What is the treatment for a patient with Hypereosinophilic Syndrome (HES)?

Treatment of Hypereosinophilic Syndrome (HES)

For patients with HES and FIP1L1-PDGFRA or PDGFRB rearrangements, imatinib is the definitive first-line therapy with doses of 100-400 mg daily achieving complete molecular remission in most cases. 1, 2, 3

Initial Classification and Risk Stratification

Before initiating treatment, classify HES into one of three categories as this determines therapeutic approach 1, 2, 3:

• Primary (neoplastic) HES (HESN): Underlying myeloid/lymphoid neoplasm with clonal eosinophils—requires molecular testing for tyrosine kinase gene fusions 1, 2
• Secondary (reactive) HES (HESR): Cytokine-driven with non-clonal eosinophils, including lymphocyte-variant HES with aberrant T-cell clones 1, 3
• Idiopathic HES: Diagnosis of exclusion after ruling out neoplastic and reactive causes 2, 3

Critical Pre-Treatment Evaluation

Mandatory Molecular Testing

Perform fluorescence in situ hybridization (FISH) and/or RT-PCR for PDGFRA, PDGFRB, and FGFR1 rearrangements before initiating any therapy, as detection of these fusions fundamentally changes treatment strategy 1, 2, 3

Cardiac Risk Assessment in High-Risk Patients

In patients with hypereosinophilic syndrome and suspected cardiac involvement, perform echocardiogram and serum troponin measurement before starting imatinib. 4 If either is abnormal, administer prophylactic systemic corticosteroids (1-2 mg/kg) for 1-2 weeks concomitantly with imatinib initiation to prevent cardiogenic shock from HES cell degranulation 4. This is particularly critical in patients with occult myocardial HES cell infiltration 4.

Treatment Algorithm by HES Subtype

For PDGFRA/PDGFRB-Rearranged Disease (Primary HES)

Imatinib is the gold standard therapy with exceptional response rates: 1, 2, 3

• Initial dose: 100-400 mg daily (most patients with FIP1L1-PDGFRA respond to 100-200 mg daily) 1
• Response assessment: Monitor at 3 months with complete blood count, cytogenetic response (FISH), and molecular response (RT-qPCR if available) 1
• Maintenance: Continue imatinib at initial dose for patients achieving complete hematologic, cytogenetic, or molecular response 1
• Long-term monitoring: Assess hematologic, cytogenetic, and molecular response every 3-6 months 1

For imatinib resistance (mediated by PDGFRA T674I/D842V or PDGFRB mutations): Consider nilotinib, ponatinib, or sorafenib, though these show limited activity 1. Refer to clinical trial or consider allogeneic hematopoietic cell transplantation 1, 2.

For FGFR1-Rearranged Disease

Pemigatinib is approved for relapsed/refractory FGFR1-rearranged neoplasms 2

For Lymphocyte-Variant HES and Idiopathic HES

Corticosteroids are first-line therapy: 2, 3, 5, 6

• Initiate systemic corticosteroids as primary treatment for cytokine-driven eosinophilia 3, 5
• Dose and duration should be sufficient to achieve organ damage mitigation 2

For steroid-refractory or steroid-dependent cases, escalate to: 2, 3, 5

1. Mepolizumab (anti-IL-5 monoclonal antibody): FDA-approved for idiopathic HES 2, 3, 5
2. Hydroxyurea: Demonstrated efficacy as initial treatment and in steroid-refractory cases 2, 3, 5, 6
3. Interferon-alpha: Effective as initial treatment and in steroid-refractory cases 2, 3, 5, 6

Emerging targeted therapies under investigation: 2, 3

• Benralizumab (anti-IL-5 receptor antibody): Phase 2 data showed 74% sustained response at 48 weeks with significant lowering of serum and tissue eosinophil counts 1, 2
• Depemokimab (anti-IL-5 monoclonal antibody): Under active investigation 2

For Chronic Eosinophilic Leukemia (CEL, NOS)

Aggressive disease requires intensive therapy: 2, 3, 5, 6

• Cytotoxic chemotherapy agents for aggressive forms 2, 3, 5, 6
• Allogeneic hematopoietic stem cell transplantation for eligible patients, though outcomes are reported for limited numbers 2, 3, 5

Watch-and-Wait Approach

For patients with milder eosinophilia (<1.5 × 10⁹/L) without symptoms or signs of organ involvement, close follow-up without immediate treatment is appropriate 2, 3, 5, 6

Monitoring for Treatment Response and Complications

Response Monitoring

• Assess hematologic response at 3 months after treatment initiation 1
• Perform cytogenetic response evaluation (FISH) at 3 and 6 months 1
• Document molecular response with RT-qPCR if available 1

Loss of Response Management

Before escalating therapy, evaluate patient compliance and potential drug interactions 1. For confirmed loss of response, evaluate for cytogenetic/molecular clonal evolution to identify resistance mutations (PDGFRA T674I/D842V or PDGFRB mutations) 1.

Organ Damage Assessment

Monitor cardiac function (ECG, troponin, NT-proBNP, echocardiography), pulmonary function tests, and organ-specific evaluations based on clinical presentation 7. Tissue biopsy remains the gold standard for documenting eosinophil-mediated organ damage 7.

Critical Treatment Pitfalls to Avoid

• Never delay treatment in patients with life-threatening end-organ damage—diagnosis can be made immediately to avoid therapeutic delay 1
• Never start imatinib in high-risk cardiac patients without cardiac evaluation and consideration of prophylactic corticosteroids to prevent cardiogenic shock 4
• Never assume treatment failure without first assessing compliance and drug interactions 1
• Never use diethylcarbamazine if Loa loa microfilariae are present, as this may cause fatal encephalopathy 7