Chronic Eosinophilic Leukemia (CEL)

Molecular diagnosis, WHO 2022 classification, and tyrosine kinase inhibitor–based treatment of chronic eosinophilic leukemia and myeloid neoplasms with eosinophilia

Key Points

• CEL is defined by clonal eosinophilia with myeloproliferative bone marrow features; the WHO 2022 classification reorganizes eosinophilic neoplasms into "Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusions" (MLN-TKF) and "CEL, NOS."
• FIP1L1-PDGFRA (4q12 deletion) is the most common driver fusion — detectable only by RT-PCR (not standard FISH or karyotype); imatinib 100–400 mg/day produces complete molecular remission in the majority and is the standard of care.
• PDGFRB rearrangements (most commonly ETV6-PDGFRB from t(5;12)) are imatinib-sensitive; FGFR1 rearrangements (8p11 myeloproliferative syndrome) are imatinib-resistant and require pemigatinib and/or allogeneic stem cell transplantation.
• PCM1-JAK2 fusion (t(8;9)) defines a distinct entity with eosinophilia and T-lymphoblastic lymphoma risk; ruxolitinib has activity; allogeneic SCT is recommended for eligible patients.
• CEL NOS (no specific fusion) is characterized by clonal eosinophilia with ≥2% blood blasts or ≥5% marrow blasts (below AML threshold); management includes hydroxyurea for cytoreduction and allogeneic SCT for eligible patients with aggressive disease.
• All patients with CEL have a risk of transformation to blast phase (acute leukemia); regular bone marrow reassessment and molecular monitoring are essential.

WHO 2022 Classification and Molecular Landscape

The 2022 WHO and ICC (International Consensus Classification) classifications reorganized eosinophilic hematologic neoplasms, reflecting the critical importance of molecular drivers for treatment selection. **Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusions (MLN-TKF):** This category encompasses diseases previously scattered across different WHO entities, unified by the presence of a recurrent kinase fusion that is directly targetable. Key entities: *MLN with PDGFRA rearrangement (most common):* - Driver: **FIP1L1-PDGFRA** fusion — results from a cryptic…

Clinical Presentation and Diagnostic Evaluation

**Clinical features shared across CEL subtypes:** - Constitutional symptoms: fatigue, night sweats, weight loss, fever - Splenomegaly (often prominent in M-HES/CEL; the spleen may be massively enlarged in PDGFRA and PDGFRB disease) - Hepatomegaly - End-organ damage identical to HES: cardiac (Loeffler endocarditis), neurologic, skin, pulmonary (see HES article) - Lymphadenopathy: more prominent in FGFR1-rearranged disease (which can present as T-LBL) **FIP1L1-PDGFRA–specific features:** - Elevated serum tryptase (reflects expanded mast cell population in the marrow) - Increased bone marrow…

Treatment by Molecular Subtype

Molecular subtype determines whether the disease is TKI-sensitive — this single determination is the most important treatment decision in CEL. **FIP1L1-PDGFRA–positive CEL:** *Imatinib — standard of care:* - Dose: 100 mg/day orally (far lower than CML dose of 400 mg/day; PDGFRA is far more imatinib-sensitive than BCR-ABL) - Responses: complete hematologic remission in >95% within weeks; complete molecular remission (RT-PCR undetectable) in the majority within 3–12 months - Durability: molecular remissions are maintained with continued therapy; relapse is near-universal upon discontinuation -…

Response Assessment and Long-Term Monitoring

**Response criteria (adapted from ELN/IWG):** - **Complete hematologic remission (CHR)**: normalization of CBC (eosinophils <500/μL), resolution of splenomegaly and organ infiltration, no symptoms - **Partial hematologic remission (PHR)**: ≥50% reduction in eosinophil count without CHR - **Complete cytogenetic remission (CCyR)**: no cytogenetic abnormality detected by conventional karyotype - **Complete molecular remission (CMR)**: no detectable disease by the relevant molecular assay (RT-PCR for FIP1L1-PDGFRA, FISH for others) **Treatment goals by subtype:** - PDGFRA-positive: CMR is the…