From the Guidelines
The FIP1L1-PDGFRA gene fusion is a genetic abnormality that causes a rare form of chronic eosinophilic leukemia (CEL) and is typically treated with imatinib mesylate (Gleevec) at a dose of 100 mg daily, as recommended by the NCCN guidelines 1. The FIP1L1-PDGFRA fusion occurs when parts of two genes, FIP1L1 and PDGFRA, join together due to a deletion on chromosome 4, resulting in a fusion protein with constitutively active tyrosine kinase activity, leading to uncontrolled cell growth and proliferation of eosinophils. Patients with this genetic abnormality typically present with:
- Persistent eosinophilia
- Organ damage (particularly heart, skin, and nervous system)
- Splenomegaly The diagnosis of FIP1L1-PDGFRA rearrangement can be made using:
- FISH with specific probes
- Nested RT-PCR and quantitative RT-PCR (RT-qPCR) in peripheral blood or bone marrow
- A combination of RT-PCR and FISH is the most sensitive method for detection 1. Imatinib mesylate (Gleevec) is the first-line treatment for FIP1L1-PDGFRA positive CEL, with most patients responding rapidly to treatment with normalization of eosinophil counts within days to weeks 1. Regular monitoring of blood counts and molecular testing for the fusion gene is essential to assess treatment response. For patients who develop resistance to imatinib, second-generation tyrosine kinase inhibitors like nilotinib or dasatinib may be effective alternatives. Early diagnosis and treatment are crucial to prevent irreversible organ damage from eosinophilic infiltration. The NCCN guidelines recommend imatinib 100 mg daily as the induction therapy for chronic phase disease in patients with FIP1L1-PDGFRA rearrangement, with reduction to 100 mg daily possible after achievement of complete hematologic response and complete cytogenetic response (CCyR) 1.
From the FDA Drug Label
A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease Cytogenetic Abnormality Number of Patients Complete Hematological Response N (%) Partial Hematological Response N (%) Positive FIP1L1-PDGFRα Fusion Kinase 61 61 (100) 0
The FLP1L1::PDGFRA gene fusion, also referred to as FIP1L1-PDGFRα fusion kinase, is significant because it is associated with:
- Complete hematologic response in patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) and hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL)
- Eosinophilia in patients with systemic mast cell disease
- Response to imatinib mesylate therapy in patients with MDS/MPD, aggressive systemic mastocytosis (ASM), and HES/CEL 2 2
From the Research
Significance of FLP1L1::PDGFRA Gene Fusion
The FLP1L1::PDGFRA gene fusion, also referred to as FIP1L1-PDGFRA, is a significant genetic abnormality associated with various hematological malignancies. Key aspects of this gene fusion include:
- Association with hematological malignancies: The FIP1L1-PDGFRA fusion gene has been identified in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD) 3, chronic eosinophilic leukemia (CEL) 4, 5, B-cell lymphoblastic leukemia (B-LL) 6, and T-cell lymphoblastic leukemia/lymphoma 7.
- Response to tyrosine kinase inhibitors: Patients with the FIP1L1-PDGFRA fusion gene have shown excellent responses to tyrosine kinase inhibitors, such as imatinib 3, 4, 6, 5.
- Importance of screening: Screening for the FIP1L1-PDGFRA fusion gene is crucial in patients with eosinophilia-associated hematological malignancies, as it enables targeted therapy with tyrosine kinase inhibitors 3, 5.
- Variability in presentation: The FIP1L1-PDGFRA fusion gene can present with or without eosinophilia, and in different age groups, including pediatric patients 6, 7.
- Treatment outcomes: Patients with the FIP1L1-PDGFRA fusion gene have shown favorable treatment outcomes, with high rates of complete hematologic and molecular remission, and improved overall prognosis 3, 4, 5.
Key Findings
Some key findings related to the FLP1L1::PDGFRA gene fusion include:
- The FIP1L1-PDGFRA fusion gene is a common clonal genetic abnormality in chronic eosinophilic leukemia (CEL) 4.
- Imatinib therapy has been shown to be effective in inducing complete hematologic and molecular remission in patients with the FIP1L1-PDGFRA fusion gene 3, 4, 5.
- A low dose of imatinib (100 mg/day) is often sufficient to induce remission, and a single 100 mg weekly dose can maintain a durable remission 4.
- The FIP1L1-PDGFRA fusion gene can be difficult to detect on routine testing, and may not always be associated with eosinophilia 6, 7.