Myeloid Variant Hypereosinophilic Syndrome

Myeloid variant hypereosinophilic syndrome is a myeloid neoplasm with eosinophilia, caused by clonal rearrangements of PDGFRA, PDGFRB, FGFR1 or JAK2 (or chronic eosinophilic leukaemia not otherwise specified). It is mostly found in men, causes cardiac and haematological damage, and several forms respond to targeted drugs.

Pathophysiology. Fusion genes (FIP1L1-PDGFRA from a cryptic 4q12 deletion, ETV6-PDGFRB, FGFR1 partner genes, PCM1-JAK2) create constitutively active tyrosine kinases that drive eosinophil proliferation. Eosinophil granule proteins then injure the endomyocardium and other organs.

It is rare and mainly affects men aged 20 to 50 (PDGFRA). Features include splenomegaly, raised vitamin B12 and tryptase, anaemia and thrombocytopenia.

Imatinib sensitive PDGFRA and PDGFRB disease has an excellent outlook, while FGFR1 disease is aggressive.

• Fatigue, fever, weight loss and night sweats
• Splenomegaly and hepatomegaly
• Cardiac involvement: endomyocardial fibrosis, mural thrombus, restrictive cardiomyopathy
• Anaemia, thrombocytopenia and leucocytosis
• Itching, rash, mucosal ulcers
• Pulmonary infiltrates and cough
• Thromboembolism and neuropathy

• Blood eosinophil count: 1.5 x 109/L or more, with exclusion of secondary causes (parasites, drugs, allergy, EGPA, lymphoma).
• FIP1L1-PDGFRA by FISH (CHIC2 deletion) or RT-PCR on blood, in all patients.
• Bone marrow biopsy with cytogenetics, FISH and molecular panels: PDGFRB (t(5;12)), FGFR1 (8p11 rearrangements), JAK2, KIT, and tryptase staining.
• Tryptase and vitamin B12: raised in many.
• Cardiac assessment: troponin, ECG, echocardiogram and cardiac MRI.
• Imaging: CT for spleen and lymph nodes.
• Exclusion of lymphocytic variant: T cell phenotype and clonality.

Differential diagnosis.

• Lymphocytic variant hypereosinophilic syndrome
• Reactive eosinophilia (parasites, drugs, allergy)
• Chronic myeloid leukaemia and other myeloproliferative neoplasms
• Systemic mastocytosis with eosinophilia
• Eosinophilic granulomatosis with polyangiitis
• Acute leukaemia with eosinophilia

• PDGFRA-positive disease: imatinib 100 mg orally once daily (some start at 400 mg), with monitoring of troponin and echocardiogram. In patients with raised troponin or cardiac involvement, give prednisolone 1 mg/kg daily (maximum 60 mg) for the first 1 to 2 weeks, and then taper, to prevent imatinib triggered cardiogenic shock.
• PDGFRB-positive disease: imatinib 400 mg orally once daily.
• FGFR1 rearrangement: aggressive, so refer for FGFR inhibitor treatment (pemigatinib) and allogeneic stem cell transplant.
• JAK2 rearrangement: ruxolitinib 10 to 20 mg orally twice daily (adjusted to blood count), and consider transplant.
• Chronic eosinophilic leukaemia, not otherwise specified: prednisolone, hydroxycarbamide 500 mg orally twice daily or interferon alpha, and allogeneic transplant for suitable patients.
• Parasite cover: ivermectin 200 microgram/kg orally once daily for 2 days before corticosteroid in patients from or travelling to endemic regions.
• Cardiac disease and thrombosis: heart failure treatment, anticoagulation, and surgery for valve disease or endomyocardial fibrosis in selected patients.
• Supportive care: co-trimoxazole 960 mg orally three times weekly on prolonged immunosuppression, and bone protection.

Special groups.

• Pregnancy: imatinib is avoided, and treatment is individual.
• Patients with imatinib resistance: sequence testing for kinase domain variants (for example T674I) to select another drug.

Monitoring. FIP1L1-PDGFRA by RT-PCR every 3 months until remission, then every 6 to 12 months. Eosinophil count, blood count and troponin at every visit. Echocardiogram every 6 to 12 months. Liver enzymes monthly in the first 3 months of imatinib.

Referral and escalation. Refer urgently to haematology. Emergency for heart failure, stroke, thromboembolism or rapidly rising blood counts.