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Hypereosinophilic Syndrome Treatment & Management

  • Author: Venkata Anuradha Samavedi, MBBS, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Feb 23, 2016
 

Approach Considerations

Whether and how to treat symptomatic hypereosinophilic syndrome depends on the clinical presentation, laboratory findings, and mutational analysis.[27] 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.[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.[28] 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.

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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.[29]

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.[30] 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.[31, 32, 33] Hydroxyurea has also demonstrated efficacy for steroid-refractory cases.[29]

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.[36]

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.[37]

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Contributor Information and Disclosures
Author

Venkata Anuradha Samavedi, MBBS, MD Internist in Houston, TX

Disclosure: Nothing to disclose.

Coauthor(s)

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Ronald A Sacher, MB, BCh, FRCPC, DTM&H Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada, American Clinical and Climatological Association, International Society of Blood Transfusion

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: GSK Pharmaceuticals,Alexion,Johnson & Johnson Talecris,,Grifols<br/>Received honoraria from all the above companies for speaking and teaching.

Vincent E Herrin, MD, FACP Professor of Medicine, Division of Hematology and Medical Oncology, Director, Medicine Residency Program, University of Mississippi School of Medicine

Vincent E Herrin, MD, FACP is a member of the following medical societies: American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Society of Clinical Oncology, Southern Society for Clinical Investigation, American Society of Hematology

Disclosure: Nothing to disclose.

Joe C Files, MD Director, Division of Hematology, Associate Chairman, Professor, Department of Internal Medicine, University of Mississippi Medical Center

Joe C Files, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association for Cancer Education, American College of Physicians, American Federation for Medical Research, American Heart Association, American Medical Association, American Society of Human Genetics, Mississippi State Medical Association, New York Academy of Sciences, Southern Medical Association

Disclosure: Nothing to disclose.

Youwen Zhou, MD, PhD, FRCPC Associate Professor, Department of Dermatology and Skin Science, University of British Columbia Faculty of Medicine; Director, Hyperhidrosis Specialty Clinic, Co-Director, Psoriasis and Phototherapy Centre, Consulting Physician, Department of Dermatology, Vancouver General Hospital; Co-Director, Vitiligo and Pigmentation Clinic, Oncologist Consultant, Skin Tumor Program, BC Cancer Agency

Youwen Zhou, MD, PhD, FRCPC is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Antoni Ribas, MD Assistant Professor of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center

Disclosure: Nothing to disclose.

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