Hypereosinophilic Syndromes â Recent Advances In Definition

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M K pag 149M K pag 149HYPEREOSINOPHILIC SYNDROMES – RECENT ADVANCES IN DEFINITION, CLASSIFICATION AND THERAPEUTIC APPROACH– Lymphocytic-HES (L-HES): patients withchronic reactive eosinophilia in responseto IL-5 over-production by T cells.– Myeloproliferative-HES (M-HES): patientswith a large array of clinical and biologicalfeatures (elevated levels of vitaminB12, hepatomegaly, splenomegaly, anemia,thrombocytopenia, circulating myeloid,displastic eosinophils, bone marrowhypercellularity with increased numberof myeloid precursors, myelofibrosis,increased serum tryptase and responseto imatinib), suggesting an underlyingmyeloproliferative disorder associatedwith eosinophilia but having no evidenceof molecular defects.– Idiopathic hypereosinophilic syndrome(HES): patients with eosinophilia of unknowncause.– Organ-restricted eosinophilic disease:only one specific tissue or organ involvement(e.g. eosinophilic esophagitis, eosinophilicgastroenteritis, eosinophilic pneumonia,Kimura disease, eosinophilic dermatitis,eosinophilic fasciitis)Although this rather complicated classificationraised multiple debates regarding its accuracy,it proved to be useful for defining certainpathogenic entities (11).Lately, new molecular data improved thediagnosis guidelines of the eosinophilic disordersand an entirely new classification emerged(WHO classification of tumors ofhaematopoietic and lymphoid tissues 2008).The following entitis are now acknowledged(12):Chronic eosinophilic leukemia (CEL) definedas a clonal proliferation of eosinophilicprecursors, accumulation of eosinophils in peripheralblood and bone marrow, causing endorgan damage due to the tissue eosinophilicinfiltration and release of eosinophilic proteins.Patients expressing Philadelphia chromosome,BCR-ABL1, PDGFRA, PDGFRB and FGFR1 fusiongenes are excluded.Diagnosis criteria:– AEC>1.5 x 10 9 /L in peripheral blood orbone marrow eosinophilia– exclusion of reactive causes of eosinophiliaincluding hematological malignancies(e.g. aCML, CML, CMML andlymphoproliferative disorders)– exclusion of a T-cell abnormal populationthat produces increased eosinophilopoieticcytokines– peripheral blood blasts >2% and bonemarrow blasts 5% – 20%or– evidence of eosinophil clonalityIf the clonality of the eosinophils cannot bedemonstrated and bone marrow blasts are lessthan 5%, the term “Idiopathic HES” must beused.Idiopathic HES: is a diagnosis of exclusion.<strong>In</strong> time, some of these patients initially diagnosedas Idiopathic HES may develop clinicalfeatures resembling CEL or hypereosinophiliainduces by cytokines (IL-2, IL-3, IL-5).Diagnosis criteria:– persistent eosinophilia (AEC >1,5 x 10 9 /L) for more than 6 months– exclusion of reactive causes of eosinophilia– exclusion AML, MPD, MDS, MPD/MDSand SM– exclusion of a T-cell abnormal populationwith increased production of eosinophilopoieticcytokines– end organ damage– no the evidence of eosinophilic clonality(exclusion of Philadelphia chromosome,BCR-ABL1, PDGFRA, PDGFRB andFGFR1 fusion genes, myeloproliferativedisorders as PV, ET, IMF or MPD/MDSare excluded).Idiopathic hypereosinophilia includes allthese criteria except for end organ damage.Myeloid neoplasms (MPN) with eosinophiliaand PDGFRA, PDGFRB and FGFR1 rearrangements:three distinct entities with cytogeneticabnormalities resulting in fusion geneswith tyrosine-kinase activity; some of them areimatinib sensitive. The hematological featuresare those of myeloid or lymphoid neoplasms.PDGFRA rearrangement: usually presentsas CEL +/- mastocitosis and less often as AMLor lymphoblastic lymphoma with eosinophilia.These patients present clinical features of achronic disease with constitutional symptoms(weakness, weight loss, night sweats, pruritus)and virtually any organ may be involved: heart,lungs (restrictive dysfunction with fibrosis), gastrointestinaltract, skin, spleen, rarely liver. Somepatients progress to acute forms. Prognosis dependsmainly on the cardiac involvement(endomyocardial fibrosis with restrictive cardi-Mædica A Journal of Clinical Medicine, Volume 4 No.2 2009 149
M K pag 150M K pag 150HYPEREOSINOPHILIC SYNDROMES – RECENT ADVANCES IN DEFINITION, CLASSIFICATION AND THERAPEUTIC APPROACHomyopathy, heart failure, mitral or tricuspidvalves dysfunctions, mural thrombi with highthromboembolic risk). Both chronic and acuteforms are associated with imatinib response. Themost frequent genetic abnormality is a crypticinterstitial deletion in chromosome 4 (4q12)leading to FIP1L1-PDGFRA fusion geneDiagnosis criteria:– AEC >1,5 x 10 9 /L– 5-19% bone marrow blasts– no evidence of Philadelphia chromosome– no evidence of BCR-ABL fusion gene– demonstration of del 4q12 (being a crypticfusion gene FISH exam is required,cytogenetic analysis alone is insufficient)or of FIP1L1-PDGFRA fusion gene (confirmedby RT-PCR or nested RT-PCR).Other PDGFRA molecular variants areassociated with imatinib sensibility.(13,14)PDGFRB rearrangement: the hematologicalfeatures are most often those of CMML witheosinophilia and a variable degree of mastocytosis.Mandatory for the diagnostic of thesemyeloproliferative neoplasms is the presenceof PDGFRB gene. Patients often have splenomegaly,skin infiltration and cardiac damage butrare liver involvement. Peripheral blood andbone marrow are always involved. Evolution toacute leukemia may occur. Imatinb producesclinical response. Prognosis mainly depends onthe cardiac damage. Cytogenetic analysis usuallyshows t(5;12)(q31~33;p12) with the translocationresulting in formation of an ETV6-PDGFRB fusion gene.Diagnosis criteria:– myeloid neoplasm with prominent eosinophilia+/- neutrophila or monocytosis– evidence of t(5;12)(q31~33;p12) or avariant translocation (cytogenetic analysis)or demonstration of an ETV6-PDGFRB fusion gene or rearrangementsof PDGFRB (PCR or FISH)– no evidence of Philadelphia chromosomeFGFR1 rearrangement: some patientspresent as T cell lymphoblastic leukemia/lymphoma,CEL, AML and less often as precursorB cell lymphoblastic leukemia/lymphoma. It representsa heterogeneous group of disorderscharacterized by lymph nodes involvement,splenomegaly, fever, weight loss and nightsweats. A variety of translocations with an 8q11breakpoint can underlie this syndrome. Theprognosis is poor since no TKI has proved effectivein FGFR1 rearrangement neoplasms. <strong>In</strong>terferonhas induced a cytogenetic response inseveral cases. Haematopoietic stem cell transplantationshould be considered even in thosepatients who present in chronic phase.Diagnosis criteria:– myeloid neoplasm with increased eosinophilia+/- neutrophila and/or monocytosisor– acute myeloid leukemia or precursor Tor B cell lymphoblastic leukemia/ lymphomaprecursors AND– presence of t(8;13)(p11;q12) or a varianttranslocation leading to FGFR1 rearrangementdemonstrated in myeloidcells, lymphoblasts or both.The above mentioned data represents thenew approach of the clonal hypereosinophilias,based mainly on cytogenetic and molecular assays.Several conclusions must be emphasized:1. According to this classification, older entitiesas myeloproliferative-HES and lymphocytic-HESare no longer used, beingconsidered as secondary hypereosinophilia.2. New entities with major therapeutic impactare defined based on cytogeneticand molecular criteria3. Immunophenotypic analysis is less importantin diagnosis as long as the clonal eosinophilshave no particular characters butit has its role in identification, characterizationand following of the abnormal T-cell population that produces excessivelyIL-5.4. The cytogenetic analysis should alwaysbe followed by molecular assays, especiallyin myeloproliferative-like disordersthat may have cryptic anomalies.5. Any MPN or lymphoblastic leukemia/lymphoma with eosinophilia require cytogeneticanalysis for PDGFRB, FGFR1 rearrangementsand molecular assays (RT-PCR or FISH) for PDGFRA rearrangements.150Mædica A Journal of Clinical Medicine, Volume 4 No.2 2009
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Hypereosinophilic Syndromes â Recent Advances In Definition