Eosinophilic leukemia is a rare blood cancer in which a single abnormal (clonal) line of cells in the bone marrow produces far too many eosinophils. It is usually chronic: chronic eosinophilic leukemia, or CEL. The eosinophil count is persistently raised above 1.5 × 10^9/L, and the excess cells can damage organs, especially the heart. The most important question at diagnosis is whether the disease carries a tyrosine kinase fusion such as FIP1L1::PDGFRA, because those cases respond dramatically to low-dose imatinib.
Eosinophilic leukemia belongs to the wider group of hematologic disorders. Its diagnosis is largely a process of exclusion: most people with a high eosinophil count do not have leukemia. The rest of this article covers how the disease is classified today, how it damages the heart, how the key fusion gene is found in the lab, and how treatment is sequenced in practice.
Normal Eosinophils and Hypereosinophilia
Eosinophils are white blood cells with bright orange-red granules. They help defend against parasites and take part in allergic inflammation. A normal absolute eosinophil count (AEC) is up to about 0.5 × 10^9/L (500/μL). The counts are graded as follows:
| Term | Absolute eosinophil count | Comment |
|---|---|---|
| Normal | Up to 0.5 × 10^9/L | Varies through the day; lowered by steroids |
| Eosinophilia | Above 0.5 × 10^9/L | Most often reactive (allergy, parasites, drugs) |
| Hypereosinophilia (HE) | 1.5 × 10^9/L or more, persistent | Warrants a structured workup for organ damage and cause |
| Hypereosinophilic syndrome (HES) | HE plus organ damage attributable to eosinophils | Can be reactive, clonal, lymphocytic-variant, or idiopathic |
Eosinophilic leukemia accounts for only a small minority of people with hypereosinophilia. That is why the first job is always to exclude the common reactive causes before labeling anyone with a leukemia.
Classification: From WHO 2016 to WHO 2022 and ICC
The names in this field have changed several times, and papers from different eras use different terms. That confuses patients and trainees alike.
Before 2022
From the 2008 WHO classification onward, cases driven by rearrangements of PDGFRA, PDGFRB, or FGFR1 were taken out of “CEL” and put in a separate category. In the 2016 revision it was called “myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2”. Cases without one of these rearrangements, but with evidence of clonality or increased blasts, were called CEL, not otherwise specified (CEL-NOS). Everything else with organ damage was called idiopathic HES.
Current classifications
In 2022 two classifications were published: the WHO 5th edition and the International Consensus Classification (ICC). Both keep the fusion-driven cases as their own group, now called myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK). The group has been widened to include fusions of JAK2, FLT3, and ETV6::ABL1. Strictly speaking, then, a patient with FIP1L1::PDGFRA now has an MLN-TK, not “CEL”. Clinicians and patients still often call it eosinophilic leukemia, and this article uses the everyday term where the meaning is clear. For how it fits among the other leukemias, see our leukemia guide.
The WHO 2022 edition dropped the “NOS” label, so the term is now simply CEL. It also tightened the definition: CEL now needs evidence of clonality or abnormal bone marrow morphology, and the required duration of hypereosinophilia was shortened.
| Criterion | Chronic eosinophilic leukemia (WHO 2022 / ICC, summarized) |
|---|---|
| Eosinophil count | Persistent hypereosinophilia: AEC 1.5 × 10^9/L or more, with eosinophils making up at least 10% of blood white cells |
| Duration | Documented over an interval of weeks (WHO 2022 shortened this from the older 6-month requirement) |
| Blasts | Below 20% in blood and marrow (20% or more means acute leukemia) |
| Clonality | A clonal cytogenetic or molecular abnormality, or (WHO) abnormal marrow morphology such as dysplastic megakaryocytes; ICC also accepts increased blasts |
| Exclusions | No tyrosine kinase fusion (those are MLN-TK); criteria for CML, other myeloproliferative neoplasms, myelodysplastic/myeloproliferative neoplasms, systemic mastocytosis, and AML not met |
If a patient has hypereosinophilia and organ damage but no clonal marker, no increased blasts, and no reactive cause, the diagnosis is idiopathic HES.
Pathogenesis: The 4q12 Deletion and Other Drivers
FIP1L1::PDGFRA is the classic driver. It is made by a small deletion within chromosome 4 at band 4q12, too small to see on a routine karyotype. Picture the chromosome as a string: the FIP1L1 gene sits at one end of a short segment, and PDGFRA sits a little further along. In between lies the CHIC2 gene. When the whole segment containing CHIC2 is deleted, the front of FIP1L1 is joined directly to the kinase part of PDGFRA. The resulting fusion protein is a tyrosine kinase that is permanently switched on. It drives eosinophil production and survival without needing any outside growth signal.
Because this deletion is invisible on standard chromosome analysis, a normal karyotype does not exclude the disease. FIP1L1::PDGFRA-positive disease occurs almost exclusively in men. Serum vitamin B12 and serum tryptase are often raised, and the spleen is often enlarged.
Other drivers include:
- PDGFRB fusions (for example ETV6::PDGFRB, involving 5q32–33). These are sensitive to imatinib and often come with monocytosis.
- FGFR1 fusions (8p11). These are aggressive, resistant to imatinib, and can present as, or transform into, AML or T-lymphoblastic lymphoma.
- JAK2 fusions (for example PCM1::JAK2). These may respond to JAK inhibitors, but responses are often temporary.
- FLT3 and ETV6::ABL1 fusions, now recognized in the MLN-TK group.
- Point mutations in myeloid genes (for example STAT5B, ASXL1, TET2) without a fusion. These point to CEL rather than MLN-TK.
In lymphocytic-variant HES, a clone of abnormal T cells overproduces IL-5 (and often IL-3 and GM-CSF). This drives a reactive eosinophilia even though the eosinophils themselves are not clonal. Flow cytometry and T-cell receptor gene rearrangement studies identify it.
How Eosinophils Damage Organs
Activated eosinophils release toxic granule proteins, such as major basic protein and eosinophil cationic protein, along with other inflammatory mediators. Tissue damage from these products, not the raised count itself, is what makes the disease dangerous. The organs most often affected are:
- Heart: endomyocardial damage, clots in the heart, restrictive cardiomyopathy (discussed below). This is the most important cause of serious illness and death.
- Lungs: cough, wheeze, lung infiltrates, and eventually fibrosis.
- Skin: itchy papules, hives, angioedema, mucosal ulcers.
- Nervous system: peripheral neuropathy, encephalopathy, and embolic stroke from clots in the heart.
- Gut and liver: diarrhea, eosinophilic gastroenteritis, enlarged liver and spleen.
- General symptoms: fatigue, fever, night sweats, weight loss.
Cardiac Involvement: Loeffler Endocarditis
Eosinophil-mediated heart disease is traditionally called Loeffler endocarditis (eosinophilic endomyocardial disease). It classically moves through three overlapping stages:
- Acute necrotic stage: eosinophils infiltrate the heart muscle and cause myocarditis. Troponin may be raised and there may be few symptoms, so it is easy to miss.
- Thrombotic stage: clots form on the damaged inner lining of the heart, typically filling the apex of one or both ventricles. These clots can embolize to the brain or limbs.
- Fibrotic stage: scarring of the inner lining stiffens the ventricles, causing restrictive cardiomyopathy. It also tethers the valve apparatus, especially the posterior mitral leaflet.
Echocardiographic and MRI findings
| Finding | What it reflects |
|---|---|
| Endomyocardial thickening; apical obliteration | Thrombus and fibrosis filling the ventricular apex |
| Mitral and/or tricuspid regurgitation | Valve leaflet thickening and tethering by fibrosis |
| Restrictive filling pattern, enlarged atria | Stiff, fibrosed ventricles |
| Pericardial effusion | Inflammation of the pericardium |
| Raised pulmonary pressures | Pulmonary hypertension from left-sided restriction or lung involvement |
| Subendocardial late gadolinium enhancement (cardiac MRI) | Inflammation or fibrosis; MRI is more sensitive than echo for early disease and thrombus |
Cardiac monitoring
Every patient with hypereosinophilia should have a serum troponin, an ECG, and an echocardiogram at baseline. A cardiac MRI is worthwhile if the echo is equivocal or the troponin is raised. In my practice I repeat troponin and imaging whenever symptoms change and at intervals during treatment. Cardiac damage caught in the necrotic stage can settle once eosinophils are controlled, but established fibrosis does not reverse.
Differential Diagnosis of Hypereosinophilia
Most high eosinophil counts are reactive. That means they are driven by cytokines from another condition, not by a clone in the marrow. The table below sets out the main categories.
| Category | Examples | Clues / key tests |
|---|---|---|
| Reactive: infection | Strongyloides, Toxocara, schistosomiasis, other helminths | Travel/residence history; Strongyloides serology before any steroids |
| Reactive: allergy and drugs | Asthma, atopic disease, allergic bronchopulmonary aspergillosis, drug reactions including DRESS | Timing with new drugs; IgE; rash, fever, liver tests |
| Reactive: autoimmune/inflammatory | Eosinophilic granulomatosis with polyangiitis, inflammatory bowel disease | ANCA, vasculitic features, sinus disease |
| Reactive: lung disease | Eosinophilic pneumonias | Imaging, bronchoalveolar lavage |
| Reactive: other cancers and endocrine | Hodgkin lymphoma, T-cell lymphomas, some solid tumors, adrenal insufficiency | Nodes, imaging, cortisol |
| Lymphocytic-variant HES | Aberrant IL-5-producing T-cell clone | Flow cytometry (e.g., CD3−CD4+ cells), TCR clonality |
| Clonal: MLN-TK | FIP1L1::PDGFRA, PDGFRB, FGFR1, JAK2, FLT3 fusions | FISH/RT-PCR, karyotype, targeted RNA panels |
| Clonal: CEL | Myeloid clone without a TK fusion | Marrow morphology, NGS myeloid panel, karyotype |
| Clonal: CML (eosinophilic presentation) | BCR::ABL1-positive CML | BCR::ABL1 PCR or FISH, basophilia, left-shifted neutrophilia |
| Clonal: systemic mastocytosis with eosinophilia | KIT D816V | Serum tryptase, marrow mast-cell aggregates, KIT testing |
| Idiopathic HES | No cause found despite full workup | Diagnosis of exclusion; reassess over time |
Can chronic myeloid leukemia present with high eosinophils?
Yes. Eosinophilia and basophilia are common features of chronic myeloid leukemia (CML), and occasionally eosinophils dominate the blood picture. CML is defined by the BCR::ABL1 fusion (the Philadelphia chromosome). It is managed differently, with standard-dose tyrosine kinase inhibitors and molecular monitoring of BCR::ABL1 levels. For this reason BCR::ABL1 testing is part of every hypereosinophilia workup, and CML must be excluded before a diagnosis of CEL can be made.
Diagnostic Workup Step by Step
1. Confirm persistent hypereosinophilia and look for reactive causes
Repeat the full blood count with a blood film. Take a careful travel, drug, allergy, and symptom history. Send Strongyloides serology (and treat empirically if steroids are urgent and serology is pending), stool studies, IgE, ANCA, and liver and kidney tests. Check whether any recent drug could be responsible.
2. Assess organ damage straight away
This means troponin, ECG, echocardiogram, chest imaging, and lung function if there are respiratory symptoms, plus a neurological exam. If there is evidence of organ damage, treatment to lower eosinophils should not wait for the molecular results (see below).
3. Blood molecular tests
Test for FIP1L1::PDGFRA and BCR::ABL1, and send serum tryptase and B12. Do T-cell flow cytometry and TCR clonality studies. Blood testing for KIT D816V is useful if mastocytosis is suspected.
4. Bone marrow examination
Aspirate and trephine assess blast percentage, dysplasia, fibrosis, and mast-cell aggregates. The karyotype identifies rearrangements of PDGFRB, FGFR1, and JAK2, which are often visible as translocations. FISH and a next-generation sequencing (NGS) myeloid panel look for clonal mutations.
How is FIP1L1::PDGFRA tested: FISH vs RT-PCR?
| Method | How it works | Strengths | Limitations |
|---|---|---|---|
| Karyotype | Chromosome banding under the microscope | Finds other rearrangements (PDGFRB, FGFR1, JAK2) | Cannot see the 4q12 deletion; normal result does not exclude it |
| FISH (CHIC2 deletion probe) | Fluorescent probe for CHIC2, which is lost in the deletion; loss of the signal acts as a surrogate marker | Widely available; works on blood or marrow; quick | Can miss small or variant deletions and fusions with partners other than FIP1L1; less sensitive at low disease levels |
| RT-PCR (often nested) | Amplifies the fusion messenger RNA directly | Very sensitive; confirms the fusion; used to monitor molecular response | Breakpoints vary, so primers must cover them; needs good-quality RNA |
| RNA-based NGS fusion panels | Sequences many possible fusion transcripts at once | Detects rare partners and other TK fusions | Cost and availability |
In practice many laboratories use FISH for speed and RT-PCR (or an RNA fusion panel) as confirmation and to catch cases that FISH misses. If clinical suspicion is high, a negative FISH result should not end the search.
Treatment
Urgent control before the molecular result: steroids and hydroxyurea
Molecular results can take days to weeks. If there is organ damage, particularly to the heart, or the count is very high, treatment starts straight away. High-dose corticosteroids (for example prednisone around 1 mg/kg/day) are the usual first step. They lower eosinophil counts quickly in most patients. First exclude or cover Strongyloides, because steroids can trigger a life-threatening hyperinfection. Hydroxyurea is commonly added or used as the initial cytoreductive agent. It works whatever the underlying driver, so it bridges the gap until the fusion status is known.
FIP1L1::PDGFRA (and other PDGFRA) disease: imatinib
The fusion kinase is exquisitely sensitive to imatinib, so these patients respond to doses far below those used in CML. A starting dose of 100 mg daily is standard, and some patients are later maintained on lower doses. Hematologic responses are the rule, and most patients go on to achieve molecular remission, confirmed by RT-PCR.
Steroid pre-treatment and cardiac checks before imatinib
When imatinib is started in a patient with active eosinophilic myocarditis, rapid eosinophil breakdown in the heart can occasionally cause acute left ventricular dysfunction and cardiogenic shock. The standard precaution is therefore to check troponin and an echocardiogram before starting imatinib. If troponin is raised or there is active cardiac involvement, corticosteroids are given for the first one to two weeks alongside imatinib. Troponin and cardiac function are then re-checked during the early weeks of treatment.
How quickly does imatinib lower eosinophil counts?
Quickly. In FIP1L1::PDGFRA-positive disease the eosinophil count usually falls within days and typically normalizes within the first few weeks. Molecular remission, where the fusion transcript is undetectable by RT-PCR, follows over the next several months. The table shows the typical pattern.
| Time point | Typical absolute eosinophil count | Other features |
|---|---|---|
| Diagnosis | Markedly raised (well above 1.5 × 10^9/L) | Raised B12 and tryptase common; possible splenomegaly; troponin may be raised |
| First 1–2 weeks of imatinib | Falling sharply | Steroid cover if cardiac involvement; monitor troponin |
| By about 1 month | Usually in the normal range (up to 0.5 × 10^9/L) | Complete hematologic response |
| Several months | Normal | RT-PCR for FIP1L1::PDGFRA becomes undetectable (molecular response) |
This table is illustrative of the usual course, not data from an individual patient. If the count does not respond, check that the patient is taking the drug, and consider the rare acquired resistance mutations in the PDGFRA kinase domain (for example T674I).
Whether imatinib can be stopped safely is still uncertain. Relapses after stopping are well described, so most hematologists continue it long term and monitor with RT-PCR.
PDGFRB-rearranged disease
This also responds to imatinib, usually at a higher dose (commonly 400 mg daily), and responses are generally durable.
FGFR1-rearranged disease
This is the most aggressive subgroup and does not respond to imatinib. Treatment options include the FGFR inhibitor pemigatinib, approved in the United States in 2022 for relapsed or refractory FGFR1-rearranged myeloid/lymphoid neoplasms. Intensive chemotherapy is used if the disease has transformed. Allogeneic stem cell transplantation is the only established curative approach and is considered early in eligible patients.
JAK2 and other fusions
JAK inhibitors such as ruxolitinib can control disease driven by PCM1::JAK2 and related fusions. Responses are often not durable, so transplant is often discussed.
CEL without a fusion, and idiopathic HES
Corticosteroids are first-line for idiopathic HES and are commonly used in CEL. Steroid dependence is common. Options that reduce steroid use include hydroxyurea, interferon-alpha, and mepolizumab, an anti-IL-5 antibody approved for HES in 2020. Benralizumab (anti-IL-5 receptor) is being studied. Patients with true CEL, especially those with high-risk mutations or signs of progression, may need intensive therapy and allogeneic transplant.
Acute eosinophilic leukemia
Rarely, blasts reach 20% or more and eosinophils are prominent. This is treated as acute myeloid leukemia, with induction chemotherapy followed by transplant in eligible patients.
Monitoring and Follow-Up
Follow-up is lifelong. How often you are seen depends on the subtype and how stable the disease is, and the same few checks come up at almost every visit:
- Full blood count with differential: at every visit. This is the simplest marker of control and the first sign of relapse.
- Molecular monitoring: in fusion-positive disease, RT-PCR for the fusion transcript is repeated at intervals. A transcript that becomes detectable again, or rises, can warn of relapse or poor adherence before the eosinophil count rises.
- Cardiac surveillance: troponin and echocardiography at baseline, early in treatment, and periodically after that, especially if there was heart involvement at diagnosis. New breathlessness, chest pain, or a new murmur prompts repeat imaging.
- Drug side effects: blood counts and liver tests on imatinib; bone health, glucose, blood pressure, and infection risk on long-term steroids; blood counts on hydroxyurea.
- Signs of transformation: falling hemoglobin or platelets, circulating blasts, or new lymph node enlargement should lead to a repeat bone marrow examination.
Patients on long-term corticosteroids usually need protection against steroid-induced bone loss and, depending on the dose, against certain infections. Before starting any immunosuppressive treatment it is also important to confirm that Strongyloides has been excluded or treated.
Prognosis and Survival
Outlook depends mainly on the molecular subtype and on how much damage the heart has already sustained:
| Subtype | Typical outlook |
|---|---|
| FIP1L1::PDGFRA / PDGFRB on imatinib | Excellent; long-term remission is the norm and life expectancy approaches normal if the heart is spared |
| CEL (no fusion) | Guarded; risk of progression to acute leukemia |
| FGFR1-rearranged | Poor without transplant; frequent transformation |
| Idiopathic HES | Variable; many are well controlled long term |
| Acute eosinophilic leukemia | As for high-risk AML |
Population registries confirm that eosinophilic leukemia is rare and that survival has improved since targeted therapy arrived. Because the categories were redefined over time, figures from older series are hard to compare with current ones, so I prefer to discuss prognosis by subtype rather than quote a single overall number. Cardiac involvement at diagnosis remains the strongest adverse factor across subtypes.
Frequently Asked Questions
What does chronic eosinophilic leukemia do to the heart?
Eosinophils infiltrate and damage the inner lining of the heart (Loeffler endocarditis). The damage progresses from myocarditis to clot formation in the heart chambers and then to scarring. The results can include restrictive cardiomyopathy, leaking mitral and tricuspid valves, pericardial effusion, pulmonary hypertension, and embolic strokes. Early detection with troponin, echocardiography, and cardiac MRI, followed by prompt treatment, can prevent permanent damage.
Is eosinophilic leukemia curable?
FIP1L1::PDGFRA-positive disease is usually controlled so completely by imatinib that it behaves like a cured disease, although therapy is usually continued. For other subtypes, allogeneic stem cell transplant is the main curative option.
How is it different from hypereosinophilic syndrome?
CEL and MLN-TK have proof of a clonal (neoplastic) process: a fusion, a clonal mutation or karyotype, or abnormal marrow. HES is defined by eosinophil-driven organ damage. Idiopathic HES is the label used when no clonal or reactive cause is found.
What eosinophil count suggests leukemia rather than allergy?
No single count separates the two. Allergic disease usually causes mild to moderate eosinophilia. A count that stays at or above 1.5 × 10^9/L needs investigation. Very high counts, or any count with organ damage, splenomegaly, raised B12 or tryptase, or abnormal cells on the film, need urgent hematology referral.
Is eosinophilic leukemia inherited?
No. The fusion genes and mutations that drive it are acquired in bone marrow cells during life. They are not passed on to children, and relatives do not need screening.
Can it transform into acute leukemia?
Yes. CEL can progress to AML. FGFR1-rearranged disease in particular can present as, or transform into, AML or T-lymphoblastic lymphoma.
When to See a Doctor
- An eosinophil count of 1.5 × 10^9/L or more on repeated tests
- Raised eosinophils together with chest pain, breathlessness, palpitations, or new neurological symptoms (urgent)
- Unexplained fevers, night sweats, weight loss, or an enlarged spleen
- HES that is becoming steroid-dependent or not responding to steroids
If you are being investigated, ask whether FIP1L1::PDGFRA testing has been done by FISH and by a molecular method. A normal karyotype alone is not enough.
Key Takeaways
- Eosinophilic leukemia is a rare clonal cause of persistent hypereosinophilia (AEC 1.5 × 10^9/L or more). Reactive causes and CML must be excluded first.
- Under WHO 2022/ICC, fusion-driven cases (PDGFRA, PDGFRB, FGFR1, JAK2, FLT3) are classified as MLN-TK. CEL is reserved for clonal cases without a fusion.
- The FIP1L1::PDGFRA fusion comes from a cryptic 4q12 (CHIC2) deletion. Test with FISH plus RT-PCR, because the karyotype misses it.
- The heart is the organ that matters most. Check troponin and echo at baseline, and give steroid cover when starting imatinib if the heart is involved.
- Low-dose imatinib normalizes counts within weeks in PDGFRA-positive disease. FGFR1-rearranged disease needs pemigatinib and/or transplant.
