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Acute Lymphoblastic Leukemia with Hypereosinophilia

Written2018-03Anwar N. Mohamed
Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA. amohamed@dmc.org

Abstract Acute lymphoblastic leukemia (ALL) with hypereosinophilia is a rare disease, with the majority of reported cases being B-lineage ALL. Although eosinophilia is considered a reactive, non-neoplastic epiphenomenon, it adversely affects patient outcomes, both in children and adults. It is a distinct clinical entity by World Health Organization (WHO) 2008 and commonly associated with a unique cytogenetic abnormality.

Keywords aAcute lymphoblastic leukemia; Hypereosinophilia; t(5;14); deletion 5q

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Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9817/3 B lymphoblastic leukaemia/lymphoma with t(5;14)(q31;q32); IL3-IGH
Atlas_Id 1184
Note Marked eosinophilia is an uncommon finding in ALL. It may precede the diagnosis of ALL or occur simultaneously at the time of diagnosis. Eosinophils can mask the underlying or coexisting leukemia. Therefore, comprehensive evaluation for unexplained hypereosinophilia should be carried out to rule out possibility of malignancy including ALL, even in the absence of peripheral circulating blasts.

Clinics and Pathology

Epidemiology ALL with hypereosinophilia is reported in <1% of ALL cases. The disease was first described by Spitzer and Garson in 1973. Subsequently, over 50 adult and pediatric cases have been documented in the literature (Fishel et al, 1990; Parasole et al 2014). The majority of the described cases have B-cell phenotypes. In 1980, Catovscky et al reported two cases of T-cell ALL with eosinophilia. ALL with eosinophilia cases are predominantly male patients, median age at presentation of 15 years with an age range of 2-71 years (Fishel et al, 1990; Wilson & Tefferi, 2005; Parasole et al, 2014).
Clinics Clinical presentations may be similar to other patients with ALL. Whereas some patients may be presented with signs and symptoms indistinguishable from hypereosinophilic syndrome, and death in some patients appears to have occurred as a complication of eosinophilic tissue damage (Rezamand et al, 2013; Bomken et al, 2015). Eosinophilia may precede the diagnosis of leukemia by 1-9 months and during this period, the patients may present with urticarial hyperpigmented plaques and other non-hematological features of HES such as cardiomyopathy, pneumonitis, dermatitis, sinusitis, central nervous system or peripheral neuropathy (Chien et al, 2004; Bomken et al 2015). In patients bearing this association, a significantly increased risk of cardiac and vascular thrombosis exists, and congestive heart failure represents the main cause of mortality in patients with ALL and hypereosinophilia (Nie et al, 2010; Parasole et al, 2014). Based on the literature review 30% of patients died as a result of congestive heart failure attributed to the eosinophilia (Fishel et al, 1990). Pneumonia or pulmonary infiltrates were present in 50% and chest pain was reported in 20% of patients. Thrombotic complications may occur in this subset of ALL therefore, prompt heparin prophylaxis or chemotherapic modulation of prothrombotic drugs should be planned. Eosinophilic infiltration into endomyocardial, pleural and pulmonary tissue has been documented in those patients (Parasole et al, 2014). Eosinophilia quickly resolved upon achievement of remission, but in most patients reappeared during relapse. Thus, eosinophilia is an important clinical marker to monitor this disease, which disappears with chemotherapy whereas its recurrence following remission is an indication of relapse of ALL.
Cytology Peripheral blood usually shows leukocytosis and marked eosinophilia. The initial white blood cell count ranged from 4-148x 109/L with an average eosinophilia of 55% and rare circulating blast cells. Blasts may be absent in peripheral blood which could lead to delay in the diagnosis, if bone marrow aspiration is not done (Wilson and Tefferi, 2005; D'Angelo et al 2008). Many of the laboratory abnormalities characteristic of hypereosinophilic syndrome (HES), including eosinophil dysplasia, and elevated B12 levels can also be seen in ALL with eosinophilia. Interestingly, elevation of serum tryptase, which is associated with imatinib responsive HES, has not been reported (Robyn et al 2004).
Pathology Bone marrow aspirate and biopsy show hypercellular marrow infiltrated with blasts, and the presence of marked eosinophilia; both precursor and normally maturing eosinophils. The blasts have typical morphology of lymphoblasts and express B-precursor phenotypes classically CD19+ and CD10+.
Prognosis ALL with eosinophilia is an aggressive form of ALL. Prognosis is poor both in children and adults (Sutton et al 2008; Wilson et al, 2010). Although response to initial chemotherapy was good, relapse occurred in most patients. The prognosis of patients reviewed by Fishel et al was quite poor; 22 of 24 patients died within 5 years of diagnosis, with a median time from diagnosis to death of 7.5 months. Death resulted from either complications of chemotherapy or from organ failure secondary to overwhelming infiltration by eosinophils. Sutton et al described two patients in a cohort of 391 pediatric ALL (Sutton et al 2008). Both patients had a very poor molecular response to initial chemotherapy as measured by high minimal residual disease (MRD) and were stratified to the high-risk group to receive intensive chemotherapy followed by bone marrow transplantation. One patient had subsequently relapsed and the hypereosinophilia, which also recurred, was of donor cell origin.

Cytogenetics

Note Cytogenetic abnormalities are found only in leukemic blasts whereas eosinophils have normal karyotype indicating not a clonal population. Based on limited reported cases, approximately 2/3 of ALL with eosinophilia cases have chromosomal abnormalities with the most recurrent being:
Cytogenetics Morphological t(5;14)(q31;q32) this translocation, t(5;14)(q31;q32), has been identified in almost 50% of cases (Hogan et al, 1987; Grimaldi and Meeker 1989; Bomken et al, 2015). The breakpoint of this unique translocation has been cloned and shown to juxtapose the IGH/14q32 enhancer and IL3/5q31 gene, resulting in a constitutive expression of IL3 (Meeker et al, 1990). While IL3 promotes production and survival of eosinophils, high serum levels of IL3 have been postulated to be responsible for the reactive hypereosinophilia. High serum IL3 levels have been demonstrated in one case at diagnosis and seen to recur at leukemic relapse.
t(5;9)(q31;p24) Nuñez et al reported a novel t(5;9)(q31;p24), in a patient with B-cell ALL associated with eosinophilia. In this case the t(5;9)(q31;p24) possibly led to fusion of the IL3/5q31 and JAK2/9p24 genes that may explain the simultaneous appearance of eosinophilia and ALL (Nuñez et al 2003).
Other recurrent chromosome abnormalities reported in ALL with eosinophilia are deletion of 5q, deletion of 7q, deletion of 9p21 with biallelic deletion of CDKN2A (cyclin dependent kinase 2a / p16), t(7;12)(q22;p13) (Wynn et al, 2003; Wilson et al, 2005; Rezk et al 2006; D'Angelo et al, 2008; Parasole et al, 2014; Bhatti et al, 2009). These chromosomal abnormalities are uncommon in ALL without eosinophilia suggesting that this subtype of ALL may represent a unique disease entity.

Genes involved and Proteins

Gene NameIL3
Location 5q31.1
Note Alternative symbols: showed that the product of the MYC gene has a molecular mass of 65 kD, is located predominantly in the nucleus, and binds to DNAInterleukin 3; Hematopoietic Growth Factor; Multipotential Colony-Stimulating Factor; Multilineage-Colony-Stimulating Factor; Colony-Stimulating Factor; Multiple; P-Cell Stimulating Factor; Mast-Cell Growth Factor.
Protein The protein encoded by IL3 gene is a potent growth promoting cytokine. It acts by binding to interleukin receptor. This cytokine stimulates the proliferation of a broad range of hematopoietic cell types. It is involved in a variety of cell activities such as cell growth, differentiation and apoptosis.
Gene NameJAK2
Location 9p24.1
Protein Protein tyrosine kinase of the non-receptor type.
Gene NameIGH
Location 14q32.33

Bibliography

A novel mutation in purine nucleoside phosphorylase in a child with normal uric acid levels
Al-Saud B, Alsmadi O, Al-Muhsen S, Al-Ghonaium A, Al-Dhekri H, Arnaout R, Hershfield MS, Al-Mousa H
Clin Biochem 2009 Nov;42(16-17):1725-7
PMID 19733163
 
Mitochondrial basis for immune deficiency
Arpaia E, Benveniste P, Di Cristofano A, Gu Y, Dalal I, Kelly S, Hershfield M, Pandolfi PP, Roifman CM, Cohen A
Evidence from purine nucleoside phosphorylase-deficient mice J Exp Med
PMID 10859343
 
Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency
Aust MR, Andrews LG, Barrett MJ, Norby-Slycord CJ, Markert ML
Am J Hum Genet 1992 Oct;51(4):763-72
PMID 1384322
 
Purine nucleoside phosphorylases: properties, functions, and clinical aspects
Bzowska A, Kulikowska E, Shugar D
Pharmacol Ther 2000 Dec;88(3):349-425
PMID 11337031
 
[A congenital hyperplasia of Bowman's membrane]
Daicker B, Wieser D
Ber Zusammenkunft Dtsch Ophthalmol Ges 1972;71:31-5
PMID 4582029
 
Purine nucleoside phosphorylase
Erion MD, Takabayashi K, Smith HB, Kessi J, Wagner S, Hönger S, Shames SL, Ealick SE
1 Structure-function studies
PMID 9305962
 
Correction of purine nucleoside phosphorylase deficiency by retroviral-mediated gene transfer in mouse S49 T cell lymphoma: a model for gene therapy of T cell immunodeficiency
Foresman MD, Nelson DM, McIvor RS
Hum Gene Ther 1992 Dec;3(6):625-31
PMID 1482702
 
Functional analysis of purine nucleoside phosphorylase as a key enzyme in ribavirin metabolism
Furihata T, Kishida S, Sugiura H, Kamiichi A, Iikura M, Chiba K
Drug Metab Pharmacokinet 2014;29(2):211-4
PMID 24107682
 
Lupus-Associated Functional Polymorphism in PNP Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells
Ghodke-Puranik Y, Dorschner JM, Vsetecka DM, Amin S, Makol A, Ernste F, Osborn T, Moder K, Chowdhary V, Eliopoulos E, Zervou MI, Goulielmos GN, Jensen MA, Niewold TB
Arthritis Rheumatol 2017 Dec;69(12):2328-2337
PMID 28859258
 
Adenosine deaminase and purine phosphorylase activities in lymphocytes and red blood cells of patients with carcinoma of the larynx
Gierek T, Drózdz M, Pilch J, Jendryczko A, Piekarska J
Auris Nasus Larynx 1987;14(2):97-100
PMID 3130041
 
Development of a new HPLC method using fluorescence detection without derivatization for determining purine nucleoside phosphorylase activity in human plasma
Giuliani P, Zuccarini M, Buccella S, Rossini M, D'Alimonte I, Ciccarelli R, Marzo M, Marzo A, Di Iorio P, Caciagli F
J Chromatogr B Analyt Technol Biomed Life Sci 2016 Jan 15;1009-1010:114-21
PMID 26720700
 
Novel mutations and hot-spots in patients with purine nucleoside phosphorylase deficiency
Grunebaum E, Zhang J, Roifman CM
Nucleosides Nucleotides Nucleic Acids 2004 Oct;23(8-9):1411-5
PMID 15571269
 
Intron requirement for expression of the human purine nucleoside phosphorylase gene
Jonsson JJ, Foresman MD, Wilson N, McIvor RS
Nucleic Acids Res 1992 Jun 25;20(12):3191-8
PMID 1620616
 
Purine nucleoside phosphorylase targeted by annexin v to breast cancer vasculature for enzyme prodrug therapy
Krais JJ, De Crescenzo O, Harrison RG
PLoS One 2013 Oct 3;8(10):e76403
PMID 24098491
 
Lentivirus gene therapy for purine nucleoside phosphorylase deficiency
Liao P, Toro A, Min W, Lee S, Roifman CM, Grunebaum E
J Gene Med 2008 Dec;10(12):1282-93
PMID 18924118
 
Purine nucleoside phosphorylase deficiency with a novel PNP gene mutation: a first case report from India
Madkaikar MR, Kulkarni S, Utage P, Fairbanks L, Ghosh K, Marinaki A, Desai M
BMJ Case Rep 2011 Dec 8;2011
PMID 22669887
 
Purine nucleoside phosphorylase deficiency: a new case report and identification of two novel mutations (Gly156A1a and Val217Ile), only one of which (Gly156A1a) is deleterious
Moallem HJ, Taningo G, Jiang CK, Hirschhorn R, Fikrig S
Clin Immunol 2002 Oct;105(1):75-80
PMID 12483996
 
Characterization of purine nucleoside phosphorylase in leukemia
Morisaki T, Horiuchi N, Fujii H, Miwa S
Am J Hematol 1986 Nov;23(3):263-9
PMID 3094366
 
Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient
Pannicke U, Tuchschmid P, Friedrich W, Bartram CR, Schwarz K
Hum Genet 1996 Dec;98(6):706-9
PMID 8931706
 
Adenosine deaminase and purine nucleoside phosphorylase activities in peripheral blood cells of patients with neoplastic diseases
Rendeková V, Cerná M, Cerná M, Pechánová E, Pechán I, Krizko J, Virsík K
I Bronchogenic carcinoma
PMID 6405288
 
L-Enantiomers of transition state analogue inhibitors bound to human purine nucleoside phosphorylase
Rinaldo-Matthis A, Murkin AS, Ramagopal UA, Clinch K, Mee SP, Evans GB, Tyler PC, Furneaux RH, Almo SC, Schramm VL
J Am Chem Soc 2008 Jan 23;130(3):842-4
PMID 18154341
 
Plasma purine nucleoside phosphorylase in cancer patients
Roberts EL, Newton RP, Axford AT
Clin Chim Acta 2004 Jun;344(1-2):109-14
PMID 15149878
 
Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors
Rosenthal EL, Chung TK, Parker WB, Allan PW, Clemons L, Lowman D, Hong J, Hunt FR, Richman J, Conry RM, Mannion K, Carroll WR, Nabell L, Sorscher EJ
Ann Oncol 2015 Jul;26(7):1481-7
PMID 25899782
 
Relationship between the levels of purine salvage pathway enzymes and clinical/biological aggressiveness of human colon carcinoma
Sanfilippo O, Camici M, Tozzi MG, Turriani M, Faranda A, Ipata PL, Silvestrini R
Cancer Biochem Biophys 1994 Apr;14(1):57-66
PMID 7796389
 
Identification and characterization of a novel gene of grouper iridovirus encoding a purine nucleoside phosphorylase
Ting JW, Wu MF, Tsai CT, Lin CC, Guo IC, Chang CY
J Gen Virol 2004 Oct;85(Pt 10):2883-92
PMID 15448350
 
TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice
Toro A, Grunebaum E
J Clin Invest 2006 Oct;116(10):2717-26
PMID 16964310
 
Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro
Toro A, Paiva M, Ackerley C, Grunebaum E
Cell Immunol 2006 Apr;240(2):107-15
PMID 16930574
 
Association of human papillomavirus with vulvodynia and the vulvar vestibulitis syndrome
Turner ML, Marinoff SC
J Reprod Med 1988 Jun;33(6):533-7
PMID 2841460
 
Metabolites of purine nucleoside phosphorylase (NP) in serum have the potential to delineate pancreatic adenocarcinoma
Vareed SK, Bhat VB, Thompson C, Vasu VT, Fermin D, Choi H, Creighton CJ, Gayatri S, Lan L, Putluri N, Thangjam GS, Kaur P, Shabahang M, Giri JG, Nesvizhskii AI, Asea AA, Cashikar AG, Rao A, McLoughlin J, Sreekumar A
PLoS One 2011 Mar 23;6(3):e17177
PMID 21448452
 
Purine nucleoside phosphorylase deficiency: a mutation update
Walker PL, Corrigan A, Arenas M, Escuredo E, Fairbanks L, Marinaki A
Nucleosides Nucleotides Nucleic Acids 2011 Dec;30(12):1243-7
PMID 22132981
 
Determination of plasma purine nucleoside phosphorylase activity by high-performance liquid chromatography
Yamamoto T, Moriwaki Y, Takahashi S, Nasako Y, Yamakita J, Hiroishi K, Higashino K
Anal Biochem 1995 May 1;227(1):135-9
PMID 7668372
 
Infusion of Sibling Marrow in a Patient with Purine Nucleoside Phosphorylase Deficiency Leads to Split Mixed Donor Chimerism and Normal Immunity
Yeates L, Slatter MA, Gennery AR
Front Pediatr 2017 Jun 19;5:143
PMID 28674683
 

Citation

This paper should be referenced as such :
Mohamed AN
Acute Lymphoblastic Leukemia with Hypereosinophilia;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/ALLHypereoID1184.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(5;14)(q31;q32) IGH/IL3
 t(5;9)(q31;p24) IL3/JAK2

External links

Mitelman databaset(5;14)(q31;q32) [Case List]    t(5;14)(q31;q32) [Transloc-MCList] IGH/IL3 [Fusion-MCList]
Mitelman databaset(5;9)(q31;p24) [Case List]    t(5;9)(q31;p24) [Transloc-MCList] IL3/JAK2 [Fusion-MCList]
arrayMap (UZH-SIB Zurich)Morph ( 9817/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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