Hypereosinophilic Syndrome Treatment & Management

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.^[27] 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.

Tyrosine kinase inhibitors

A tyrosine kinase inhibitor, imatinib mesylate (Gleevec) is the drug of choice for hypereosinophilic syndrome with FIP1L1/PDGFRA. It is 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.

Interferon alpha^{[28, 29, 30]}

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 is believed that interferon alpha inhibits eosinophil differentiation, proliferation, and degranulation.

Monoclonal antibodies

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.^{[31, 32]} However, durable remission was seen with maintenance therapy with alemtuzumab (30 mg q3wk) compared with single-dose therapy (1 mg/kg) with mepolizumab.

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.

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