Short summary of Chronic eosinophilicleukemia and hyper eosinophilic syndrome

1. Hypereosinophilic
syndrome & Chronic
Eosinophilic Leukemia
Neema Tiwari

2. Eosinophil granulocyte
Eosinophil granulocytes:- are white blood cell
develop and mature in the bone marrow from myeloid
precursor cells.

3. Eosinophil development,
migration and activation
Marrow
production
IL3,IL5,
GM-CSF
Tissue
migration to
site of
parasitic
infection
TH2 cell
cytokines:
IL3,IL4
GM-CSF
IL5
LTB4
Eotaxin
1 &2
cationic granule
Proteins
eosinophil
perioxidase
neurotoxin
Organ damage

4. DISTRIBUTION
 In normal individuals, eosinophils make up about 1-6% of white
blood cells.
 They are found in
 but not in the lung, skin, esophagus. The presence of eosinophils in
these latter organs is associated with disease.
 Eosinophils persist in the circulation for 8–12 hours, and can
survive in tissue for an additional 8–12 days in the absence of
stimulation..

5. Classification of Eosinophilia
• Primary(Clonal): Eosinophils are clonally
derived from an underlying hematologic
neoplasm
• Secondary(reactive)
• Hypereosnophilic syndromes

6. PATHOPHYSIOLOGY
 Clonal eosinophilic proliferation as a result of a primary molecular
defect involving hematopoietic stem cells
 Overproduction of eosinophilopoietic cytokines, such as IL-5
 Functional abnormalities of the eosinophilopoietic cytokines
 Defects in the normal suppressive regulation of eosinophil survival and
activation

7. Primary causes
 Chronic myeloproliferative syndrome.
 Chronic eosinophilic leukemia
 Certain subtypes of AML.
 Myelodysplastic syndrome.
 Systemic mastocytosis.

8. Secondary causes
 Infectious diseases:
parasitic, viral, bacterial and fungal
 Allergic disorders:
Eosinophilia commonly results from atopic conditions asthma, and various forms of
rhinitis, as well as allergic drug reactions.
 Rheumatic disease:
Eosinophilia-myalgia syndrome and toxic oil syndrome-Idiopathic eosinophilic
synovitis- Churg-Strauss ,wegener,sarcoidosis ,RA and SLE.
 Dermatologic:
atopic dermatitis,urticaria,eczema and dermatitis herpetiformis.
 Pulmonary:
cystic fibrosis-esnophilic granuloma-bronchiectasis
 GIT:
esnophilic gastroenteritis and celiac disease
 Cardiac:
Tropical endocardial fibrosis –endomyocardial fibrosis.
 Malignancy:
Breast, lung and renal cancer.
 Metabolic: adernal insufficiency.
 Immunodeficiency states: hyper-IgE syndrome

9. HES variants
 Myeloproliferative variants of HES.
 HES T-lymphocytic variants (L-HES).
 Familial HES.
 Undefined HES.
 Overlap HES.
 Associated HES.

10. Work up of eosinophilia
 History ,Physical Examination and laboratory
studies directed toward possible reactive
causes(travel, medications and systemic
disease).
 Stool or serologic studies for parasites.
 CXR, CT scan, Echocardiography.
 Biopsy of involved organs.
 Bone marrow biopsy with cytogenetic.

11. The Eosinophil Count
Normal:<500/mm3
Eosinophilia can be categorized:-
Mild (500 to 1500 cells/microL).
moderate (1500 to 5000 cells/microL).
severe (>5000 cells/microL).

12. Hyperesnophilic syndrome
Diagnostic criteria
 Blood eosinophilia of ≥1500/microliter,
present for more than six months.
 No other apparent etiologies for
eosinophilia, such as parasitic infection or
allergic disease.
 Signs and/or symptoms of eosinophil-
mediated end-organ dysfunction.

13. New diagnostic criteria
• Blood eosinophilia of ≥1500/micro liter,
present on at least two occasion.
• No other apparent etiologies for this
degree of eosinophilia.

14.  Some HES patients require theraputic
interventions well before the six month
period specified in the first criterion, in
order to treat or prevent potentially life-
threatening complications of sustained
hypereosinophilia.
 The third criterion excludes patients with
early HES, who have not yet developed
signs and symptoms of disease

16. FEATURES VHES T-
lymphocytic
variants (L-
HES).
Myeloprolifer
ative variants
of HES.
Familial
HES.
UNDEFINED
HES
OVERLAP
HES
ASSOCIATE
D HES
C/F Predominan
ce of skin.
Soft tissue
involvement
Anemia,
Thrombocyt
openia.
Splenomega
ly
Hepatomega
ly
Eosinophilia
begins at
birth
asymptomati
c mainly,
few
developefata
l
endomyocar
dial fibrosis
Benign
HES
(asymptoma
tic)
Complex-
multisystem
involvement
Episodic-
angioedema
and
eosinophilia
eosinophilic
gastrointesti
nal
disorders,
chronic
eosinophilic
pneumonia.,
Churgh-
Strauss
Immune
dysregulatio
n-
UC,sarcoid,
CVD,HIV
INVESTIG
ATION
Increased
serum level
of IGE and
IL5 by the
Vit.B12 and
Ser.Tryptase
eosinophilia
≥1500/micro
liter
eosinophilia
≥1500/micro
liter
eosinophilia
≥1500/micro
liter
≥1500/micro
liter

17. Feature HES T-
lymphocyti
c variants
(L-HES).
Myeloprolife
rative
variants of
HES.
Familial
HES.
UNDEFINE
D HES
OVERLAP
HES
ASSOCIATE
D HES
GENETIC
S FIP1L1-
PDGFRA AD
Tx/Px Better
prognosis
Respond
well to
steroids.
Worse
prognosis,
poor
response
to steroids
,conert
into AML.

18. FIP1L1 gene-Fip gene: factor
interacting polymerase alpha.
 The FIP1L1 gene provides instructions for
making part of a protein complex named
cleavage and polyadenylation specificity
factor (CPSF).
• The CPSF protein complex helps add a string
of the RNA building block adenine to the
mRNA, creating a polyadenine tail or
poly(A) tail. The poly(A) tail is important for
stability of the mRNA.

19. Serum tryptase
 The reference range is < 11.4 ng/mL.
 Tryptase can also be elevated with:-
Asthma.
Myelodysplastic syndrome.
Acute myelocytic leukemia.
Systemic mastocytosis
Detection of KIT gene mutation. Normally gene
encode Mast cell growth factor receptor:- protein
found on surface of mast cell, work as tyrosine
kinase receptor.

20. Serum IgE
 As result of B cell stimulation by TH 2 cytokines.
Causes of elevated IgE
Common
Allergic disease (eg, atopic dermatitis/eczema,
asthma, allergic rhinitis,
food allergy, eosinophilic esophagitis, urticaria,
drug allergy)
Parasitic worm infestation (eg, helminth
infection).

21. CLINICAL FEATURES
Cardiac
5%
Gastrointestinal
- 14 percent
Pulmonary
(cough and
breathlessness)
- 25 percent
Dermatologic
(eg, rash) –
37 percent

22. Cardiac disease Pulmonary disease
 Eosinophilic myocarditis is a
major cause of morbidity and
mortality among patients with
HES.
 An acute necrotic stage.
 An intermediate phase characterized
by thrombus formation along the
damaged endocardium.
 A fibrotic stage.
 Dyspnea.
 Cough.
 Wheezing.
 ground glass infiltrates

23. Gastrointestinal Neurologic disease
 Eosinophilic gastritis
&enteritis may occur
secondary to HES causing :-
 weight loss
 abdominal pain, vomiting
 diarrhea
 Hepatic involvement :-
 active hepatitis,
 focal hepatic lesions,
 Eosinophilic cholangitis
 Budd-Chiari syndrome
 Cerebral thromboemboli
 Encephalopathy.
 Peripheral neuropathy
 Longitudinal and/or
transverse sinus thrombosis.
 Skin disease-
Erythroderma,angioedema,
mucosal ulcers
 2o% infiltration with
eosinophilis is highly
suggestive of HES.
 ,

24. Thrombotic complications
 Patients have been reported to develop:-
 femoral artery occlusion .
 intracranial sinus thrombosis.
 digital gangrene in the setting of
progressive Raynaud's phenomenon.
Eosinophil-related damage to endothelium
combined with activation of the coagulation system

25. CASE OF HES
 30 yrs old female patient diagnosed at outpatient
clinic as a case of 1yr sjogren in 2003 by:
 Sicca symptoms(dry eyes, dry mouth).
 Non erosive symmetrical polyarthritis.
 Anti RO>200.
 Anti La >200.
 Generalized lymphadenopathy &parotid gland
enlargement
 methotrexate 25mg/week for arthritis with
improvement.
 During course of the disease the patient was
irregular on Tx(due to improvement).

26.  The patient presented
with angioedema.
 Generalized papular
and pustular
eruptions.
 The patient was
admitted at
dermatology
department

27. Laboratory investigations
 ESR 1st hour:130
 CBC
HB:8.2g%.
WBC:4.000/ul
Platelet:361000/ul
 Differential WC count
Neutrophils:42%
Lymphocytes:50%.
Esoinphils:45%.
Basophils:3%.
Serial CBC showed persistent eosinophilia

28. lab
 Sgpt:32u/l.
 Sgot:22u/l.
 Creatinine:0.28 mg/dl.
 Urea:38 mg/dl.
 ANA:negative.
 DNA:negative
 RF:negative.
 ANCA P & C: negative.
 ACL IGM & IGG: negative.
 HCV ab & HBSag: negative.
 Urine analysis:free.
 Stool analysis for ova & parasite:free.
 Anti bilharzial ab: negative.
 Serum IGE:9980 IU/ml(up to 100).

29. Radiological investigations
 Chest xray:normal study.
 Abdominal and pelvic ultrasound:
hepatosplenpmegaly.
 Echo cradiography :normal study.
 Other investigations:
Skin biopsy:- showed perivascular eosinophilic
infilitration with no evidence of vasculitis.
Bone marrow biopsy: normocellular bone marrow
with eosinophils and areas of fibrosis with no
lymphoid infiltrate.

30. DIAGNOSIS
So the patient was diagnosed as a case of
HES based on :
 hypereosinphilia on 2 occasions.
Skin biopsy.
Mostly T Lymphocytic type based on:
 Predominance of skin involvement
 Elevation of serum IGE.

31. TREATMENT
 The patient was treated by pulse of
methylperdinsolone followed by oral steroids
 Hydrea was added (1×2) with improvement of
her condition.

32. HOW to diagnose a case of
HES?

33. Diagnosis
 Step1:Clinical signs and symptoms.
 Step2: Peripheral blood analysis for eosinophils and blast
cells, serum tryptase and vitamin B 12.
 Step 3: Bone marrow examination for eosinophils and
blast cells
 Step 4: chromosomal testing to detect FIP1L1/PDGFRA
mutation.

34. Diagnosis of selected HES variants

35. Pathologic findings
The eosinophilic infiltration tends to affect
specific layers of the gastric or intestinal wall.
Lesions are usually multiple and patchy.
Mucosa
Edema, lymphatic dilatation as well
as an intense eosinophilic infiltrate,
epithelial cell necrosis, pit or crypt
abscesses, erosions, shallow ulcers,
or villous atrophy.
Submucosal edema is more common
and destruction of the wall and
fibrosis

36. Treatment of HES- Reduction of eosinophil level.
Prevent irreversible organ damage.
Who must be treated?
 All F/P-positive patients
 In other non-M-HES patients,
 Asymptomatic patients with chronic
eosinophilia, regardless of their eosinophil
counts

37.  High dose intravenous glucocorticoids (eg, at a dose equivalent
to 15 mg/kg of prednisone.---In response to high dose
glucocorticoids, the eosinophil count typically drops dramatically
(eg, by more than 50 percent of the original value).
 2nd Line- vincristine
 Once the patient is clinically stable, treatment will be according to
HES specific variant
 First-line therapy for all patients with FIP1L1- and PDGFRA-
positive disease is the tyrosine kinase inhibitor, imatinib mesylate
 Stem cell transplant
 TREATMENT FAILURE
 Persistent eosinophilia of 1.5 x 109/L or higher after 1 month of treatment .
 Consider shifting to other tyrosine kinase inhibitor or bone marrow transplantation

38. GENETIC APPROACH TO HES
Fish for FIP
gene
FIP -ve
Symptoms
Organ
damage
Yes:
Steroids high
dose.
Hydroxy urea
IFalpha
NO:
observeation
Fip +ve
Gleevec
1oomg
Another TKI
Bone marrow
transplant

39. Chronic Eosinophilic
Leukemia-WHO CRITERIA
 Persistent eosinophilia ≥105x109/L
 Increase number of eosinophils in bone
marrow
 Myeloblasts <20% in blood and bone
marrow
 Exclude all other causes of reactive
eosinophilia.
 Exclude all other causes of neoplastic
eosinophilia
 Exclude T-cell population with aberrant
phenotype

40. HES vs CEL
The same gene mutation found in patients
with CEL also but it is a HES mutation
predominantly.
CEL: blast cells in peripheral blood(>2%).
Increased blast cells in bone
marrow(>5%).