Should we proceed with FIP1L1 (FIP1 like 1)-PDGFRA (platelet-derived growth factor receptor alpha) testing now?

FIP1L1-PDGFRA Testing Should Be Performed Immediately

Yes, proceed with FIP1L1-PDGFRA testing now if the patient has unexplained eosinophilia, as identifying this fusion gene is critical for diagnosis and determines eligibility for highly effective imatinib therapy that can prevent life-threatening organ damage and achieve complete molecular remission. 1

When to Test: Clinical Indications

Test immediately if the patient presents with:

• Persistent eosinophilia ≥1.5 × 10⁹/L on peripheral blood, particularly in males (strong male predominance) 1
• Splenomegaly with eosinophilia 1
• Markedly elevated serum vitamin B12 in the setting of eosinophilia 1
• Elevated serum tryptase with eosinophilia 1
• Increased mast cells and/or fibrosis on bone marrow biopsy 1
• Eosinophilia without KIT D816V mutation (to distinguish from systemic mastocytosis) 1
• Signs of cardiac involvement (troponin elevation, echocardiographic abnormalities) as eosinophilic endomyocarditis is common and potentially fatal 1, 2

Optimal Testing Strategy

Use a combination approach for maximum sensitivity: 1

Primary Diagnostic Methods:

• FISH for CHIC2 deletion on peripheral blood or bone marrow (detects the cryptic 4q12 deletion that creates FIP1L1-PDGFRA) 1
• Nested RT-PCR or RT-qPCR on peripheral blood (more sensitive than FISH for detecting the fusion transcript) 1

The combination of RT-PCR and FISH is the most sensitive method for detection at diagnosis. 1

Critical Testing Pitfalls to Avoid:

• Do not rely on standard cytogenetics alone - the 800 kb deletion is submicroscopic and undetectable by conventional karyotyping 1, 3
• Peripheral blood FISH may miss low clone sizes - if negative but clinical suspicion remains high, test bone marrow 1
• Never use decalcified bone marrow for FISH (causes yellow autofluorescence that precludes interpretation) 1
• RT-qPCR is NOT appropriate for initial screening due to diverse breakpoints within FIP1L1, but is excellent for monitoring treatment response 1

Why Immediate Testing Matters: Impact on Outcomes

Therapeutic Implications:

FIP1L1-PDGFRA positive patients have excellent prognosis with imatinib: 1

• Complete hematological remission achieved in all treated patients 4, 5, 6
• Complete molecular remission in the majority of patients 4, 5, 6
• Rapid response - normalization of blood counts within 2 weeks in many cases 4
• Low-dose therapy effective - most patients respond to 100 mg/day imatinib (vs. 400-800 mg for other indications) 7, 4
• Minimal side effects at low doses 4

Prognostic Implications Without Treatment:

FIP1L1-PDGFRA positive disease has poor outcomes without imatinib: 2

• High probability of eosinophilic endomyocarditis (50% in one series) 2
• High disease-related mortality (50% in one series) 2
• Poor response to conventional therapies (steroids, hydroxyurea, interferon-alpha) 2
• Can present with aggressive phenotypes including acute myeloid leukemia or T-cell lymphoblastic lymphoma 5

Clinical Context: Who Needs Testing

Test in these specific scenarios:

• Any patient with unexplained eosinophilia being evaluated for hypereosinophilic syndrome or chronic eosinophilic leukemia 1, 8
• Patients with eosinophilia and myeloproliferative features on bone marrow (hypercellular marrow with increased eosinophil precursors, spindle-shaped CD25+ mast cells) 1
• Patients with eosinophilia-associated acute leukemia (AML or T-ALL) - these are still excellent candidates for imatinib despite aggressive phenotype 5
• Patients with eosinophilia after excluding secondary causes (parasites, allergies, drugs, malignancy) 9, 10

Do NOT delay testing for:

• Completion of parasitic workup - can test simultaneously while awaiting serologies 9, 10
• Trial of empiric steroids - FIP1L1-PDGFRA positive disease responds poorly to steroids 2
• Bone marrow biopsy results - can test on peripheral blood 1

Monitoring After Positive Result

If FIP1L1-PDGFRA is detected: 1

• Initiate imatinib 100 mg daily (per FDA labeling for HES/CEL with FIP1L1-PDGFRA) 7
• Monitor with nested RT-PCR or RT-qPCR during follow-up (not FISH) 1
• Assess for cardiac involvement immediately before starting therapy 1
• Watch for T674I resistance mutation if relapse occurs 6

The identification of FIP1L1-PDGFRA transforms a potentially fatal disease with poor response to conventional therapy into a highly treatable condition with excellent long-term outcomes, making immediate testing imperative. 4, 5, 6