Elevated serum concentrations of β-2-microglobulin are often found at the time of diagnosis of hemophagocytic lymphohistiocytosis in adults with lymphoid and myeloid malignancies

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Original research article/Praca oryginalna

Elevated serum concentrations of b-2-microglobulin are often found at the time of diagnosis of

hemophagocytic lymphohistiocytosis in adults with lymphoid and myeloid malignancies

Egle Sumskiene

^1,2

, Ewa Pawłowicz

^1,3

, Cecilia Kämpe Björkvall

⁴

, Maciej Machaczka

^1,5,

*

1Hematology Center Karolinska and Department of Medicine at Huddinge, Karolinska Institutet, Karolinska UniversityHospitalHuddinge,Stockholm,Sweden

2DepartmentofSurgery,AntakalnisOutpatientClinic,Vilnius,Lithuania

3MedicalUniversityofLodz,Lodz,Poland

4DepartmentofMedicine,SunderbyRegionalHospitalofNorrbottenCounty,Luleå,Sweden

5MedicalFaculty,UniversityofRzeszow,Rzeszow,Poland

article info

Articlehistory:

Received:10.07.2017 Accepted:17.07.2017 Availableonline:24.07.2017

Keywords:

Hemophagocytic lymphohistiocytosis

Hemophagocyticsyndrome

b-2-Microglobulin

Hematologicalmalignancy

Survival

abstract

Background:Hemophagocyticlymphohistiocytosis(HLH)isalife-threateningdisorderof immuneregulation.Inpatientsover60yearsofage,HLHassociatedwithhematological malignancies(hM-HLH)is themostprevalent.b-2-Microglobulin(B2M) playsanimpor- tant role in antigen presentation and immunological regulation. Elevated B2M levels reflectT-cellactivation.Objective: Theaimofthis studywastodetermineserum B2M concentrationsinadultswithhM-HLHandtointerpretitssignificanceinthecontextof overallsurvival(OS).Patientsandmethods:SerumB2Mconcentrationwasdeterminedin 31adultsaged22–84yearsatthetimeofhM-HLHdiagnosis.Lymphoidmalignancywas diagnosed in 22 patients and myeloid malignancy in 9 patients. Results: The serum concentrationofB2Mwaselevatedin100%oftheexaminedpatients.Meanandmedian serum B2M concentrations were 5.3 and 4.2mg/L, respectively (range 2–17mg/L). We havenotfoundanysignificantdifferencesintermsofthestudiedserumB2Mconcentra- tions between patients with T/NK-cell lymphomas, B-cell lymphomas, and myeloid malignancies. The outcome of HLH was poor in vast majority of patients with the medianOS for the entire group of46 days. Conclusions: Elevated serum B2M level is a frequentfindingat thetime ofhM-HLHdiagnosis inadults. Itseems tobea useful indicatorofHLH forits earlydetection andevaluationafterward, aswellasforimme- diatetherapeuticintervention.Furtherprospectivestudiesansweringthequestionwhe- therserumB2McanbeusedasaprognosticfactorinhM-HLHwouldbeofinterest.

*Corresponding author at: Hematology Center Karolinska, M54, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.Tel.:+46858582663;fax:+4687748725.

E-mailaddress:maciej.machaczka@ki.se(M.Machaczka).

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journalhomepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2017.07.001

zo.o.Allrightsreserved.

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Introduction

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a rare disorder with both familialand acquiredforms [1,2]. Itisanacutedisorderof immuneregulationwhichleadstoanexaggeratedinflamma- tion.MacrophagesandCD8+cytotoxicT-cellsreleasevarious pro-inflammatorymediatorssuchastumornecrosisfactora (TNF-a), interleukin(IL)-6, IL-8,IL-12, andinterferon-g [3–6]. Thesecytokines induceimmunecellsand cytokine produc- tionthatculminatesincytokine stormandhyperinflamma- tion[3,4,7].Inresponse,anti-inflammatorycytokines(IL-10, IL-18-binding protein)are produced, but they are not suffi- cienttomitigatetheexcessiveimmuneactivation[8,9].

In general, HLH is a life-threatening syndrome and has apoorprognosis[1,10–14].Inadultpatients,acquiredforms ofHLHarethemostprevalent[2,14].Malignancy-associated HLH(M-HLH)inthepatientsaged30yearsisfrequent,and inthegroup ofpatientsaged60years,M-HLHisthemost frequentformofHLH[10].Althoughtheclinicalpresentation ofHLHmaybevariable,themostcommonsignsareunremit- tingfever,cytopenia,hepatosplenomegaly, jaundice,edema, neurologicalsymptomsandhemophagocytosisinbonemar- row (BM), liveror lymph nodes [1, 7, 14]. According to the current HLH-2004guidelines, the diagnosisof HLH isbased onaconstellationofclinicalandlaboratorycriteria[15].

b-2-Microglobulin (B2M) is a low-molecular-weight (11.8kDa) protein synthesized in all nucleated cells and constitutingthelightchainsubunitofthe majorhistocom- patibility complex (MHC)classI receptor [5]. B2M plays an important role in antigen presentation and regulation of tumorimmunologicalprocesses.Approximately50%of B2M is produced by lymphocytes and is freely ﬁltered through glomerularbasementmembrane.Underphysiologicalcondi- tions B2M is produced at a constant rate. However, B2M serumlevelsriseinthepresenceofglomerularimpairment or lymphocyte activation, as well as in patients with hematologicalmalignancyorsystemicinﬂammation[5,16].

The aimof the present study was to determine serum B2Mconcentrationsinadultswithhematologicmalignancy- associatedHLH(hM-HLH)andtointerpretitssigniﬁcancein thecontextofHLHtherapyoutcome.

Patients and methods

The study population consisted of 31 adult patients diagnosed with a hematological malignancy and HLH. The enrolled patientswere admitted tothe Hematology Center Karolinska,Karolinska UniversityHospital,betweenJanuary 2009 and December2016.Ahematological malignancywas deﬁned as a neoplasm of lymphoid or myeloid origin and thediagnosiswasestablishedaccordingtoSwedishnational standardsandprotocols.

In all studiedpatients, the diagnosis of HLH was based on the criteriaproposed bythe Histiocyte Society(Table I) [15]. Noteworthy, these criteria were developed based on familial,inherited formsof HLH.Duetothelackofspeciﬁc guidelines for M-HLH, they are also used to diagnose it.

However, majority of reports published on M-HLH were examined sixorlessHLH-2004 criteria,andasarule with- out sIL-2Ra/sCD25 resultand NKcells activity data[11, 14, 17].Someauthorsarguethathyperferritinemia10000mg/L isamorespeciﬁcandsensitiveHLHcriterion[18].Therefore, weincludedinthisanalysisallpatientswithsuspectedHLH who fulﬁlledat leastfour ofsixHLH-2004criteriaincluding at least two of three additional HLH features: sIL-2Ra

2400U/mL, hemophagocytosis in BM, and hyperferritine- mia10000mg/L.

Freshbloodsamplesweredrawnanddirectlyanalyzedat the Karolinska University Laboratoryaccording tostandard practice. TheRoche B2MGTina-Quant serum kit was used to measure serum concentrations of B2M immunoturbidi- metrically; normalvalueofserum B2Mwas<2.0mg/L.The serum ferritin concentration was assessed using Roche ModularAnalyzers(RocheDiagnostics,USA).Serumconcen- trations of sIL-2Ra were determined by ELISA, using the quantitative ‘sandwich’ enzyme immunoassay, on the IMMULITE^®1000ImmunoassaySystem(DPCSiemens).

HLH treatment categories have included proapoptotic chemotherapy(etoposideat50–150mg/m²/dosei.v.)anduse of immunosuppressive drugs, targeting hyperactivated macrophages (corticosteroids,IVIG)and Tcells (corticosteroids, cyclosporine A). Treatment plan was individually adoptedforeachpatient,basedontheprotocolHLH-94[19].

The patients’ medical records were reviewed to collect relevant clinicaldata.Thepatientsprovidedtheirinformed consent.Thestudywasperformed accordingtothe ethical guidelinesoftheDeclarationofHelsinki.

Theresultsarepresentedasameanstandarddeviation (SD) or median and variable range. The distribution of continuousvalueswasassessedwiththeShapiro–Wilktest.

Depending on the variable's distribution, T test or Mann– WhitneyUtestwasusedforcomparisonsbetweenindepen- dentgroups.Chi-squarePearson,YatesorFishertestswere usedfornominalvalues.Overallsurvival(OS)wasestimated by the Kaplan–Meier method and compared with the log- rank test. An a-level of p<0.05 was required for signiﬁ- cance. Statistical analysis was performed using Statistica version12.0PLsoftware.

TableI–DiagnosticcriteriaofHLH-2004 HLHdiagnosisif(A)or(B)ismet:

(A)Theresultofmoleculardiagnosticsconﬁrmingthepresence ofmutationstypicalforHLH

(B)Fiveofthefollowingeightcriteriamustbefulﬁlledforthe diagnosisofHLH:

1.Fever 2.Splenomegaly

3.Cytopeniasaffectingatleasttwoofthreecelllineages:

a.hemoglobin<90g/L b.platelets<10010⁹/L c.neutrophils<1.010⁹/L

4.Hypertriglyceridemia3.0mmol/Land/or hypoﬁbrinogenemia1.5g/L

5.Hemophagocytosisinbonemarrow,spleen,orlymphnodes 6.LoworabsentNK-cellactivity

7.Hyperferritinemia500mg/L

8.Elevatedconcentrationofsolubleinterleukin2receptora (sIL-2Ra/sCD25)2400U/mL

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Results

Twenty-two men (71%) and 9 women (29%), aged 28–84 years(meanandmedianage61years)wereenrolledinthe study.Lymphoid malignancywas diagnosedin 22 patients and myeloid malignancy in 9 patients. T-cell lymphoid malignancies included anaplastic large cell lymphoma in 2 patients, angioimmunoblastic T-cell lymphoma in 2 patients, enteropathy-associated T-cell lymphoma in 1 patient, and peripheral T-cell lymphoma not otherwise speciﬁed in 4 patients. B-cell lymphoid malignancies includedfollicularlymphomain2patients,chroniclympho- cytic leukemia (CLL) in 3 patients, diffuse large B-cell lymphoma in 3 patients, T-cell/histiocyte-rich B-cell lymphoma in 1 patient, and gray-zone diffuse large B-cell lymphoma/Burkitt lymphoma in 1 patient. Hodgkin lymphoma(HL) includedlymphocyte depletedin1patient,not speciﬁedHLin1patient, composite EBV-driven HL/non-HL in1patient.PatientcharacteristicsareshowninTableII.

DiagnosisofHLHcriteria

Fever (median 398C; range 38.2–40.68C) was present in 28 (90%) patients. The remaining three patients had median bodytemperatureof37.48C(range36.9–37.88C).

Splenomegaly occurred in 17/28 (61%) patients; one patient had earlier undergone splenectomy and in two patientsaspleensizewasnotdetermined.

ExaminationofﬁneneedleBMaspiratesdisclosedhemo- phagocytosis in 22/30 (73%) patients. BM examination was notperformedin1patient.

Wholebloodhemoglobinconcentration(Hb)rangedfrom 69to129g/L(ref.: 134–170g/L).Thus,anemiawas foundin

all patients and mean Hb was 88.612.5g/L. HLH-2004 criterionofHb<90g/Lwasfulﬁlledin17/31(55%)patients.

Neutropeniawithneutrophils<1.010⁹/Lwaspresentin 12/31(39%)patients.

Thrombocytopenia (platelets /PLT/ ref.: 145–34810⁹/L) was revealed in30/31 (97%) patients. Mean PLT count was 44.146.710⁹/L, median PLT was 2810⁹/L, and PLT range was 5–34410⁹/L. HLH-2004 criterion of PLT

<10010⁹/L was fulﬁlled in vast majority (29/31, 93%) of studiedpatients.

Serum triglyceride level 3.0mmol/L(ref.: 0.45–2.6) was found in35%(11/31) of patients. Serum fibrinogenconcen- tration(ref.:2.0–4.2g/L)wasdecreased1.5g/Lin29%(9/31) patients. However, HLH-2004 criterion of hypertriglyceridemia 3.0mmol/L and/or hypofibrinogenemia 1.5g/L was fulfilledin48%(15/31)patients.

Serum ferritin concentration (ref.: 30–350mg/L) at the time of hM-HLH diagnosis was elevated in all but one patient. Mean ferritinemia was 48635119886mg/L (median 14727mg/L, range 96–645291mg/L). HLH-2004 criterion, hyperferritinemia 500mg/L was met in 97% (30/31) of patientsatthetimeofHLHdiagnosis.

The level of sIL-2Ra in serum was measured in 30/31 patientsandin97%(29/30)ofcasesitwaselevated2400U/

mL.

Twenty-one patients fulfilled at least five HLH-2004 criteria and10 patientsfulfilledat leastfourHLH-2004criteria (allofthempresentingatleasttwoofthefollowingfeatures:

sIL-2Ra2400U/mL,hemophagocytosisinBM,andhyperfer- ritinemia10000mg/L)(Fig.1).TheincidencesoftestedHLH- 2004criteriaforthestudygroupareshowninFig.2.

SerumB2MinnewlydiagnosedhM-HLH

Theserumconcentration of B2Mwaselevated inallof the examinedhM-HLHpatientsatthetimeof diagnosisofhM- HLH.MeanandmedianserumB2Mconcentrations were5.3 and 4.2mg/L, respectively (range 2–17mg/L). We have not found any signiﬁcant differences in terms of the studied serum B2MconcentrationsbetweenpatientswithT/NK-cell lymphomas, B-cell lymphomas, and myeloid malignancies (Fig.3).

TableII–Patientcharacteristics

Characteristic Numberofpatients(%) Gender

Male 22(71%)

Female 9(29%)

AgeatthetimeofHLHdiagnosis(years)

MeanSD 60.714.3

Median(range) 61(22–84)

Hematologicalmalignancies

Lymphoid 22(71%)

Myeloid 9(29%)

Lymphoidmalignancies

NK/T-celllymphoma 9(29%)

B-celllymphoma 10(32%)

Hodgkinlymphoma 3(10%)

Myeloidmalignancies

AML 4(13%)

MDS-AML 2(6%)

MDS 2(6%)

Polycythemiavera 1(3%)

AML,acutemyeloidleukemia;MDS,myelodysplasticsyndrome;

SD,standarddeviation.

Fig.1–ThenumberofexaminedandfulfilledHLH-2004 criteriaatthetimeofHLHdiagnosisin31patientswith hematologicalmalignancies

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TherapyandOutcomeofHLH

In 10 patients HLH therapy started before conﬁrmation of HLH diagnosis, based on clinical suspicion of HLH. Eight patients startedHLH therapyon the dayof HLH diagnosis.

In 13patients, HLHtherapy startedinmedian4days after theHLHdiagnosis.

ThemedianOSfortheentirestudiedgroupwas46days (Fig.4).Probably duetothe smallsubgroups,wehavenot foundanysigniﬁcantdifferenceintermsofsurvivalamong patientsdependingontheir backgroundmalignancy.How- ever, the median OS forpatients with hM-HLH andB-cell lymphomawas228dayscomparedwith44daysforT/NK- cell lymphoma and 40 days for myeloid malignancy (Fig.5).

Discussion

M-HLH can occur as the ﬁrst manifestation of an occult malignancy,beforethestartorduringtreatmentofaknown malignancy, or as the sign of a malignancy relapse or transformation to a more aggressive disease form [7, 14].

ThereisarisingbodyofevidencethatM-HLHcanoccurin the course of all hematological malignancies, and not mainly in T/NK-cell lymphomas as it was thought previously [2, 10–14, 17, 20]. The association between serum B2M levels and HLH has previously rarely been reported, and we were able to ﬁnd only a few such studies in the literature[5,16,21–23].

Increased concentrations of B2M were observed in patientswithhematopoieticmalignancies,suchasmultiple myeloma, CLL, and HL. Moreover, serum concentration of B2Mhasbeenshowntobeanindependentprognosticfactor for these diseases [24–26], as well as a predictor of total mortalityinageneralpopulationofolderadults[27].

ElevatedlevelsofserumB2MreﬂectT-cellactivation[5].

In this study,wehave foundthatserum concentrations of B2M wereelevated in100%of adult patientswithhM-HLH, Fig.3–SerumB2MconcentrationinhM-HLHdependingon

backgroundmalignancy

Fig.4–OverallsurvivalofpatientswithhematologicalmalignanciesandHLH Fig.2–TheincidenceofclinicalandlaboratoryHLH-2004

criteriain31patientswithnewlydiagnosedHLHand hematologicalmalignancy

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whereas their kidney functions were normal (data not shown).

Similarly,inthestudybyJiangetal.theserumlevelsof B2M weremarkedly high in almost all patients withHLH, especiallythosewithlymphoma-associatedHLH(LAHS)[21].

The authors have also found that OS was signiﬁcantly shorterinLAHSpatientswithserumB2Mlevels4.03mg/L comparedto<4.03mg/L(p<0.001).However,we couldnot conﬁrm the aforementioned resultsusing the above cutoff for serumB2M inourcohort (Fig. 6).Based ontheir study, Jiang et al. proposed that serum B2M concentration was a powerful and independent prognostic factor for OS in patientswithLAHS[21].

Wakabayashi et al. analyzed serum B2M levels in 23 females (aged 3916.4 years, range 16–75 years) with autoimmune-associatedHLH.Sixteenpatientshadsystemic lupus erythematosus (SLE) and 7 patients had adult-onset Still's disease (AOSD) [16]. Serum B2M concentration was

compared betweenthe activeand inactive statuses of SLE and AOSD. The serum B2M level was high in the active status of underlying diseases and decreased signiﬁcantly after the therapy (3.51.4 vs. 2.10.8mg/L, p<0.001).

Among patients with active disease status, the B2M level washigherin5patientswithHLHthaninpatientswithout HLH (4.91.8 vs. 3.31.4mg/L, p<0.05). These authors conclude thatserum B2M concentration would bea useful indicator of disease activity and development of HLH in patientswithSLEandAOSD[16].

In another study Kaito et al. analyzed34 patientswith HLH (5 patients had hematological malignancy; 6 patients had infections; 1patienthad SLE,AOSD,and chronicrenal failure each; and 20 patients had no obvious underlying disease)[28].Theyconcludedthattheriskfactorsassociated with deathwereage >30 years, DIC, increasedferritin and B2Mconcentrations,andanemiaaccompaniedbythrombo- cytopeniaandjaundice.

In the abstract, Machowicz et al. showed that 12 of 13 patients with unspeciﬁed forms of HLH (median age 30 years, range 17–80years) had elevatedserum B2Mconcen- trations (median 5.1mg/L, range 1.83–15.3mg/L) [23]. The authorsspeculatewhetherB2Mcouldbeusefulasamarker ofHLHactivity.

The mechanism inducing secondary HLH, including M- HLH,isnotfullyunderstood.Itisbelievedthatimmunologi- cal dysregulation associated with an underlying disease mightbecrucial[16].Ithasbeensuggestedthatthelevelsof sIL-2Ra, whichis reﬂective ofT-cell activation, andsoluble CD163, which isrelated toactivation of phagocytic macrophages, mightbeuseful asdiagnostic markersof HLH and helpful in monitoring disease activity and response to treatment.Measurementsofthelevelsofthesefactorsorof cytokinessuchasIFN-g,TNF-a,andIL-18maynotbeeasily availableinatimelyfashiontoaidintheearlydiagnosisof HLH[1,3,4,7].Incontrast,serumB2Mconcentrationcanbe measured incommon clinicallaboratories of hospitals and the result can beobtained in atimely fashion [16]. Serum B2M level would bea useful indicator of HLH for its early detectionand evaluationafterward, aswell asfor immedi- atetherapeuticintervention.

M-HLHisahighlylethaldisorderintheadultpopulation and has the worst outcome incomparison withany other form ofHLH[10,28–32]. ThepresentstudyshowedthatOS of adults withhM-HLH isparticularlydismal.Itis possible that high serum B2M concentrations indicateda high HLH and/or malignancy activity, which was responsible for a poor outcome in the present study. Although in many patientspooroutcomedependsonmalignancyprogression, in somepatients the lackof effective M-HLHtherapy may further impede adequate treatmentof malignancy. Further prospectiveinvestigationsfocusingonthequestionwhether serum B2Mcan beusedasa markerand prognostic factor inM-HLHorgenerallyinHLHwouldbeofinterest.

Authors’ contributions/Wkład autorów

ES – assisted in study planning, gathered the clinical and laboratory data,analyzedthedata, draftedthe manuscript;

Fig.6–OverallsurvivalofpatientswithhM-HLHin subgroupswithserumB2MconcentrationI4.03mg/L (curveA)and<4.03mg/L(curveB)

Fig.5–OverallsurvivalofpatientswithhM-HLHdepending onmalignancytype

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EP–performed statisticalanalysis, drafted themanuscript;

CKB – assisted in studyplanning, drafted the manuscript;

MM –planned the study,gathered the clinicaland labora- torydata,analyzedthedata,draftedthemanuscript.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

Financial support/Finansowanie

Nonedeclared.

Ethics/Etyka

Thework described inthis article has been carriedout in accordance with The Code of Ethics of the World Medical Association(Declaration of Helsinki)for experimentsinvol- ving humans; EU Directive 2010/63/EU for animal experi- ments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.

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