CHRONIC EOSINOPHILIC LEUKEMIA

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 E osinophil 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

15. FEATURES HES T-lymphocytic variants (L-HES). Myeloproliferative variants of HES. Familial HES. UNDEFINED HES OVERLAP HES ASSOCIATED HES C/F Predominance of skin. Soft tissue involvement Anemia, Thrombocytopenia. Splenomegaly Hepatomegaly Eosinophilia begins at birth asymptomatic mainly, few developefatal endomyocardial fibrosis Benign HES (asymptomatic) Complex -multisystem involvement Episodic - angioedema and eosinophilia eosinophilic gastrointestinal disorders, chronic eosinophilic pneumonia.,Churgh -Strauss Immune dysregulation-UC,sarcoid,CVD,HIV INVESTIGATION Increased serum level of IGE and IL5 by the abnormal T cells Vit.B12 and Ser.Tryptase eosinophilia ≥1500/ microliter eosinophilia ≥1500/ microliter eosinophilia ≥1500/ microliter ≥1500/ microliter

16. Feature HES T-lymphocytic variants (L-HES). Myeloproliferative variants of HES. Familial HES. UNDEFINED HES OVERLAP HES ASSOCIATED HES GENETICS FIP1L1-PDGFRA AD Tx / Px Better prognosis Respond well to steroids. Worse prognosis,poor response to steroids , conert into AML.

17. 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.

18. FIP1L1 gene mutations in HES - When the FIP1L1-PDGFRA fusion gene occurs in blood cell precursors, the growth of eosinophils (and occasionally other blood cells) is poorly controlled. It is unclear why eosinophils in particular is affected by this genetic change.

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  

22. Cardiac disease   P ulmonary 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 1 st 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) . 2 nd 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

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%).