Prognostic significance of the number and type of extra nodal localizations of DLBCL in the rituximab era

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Original research article/Praca oryginalna

Prognostic signiﬁcance of the number and type of extra nodal localizations of DLBCL in the rituximab era

Znaczenie prognostyczne liczby zmian pozaw ęzłowych oraz typu zaj ętego narz ądu u chorych na DLBCL w dobie leczenia

rytuksymabem

Agnieszka Badora-Rybicka *, Sebastian Giebel, Maciej Studzi ński, Ewa Chmielowska, El żbieta Nowara

MariaSklodowska-CurieMemorialCancerCenterandInstituteofOncologyGliwiceBranch,Gliwice,Poland

article info Articlehistory:

Received:01.08.2014 Accepted:07.01.2015 Availableonline:14.01.2015

Keywords:

DLBCL

Extranodallocalization

Rituximab

Słowakluczowe:

DLBCL

lokalizacjapozawęzłowa

rytuksymab

abstract

Introduction: Theaimofthestudywastoassesstheprognosticsigniﬁcanceofthenum- berandtypeofextranodallocalizationsofDLBCLaswellasotherfactorsincludedinIPI intherituximabera.Materialsandmethods: Weconducteda retrospectiveanalysisof medicaldocumentationof178patientswithDLBCLtreatedintwooncologycentersbet- ween2006and2011.Wedistinguished3subgroupsofpatients:withonlynodallocaliza- tionofDLBCL(A,n=80),with1extranodalsite(B,n=66)andwith2extranodalsites (C,n=32). Results: Thepresence and thenumber of extranodal lesions didnot have aprognosticimpactbothontheresponse andsurvival.ProbabilitiesforOSwere79.4%

6, 85.5%5 and 78.5%8 for groups A, B and C respectively. Most common extra nodallocalizations ofDLBCLwere:digestive duct,bones andskin. Thesiteofinvolve- ment also didnot have a prognostic signiﬁcance. In a multivariate analysis negative prognosticfactorsforOSprobabilitywere:elevatedLDHlevel(HR:3.12[95%CI:1.3–7.47], p=0.01)anddiseasestageIII(HR:4.61[95%CI:1.32–16.1],p=0.02).Conclusions: Neither thenumberofextranodallesionsnortheirlocalizationaffectsprognosisinpatientswith DLBCLintherituximabera.

*Correspondingauthorat:KlinikaOnkologiiKlinicznejiDoświadczalnej,ul.WybrzeżeArmiiKrajowej15,44-101Gliwice,Poland.

Tel.:+48322788704.

E-mailaddress:agnieszka.k.badora@gmail.com(A.Badora-Rybicka).

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journalhomepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2015.01.001

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Introduction

DiffuselargeB-celllymphoma(DLBCL)isthemostcommon non-Hodgkinlymphomaamongadults,accountingfor25–50%

ofcases[1,2].DLBCLisaheterogeneousdisease,withmulti- plemorphologicvariantsandhistologicalsubtypes[1–3].We can distinguish, inter alia, nodal and primary extra nodal disease [1]. For last few decades CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen was the gold standard of care in case of DLBCL [4]. Attempts to improveoutcomes byadding othercytostatic agents tothis regimenorchangingdoseintensityfailedtoshowlong-term beneﬁt with increased toxicity of such treatment [5–10]. Addingrituximab, amonoclonal antibodytargeting CD20,to CHOPchemotherapyledtosigniﬁcantimprovementoftreat- mentoutcomeswithacceptabletoxicityinelderly(60-years- old) as well as younger (18–60-years-old) patients with low risk according to age adjusted IPI (aaIPI) [11–14]. R-CHOP immunochemotherapyistodatethemainstayof therapyin patients suffering from DLBCL, although its role in case of extranodaldiseaseiscontroversial[3,15–18].

Despitethesepromisingoutcomes,about30%ofpatients stillexperienceDLBCLrelapse[3,19,20].Patientsnotcured bythe first-line therapyhave significantly worse prognosis andearlyidentificationofthesepoor-riskpatientsmaylead toalternatetreatmentstrategiesconsideration[21].Interna- tional Prognostic Index (IPI) was the first tool to predict outcome for patients withDLBCL [20]. Accordingto IPI we distinguish four outcome groups and negative prognostic factors are: age>60, clinical stage of the disease III/IV accordingtoAnn-Arborclassification,elevatedlactatedehy- drogenase(LDH) level,EasternCooperativeOncology Group performancestatus (ECOG-PS)2 and 2extra nodal sites of the disease. For patients younger than 60 years age adjusted IPI (aaIPI), based on three risk factors (CS III/IV, elevated LDH and ECOG-PS 2) was applied. IPI was designed before rituximab era and, in the face of more effectivetreatment,itsutilityisamatterofdebate[22].For patientstreated withimmunochemotherapy revised IPI(R- IPI),whichidentifiesthreeoutcomegroups,wascreated[21].

NeitherIPInorR-IPIidentifiesagroupofpatientswithless than 50% chance of survival [20, 21]. New prognostic markers defined by gene expression profiling are still not helpfulintherapeuticdecisionmaking[3].

The aim of this study was to assess the prognostic signiﬁcanceof thenumberand typeofextranodallocaliza- tionsaswellasotherfactorsincludedinIPIintherituximab era.

Materials and methods

Studydesign

We conducted a retrospective analysis of an unselected population of patients treated in Maria Skłodowska-Curie MemorialCancer Centerand Instituteof Oncology,Gliwice Branchand FranciszekŁukaszczykMemorialCancerCenter inBydgoszczbetween2006and2011.Inclusioncriteriawere:

newly diagnosed,histologicallyprovenDLBCL,patient'sage above 18 years and ﬁrst-line treatment with R-CHOPregi- men administered at a 21-day interval. Patients suffering from primary central nervous system lymphoma, primary mediastinal B-celllymphomaorwithincompletedocumen- tationwereexcluded.Responsetotreatmentwasevaluated accordingtoTheInternationalWorkshopCriteria1999[23].

Patientcharacteristics

On the basis of abovementioned criteriaweidentiﬁed 178 eligiblepatients.Nodosereductionwasnoted.Themedian time of observationwas21 months.Clinicalcharacteristics ofpatientsatdiagnosisarelistedinTableI.

Wedistinguishedthreesubgroupsofpatients–withonly nodal involvement(groupA;n=80),with1extranodalsite of the disease (groupB;n=66) and with2and moreextra nodalsitesofDLBCL(groupC;n=32).

Statisticalanalysis

Overall survival (OS) was calculated from the date of diagnosisuntildeathofanycauseordatelastknownalive.

TableI–Patient'sclinicpathologicalcharacteristics TabelaI–Charakterystykachorych

Medianage(range) 57(20–80)years

Age>60 73(41%)

Gender

M 88(49.4%)

F 90(50.6%)

Clinicalstage

I 41(23%)

II 37(20.8%)

III 42(23.6%)

IV 58(32.6%)

B-symptoms 77(43.3%)

ECOG-PS

0 66(37.1%)

1 76(42.7%)

2 31(17.4%)

3 5(2.8%)

4 0

Numberofextranodallesions

0 80(44.9%)

1 66(37.1%)

2 17(9.5%)

3 11(6.2%)

4 3(1.7%)

5 1(0.6%)

MedianKi67 80%(20–100)

Radiotherapyafter1stlinetreatment 47(26.4%) IPI

0 36(20.2%)

1 48(27%)

2 47(26.4%)

3 29(16.3%)

4 14(7.9%)

5 4(2.2%)

Relapse/progression 33(18.5%)

ECOG-PS – Eastern Cooperative Oncology Group Performance Status;IPI–InternationalPrognosticIndex.

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Progressionfreesurvival(PFS)wascalculatedfromthedate ofachievingCR/CRuuntildiseaseprogression,patientdeath or date last known alive. Event free survival (EFS) was calculated from the date of diagnosis until one of the followingevents:diseaseprogression,notreachingcomplete remission/uncertaincomplete remission (CR/CRu), death of anycause or datelast known alive. OS, PFS and EFS were estimated bytheKaplan–Meyer method.Foramultivariate analysisweusedtheCoxproportionalhazardsmodel.

Theresponse rates werecompared usingFisher's exact test.Foramultivariateanalysislogisticregressionwasused.

Results

Prognosticsigniﬁcanceofthenumberofextranodal localizations

Thepresence and the number of extra nodal localizations did not have a prognostic impact on neither treatment responsenorsurvival.62(81.6%)ofpatientswithonlynodal involvement achieved CR or CRu in comparison with 45 (65.2%)patientswithoneextranodalsiteinvolved(p=0.03) and21 (63.6%) patientswithtwoor moreextranodal sites ofDLBCL(p=0.05).Amongpatientswithnoextranodalsite ofthedisease6(7.9%)experiencedprogressionafterimmu- nochemotherapy in comparison to 5 (7.2%) patients with oneextranodalsiteinvolved(p=0.5)and4(12.1%)patients withtwoor moreextranodalsites(p=0.49).OSprobability at3yearsofobservationwas79.8%6amongpatientswith onlynodalpresentation ofDLBCLincomparisonto83%5 among patients with one extra nodal DLBCL localization (p=0.71)and79.3%7inpatientswithmorethanoneextra nodalsiteinvolved(p=0.42).Moredetaileddataconcerning the prognostic impact of the presence and number of extranodal sites on treatment response and survival are presentedinTableII.

Prognosticsigniﬁcanceofthetypeofextranodallocalizations

Three most commonly involved extra nodal sites were digestive duct (stomach, small and large intestine), bones

and skin. Patients with DLBCL involving digestive duct achievedCRorCRuin66.7%(28patients),whereaswenoted CR/CRuin14(53.8%)patientswithboneinvolvement(p=0.31) and in 12 (66.7%) patients with skin localization (p=1.00).

Disease progression occurred in3 (7.1%)patients diagnosed with digestive duct involvement in comparison to 1 (3.8%) patient with bones involvement (p=1.00) and 4 (22.2%) patients with DLBCL of the skin (p=0.18).OS probability at 3yearsofobservationwas77.6%7inpatientswithDLBCL of the digestive duct in comparison to 86%7 in patients with bone lesions (p=0.8) and 78.7%11 among patients withDLBCLof theskin(p=0.99).Thetypeofinvolvedorgan didnothaveaprognosticimpact(TableIII).

PrognosticsigniﬁcanceoffactorsincludedinIPI

InaunivariateanalysiselevatedLDHlevelnegativelyaffected responserates,OSandEFS(TableIV).WeobservedCRorCRu in85(79.4%)patientswithLDHlevelwithinthestandardand in 43 (60.6%) patients with elevated LDH level (p=0.01).

Moreover,signiﬁcantlymorepatientswithelevatedLDHlevel experienceddiseaseprogression–12(16.9%)vs.3(2.8%)with LDH level within the standard (p=0.001). OS probability at 3 years of observation was 92.3%3 among patients with normalLDHlevelvs.61.7%8inpatientswithelevatedLDH level (p=0.0004).Asimilar correlationwas observedfor EFS probability (77%4.6 vs. 51.6%7.5; p=0.003) but not PFS probability (87.6%5 vs. 82%8.5; p=0.43). In univariate analysispatientswithpoorperformancestatus(ECOG-PS2) rarelyachievedCR/CRuincomparisontopatientswithECOG- PS<2 (20 (55.5%) vs. 108 (76.1%);p=0.02) and more often experienced disease progression (7 (19.4%) vs. 8 (5.6%);

p=0.01).Moreover, OS probability at 3 yearsof observation wassigniﬁcantlyloweramong patientswithECOG-PS2in comparisontopatientswithECOG-PS>2(68%8.5 vs.84%

4.2;p=0.008)aswellasEFSprobability(48%9.5vs.42.5%

4.4;p=0.004)andPFSprobability(70%13.6vs.89%4.6;

p=0.03).Alsopatientswithadvanceddiseasestage(IIIorIV) moreoftenexperienceddiseaseprogressionincomparisonto patients with DLBCL at stage I or II (14 (14%) vs. 1 (1.3%);

p=0.002).Theyalso rarelyachievedCR/CRu (62(62%)vs.66 (84.6%);p=0.01).OSprobabilityat3yearsofobservationwas

TableII–Theprognosticimpactofthepresenceandnumberofextranodalsitesontreatmentresponseandsurvival TabelaII–Znaczenieprognostyczneobecnościiliczbyzmianpozawęzłowychdlaodpowiedzinaleczenieiprzeżycia

Onlynodalinvolvement(A) n=80

1extranodalsite(B) n=66

2extranodalsites(C) n=32

p (Avs.B)

p (Avs.C)

p (Bvs.C)

CR 48(63.1%) 38(55%) 15(45.4%) 0.39 0.09 0.4

CRu 14(18.4%) 7(10.1%) 6(18.2%) 0.23 1.00 0.34

CR+CRu 62(81.6%) 45(65.2%) 21(63.6%) 0.03 0.05 1.00

PR 5(6.6%) 15(21.7%) 7(21.2%) 1.00 0.75 0.76

CR+CRu+PR 67(88%) 60(86.9%) 28(84.8%) 0.014 0.04 1.00

SD 3(3.9%) 4(5.8%) 1(3%) 0.7 1.00 1.00

PD 6(7.9%) 5(7.2%) 4(12.1%) 0.5 0.49 0.46

OS(%,SE) 79.86 835 79.37 0.71 0.42 0.54

EFS(%,SE) 696 656 68.18 0.21 0.19 0.7

PFS(%,SE) 716 725.8 55.614 0.72 0.35 0.53

CR–completeremission;Cru–uncertaincompleteremission;PR–partialresponse;SD–stabledisease;PD–progressivedisease;OS–overall survival;EFS–eventfreesurvival;PFS–progressionfreesurvival;SE–standarderror.

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signiﬁcantly lower among patients with DLBCL CSIII in comparisontopatientswithDLBCLCS<III(70%6vs.95%

2.8;p=0.0004). Similar correlationswere observedfor EFS probability(55.4%6vs.84.8%4;p=0.0006)andPFS probability(74.6%8vs.97.9%2;p=0.008).

In contrast the presence of 2 extra nodal lesions and patients age>60 years did not have negative prognostic impact on neither response to treatment nor survival. 108 (74%) patients with no or one extra nodal site of DLBCL experiencedCR/CRuincomparisonto20(62.5%)patientswith twoormoreextranodallesions(p=0.2).54(74%)patients>60 yearsoldachievedCRorCRuincomparisonto74(70.5%)of patientsat theageof 60orless(p=0.73). OSprobabilityfor patients with2vs. <2extra nodalsites was 78.5%8 vs.

81.5%4;p=0.39andOSprobabilityforpatients>60vs.<60 years old was 81.8%7.5 vs. 79.9%4.5; p=0.45. Similar correlations were observed for EFS and PFS probabilities.

Survivaldataarereportedat3yearsofobservation.

Inamultivariateanalysistheonlyindependentnegative prognostic factor for the chance of achieving CR/CRu was elevated LDH level (HR=0.43, 95% CI, 0.21–0.89; p=0.002).

Independentnegative prognostic factorsfor OS werestage of the disease III/IV (HR=4.61, 95% CI, 1.32–16.1; p=0.02) andelevatedLDHlevel(HR=3.12,95%CI, 1.3–7.47;p=0.01).

DiseasestageIII/IVwastheonlyindependentnegativeprog- nosticfactorforPFS(HR=10.21,95%CI,1.23–85.1;p=0.03)and

EFS(HR=2.29,95%CI,1.11–4.71;p=0.02).Multivariateanalysis of CR/CRu,OS,EFS andPFSinrelationtoIPI components is presentedinTableIV.

Discussion

We evaluatedtheperformanceofIPIcomponentsinDLBCL patientstreatedwithR-CHOPregimentoassessifimmuno- chemotherapy influenced their prognostic value. IPI is aclinicalprognosticmodelthatpredictsoutcome[20].Based on five independent prognostic factors it identifies four prognostic groups: low risk, low intermediate risk, high- intermediateriskandhighriskwith5-yearsOSvalues73%, 51%, 43% and 26%, respectively [20]. It is worth to note, however,thatIPIwasdesignedbeforeintroducingrituximab to standard treatment of DLBCL patients. In the rituximab era a revised IPI (R-IPI), redistributing the five IPI components into three prognostic groups (very good, good and poor) was designed, but it does not identify the group of patientswhose4-yearOSprobabilityislowerthan50%[21].

This group willprobably require more intensive treatment immediatelyafterDLBCLdiagnosis[3].

New molecular prognostic markers were identiﬁed, but none of them gain wide practical acceptance. According to geneexpression proﬁlingwe distinguish germinalcenter TableIII–Theprognosticimpactofthetypeofextranodalsitesontreatmentresponseandsurvival

TabelaIII–Znaczenieprognostycznetypuzajętegonarządupozawęzłowegodlaodpowiedzinaleczenieiprzeżycia Digestiveduct

(A) n=42

Bones (B) n=26

Skin (C) n=18

p (Avs.B)

p (Avs.C)

p (Bvs.C)

CR 22(52.4%) 10(38.5%) 10(55.5%) 0.32 1.00 0.36

CRu 6(14.3%) 4(15.4%) 2(11.1%) 1.00 1.00 1.00

CR+CRu 28(66.7%) 14(53.8%) 12(66.7%) 0.31 1.00 0.53

PR 9(21.4%) 9(34.6%) 1(5.5%) 0.27 0.25 0.03

CR+CRu+PR 37(88.1%) 23(88.5%) 13(72.2%) 1.00 0.15 0.24

SD 2(4.8%) 2(7.7%) 1(5.5%) 0.63 1.00 1.00

PD 3(7.1%) 1(3.8%) 4(22.2%) 1.00 0.18 0.14

OS(%,SE) 77.67 867 78.711 0.8 0.99 0.97

EFS(%,SE) 687.3 5411.4 56.612.7 0.58 0.53 0.83

PFS(%,SE) 88.910.5 88.910.5 909.5 0.44 0.87 0.87

CR–completeremission;Cru–uncertaincompleteremission;PR–partialresponse;SD–stabledisease;PD–progressivedisease;OS–overall survival;EFS–eventfreesurvival;PFS–progressionfreesurvival;SE–standarderror.

TableIV–MultivariateanalysisofCR/CRu,OS,EFSandPFSinrelationtoIPIcomponents

TabelaIV–AnalizawielowariantowazależnościodposzczególnychskładowychIPIszansyuzyskaniaCR/CRu,OS,EFSiPFS

Variables CR/CRu OS EFS PFS

HR 95%CI p HR 95%CI p HR 95%CI p HR 95%CI p

CSIII 0.47 (0.21–1.0) 0.06 4.61 (1.32–16.1) 0.02 2.29 (1.11–4.71) 0.02 10.21 (1.23–85.1) 0.03 ECOG-PS2 0.65 (0.28–1.48) 0.3 1.9 (0.83–4.35) 0.1 1.79 (0.96–3.3) 0.06 2.12 (0.51–8.76) 0.3 Age>60 1.54 (0.74–3.21) 0.2 0.53 (0.23–1.25) 0.1 0.94 (0.53–1.67) 0.83 0.92 (0.23–3.63) 0.9 LDH>N 0.43 (0.21–0.89) 0.002 3.12 (1.3–7.47) 0.01 1.73 (0.95–3.13) 0.07 0.97 (0.25–3.76) 0.9 Extranodal

lesions2

0.71 (0.29–1.76) 0.5 1.34 (0.51–3.53) 0.55 1.2 (0.59–2.43) 0.6 0.33 (0.04–2.79) 0.3

HR– hazardratio;CR–completeremission;CRu–uncertain completeremission;OS–overallsurvival;EFS–eventfreesurvival;PFS– progressionfreesurvival;ECOG-PS–EasternCooperativeOncologyGroupPerformanceStatus;CS–clinicalstage;LDH–lactatedehydrogenase.

Variableswereregardedassigniﬁcantatalevelof0.05andareshowninbold.

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B-celllikeDLBCL(GCB)andactivatedB-celllikeDLBCL(ABC) [24–26].IntherituximaberapatientswithGCBsubtypegain significantlylongerPFSandOS[27].Geneexpressionprofiling is still an expensive procedure and immunohistochemistry models, identifying GCB or non-GCB subtype, are not fully consistentwiththerealstate[28].Todate diagnosisof GCB ornon-GCBsubtypeshouldnotinfluencetreatmentdecision making [3]. The mechanism of BCL-2 overexpression, MYC and TP 53 dysfunction, MHC loss, some micro-RNA signa- tures,highKi67ortypeoftumormicroenvironmentarealso supposed to be adverse prognostic factors, but without impactontreatmentstrategy[27,29–35].

Extra nodal DLBCL accounts for 25–40% cases [1]. It is a heterogeneous entity, with various clinical course. The roleofimmunochemotherapyintreatmentofpatientswith extranodalDLBCLwaslastlydiscussed,butdataaresparse and controversial. The studies are retrospective in their natureandthelargestanalysesarebasedonAsianpopula- tion [15–18].It seemsthat adding rituximab tochemother- apydoesnotimproveoutcomesinpatientswithextranodal DLBCL,at leastamong casesinearly clinicalstage[36,37].

However, in rituximab era extra nodal involvement is no longer independent prognostic factor, so one could con- clude, that immunochemotherapy improves outcomes in thesepatients.TheseobservationsmightdependonDLBCL localization. Few retrospective studies identiﬁed localizations like pleura, peritoneum, esophagus, adrenals, pan- creas,ovaries, uterus,testis, smallintestine, bonemarrow, which are associated with signiﬁcantly worse prognosis, even when treated with rituximab [38, 39]. In contrast patients with DLBCL affecting Waldeyer's ring or stomach havebettertreatmentoutcomes[40,41].Inouranalysisthe presence and number of extra nodal lesions were not prognostic in patients treated with R-CHOP regimen. Also thetypeofextranodallocalizationsdidnotaffectprognosis, butsubgroupsof patientswererelativelysmall andhetero- geneous.ItisworthtonotethatinenhancedIPI(NCCN-IPI) extra nodal DLBCL is an independent negative prognostic factor, irrespective of the number of extra nodal localizations[42].InaaIPIextranodalinvolvementisnottakeninto account[20].

Inouranalysistheonlyindependentnegativeprognostic factorforthechanceofachievingCR/CRuwaselevatedLDH level. CSIII was within statistical signiﬁcance. Elevated LDH level and advanced stage of the disease were also negative prognostic factors for OS. On the basis of these results,itseems thatintherituximab erathe ‘‘volume’’of DLBCL is the most powerful prognostic marker. These observationsare inaccordancewithavailableliterature[17, 18,43,44].

Patient's age>60 was not an independent prognostic marker in our analysis. Some authors postulate changing the age cut-off pointinto 70 (elderlyIPI, E-IPI) or 75 years (NCCN-IPI) [42, 45]. Further analyses of randomized trials likeRIVOVER60 trialshowed thatpatient'sage70but not 60 isanadverse prognostic factor[13]. Inthese cases age- relatedco-morbiditiesplaycrucialrole[46].Thepresenceof co-morbidities often does not allow conducting full-dose treatmentandaffectsOS.Italsohasinﬂuenceon patient's performance status, independent of DLBCL. On the other

hand,eveninpatients>80yearswithoutsigniﬁcantcontra- indicationsapplyingR-CHOPissafeandimprovestreatment outcomes[3].R-miniCHOP,withreduceddosesof cytostatic agents,isalsoworthconsidering [3,36]. Inelderlypatients treatmentdecisionmakingshouldbebasednotonlyonIPI or E-IPI but alsoon co-morbidityscore andcomprehensive geriatricassessment(CGA)[47].

Itseemsthat inrecentyearstheprognosticsigniﬁcance of poor performance status decreased. Poor PS is often caused by advanced DLBCL or its unfavorable localization.

Immunochemotherapy, assisted by appropriate supportive care,couldinshorttimeleadtomarkedimprovement.Even if poor performance status results from co-morbidities, additional treatmentcan allow an optimal DLBCL therapy.

In such cases, however, the risk of death is higher and independentofDLBCLprogression.

Ourstudyisretrospectiveinnature,withtheconsequent limitations,likepotentialinterpretativeerrorsresultingfrom differentconditionsduringtreatmentofindividualpatients.

Theweakpointofthisanalysisisalsorelativelysmallgroup of patients, especially in subgroups with different extra nodallocalizations.Ontheotherhand,extranodalDLBCLis relatively rare and very heterogeneous disease entity, so conducting statistically powerful studywith such group of patientsisdifﬁcult.Further,multicenterstudiesareneeded to determine applicability of ourobservations for different DLBCLlocalizations.

In conclusion, neither presence of extra nodal involvement, nor the typeof DLBCLlocalization has a prognostic impactintherituximab era.Among DLBCLpatientsreceiv- ing R-CHOP regimen elevated LDH level and clinical stage III/IV were independent negative prognostic factors, in contrast to performance status and patient's age. These observations should be veriﬁed in studies on independent patient'spopulations,preferablyprospectiveclinicaltrials.

Authors' contributions/Wkład autorów

A.B.-R. – study design, data collection and interpretation, statistical analysis, manuscript preparation, and literature search. S.G. – study design, data interpretation, statistical analysis,andmanuscriptpreparation.E.N.–studydesign.M.S.

–datacollectionandliteraturesearch.E.C.–datacollection.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

Financial support/Finansowanie

Nonedeclared.

Ethics/Etyka

The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical

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Association(DeclarationofHelsinki)forexperimentsinvolving humans; EU Directive 2010/63/EU for animal experiments;

UniformRequirementsformanuscriptssubmittedtoBiomedi- caljournals.

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