The outcome of primary mediastinal B-cell lymphoma in a single center experience

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Original research article/Praca oryginalna

The outcome of primary mediastinal B-cell lymphoma in a single center experience

Anna Armatys

¹

, Magdalena Szcze śniak

¹

, Grzegorz Helbig

^2,

*,

Krzysztof Wo źniczka

²

, Agata Wieczorkiewicz-Kabut

²

, Jacek Paj ąk

³

, Małgorzata Krawczyk-Kuliś

²

, Anna Kopińska

²

,

S ławomira Kyrcz-Krzemie ń

²

1Students'ResearchGroup,DepartmentofHematologyandBoneMarrowTransplantation,SilesianMedical University,Katowice,Poland

2DepartmentofHematologyandBoneMarrowTransplantation,SilesianMedicalUniversity,Katowice,Poland

3DepartmentofPathology,SilesianMedicalUniversity,Katowice,Poland

article info

Articlehistory:

Received:26.10.2014 Accepted:18.12.2014 Availableonline:26.12.2014

Keywords:

PrimarymediastinalB-cell lymphoma

Immunochemotherapy

Autologoushematopoieticstem celltransplantation

Radiotherapy

Outcome

Słowakluczowe:

pierwotny chłoniak śródpiersia zkomórekB

immunochemioterapia

autologicznyprzeszczep komórek macierzystychukładu

krwiotwórczego

radioterapia

wyniki

abstract

Introduction: PrimarymediastinalB-celllymphoma(PMBCL)isanaggressivedistinctsub- typeofdiffuselargeB-celllymphoma(DLBCL).ThereisnostandardtreatmentforPMBCL andthevalueofmediastinalradiotherapyandautologoushematopoieticstemcelltrans- plantation(AHSCT)remainstobeelucidated.Materialandmethods: Aretrospectiveana- lysisof12patientswithPMBCL(8maleand4female)atmedianageof36yearshasbeen performed.Induction chemotherapyconsistedofR-DA-EPOCH(n=7),R-CHOP (n=4)and R-CVP(n=1).Second andthirdline treatments wereadministered in6 and2 patients, respectively. Nine patients weregiven involved ﬁeld mediastinal radiotherapy. Finally, 8patients wereproceededtoAHSCT.Results: Fourpatients achievedCRand4PRafter inductiontherapywithanoverallresponserateof66%.Intotal,aftercompletionalllines of the combined chemotherapy, the following disease responses have been observed:

completeresponse(CR)in4patients,partialresponse(PR)in6andnoresponse/disease progression(NR/PD)in2.Theoverallresponseratewas83%.Eightpatientswereprocee- dedtoAHSCT(4inCRand4inPR).Thetransplant-relatedmortalitywas0%atday100.

Medianfollow-upsfromdiagnosisandfromAHSCTwere39.5months(range8–106)and 32months(range3–95),respectively.AlltransplantedpatientsarealivewithCRconﬁrmed inPETscans.Conclusions:ThevastmajorityofPMBCLpatientsaresusceptibletoimmu- nochemotherapywithahighresponserateachievedafterR-DA-EPOCH/R-CHOPregimens.

AHSCTseemstobeanoptionforﬁtpatientswithdiseasechemosensitivity.

*Correspondingauthorat:DepartmentofHematologyandBoneMarrowTransplantation,SilesianMedicalUniversity, DabrowskiStreet25,Katowice,Poland.Tel.:+48322591281;fax:+48322554985.

E-mailaddress:ghelbig@o2.pl(G.Helbig).

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journal homepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2014.12.002

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Introduction

PrimarymediastinalB-celllymphoma(PMBCL)isanaggres- sive distinct subtype of diffuse large B-cell lymphoma (DLBCL)thatarises inthethymus,and presentsasabulky mediastinal mass, often with pleural and pericardial effu- sions. Thedisease occasionally disseminates toextranodal sites including kidneys, brain, lungs or gastrointestinal organs. PMBCL affects females more frequently than men and median age at diagnosis is 30–40 years [1, 2]. A large proportion of patients have mutations in the B-cell lymphoma 6 gene (BCL6). PMBCL is also characterized by an ampliﬁcation of the RELproto-oncogene and theJAK2 tyro- sine kinase gene which are normally observed in patients with Hodgkin'slymphoma, suggesting their commonorigin [3,4].Anoptimalchemotherapyschemaaswellastheroleof radiotherapy inthe managementof PMBCLare tobeeluci- dated.Cyclophosphamide,doxorubicin, vincristine,and prednisone (CHOP) regimen with or without radiotherapy was foundtobeeffectivein50–60%ofpatients[5,6].Theresults of CHOPplusrituximabfollowedby radiotherapywere also foundnottobefullysatisfactory.Inaddition,thelong-term sideeffectsofmediastinalradiationespeciallyinyoungadult patients might be devastating [7, 8]. A recently published studyhassuggestedthatmoredose-intenseregimenconsist- ing of dose-adjusted etoposide, doxorubicin, cyclophospha- midewith vincristineandprednisoneplusrituximab(R-DA- EPOCH) without consolidation radiotherapy may improve outcomeinpatientswithPMBCL[9].

Herein we report on the clinical outcome of our 12 patientswithPMBCLtreatedinourcenterbetween2005and 2013.

Material and methods

Patientsselectionandcharacteristics

BetweenFebruary2005andDecember2013,twelvepatients (8maleand4female)atmedianageatdiagnosisof36years (range 22–58 years), with PMBCL were admitted to our institution. There werefollowing complaints at admission:

chest pain (n=7),dyspnea (n=6),fatigue (n=5) and cough (n=8). At diagnosis 3 patients demonstrated vena cava superiorsyndrome.FivepatientspresentedwithBsymptoms.

The disease stage was evaluated according to the Ann Arborstagingsystemand8patientshadstageIV(pericardial and/or pleural effusion). The diagnostic work-up includeda complete physicalexamination, routine hema- tology and biochemistry studies, chest X-ray, computed tomographyoftheneck,chest,abdomen,andpelvicand/or positronemission tomography(PET)scans andbonemar- rowbiopsy. The ﬁnal diagnosis was based on histological examination of the excised lymph node obtained during mediastinoscopy and performed by a local pathologist.

Due to the fact that some patients were referred from other centers, not all data were available for all our patients.Theclinicalcharacteristicsofstudypatients were presentedinTableI.

TreatmentbeforeAHSCT

Chemotherapy was not uniformin all studied patients and depended on thepatient'soverall condition (co-morbidities), yearofdiagnosisandphysician'sdiscretion.Inductiontherapy consisted of R-DA-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; n=7), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone;n=4)andR-CVP(rituximab, cyclophosphamide,vincristine, prednisone;n=1). Due tothe insufﬁcient response/

earlyrelapseafterinduction,6patientsweregivenasecond- line treatment consisting of R-ESHAP (rituximab, cisplatin, methylprednisolone, etoposide,cytarabine;n=4)andR-CHOP (n=2).Twopatientsreceivedthird-lineschema:R-CHOP(n=1) andIVAC(ifosfamide,etoposide,cytarabine;n=1).Inaddition, 9patientsreceivedinvolvedﬁeldradiotherapyatadoseof36 Grey(Gy).Finally,8patientswereproceededtoAHSCT.

Responsecriteria

Completeremission(CR)wasdeﬁnedasadisappearanceof all measurable lesionsand symptomsfor at least4weeks.

Partialremission(PR)wasdeﬁnedas50%reduction.Progres- sive disease (PD) wasdeﬁned by anyincrease>25% inthe sum of the diameter of any measurable lesions, or the appearance of a new lesion. CT was performed in all patients before treatment and after each line of therapy.

The further evaluation using CT supported by PET was performed3and6monthsafterAHSCT[10].

Transplantprocedure

Mobilizedperipheralblood wasthesource ofstemcells for AHSCT in all transplanted patients. The regimen used for mobilization wasIVE (ifosfamide,etoposide, epirubicine)in all 8 patients. The preparative regimens included CBV (cyclophosphamide, BCNU, etoposide; n=5) and BEAM (BCNU,cytarabine,etoposide,melphalan;n=3).Sixpatients required granulocyte colony stimulating factor (G-CSF) to expeditepost-transplantregeneration.

TableI–Baselinepatientscharacteristics

Parameter n=12(%)

Gendermale/female 8/4

Medianage,year(range) 36(22–58)

Bulkytumor10cm 5(42)

Enlargementofsubclavicular lymphnodes

4(33)

Superiorvenacavasyndrome 3(25)

Bonemarrowinvolvement 0(0)

Bsymptoms 5(42)

StageIVdisease 8(67)

Medianhemoglobinconcentration, g/dL(range)

12.5(10–14.3)

MedianWBCcount,10⁹/L(range) 8.7(5–11.2) MedianPLTcount,10⁹/L(range) 354(97–637)

ElevatedLDHlevel 9(75)

Elevatedb2microglobulin 1(8)

LDH:lactatedehydrogenase,WBC:whitebloodcells,PLT:platelets.

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Results

TherapybeforeAHSCT

FourpatientsachievedCRand4PRafterinductiontherapy with an overall response rate of 66%. Four patients had stable disease after induction: R-DA-EPOCH (n=2), R-CHOP (n=1) and R-CVP (n=1).Second-linetherapy was adminis- teredin6patients:4withSDafterinduction,1withPRand 1withearlyrelapse fromCR. Among these6patients,one patientachievedCR,4-PRand1remainedinSD.Third-line treatmentreceived2patients,all withPRafterthe second- line.OneofthemremainedinPRandonedevelopeddisease progression. In total, after completion the 3 lines of the combined chemotherapy, the following disease responses havebeenobserved:CRin4patients,PRin6andNR/PDin 2. The overall responserate was 83%. Eight patients were proceeded to AHSCT (4 in CR and 4 in PR). Two patients remained in PR without AHSCT whereas 2 remaining patients died from disease progression and subsequent chemoresistance. The treatment details were listed in TableII.

Celldoseandengraftmentintransplantedpatients

The median number of transplanted nucleated cells was 310⁸/kg(range0,8–8.4)and themediannumber ofCD34- positive cells was 6.810⁶/kg (range 3–19). All patients engrafted. Themediantime toneutrophil recovery for our four patients was 13 days (range 7–19) and platelet count

>5010⁹/L was noted after a median of 14 days (range 10–19).Nopatientdiedwithin100daysafterthetransplant.

AdverseeventsofAHSCT

Six transplanted patients demonstrated complications in thepost-transplant period.Grade3or 4non-hematological

adverse events were not observed. One patient developed fever withpositivefungalcultures.Theothercomplications included proctitis (n=2), gastritis (n=1) and pharyngitis (n=2).One patientsuffered from cardiac failure, but prob- ablyduetopriorradiotherapy.

AHSCToutcome

Thetransplant-relatedmortalitywas0%atday100.Median follow-ups from diagnosis and from AHSCT were 39.5 months (range 8–106) and 32 months(range 3–95), respectively.AlltransplantedpatientsarealivewithCRconﬁrmed inPETscans.

Discussion

There wereonlysingleprospectivestudies inPMBCL,however no consensus in terms of therapeutic standard has beenestablished [5,11, 12]. Thevalueofmediastinalradio- therapywasraisedinseveralstudies,butoneshouldrealize its long-term effects [5, 11]. It was demonstrated that aggressive combined chemotherapyresulted inhigher rate of CRandfewerrelapsesifcompared withstandardCHOP/

CHOP-likeregimen [5].Theresultsof treatmentwithR-DA- EPOCH in PMBCL seem to be the most encouraging. The event-free (EFS) and overall survival (OS) rates at 5 years were 93% and 97%, respectively. Three patientshad active disease after R-DA-EPOCH completion and 2 out of them received mediastinalradiotherapy beingdisease-free at the lastcontact.Onepatientdevelopedacutemyeloidleukemia and died while in remission of his PMBCL. To verify the outcomes, the results were then compared with those presented in a retrospective analysis from another center.

TheoutcomewasalsohighlysatisfactorywithEFSratewas 100%after medianof3of follow-up.Theradiotherapy was omitted inthisstudy[9].TheEFS andOS ratesat 16years using the same regimen but without rituximab were 67%

TableII–TherapyforprimarymediastinalB-celllymhoma Patient Ageat

diagnosis (years)

First-line treatment

Response Second-line treatment

Response Third-line therapy

Disease statusafter completion oftherapy

AHSCT Status atlast contact

1. 39 R-DA-EPOCH PR R-ESHAP PR R-CHOP PR YES CR

2. 33 R-DA-EPOCH CR CR YES CR

3. 37 R-DA-EPOCH SD R-ESHAP NR NR/PD NO DEATH

4. 26 R-DA-EPOCH CR CR YES CR

5 32 R-DA-EPOCH PR PR YES CR

6. 34 R-DA-EPOCH SD R-ESHAP PR IVAC PD NO DEATH

7. 40 R-DA-EPOCH PR PR NO PR

8. 33 R-CHOP SD ESHAP PR PR YES CR

9. 30 R-CHOP CR CR YES CR

10. 52 R-CHOP CR/REL R-CHOP CR CR YES CR

11. 22 R-CHOP CR/REL R-CHOP CR CR YES CR

12. 58 R-CVP SD R-CHOP PR PR NO PR

CR:completeresponse,PR:partialresponse,SD:stabledisease,NR:noresponse,PD:progressiondisease,REL:relapse;AHSCT:autologous hematopoieticstemcelltransplantation.

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and78%respectively[13].Thisfindingseemstoconfirmthe benefit of rituximab added to conventional chemotherapy.

This combination improved EFS and OS rates if compared withchemotherapyalone[12].However,thesurvivaladvan- tageof rituximab addedtochemotherapy wasnot demon- stratedbyother reports[14]. Basedon theresultsprovided byDunleavyetal.[9],theR-DA-EPOCHregimenseemstobe highlyeffective withno furtherneed of mediastinal radio- therapyinavastmajorityof treatedpatients.Thisregimen was found to be safe with no serious late effects. It is difﬁcult to interpret data on the efﬁcacy of R-DA-EPOCH fromouranalysisduetosmallnumberofincludedpatients.

Nevertheless, after the median number of 6 cycles (range 3–8),theresponseratewas71%withCRattainedinmerely 30%of patients.Two patientsfrom thiscohortdied dueto disease progression and subsequent resistance to chemotherapy,four patientsareinCR,but alltheyunderwent AHSCT. One patient remained in PR without AHSCT. It should be mentioned that toxicity of R-DA-EPOCH was manageable with no late morbidity. Keeping in mind all drawbacks of our study, the response rates were not as satisfactory as reported by Dunleavy [9]. Moreover, they were even worse if compared with those achieved by R- CHOPregimen where CRratewas 75%.However,the rapid relapseoccurredin2patientsshortlyafterR-CHOPcomple- tion. Nevertheless, our data are insufﬁcient to draw any conclusions. The role of mediastinal radiotherapy after completionofthechemotherapyseemedtobecrucialinthe therapeutic algorithm of PMBCL at least in some reports.

Namely,CRratewas26%afterintensiveMACOP-Bregimen andincreasedto88%afterlocalradiotherapy.Theestimated 9-yearrelapse-freesurvivalwas91%aftermedianof4years offollow-upwithallrelapsesoccurringwithintheﬁrstyear.

Thisstudystronglydemonstratedthepivotal role of radiotherapy inthe treatmentof PMBCL [11]. Mediastinal radiotherapy was also used in 75% of patients included to our studywithanintentiontoconsolidateCR(n=3),toconvert patientsfrom PRtoCRbeforeAHSCT(n=4) orasasalvage regimeninresistantcases(n=2).However,intherituximab era, the value of radiotherapy remains unclear and one should realize the risk of long-term toxicity. In fact, one patient from our study developed cardiac failure several weekslater.

The beneﬁt of high-dose chemotherapy with stem cell rescueasaCRconsolidationinPMBCListobevalidatedin clinicaltrials.TheresultsofAHSCTinPMBCLarescarceand inconclusive. The largest study published to date, came fromthe GEL-TAMO registry andincluded71 patientswith high-riskclinicalfeatures.Nearly50%ofpatientswereinCR at transplant and received prior radiotherapy. After the medianfollow-up of4years theOSandPFS ratewere80%

forpatientstransplantedinCRandlessthan50%forthose inPRor less[15].Thehighratesof OSandPFS inpatients transplantedinCRwerealsodemonstratedbyothers[5,16].

Our study has reported the high efﬁcacy of AHSCT with 100%ofCRmaintainednearly3yearsaftertransplantation.

However,oneshouldbeawarethatonlyrandomizedstudy coulddemonstratethevalueofAHSCTinthisstudypopula- tion.Thevastmajorityofreportswereperformedbeforethe additionofrituximab toconventionalchemotherapy.Based

ontheexcellentresultsofR-DA-EPOCHstudy[9],thefrontline AHSCT as wellas radiotherapy could be redundant.Never- theless,oursmallserieshasdemonstratedthehighefﬁcacy of AHSCTinpatientswithrelapsedchemo-sensitive disease.

It was demonstrated that disease status before transplant may inﬂuence its outcome and the incorporation of PET imagingallowedforbetterresponseevaluation.However,one should keep in mind the high proportion of false positive resultsof PETafterchemotherapy completionfor PMBCL.In fact, 18 patients out of 36 from Dunleavy study had an excellent outcome without further therapy despite the pre- senceofpositivePETscanaftertherapy[9].Itturnedoutthat PMBLCpatientstransplantedinPRfaredworsethanthosein CR, but signiﬁcantly better than patients with refractory disease [15].Relapsed andrefractoryPMBCLpatientshadan inferior responserateand survivalifcompared with diffuse largeB-celllymphoma(DLBCL),butthepost-AHSCToutcome issimilarforchemo-sensitivePMBCLandDLBCLpatients[17].

Conclusions

The vast majority of PMBCL patients are susceptible to immunochemotherapy with high response rate achieved afterR-DA-EPOCH/R-CHOPregimen.Theroleofradiotherapy should belimited topatients withresidual tumor massin mediastinum, but one should keep on mind its long-term toxic effects. AHSCTseems tobe anoption for ﬁtpatients withdiseasechemo-sensitivity.

Authors' contributions/Wkład autorów

AA–studydesign,manuscriptpreparation,literaturesearch.

MS – data collection, literature search, manuscript preparation. GH– study design, data collection and interpretation, manuscript preparation, literature search. KW and AWK – data collection. SKK – study design, data interpretation.

JP – histological examination and data interpretation. AK – datacollection.MKK–datainterpretation.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

Financial support/Finansowanie

Nonedeclared.

Ethics/Etyka

The work described in this articlehas been carried out in accordance with The Code of Ethics of the World Medical Association (Declarationof Helsinki)for experiments invol- ving humans; EU Directive 2010/63/EU for animal experiments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.

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