJ, et al, and The Hypereosinophilic Syndromes Working Group. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol. Jun 2006;117(6):1292-302. [Medline].
Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). Jan 1975;54(1):1-27. [Medline].
Hardy WR, Anderson RE. The hypereosinophilic syndromes. Ann Intern Med. Jun 1968;68(6):1220-9. [Medline].
Wardlaw AJ, Kay AB. Eosinopenia and eosinophilia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 5th ed. New York, NY: McGraw- Hill; 1995:844-52.
Tefferi A, Patnaik MM, Pardanani A. Eosinophilia: secondary, clonal and idiopathic. Br J Haematol. Jun 2006;133(5):468-92. [Medline].
Rothenberg ME. Eosinophilia. N Engl J Med. May 28 1998;338(22):1592-600. [Medline].
Gleich GJ, Leiferman KM. The hypereosinophilic syndromes: current concepts and treatments. Br J Haematol. May 2009;145(3):271-85. [Medline].
Helbig G, Wieczorkiewicz A, Dziaczkowska-Suszek J, Majewski M, Kyrcz-Krzemien S. T-cell abnormalities are present at high frequencies in patients with hypereosinophilic syndrome. Haematologica. Sep 2009;94(9):1236-41. [Medline].
Cincin AA, Ozben B, Tanrikulu MA, Baskan O, Agirbasli M. Large apical thrombus in a patient with persistent heart failure and hypereosinophilia: Löffler endocarditis. J Gen Intern Med. Oct 2008;23(10):1713-8. [Medline].
Bain B. The idiopathic hypereosinophilic syndrome and eosinophilic leukemias. Haematologica. Feb 2004;89(2):133-7. [Medline]. [Full Text].
Bain BJ. Eosinophilia--idiopathic or not?. N Engl J Med. Oct 7 1999;341(15):1141-3. [Medline].
Oliver JW, Deol I, Morgan DL, Tonk VS. Chronic eosinophilic leukemia and hypereosinophilic syndromes. Proposal for classification, literature review, and report of a case with a unique chromosomal abnormality. Cancer Genet Cytogenet. Dec 1998;107(2):111-7. [Medline].
Weller PF. The idiopathic hypereosinophilic syndrome. Arch Dermatol. May 1996;132(5):583-5. [Medline].
Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood. May 15 1994;83(10):2759-79. [Medline]. [Full Text].
Fauci AS, Harley JB, Roberts WC, et al. NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med. Jul 1982;97(1):78-92. [Medline].
Yamada Y, Sanchez-Aguilera A, Brandt EB, et al. FIP1L1/PDGFRalpha synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome. Blood. Sep 15 2008;112(6):2500-7. [Medline].
Simon HU, Plötz SG, Dummer R, Blaser K. Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med. Oct 7 1999;341(15):1112-20. [Medline]. [Full Text].
Brugnoni D, Airó P, Rossi G, et al. A case of hypereosinophilic syndrome is associated with the expansion of a CD3-CD4+ T-cell population able to secrete large amounts of interleukin-5. Blood. Feb 15 1996;87(4):1416-22. [Medline]. [Full Text].
Bain BJ. Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis. Am J Hematol. Sep 2004;77(1):82-5. [Medline]. [Full Text].
Lefebvre C, Bletry O, Degoulet P, et al. [Prognostic factors of hypereosinophilic syndrome. Study of 40 cases] [French]. Ann Med Interne (Paris). 1989;140(4):253-7. [Medline].
Klion A. Hypereosinophilic syndrome: current approach to diagnosis and treatment. Annu Rev Med. 2009;60:293-306. [Medline].
Adams JC, Dal-Bianco JP, Kumar G, Callahan MJ. Hypereosinophilic syndrome with characteristic left ventricular thrombus demonstrated by contrast echocardiography. Neth Heart J. Apr 2009;17(4):169-70. [Medline].
Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Intern Med. Aug 1978;89(2):167-72. [Medline].
Luciano L, Catalano L, Sarrantonio C, et al. AlphaIFN-induced hematologic and cytogenetic remission in chronic eosinophilic leukemia with t(1;5). Haematologica. Jul 1999;84(7):651-3. [Medline]. [Full Text].
Yamada O, Kitahara K, Imamura K, et al. Clinical and cytogenetic remission induced by interferon-alpha in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation. Am J Hematol. Jun 1998;58(2):137-41. [Medline]. [Full Text].
Malbrain ML, Van den Bergh H, Zachée P. Further evidence for the clonal nature of the idiopathic hypereosinophilic syndrome: complete haematological and cytogenetic remission induced by interferon-alpha in a case with a unique chromosomal abnormality. Br J Haematol. Jan 1996;92(1):176-83. [Medline].
Verstovsek S, Tefferi A, Kantarjian H, Manshouri T, Luthra R, Pardanani A, et al. Alemtuzumab therapy for hypereosinophilic syndrome and chronic eosinophilic leukemia. Clin Cancer Res. Jan 1 2009;15(1):368-73. [Medline].
Bain BJ. Hypereosinophilia. Curr Opin Hematol. Jan 2000;7(1):21-5. [Medline].
Broustet A, Bernard P, Dachary D, et al. Acute eosinophilic leukemia with a translocation (10p+;11q-). Cancer Genet Cytogenet. Apr 15 1986;21(4):327-33. [Medline].
Felice PV, Sawicki J, Anto J. Endomyocardial disease and eosinophilia. Angiology. Nov 1993;44(11):869-74. [Medline].
Fischkoff SA, Testa JR, Schiffer CA. Acute eosinophilic leukemia with a (10;11) chromosomal translocation. Leukemia. Jun 1988;2(6):394-7. [Medline].
Maubach PA, Bauchinger M, Emmerich B, Rastetter J. Trisomy 7 and 8 in Ph-negative chronic eosinophilic leukemia. Cancer Genet Cytogenet. Jun 1985;17(2):159-64. [Medline].
Salmon-Nguyen F, Busson M, Daniel M, et al. CALM-AF10 fusion gene in leukemias: simple and inversion-associated translocation (10;11). Cancer Genet Cytogenet. Oct 15 2000;122(2):137-40. [Medline].
Schwartz RS. The hypereosinophilic syndrome and the biology of cancer. N Engl J Med. Mar 27 2003;348(13):1199-200. [Medline].
Further Reading
Related eMedicine Topics
- Hypereosinophilic Syndrome [in the Dermatology section]
- Hypereosinophilic Syndrome [in the Pediatrics: General Medicine section]
- Loeffler Endocarditis [in the Cardiology section]
- Mastocytosis, Systemic
Keywords
hypereosinophilic syndrome, HES, idiopathic hypereosinophilic syndrome, Loeffler endocarditis, Loeffler's endocarditis, chronic eosinophilic leukemia, CEL, eosinophilia, systemic mastocytosis –associated eosinophilia, SM-CEL, FIP1L1-PDGFRA mutation, C-KIT mutation, tyrosine kinase inhibitors
