HAEM5:Chronic eosinophilic leukaemia: Difference between revisions

CEL, NOS is sometimes discovered incidentally in otherwise asymptomatic individuals. In other instances, patients experience constitutional symptoms including weight loss, night sweats, fever, fatigue, cough, angioedema, muscle pain, pruritis and diarrhea. Endomyocardial fibrosis with ensuing restrictive cardiomegaly is known to precipitate the most severe clinical presentation. Scarring of the bicuspid and mitral valves can lead to valvular regurgitation and intracardiac thrombi formation which may embolize to the brain and other organs. Cardiac failure may also occur. Peripheral neuropathy, central nervous system dysfunction and pulmonary symptoms due to lung infiltration as well as rheumatological findings are also common. [1]

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==Sites of Involvement==

No single or specific genetic abnormality has been identified in CEL, NOS. Rearrangement of PDGFRA, PDGFRB, or FGFR1 excludes the diagnosis of CEL, NOS. PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 are also specifically excluded. [1] Three unique cases of myeloid/lymphoid neoplasm with eosinophilia have shown ''FLT3'' rearrangement: one with t(13;14)(q12;q32)/''TRIP11-FLT3'' rearrangement, and two with ''ETV6-FLT3''. Eosinophilia and ''FLT3'' rearrangement typically shows myeloproliferative neoplasms, most frequently CEL, NOS, and T-ALL. [5] A unique case of CEL,NOS with a novel fusion gene between exon 22 of GCC2 and exon 12 of PDGFRB was detected and confirmed by PCR in a 54 year old man presenting with cough and dyspnea. [6]  

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

Although survival is variable, acute transformation is common and prognosis is typically poor. The median survival time in one small series was 22.2 months. Response to imatinib has been reported but is uncommon. Treatment with Interferon alpha leading to cytogenic remission has been reported in 3 cases with translocations with a 5q31-33 breakpoint. Complete hematologic response has been achieved in one reported case of CEL with ETV6/FLT3 fusion, with the off-label use of FLT3-inhibitor, sorafenib.[2] Unfavorable prognostic findings include marked splenomegaly, blasts in the blood or increased blasts in bone marrow, cytogenetic abnormalities, and dysplastic features in other myeloid lineages. [1] According to a study of 17 cases defined by WHO-2016 standards,  univariate survival analysis showed predictors of inferior survival included megakaryocytic atypia (''P'' = .01), peripheral blood eosinophilic atypia (''P'' = .024), LDH (''P'' = .046) and abnormal karyotype (''P'' = .020). [4] Of these patients, the most frequently utilized first line agents were hydroxyurea as a single agent or in combination with steroids,  steroids as a single agent, or in combination. Half of patients treated with hydroxyurea based regimens responded with a persistent decline in eosinophil count over 17.5 months. Approximately one third of patients demonstrated response to steroids for a median duration of 13 months. Three of these patients were treated with imatinib of which two had normalization of eosinophil count. [4] Imatinib was successful in treatment of the individual case of CEL,NOS with novel fusion gene involving PDGFRB and GCC2 with disappearance of the fusion gene in bone marrow after three months. [6]  

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==Individual Region Genomic Gain / Loss / LOH==

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==Characteristic Chromosomal Patterns==

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A recurrent karyotypic abnormality typically observed in myeloid disorders such as gain of chromosome 8, loss of chromosome 7 or isochromosome 17q supports a diagnosis as well as the presence of a translocation. [1] [1] Morsia et al demonstrated cytogenetic abnormalities in 15 of 17 (88.2%) patients diagnosed with CEL, NOS including trisomy 8 (n = 4), and complex karyotype (n = 3). [4]  

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==Gene Mutations (SNV / INDEL)==

JAK2 mutations have been identified, however mutations in ASXL1, TET2 and EZH2 appear to be common. [1] The study by Morsia et al. of 17 CEL patients demonstrated two patients each with 13q, 20q deletion, and chromosome 1 abnormalities, one patient with monosomy 7 and one with 3q deletion. All seven patients with NGS studies harbored one or more mutations; ''ASXL1'' (42.9%); ''IDH1'' (28.6%), and one each (14.3%) with ''TP53'', ''SRSF2'', ''SH2B3'', ''STAT5B'', ''KDM6A'' and ''NF1'' mutations. [4] A novel ''JAK2'' exon 13 insertion/deletion mutant has been identified and described by Patel et al. in a patient fulfilling diagnostic criteria for both PV and CEL. This study demonstrated that JAK2ex13InDel bears mechanistic resemblance to JAK2V617F but can activate STAT5 in the absence of βc family cytokines IL-3, IL-5, and GM-CSF, potentially promoting eosinophilic differentiation. [7] Keleman et al. discussed STAT5B mutations as reported in four cases: two cases of CEL, NOS; one case of CMML with eosinophilia; and one case of MDS with eosinophilia, respectively. While the presence of a STAT5B N642H mutation may be a potential marker of chronic eosinophilic neoplasms, similar mutations have been described in nonclonal HE and may not be independently sufficient to establish a diagnosis of CEL, NOS. [8]  

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==Epigenomic Alterations==

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==Genetic Diagnostic Testing Methods==