w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Original
article
High
frequency
of
primary
refractory
disease
and
low
progression-free
survival
rate
of
Hodgkin’s
lymphoma:
a
decade
of
experience
in
a
Latin
American
center
José
Carlos
Jaime-Pérez
∗,
Carmen
Magdalena
Gamboa-Alonso,
José
Ramón
Padilla-Medina,
Raúl
Alberto
Jiménez-Castillo,
Leticia
Alejandra
Olguín-Ramírez,
César
Homero
Gutiérrez-Aguirre,
Olga
Graciela
Cantú-Rodríguez,
David
Gómez-Almaguer
UniversidadAutónomadeNuevoLeón,Monterrey,Mexico
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received10May2017 Accepted10August2017
Availableonline14September2017
Keywords:
ClassicHodgkin’slymphoma RefractoryHodgkin’slymphoma ABVD
Survivalrates LatinAmerica
a
b
s
t
r
a
c
t
Background:ReportsdealingwithclinicaloutcomesofclassicalHodgkin’slymphomain low-to middle-incomecountriesare scarce andresponsetotherapy ispoorlydocumented. Thisreportdescribesthecharacteristicsandclinicaloutcomesofpatientswithclassical Hodgkin’slymphomafromasingleinstitutioninLatinAmerica.
Method:A retrospectivestudy wasconducted overten years of patients with classical Hodgkin’slymphomatreatedatareferralcenter.Progression-freeandoverallsurvivalrates wereestimatedbyKaplan–Meieranalysis.TheunivariateCoxregressionmodelwasused toestimateassociationsbetweenimportantvariablesandclinicaloutcomes.
Mainresults:Onehundredandtwenty-eightpatientswereanalyzed.Themeanagewas28.5 years.Thefive-yearprogression-freeandoverallsurvivalwere37.3%and78.9%,respectively. Ofthewholegroup,55(43%)wereprimaryrefractorycases.Only39/83(47%)patientswith advanceddiseasevs.34/45(75.6%)inearlystages(p-value=0.002)achievedcomplete remis-sion.Thosewithadvanceddiseasehadafive-yearoverallsurvivalof68.7%vs.91.8%for earlydisease(p-value=0.132).Thirty-onepatientsrelapsed(24.2%)and20(64.5%)received atransplant.Thehazardratioforprogressionwithbonemarrowinfiltrationwas2.628(p -value=0.037).Fordeath,anInternationalPrognosticScore≥4hadahazardratioof3.355 (p-value=0.050)inunivariateanalysis.Two-thirdsofclassicalHodgkin’slymphomapatients diagnosedatadvancedstageshadalowprogression-freesurvivalbutanoverallsurvival similartohigh-incomecountries.
∗ Correspondingauthorat:HospitalUniversitarioDr.JoséE.González,Hematología,Edificio“Dr.RodrigoBarragánVillarreal”,2◦pisoAve.
MaderoyAve.Gonzalitoss/n,ColoniaMitrasCentro,64460Monterrey,N.L.,Mexico. E-mailaddress:[email protected](J.C.Jaime-Pérez).
http://dx.doi.org/10.1016/j.bjhh.2017.08.001
Conclusion: PatientsbelongingtothegeneralpopulationdiagnosedwithclassicalHodgkin’s lymphomainNortheasternMexicohadasignificantlylowprogression-freesurvivalrateand presentedwithadvanceddisease,underscoringtheneedforearlierdiagnosisandimproved contemporarytherapeuticstrategiesinthesemainlyyoungproductive-ageHodgkin’s lym-phomapatients.
©2017PublishedbyElsevierEditoraLtda.onbehalfofAssociac¸ ˜aoBrasileirade Hematologia,HemoterapiaeTerapiaCelular.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Hodgkin’slymphoma(HL)isoneofthemostcommon malig-nanciesintheyoungpopulation;ithasabimodaldistribution, firstbetween15and34yearsofageandthenafter55years.1 Thishematologicneoplasmaffectsapproximately9050new patients in the United States each year and 5000 in Latin America,2 thus a low incidencebut with high mortality is observedinMexico.3Furthermore,aloweroverallsurvival(OS) hasbeenobservedinHispanicslivinginthe UnitedStates, withthediagnosisestablishedatmoreadvancedstagesand withagreatermaleprevalence.4,5
Contrary to non-Hodgkin lymphoma, the incidence of HLhasremained constantover time.1 Twodistinct disease entitiescomposeHL,classical(cHL)andtherarenodular lym-phocyte predominant HL, which comprises only 5% of all cases.6 AlthoughHL ishighly responsiveto chemotherapy, approximatelyonethirdofpatientswithanadvancedstage willhaveprimaryresistantdisease7orwillrelapseafter con-ventional treatment.8 Standard treatmentinthese casesis basedonautologoushematopoieticstemcelltransplantation (HSCT)orhighdosesofchemotherapy,withthe PFS reach-ing30–50%inpatientswithrelapseddiseaseand20–40%in patientswithrefractoryHL.9–11
Thereisscarceinformationonthe characteristics ofHL patients in populations where most individuals are diag-nosedinadvancedstages.Thisstudyreportsacomprehensive descriptiveanalysisofincidencepatterns,clinicalevolution, andtreatmentoutcomes oflow-income uninsuredpatients withHLattendingapublicreferralcenterforthegeneral pop-ulationinNortheasternMexicooveraten-yearperiod.
Methods
This observational, longitudinal and retrospective study includedpatientswithadiagnosisofHLtreatedatthe Hema-tology Department of the Dr. José E. González University Hospitalofthe School ofMedicine,UniversidadAutónoma deNuevo LeóninMonterrey,MexicobetweenJanuary2005 andSeptember2015.Clinicalandelectronicrecordsaswell ashistopathologyrecordswerereviewedandfrequenciesfor eachsubtypeoflymphomaweredetermined.Thestudy pro-tocolwasapprovedbytheResearchEthicsCommitteeofthe institution.
Clinical data including age, gender, Ann Arbor stage, presenceorabsenceofB-symptoms,initialcomplete blood count(CBC),InternationalPrognostic Score(IPS),bulky
dis-ease, treatment regimen and survival data were accrued and analyzed. Advanced disease wasdefined asbulky dis-easeoranAnnArborstageIII–IV. Twogroupsweredefined according to the IPS: low risk (score: 0–3) and high risk (score:4–7). TodefineHLsubtypes,caseswere reviewedby a hematopathologist with the immunohistochemical pro-fileofHLbeing investigatedin83% ofthe studiedpatients includingthefollowingbiomarkers:CD30,CD15,CD20,CD3, CD45,ALK-1,andPAX-5.12Duetofinancialrestrictionsatthis public institution caringfor patients without health insur-ance coverage,the Epstein–Barrvirus (EBV)status wasnot documented inthe biopsies. A computed tomography(CT) scan was performed in all patients for stratification and wasreviewedbyradiologistswithexpertiseinstaging lym-phomas. Only selected patients were submitted to a bone marrow(BM)biopsy–patientswithanAnnArborstage≥III orwithB-symptomshadanindicationforthisprocedure.In this respect, it haspreviouslybeen shown that onlyabout 2% of patients in this population with HL have a positive BMbiopsy.13
Treatment
Patients received a chemotherapy regimen chosen by the treatingphysicianaccordingtostandardprotocolsincluding ABVD (adriamycin,bleomycin,vincristineand dacarbazine) or COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine,doxorubicin,bleomycinandvinblastine).14 All drugs were from original manufacturers with no generic brands administered. Some patients with bulky disease received complementaryradiotherapy(RT), using intensity-modulatedradiotherapy(IMRT)atdosesof30–36Gy depend-ingonthetumorsize.Theprotocolconsistsofthedelivery of 1.5–2Gy per day until completion.15 However, notall of these patients were treatedatthe study center and radio-therapy isnota regular partofthe standardprotocol; this is intended to limit radio-toxicity in patients customarily presentingwithadvanceddisease.AutologousHSCT,based on areducedintensityconditioning regimen,16 wascarried out inpatientswithapoorprognosis, includingthose who relapsed in <12 months, those who relapsed atpreviously irradiatedsites,haddiseaseregression<50%after4–6cycles ofchemotherapy,ordiseaseprogressionduringinductionor within90daysaftertheendoffirst-linetreatment.
Follow-up
responsewasaccordingtothecriteriaspecifiedintheLugano Classification,17basedonsizereductionoftheaffectedlymph nodesmeasuredbyCTscaninallpatients.
Definitionofresponse
CRwasdefinedasdisappearanceofallclinicalandradiological symptoms,nofurthertherapeuticinterventionisnecessary. Partialremission(PR)wasdefinedasatleasta50%decrease inthesumofthe productofthe diametersofup tosixof thelargestdominantnodesornodalmasses.Stabledisease was considered when a patient failed tomeet the criteria forCRorPR,butdidnotfulfillthoseforprogressivedisease (PD).RelapseddiseaseorPDwasdefinedastheoccurrenceof newlesionsoranincreaseof≥50%fromnadirofpreviously involvedsites.17
Statisticalanalysis
AllstatisticaltestingwasperformedusingSPSSversion22.0. Descriptiveanalysisincludingmedianandrangeswasapplied tocontinuousvariables.TheKaplan–Meiermethodwasused toobtaintheOSfromthedateofdiagnosisuntilthedateof deathorlastupdateofclinicalstatus.PFSwasdefinedfrom thedateofdiagnosistothedateofthefirstevent (progres-sion/relapseordeathforanyreason)orthelastfollow-up.17 TheCox proportionalhazardregression modelwasusedto examinetheassociationbetweenthedifferentvariablesand theireffectonOSandPFSinHL.
Results
Baselinecharacteristics
Datafor128patientswithadiagnosisofHLwerecollected. Clinical characteristics are shown in Table 1. B-symptoms were reported by 45 (35.1%) patients at the time of initial clinical history. Complete blood count (CBC) at diagnosis showedamedianhemoglobin(Hb)levelof11.4g/dL(range: 5.9–17g/dL),a whiteblood cell countof8.29×109/L(range: 1.11–25.57×109/L)andaplateletcountof308×109/L(range: 41.0–629.0×109/L).Bonemarrowbiopsywasperformedin46 (35.9%)patientsinadvancedstageswithapositiveresultbeing foundin14(30.4%).
ClinicaloutcomeinclassicalHodgkin’slymphoma
Onehundred andtwenty-eightpatientswereanalyzed,112 (87.5%)receivedABVD(median:6cycles;range:1–8cycles)and 16(12.5%)receivedtheCOPP/ABVregimen(median:6cycles; range:2–8cycles).CRwasachievedin73/128(57%)patients; 30/73(41%)relapsedatamedianof23.7 months.Fromthe groupof30 relapsedpatients, 26(86.7%)arealiveafterfive yearsoffollow-upandfourdeathshavebeendocumented.Of thewholegroup,55(43%)wereprimaryrefractorycases;from thissubgroup20(36.4%)hadpartialremission,29(52.7%) sta-blediseaseafterfirstfrontlinechemotherapy,andsix(10.9%) presenteddisease progressionduringadministrationofthe primarytherapyprotocol.Elevendeaths(7.75%)were
docu-Table1–Epidemiologicalandclinicalcharacteristicsof
128patientsdiagnosedwithHodgkin’slymphomainthe
HospitalUniversitarioDr.JoséE.González,Universidad
AutónomadeNuevoLeón,Monterrey,Mexico.
Characteristic
Age(years)–median(range) 28.5(5–81)
Sex–n(%)
Male 69(53.9%)
Female 59(46.1%)
Bulkydisease–n(%)
Present 27(21.1%)
Absent 101(78.9%)
Subtype–n(%)
Nodularsclerosis 75(58.6)
Mixedcellularity 23(18.0)
Lymphocyte-rich 5(3.9)
Lymphocytedepleted 3(2.3)
Unclassified 22(17.2)
Clinicalstage–n(%)
I 16(11.7)
II 38(29.7)
III 35(27.3)
IV 40(31.3)
IPSscore–n(%)
0–3 98(76.6)
4–7 30(23.4)
Diseasestatus–n(%)
Earlydisease 45(35.2)
Advanceddisease 83(64.8)
IPS:InternationalPrognosticScore.
mented after receiving atleast onecycle ofchemotherapy withsepsisbeingthemostcommoncause.Twenty-two(17.2%) patientswhocompletedtherapyasscheduledhada reduc-tion indose due totoxicity.Twenty-eight (21.87%) patients didnotcompleteplannedtreatmentwiththemostcommon causebeingdiseaseprogressionin19,whereasninepatients abandonedtreatment.Sixpatientsthatabandonedtreatment wentontocontinuechemotherapyinotherinstitutions;three patientsweretoosicktoreceivefulldosesandcyclesof ther-apy.Therewerenoinstancesofmissingdrugs.
Median follow-ups for PFS and OS were 15.88 (range 1.2–87.8) and 24.26 (range 1.43–176) months, respectively. PFS atfive years forthe whole group of 128 patients was 37.3±6.9%.MedianPFSatfiveyearswas46.09months[95% confidenceinterval(CI):34.06–58.12].Afterfiveyearsof follow-up,theOSwas78.9±6.8%andthemedianOSwasnotreached. PatientswhoachievedCRwithfirstlinetreatmenthada five-year OS of88.1±6.3%vs. 59±15.7%,inthose who didnot (p-value=0.012).
Of11patientswhodied,twodidsofromsepsisand neu-tropeniarelatedtodrugtoxicityandinseven,deathwasdue todiseaseprogression;twopatientsdiedatotherinstitutions andthecausewasnotreported.
COPP/ABV(p-value=0.057).Mediantimetoreceivesixcycles oftherapywassixmonths(range:6–9months).
Ofthepatientswithadvanceddisease,aCRwasreached in39/83(47%) vs.34/45 (75.6%)inthose inearlyHL stages (p-value=0.002). Five-yearPFS forpatients presenting with advanced disease was 38.3±8.9% vs. 39.1±11.5% in indi-viduals with early disease (p-value=0.893). MedianPFS for advanced and early disease was 42.7 months (95% CI 27.51–57.90)and 49.5 months (95% CI 39.28–59.81), respec-tively.Overallsurvivalatfiveyearswas69.7±10.6%inpatients withadvanceddiseasecomparedto91.8±5.6%inthosewith earlydisease(p-value=0.132;datanotshown).MedianOSwas notreachedineithergroup.
Fifteenpediatric HL patients (11.7%) ≤16 years and 113 (88.3%)>16yearswere treated.PFSatfiveyearswashigher inthose>16yearsofage,butitwasnotstatistically signifi-cant(20.9±12.9%vs.36.0±8.4%,respectively),medianofPFS was34.72 months(95%CI 16.59–52.86)vs. 48months(95% CI37.41–58.59;p=0.240),respectively.Pediatricpatientshad a non-significantlyhigher five-year OS than older patients (80.0±12.6%vs.76.2±9.3%;p-value=0.871).Afteranalyzing survivalaccordingtotheIPS,patientswithascore≥4hada five-yearPFSof33.7±14.9%vs.34.9±8.4%inthosewithan IPS<4(p-value=0.786).Thefive-yearOSbetweenthesegroups was66.1±13.8%vs.84.1±7.1%,respectively(p-value=0.036). Thirty-two patients (25%) underwent autologous HSCT, achievingafive-yearPFSof32.6%(95%CI:32.40–32.80)after HSCTatamedian of20monthsand the five-year OSwas 73.1%;themedianOSwasnotreached.Ofthe32autografted patients,six(18.8%)deathsweredocumentedand15(46.9%) suffereddiseaseprogressionorrelapsedafterHSCT.
Outcomeafterrelapse
Of 30 relapsed patients, 20 (66.7%) underwent autologous HSCTand11(55%)sufferedasecondrelapse.Five-yearPFSand OSforthese20HSCTpatientswere31.4±9.1%and81.4±9.7%, respectively; median PFS was 12 months and the median OSwasnotreached.Threedeathsweredocumentedinthis groupduetodiseaseprogression.Oftheremaining10relapsed patients who were not transplanted, two went to another institutionafterrelapseandeightwerelosttofollow-upafter amedian6.4months.
Predictivefactorsofrelapse,progressionanddeath
InunivariateanalysisforPFS,BMinfiltrationandincomplete treatmentwere significantfordiseaseprogression(Table2). ForOS,anIPS≥4andincompletetreatmentweresignificant predictorsofdeath(Table2).
Discussion
Althoughrecentresearchhasprovidedmeaningfulinsights into the biological and molecular characteristics of HL, it remainsanintriguingdisease,withmanyfactorsimplicated initspathogenesisbutwithnonedefinitelyestablished.18 Pre-viousepidemiologicstudieshavecontributedinelucidating specificfeaturesandcurrentstatusofHLintheAmericas.3
Table2–Hazardratiosforrelapse,progressionordeath
accordingtounivariateCoxproportionalregression
analysisfor128patientswithclassicalHodgkin’s
lymphomaandassociationswithclinical,laboratory
andhistopathologicalcharacteristics.
Factor n Progressionfreesurvival Overallsurvival
HR(95%CI) p-value HR(95%CI) p-value
Bulkydisease Present 27 0.965
(0.458–2.030)
0.925 0.812 (0.161–4.095)
0.801
Absent 71
IPS
≥4 30 0.912
(0.439–1.895)
0.805 3.355 (1.000–11.256)
0.050
<4 98
Bonemarrowinfiltration Positive 14 2.628
(1.058–6.525)
0.037 4.511 (0.408–49.863)
0.219
Negative 32
B-symptoms
Yes 41 0.672
(0.358–1.263)
0.217 0.384 (0.083–1.789)
0.222
No 87
Incompletetreatment
Yes 28 2.793
(1.364–5.719)
0.005 8.246 (2.483–27.377)
0.001
No 100
HR:hazardratio;CI:confidenceinterval;IPS:International Prognos-ticScore.
Subtypedistributioninthisgroupwassimilartothatinthe UnitedStatesandCanada.19Interestingly,theHLcohortinthis studywasadecadeyoungerthanthatreportedindeveloped countries1,2asobservedinapreviousall-ageinclusivestudy focusedonHispanics.20
In low- to middle-income countries, more than 60% of cHL patients are diagnosed in advanced clinical stages at presentation.21 Progressinsurvivalisevidentinthosewith earlystages,whereasinadvanceddiseaseanunsubstantial improvementhasbeen reportedinthelast30years.22This studyfoundanOSclosetothatreportedbycentersin devel-opedcountries,yetalowPFS,highlightingthelowercurerate for advanceddisease.23 A higherPFS wasfound incentral Mexicothan that identifiedinthis study;however,OS was similar,21showingregionaldifferencesintheclinicalcourse ofHL.
stagecasesrelated tolatediagnosis,biologicheterogeneity in lymphoma behavior, as well as epigenetic modifiers of responsetocHL.Additionalfactorsthatcancontributeto fur-therexplainthesesuboptimalresultsincludedosereductions due to high toxicity in 22% of patients, treatment aban-donmentwasimportantat7%,andsocioculturalaswell as financial limitations of this population. Furthermore, lack offluorodeoxyglucose (FDG)-PET studies could have led to lowerintensitytreatment,althoughthereareheterogeneous resultsregardingtheimpactofinterimFDG-PET;itsuse how-everisavaluablemethodforriskstratification.17Developing countriesarejuststartingtousethisresourceduetoitshigh cost,limitingcomparisonoftreatmentresponseratesforHL betweendevelopingandindustrializedregions.
Overathirdofthepatientsinthisstudyhadprimary refrac-torydisease,morethantwotimesthe15%reportedinmost studies1,8;thisfindinghelpstoexplainthelowPFSobserved. Forthisgroup,high-dosechemotherapyfollowedby autolo-gousHSCThasbecomethetreatmentofchoice.26,27Thisleads toasignificantincreaseinPFS,buthasnoeffectonOS.Of 30 relapsedpatients inthis study, 20 underwent an autol-ogousHSCTafterachievingasecondremissioninduced by chemotherapyand85%ofthemarealiveatfiveyears.Thus, theOSaftertransplantationiscomparabletootherstudies reportingratesrangingfrom66%to77%.28
Theprognosisofrelapsedpatientsisalsoinfluenced by thepresenceofnegativeprognosticriskfactorssuchasearly relapse threeto 12 monthsafter treatment, stageIII or IV disease,and anemiaatthetimeofrelapse.Aretrospective analysisofthe German Hodgkin StudyGroup showedthat patientspresentingallthreeriskfactorshadalowerfour-year freedomfromsecondtreatmentfailureof17%andalowOSof 27%comparedtopatientswithoutriskfactors(48%and83%, respectively).29Althoughmostofthepatientsinthiscohort werediagnosedatanadvancedstage,themedianofrelapse was22.8monthsandthiswasassociatedwithhighsurvival ratesafterrelapse.
Limitationsinthisreportincludeitsretrospectivedesign, reduced sample size, lack of PET scan staging, and the numberofpatientslosttofollow-up.However,thisreport pro-videsanoverviewofthecontemporarylandscapeofclinical andhistopathologycharacteristicsofawell-definedHL low-incomegroupovertenyearsinasingleinstitutionofLatin America.
Inconclusion,itisnecessarytoanalyzecHL epidemiologi-caldataindevelopingcountriesandassessefficacyofcurrent diagnostic methods and modalities of treatment, with the maingoalofimprovingthelowPFSdocumentedinthis pop-ulation.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgments
We thank Sergio Lozano-Rodríguez for his review of the manuscript.
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1.ThomasR,ReD,ZanderT,WolfJ,DiehlV.Epidemiologyand etiologyofHodgkin’slymphoma.AnnOncol.
2002;13(4):147–52.
2.SiegelRL,MillerKD,JemalA.Cancerstatistics,2015.CA CancerJClin.2015;65(1):5–29.
3.ChatenoudL,BertuccioP,BosettiC,RodriguezT,LeviF,Negri E,etal.Hodgkin’slymphomamortalityintheAmericas, 1997–2008:achievementsandpersistentinadequacies.IntJ Cancer.2013;133(3):687–94.
4.KahnJM,KeeganTH,TaoL,AbrahaoR,BleyerA,VinyAD. RacialdisparitiesinthesurvivalofAmericanchildren, adolescents,andyoungadultswithacutelymphoblastic leukemia,acutemyelogenousleukemia,andHodgkin lymphoma.Cancer.2016;122(17):2723–30.
5.EvensAM,AntillonM,Aschebrook-KilfoyB,ChiuBC.Racial disparitiesinHodgkin’slymphoma:acomprehensive population-basedanalysis.AnnOncol.2012;23(8):2128–37.
6.SavageKJ,MottokA,FanaleM.Nodular
lymphocyte-predominantHodgkinlymphoma.Semin Hematol.2016;53(3):190–202.
7.HoskinPJ,LowryL,HorwichA,JackA,MeadB,HancockBW, etal.RandomizedcomparisonoftheStanfordVregimenand ABVDinthetreatmentofadvancedHodgkin’slymphoma: UnitedKingdomNationalCancerResearchInstitute LymphomaGroupStudyISRCTN64141244.JClinOncol. 2009;27(32):5390–6.
8.SkoetzN,TrelleS,RanceaM,HaverkampH,DiehlV,EngertA, etal.Effectofinitialtreatmentstrategyonsurvivalof patientswithadvanced-stageHodgkin’slymphoma:a systematicreviewandnetworkmeta-analysis.LancetOncol. 2013;14(10):943–52.
9.SchmitzN,PfistnerB,SextroM,SieberM,CarellaAM,Haenel M,etal.Aggressiveconventionalchemotherapycompared withhigh-dosechemotherapywithautologoushaemopoietic stem-celltransplantationforrelapsedchemosensitive Hodgkin’sdisease:arandomisedtrial.Lancet. 2002;359(9323):2065–71.
10.BiasoliI,SpectorN.Newagentsinrelapsed/refractory Hodgkin’slymphoma.RevBrasHematolHemoter. 2017;39(3):193–6.
11.FedeleR,MartinoM,RecchiaAG,IrreraG,GentileM,Morabito F.ClinicaloptionsinrelapsedorrefractoryHodgkin
lymphoma:anupdatedreview.JImmunolRes.2015;2015, 968212.
12.ChanJK.ThenewWorldHealthOrganizationclassificationof lymphomas:thepast,thepresentandthefuture.Hematol Oncol.2001;19(4):129–50.
13.Gomez-AlmaguerD,Ruiz-ArguellesGJ,Lopez-MartInezB, EstradaE,Lobato-MendizabalE,Jaime-PerezJC.Roleofbone marrowexaminationinstagingHodgkin’sdisease:
experienceinMexico.ClinLabHaematol.2002;24(4):221–3.
14.FollowsGA,ArdeshnaKM,BarringtonSF,CulliganDJ,Hoskin PJ,LinchD,etal.Guidelinesforthefirstlinemanagementof classicalHodgkinlymphoma.BrJHaematol.
2014;166(1):34–49.
15.LuN-N,LiY-X,WuR-Y,ZhangX-M,WangW-H,JinJ,etal. Dosimetricandclinicaloutcomesofinvolved-field intensity-modulatedradiotherapyafterchemotherapyfor early-stageHodgkin’slymphomawithmediastinal involvement.IntJRadiatOncolBiolPhys.2012;84(1):210–6.
17.ChesonBD,FisherRI,BarringtonSF,CavalliF,SchwartzLH, ZuccaE,etal.Recommendationsforinitialevaluation, staging,andresponseassessmentofHodgkinand non-Hodgkinlymphoma:theLuganoclassification.JClin Oncol.2014;32(27):3059–68.
18.LinaberyAM,ErhardtEB,FonstadRK,AmbinderRF,BuninGR, RossJA,etal.Infectious,autoimmuneandallergicdiseases andriskofHodgkinlymphomainchildrenandadolescents:a Children’sOncologyGroupstudy.IntJCancer.
2014;135(6):1454–69.
19.NiedobitekG,MeruN,DelecluseHJ.Epstein–Barrvirus infectionandhumanmalignancies.IntJExpPathol. 2001;82(3):149–70.
20.HuE,HuffordS,LukesR,Bernstein-SingerM,SobelG,GillP, etal.Third-WorldHodgkin’sdiseaseatLosAngeles County-UniversityofSouthernCaliforniaMedicalCenter.J ClinOncol.1988;6(8):1285–92.
21.AvilesA,CletoS,NeriN,Huerta-GuzmanJ,TalaveraA, CastanedaC,etal.TreatmentofadvancedHodgkin’sdisease: EBVDversusintensivebriefchemotherapy.LeukLymphoma. 2003;44(8):1361–5.
22.KoshyM,FairchildA,SonCH,MahmoodU.Improvedsurvival timetrendsinHodgkin’slymphoma.CancerMed.
2016;5(6):997–1003.
23.Guisado-VascoP,Arranz-SaezR,CanalesM,CanovasA, Garcia-LaranaJ,Garcia-SanzR,etal.StageIVandageover45 yearsaretheonlyprognosticfactorsoftheInternational
PrognosticScorefortheoutcomeofadvancedHodgkin lymphomaintheSpanishHodgkinLymphomaStudyGroup series.LeukLymphoma.2012;53(5):812–9.
24.MerliF,LuminariS,GobbiPG,CascavillaN,MammiC,Ilariucci F,etal.Long-termresultsoftheHD2000trialcomparing ABVDversusBEACOPPversusCOPP-EBV-CADinuntreated patientswithadvancedHodgkinlymphoma:astudyby FondazioneItalianaLinfomi.JClinOncol.2016;34(11):1175–81.
25.CanellosGP,RosenbergSA,FriedbergJW,ListerTA,DevitaVT. TreatmentofHodgkinlymphoma:a50-yearperspective.J ClinOncol.2014;32(3):163–8.
26.vonTresckowB,MoskowitzCH.Treatmentofrelapsedand refractoryHodgkinlymphoma.SeminHematol.
2016;53(3):180–5.
27.CortezAJ,DulleyFL,SaboyaR,MendroneJuniorA,Amigo FilhoU,CoracinFL,etal.Autologoushematopoieticstemcell transplantationinclassicalHodgkin’slymphoma.RevBras HematolHemoter.2011;33(1):10–4.
28.GoodmanKA,RiedelE,SerranoV,GulatiS,MoskowitzCH, YahalomJ.Long-termeffectsofhigh-dosechemotherapyand radiationforrelapsedandrefractoryHodgkin’slymphoma.J ClinOncol.2008;26(32):5240–7.
