Hypereosinophilic Syndrome Treatment & Management
- Author: Venkata Anuradha Samavedi, MBBS, MD; Chief Editor: Emmanuel C Besa, MD more...
Whether and how to treat symptomatic hypereosinophilic syndrome depends on the clinical presentation, laboratory findings, and mutational analysis. 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 without FIP1L1/PDGFRA mutation, glucocorticoids are the first-line therapy. 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. 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 with FIP1L1/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.
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.
Evidence of hypersplenism and pain due to splenic infarction are indications for splenectomy.
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.
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:
Life-threatening eosinophilic myocarditis
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.
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. 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).
Interferon alpha is a second-line drug of choice for patients whose condition does not respond to glucocorticoids.[31, 32, 33] Hydroxyurea has also demonstrated efficacy for steroid-refractory cases.
Alemtuzumab (CamPath), an anti-CD52 monoclonal antibody, has been shown to control symptoms as well as eosinophilia in patients with refractory hypereosinophilic syndrome.[34, 35] 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.
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.
Seifert M, Gerth J, Gajda M, et al. [Eosinophilia - a challenging differential diagnosis] [German]. Med Klin (Munich). 2008 Aug 15. 103(8):591-7. [Medline].
Galli SJ, Goetzl EJ. Eosinophils, basophils, and mast cells. 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. 2006 Jun. 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). 1975 Jan. 54(1):1-27. [Medline].
Simon HU, Rothenberg ME, Bochner BS, Weller PF, Wardlaw AJ, Wechsler ME, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol. 2010 Jul. 126(1):45-9. [Medline].
Klion AD. Eosinophilic myeloproliferative disorders. Hematology Am Soc Hematol Educ Program. 2011. 2011:257-63. [Medline].
Liao W, Long H, Chang CC, Lu Q. The Eosinophil in Health and Disease: from Bench to Bedside and Back. Clin Rev Allergy Immunol. 2015 Sep 26. [Medline].
Hardy WR, Anderson RE. The hypereosinophilic syndromes. Ann Intern Med. 1968 Jun. 68(6):1220-9. [Medline].
Wardlaw AJ, Kay AB. Eosinopenia and eosinophilia. 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. 2006 Jun. 133(5):468-92. [Medline].
Rothenberg ME. Eosinophilia. N Engl J Med. 1998 May 28. 338(22):1592-600. [Medline].
Gleich GJ, Leiferman KM. The hypereosinophilic syndromes: current concepts and treatments. Br J Haematol. 2009 May. 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. 2009 Sep. 94(9):1236-41. [Medline]. [Full Text].
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. 2008 Oct. 23(10):1713-8. [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. 2008 Sep 15. 112(6):2500-7. [Medline].
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. 1996 Feb 15. 87(4):1416-22. [Medline]. [Full Text].
O'Connell EM, Nutman TB. Eosinophilia in Infectious Diseases. Immunol Allergy Clin North Am. 2015 Aug. 35 (3):493-522. [Medline].
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].
Schreiber A, LeBlanc M, Thibeault MM, Mathieu S. Generalized Recalcitrant Pruritus as the Presenting Manifestation of Hypereosinophilic Syndrome. J Cutan Med Surg. 2016 Jan 29. [Medline].
Curtis C, Ogbogu PU. Evaluation and Differential Diagnosis of Persistent Marked Eosinophilia. Immunol Allergy Clin North Am. 2015 Aug. 35 (3):387-402. [Medline].
Adams JC, Dal-Bianco JP, Kumar G, Callahan MJ. Hypereosinophilic syndrome with characteristic left ventricular thrombus demonstrated by contrast echocardiography. Neth Heart J. 2009 Apr. 17(4):169-70. [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. 1982 Jul. 97(1):78-92. [Medline].
Kuchynka P, Palecek T, Masek M, Cerny V, Lambert L, Vitkova I, et al. Current Diagnostic and Therapeutic Aspects of Eosinophilic Myocarditis. Biomed Res Int. 2016. 2016:2829583. [Medline].
Roufosse F. Management of Hypereosinophilic Syndromes. Immunol Allergy Clin North Am. 2015 Aug. 35 (3):561-75. [Medline].
Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Intern Med. 1978 Aug. 89(2):167-72. [Medline].
Khoury P, Desmond R, Pabon A, Holland-Thomas N, Ware JM, Arthur DC, et al. Clinical features predict responsiveness to imatinib in platelet derived growth factor receptor alpha-negative hypereosinophilic syndrome. Allergy. 2016 Jan 21. [Medline].
Luciano L, Catalano L, Sarrantonio C, et al. AlphaIFN-induced hematologic and cytogenetic remission in chronic eosinophilic leukemia with t(1;5). Haematologica. 1999 Jul. 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. 1998 Jun. 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. 1996 Jan. 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. 2009 Jan 1. 15(1):368-73. [Medline].
Schwartz LB, Sheikh J, Singh A. Current strategies in the management of hypereosinophilic syndrome, including mepolizumab. Curr Med Res Opin. 2010 Aug. 26(8):1933-46. [Medline].
Strati P, Cortes J, Faderl S, Kantarjian H, Verstovsek S. Long-term follow-up of patients with hypereosinophilic syndrome treated with Alemtuzumab, an anti-CD52 antibody. Clin Lymphoma Myeloma Leuk. 2013 Jun. 13(3):287-91. [Medline].
Roufosse FE, Kahn JE, Gleich GJ, Schwartz LB, Singh AD, Rosenwasser LJ, et al. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol. 2013 Feb. 131(2):461-7.e1-5. [Medline]. [Full Text].
Bain BJ. Eosinophilia--idiopathic or not?. N Engl J Med. 1999 Oct 7. 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. 1998 Dec. 107(2):111-7. [Medline].
Weller PF. The idiopathic hypereosinophilic syndrome. Arch Dermatol. 1996 May. 132(5):583-5. [Medline].
Hsieh FH. Hypereosinophilic syndrome. Ann Allergy Asthma Immunol. 2014 Jun. 112(6):484-8. [Medline].
Schwartz RS. The hypereosinophilic syndrome and the biology of cancer. N Engl J Med. 2003 Mar 27. 348(13):1199-200. [Medline].