Evaluation of prognostic factors among patients with chronic graft-versus-host disease

G a -Ve sus-HOs Disease A icles and B ie Repo s haema ologica | 2012; 97(8) 1187 Manusc ip ecei ed on Sep embe 21, 2011. Re ised e sion a i ed on Janua y 12, 2012. Manusc ip accep ed Feb ua y 3, 2012. Co espondence: Jose A Pé ez-Simón, MD, PhD, Hospi al Uni e si a io Vi gen del Rocío, Ins i u o de Biomedicina de Se illa (IBIS) /CSIC/Uni e sidad de Se illa A enida de Manuel Siu o s/n 41013, Se illa, Spain. Phone: in e na ional +34.9.55013260. Fax: in e na ional +34.9.55013265. E-mail: josea.pe ez.simon.sspa@jun ade- andalucia.es Backg ound Ch onic g a - e sus-hos disease (cGVHD) is a majo complica ion a e allogeneic s em cell ans- plan a ion wi h an ad e se e ec on bo h mo ali y and mo bidi y. In 2005, he Na ional Ins i u e o Heal h p oposed new c i e ia o diagnosis and classi ica ion o ch onic g a - e sus-hos disease o clinical ials. New sub-ca ego ies we e ecognized such as la e onse acu e g a - e sus-hos disease and o e lap synd ome. Design and Me hods We e alua ed he p ognos ic impac o he new sub-ca ego ies as well as he clinical sco ing sys- em p oposed by he Na ional Ins i u e o Heal h in a e ospec i e, mul icen e s udy o 820 pa ien s unde going allogeneic s em cell ansplan a ion be ween 2000 and 2006 a 3 di e en ins i u ions. Pa ien s we e e ospec i ely ca ego ized acco ding o he Na ional Ins i u e o Heal h c i e ia om pa ien s’ medical his o ies. Resul s As a as he new sub-ca ego ies a e conce ned, in uni a ia e analysis diagnosis o o e lap syn- d ome ad e sely a ec ed he ou come. Also, he numbe o o gans in ol ed o a cu -o alue o 4 signi ican ly in luenced bo h cGVHD ela ed mo ali y and su i al. In mul i a ia e analysis, in addi ion o NIH sco e, pla ele coun and pe o mance sco e a he ime o cGVHD diagnosis, plus gu in ol emen , signi ican ly in luenced ou come. These 3 a iables allowed us o de elop a sim- ple sco e sys em which iden i ies 4 subg oups o pa ien s wi h 84%, 64%, 43% and 0% o e all su i al a i e yea s a e cGVHD diagnosis (sco e 0: HR=15.96 (95% CI: 6.85-37.17), P<0.001; sco e 1: HR=5.47 (95% CI: 2.6-11.5), P<0.001; sco e 2: HR=2.8 (95% CI: 1.32-5.93), P=0.007). Conclusions In summa y, we ha e iden i ied a powe ul and simple ool o disc imina e di e en subg oups o pa ien s in e ms o ch onic g a - e sus-hos disease ela ed mo ali y and su i al. Key wo ds: cGVHD, p ognos ic ac o s, NIH classi ica ion, o e lap synd ome, delayed acu e GVHD. Ci a ion: Pé ez-Simón JA, A am G, Ma ino R, Piñana JL, Caballe o-Velazquez T, Ringden O, Valca cel D, Caballe o D, Rembe ge M, de Paz Y, Sie a J, San Miguel J, and Hagglund H. E alua ion o p ognos ic ac o s among pa ien s wi h ch onic g a - e sus-hos disease. Haema ologica 2012;97(8):1187-1195. doi:10.3324/haema ol.2011.055244 © 2012 Fe a a S o i Founda ion. This is an open-access pape . E alua ion o p ognos ic ac o s among pa ien s wi h ch onic g a - e sus -hos disease Jose A. Pé ez-Simón,1,2 Gab iel A am,3Rod igo Ma ino,4Jose L Piñana,4Te esa Caballe o-Velazquez,1,2 Olle Ringden,3 Da id Valca cel,4Dolo es Caballe o,1Ma s Rembe ge ,3Yani a de Paz,1Jo di Sie a,4Jesús San Miguel,1 and Hans Hagglund3 1Se icio de Hema ología, Hospi al Uni e si a io de Salamanca, IBSAL, IBMCC (USAL-CSIC), Salamanca; 2Hospi al Uni e si a io Vi gen del Rocío, Ins i u o de Biomedicina de Se illa (IBIS) /CSIC/Uni e sidad de Se illa; 3Ka olinska Ins i u e S ockholm; and 4Hospi al San a C eu I San Pau, Ba celona, Spain ABSTRACT ©Fe a a S o i Founda ion In oduc ion Ch onic g a - e sus-hos disease (cGVHD) is a majo complica ion ollowing allogeneic hema opoie ic s em cell ansplan a ion (HSCT) which impai s pa ien s’ quali y o li e and hampe s long- e m su i al.1His o ically, cGVHD has been classi ied as ‘limi ed’ o ‘ex ensi e’ on he basis o he esul s om a small e ospec i e s udy.2This sys- em was de eloped p ima ily o dis inguish be ween pa ien s equi ing sys emic immune supp ession om hose o whom local ca e migh su ice. Ne e heless, a majo i y o pa ien s expe ience ex ensi e s age cGVHD3 ha cons i u es an ex emely he e ogeneous popula ion. In addi ion, diagnosis o cGVHD was classically based on he p esence o any mani es a ion o GVHD beyond 100 days a e allogeneic ansplan a ion. Based on expe opinion, in 2005 he Na ional Ins i u e o Heal h (NIH) p oposed new c i e ia o he diagnosis and classi ica ion o cGVHD based on he clinical mani es a ions and no on he ime o onse .4Acco ding o his p oposal, new sub- ca ego ies we e ecognized bo h o acu e (classic aGVHD and la e-onse aGVHD) and o cGVHD (classic ch onic and o e lap synd ome). As a as he p ognos ic alue o hese ca ego ies is conce ned, ew epo ed s udies ha e analyzed he impac o delayed aGVHD on ou come,5and no s udy has e alua ed he ou come o pa ien s wi h o e - lap synd ome in a la ge se ies o pa ien s. Also, he NIH p oposed a new clinical sco ing sys em o he global assessmen o cGVHD se e i y based on he numbe o o gans in ol ed (wi h an a bi a y cu -o alue o in ol emen o mo e o less han 3 o gans o dis inguish be ween mild e sus mode a e) and he deg ee o unc ion- al impai men in he a ec ed o gans (mild, mode a e o se e e) which should allow pa ien s equi ing a pu ely opical app oach e sus sys emic immune supp ession o be iden i ied, as well as acili a ing decisions ega ding he iming and in ensi y o he apy. Ne e heless, ew s udies ha e been pe o med o alida e his sco ing sys em in a la ge se ies o pa ien s.3,6 Fu he mo e, his sco ing sys em is qui e ime-consuming which makes i di icul o sa is y all he equi emen s du ing a ou ine ou -pa ien consul a- ion.4 In his cu en s udy, we e alua ed he p ognos ic impac o he new sub-ca ego ies as well as he clinical sco ing sys em p oposed by he NIH Consensus De elopmen P ojec . We also ied o iden i y he mos impo an a iables p edic ing ou come in a se ies o 747 pa ien s unde going allogeneic s em cell ansplan a ion in 3 di e en ins i u ions in o de o build up a simpli ied sco ing sys em. Design and Me hods Pa ien s’ cha ac e is ics Eigh hund ed and wen y pa ien s unde going allogeneic s em cell ansplan a ion in 3 di e en ins i u ions om Janua y 2000 o Decembe 2006 we e included in he analysis. The analysis was es ic ed o hose 747 pa ien s su i ing mo e han 100 days a e ansplan a ion. The s udy p o ocol was app o ed by he e hics commi ee a Ka olinska Ins i u e and was pe o med in acco - dance wi h he decla a ion o Helsinki. W i en in o med consen was ob ained om all pa ien s in Salamanca and San Pau. Pa ien s we e e ospec i ely ca ego ized acco ding o he NIH sco ing sys- em based on he da a collec ed om pa ien s’ medical his o ies. The speci ied o gan in ol emen and g ading was also ca ego ized acco ding o he classical limi ed e sus ex ensi e classi ica ion. Cha ac e is ics o he pa ien s who de eloped cGVHD a e sum- ma ized in Table 1. Median age a he ime o ansplan a ion was 50 yea s. Median ollow up was 41 mon hs. The mos common diagnosis was acu e myeloid leukemia in 24% o pa ien s, acu e lymphoblas ic leukemia in 11% and myelodysplas ic synd ome in 11%. Twen y- se en pe cen o pa ien s we e in 1s o subsequen comple e emission a he ime o ansplan . Eigh y- ou pe cen ecei ed hema opoie ic s em cells om a ela ed dono and 71% ecei ed educed in ensi y condi ioning egimens. Six y pe cen o he pa ien s ecei ed cyclospo ine plus me ho exa e and 27% ecei ed in i o T-cell deple ion. The i s -line ea men o ex ensi e cGVHD was based on CsA o ac olimus plus p ednisone a 1 mg/kg/day ha was swi ched o al e na e days a e ou weeks o ea men . The disease esponse was gene ally e alua ed i e weeks a e he in oduc ion o s e oid and hen e e y h ee mon hs un il he end o ea men . All pa ien s ecei ed an ibac e ial, an i ungal and an i i al p o- phylaxis acco ding o s anda d p ocedu es. J.a. Pé ez-simón e al. 1188 haema ologica | 2012; 97(8) Table 1. Pa ien s’ cha ac e is ics. Cha ac e is ics o he pa ien s N=336 N (%) Age Median ( ange) 50 (1-69) Diagnosis (%) Acu e myeloid leukemia 81 (24) Acu e lymphoblas ic leukemia 37 (11) Ch onic myeloid leukemia 30 (9) Myelodysplas ic synd omes 37 (11) Mul iple myeloma 31 (9) Non-Hodgkin's lymphoma 37 (11) Ch onic lymphocy ic leukemia 20 (6) O he s 63 (19) Disease s a us a ansplan (%) 1s CR 91 (27) 2nd o subsequen CR 64 (19) PR 60 (18) P og essi e / elapsed disease 71 (21) O he s 50 (15) Sex (%) Male / emale (63%) / (37%) Sex misma ched 148 (44) HLA ma ched (%) 302 (90) Sou ce o p ogeni o cells (%) Pe iphe al blood 279 (83) Bone ma ow 54 (16) Co d blood 3 (1) Type o dono (%) Rela ed 282 (84) Un ela ed 54 (16) Type o condi ioning Myeloabla i e 97 (29) RIC 239 (71) GVHD p ophylaxis (%) CsA-Tac o plus MTX 202 (60) CsA-Tac o plus MMF 37 (11) T-cell deple ion 91 (27) O he s 6 (2) ©Fe a a S o i Founda ion De ini ions Acco ding o he NIH sco ing sys em, mild cGVHD was diag- nosed when only one o 2 o gans o si es (excep he lung) we e in ol ed, wi h no clinically signi ican unc ional impai men (maximum sco e 1 in all a ec ed o gans o si es). Mode a e cGVHD in ol ed a leas one o gan o si e wi h clinically signi i- can impai men bu no majo disabili y (maximum sco e 2 in any a ec ed o gan o si e), o 3 o mo e o gans o si es wi h no clini- cally signi ican unc ional impai men (maximum sco e 1 in all a ec ed o gans o si es). A lung sco e o 1 was also conside ed mode a e cGVHD. Se e e cGVHD was indica ed by a majo dis- abili y caused by cGVHD (sco e 3 in any o gan o si e). A lung sco e o 2 o o e was also conside ed ‘se e e cGVHD’.4 Pa ien s who we e ecei ing p ednisone, o who we e s ill on a he apeu ic dose o cyclospo ine due o p io aGVHD ha had e ol ed in o cGVHD wi hou he esolu ion o symp oms, we e conside ed as ha ing ‘p og essi e cGVHD’. Pa ien s who we e on cyclospo ine ape wi h a esolu ion o symp oms, o who we e ee om immunosup ession a he ime o diagnosis, we e ca ego ized ‘quiescen ’, while hose wi hou a p io his o y o aGVHD we e diagnosed wi h ‘de no o cGVHD’. O he wise, acu e and limi ed e sus ex ensi e ch onic GVHD we e g aded by es ablished c i e ia.2Assignmen o he pa ien s o he di e - en ca ego ies o he di e en classi ica ions was es ablished acco ding o he o gan in ol emen obse ed wi hin he i s mon h o cGVHD diagnosis. S a is ical analysis Mean and median alues, as well as hei 95% con idence in e - als (CI) and anges, we e calcula ed o each con inuous a iable. The χ2o Fishe ’s exac es was used o es ablish di e ences in he dis ibu ion o discon inuous a iables, whe eas S uden 's - es o Mann-Whi ney’s U es was applied o compa e con inuous a i- ables. All epo ed P alues a e wo-sided. P=0.05 was conside ed signi ican . O e all su i al was calcula ed using he Kaplan-Meie es ima e. The log ank es was used o uni a ia e compa isons. Pa ien s who su i ed mo e han 100 days we e e aluable o cGVHD. The incidences o cGVHD and i s di e en sub ypes we e calcula ed om he ime o ansplan a ion using cumula i e incidence es ima es. Non- elapse mo ali y (NRM) was de ined as “dea h due o causes un ela ed o he unde lying disease” and elapsing pa ien s we e censo ed a he ime o elapse. GVHD ela ed mo ali y (cGVHD-RM) was calcula ed om he ime o cGVHD onse un il cGVHD ela ed dea h, de ined as “dea h due o causes di ec ly ela ed o GVHD acco ding o p ima y physician c i e ia”. Mo e speci ically, among pa ien s diagnosed wi h cGVHD, hose dea hs a ibu ed o complica ions o ailu e in cGVHD- a ge o gans, as well as dea hs ela ed o immunosup es- sion such as in ec ious complica ions, in pa ien s equi ing ea - men o cGVHD we e conside ed as cGVHD ela ed mo ali ies. P og ession o he unde lying malignancy and non- elapse mo - ali y (NRM) wi hou p io cGVHD we e compe ing e en s o cGVHD. The s a ing poin (Day 0) o he landma k analysis o he incidence o cGVHD-RM and NRM was he ime o onse o cGVHD, and he compe ing e en s we e disease p og ession and dea h no ela ed o cGVHD. Pa ien s who we e s ill ali e and p o- g ession- ee a he ime o analysis we e censo ed a he las ol- low up o a i e yea s pos ansplan . Uni a ia e analyses o he a iables ha in luenced cGVHD-RM and NRM we e pe o med using p opo ional haza ds models o compe ing isks (G ay’s es ). The a iables ha showed a leas a end in uni a ia e analysis (P<0.1) we e used in a mul i a ia e Cox’s p opo ional haza ds eg ession analysis, checking o he assump ion o p o- po ional haza ds o e ime o each es ed a iable. To analyze he incidences and p obabili ies o la e ou comes, and de e mine hei isk ac o s in pa ien s who de eloped cGVHD, we pe o med a landma k analysis including only pa ien s who de eloped cGVHD. Fo he analysis o la e ou - comes, he s a ing poin o ollow up was he day o onse o cGVHD and no he day o ansplan . The me hods used o gen- e a ing landma k cumula i e incidence es ima es, su i al p oba- bili ies, and uni a ia e and mul i a ia e landma k analyses we e iden ical o hose p e iously desc ibed, bu o cou se using he cGVHD landma k da abase. O e all su i al (OS) was calcula ed om ansplan un il dea h om any cause, and su i ing pa ien s we e censo ed a he las ollow up. In addi ion, o e all su i al om cGVHD onse (OS- cGVHD) was also calcula ed om he ime o cGVHD diagnosis un il dea h om any cause. All ac o s ha signi ican ly o ma ginally (P<0.1) in luenced he incidence o ou come o cGVHD in he uni a ia e analysis we e included in a mul i a ia e analysis using a o wa d s ep Cox’s eg ession model. The s a is ical analyses we e pe o med using SPSS e sion 18.0 (SPSS, Chicago, IL, USA), wi h he excep ion o he cumula i e incidence plo s which we e ca ied ou wi h NCSS 2004 (Numbe C unche S a is ical Sys em, Kays ille, UT, USA) and he uni a ia e G ay’s es which was ca ied ou using he Cmp sk package R so wa e (The R Founda ion, Vienna, Aus ia). Resul s Incidence and cha ac e is ics o g a - e sus-hos disease Fi s o all, we con i med ha esul s we e simila among he 3 cen e s in e ms o su i al (53%, 52% and 49% a i e yea s, espec i ely) and NRM (26%, 21% and 30% a i e yea s, espec i ely). The cumula i e incidence o cGVHD was 48%. Respec i e alues we e 26% and 22% o limi ed and ex ensi e cGVHD, and 14%, 22% and 17% o mild, mode a e and se e e cGVHD, espec- i ely. Fou een pe cen o pa ien s de eloped o e lap syn- d ome while 13% de eloped delayed aGVHD. Ou o 54 cases o delayed aGVHD, 12 achie ed comple e emission a e i s -line ea men , one p og essed and died while he emaining pa ien s ei he p og essed o cGVHD o had ecu en delayed aGVHD. Cumula i e incidences o de no o, quiescen and p o- g essi e cGVHD we e 18%, 22% and 8%, espec i ely. As a as o gan in ol emen a ime o onse is conce ned (Table 2), he mos commonly in ol ed o gan was o al mucosa in 65% o pa ien s ollowed by li e in 56% and skin in 55% o pa ien s. A he ime o cGVHD diagnosis, 36% had a pe o mance sco e o 0 acco ding o he ECOG scale and 44% had ECOG 1. Finally, 51% o pa ien s had in ol emen o 3 o mo e o gans. As a as he cha ac e is ics o cGVHD among pa ien s wi h classic e sus o e lap cGVHD is conce ned (Table 3), a signi ican ly highe pe cen age o pa ien s wi h o e lap synd ome had a p og essi e ype o onse . In ac , a high co ela ion was ound be ween o e lap synd ome and p og essi e onse ( =0.44, P<0.001). Finally, conside ing NIH c i e ia, a highe numbe o pa ien s displayed ea- u es o se e e cGVHD among hose wi h o e lap syn- d ome compa ed o hose wi h classic cGVHD. P ognos ic ac o s o cGVHD- ela ed mo ali y Causes o NRM included cGVHD-RM in 21 pa ien s, ungal in ec ion in 10, i al in 3, espi a o y ailu e in 3, P ognos ic ac o s in cGVHD haema ologica | 2012; 97(8) 1189 ©Fe a a S o i Founda ion b ain hemo hage in 2, TTP in one and hea ailu e in one. As p e iously speci ied, in addi ion o dea hs due o caus- es di ec ly a ibu ed o complica ions o ailu e in cGVHD a ge o gans, dea hs ela ed o immunosup ession such as in ec ious complica ions we e also conside ed cGVHD ela ed mo ali ies. Va iables ha signi ican ly in luenced cGVHD-RM a e summa ized in Table 4. Type o onse , limi ed e sus ex ensi e cGVHD, as well as NIH sco e sys- em signi ican ly in luenced cGVHD-RM. Among a i- ables included in he NIH sco e, skin, gu , li e and lung in ol emen had he highes impac on mo ali y oge he wi h pe o mance s a us. As a as he numbe o o gans in ol ed is conce ned, bo h a cu -o alue o 3 and 4 sig- ni ican ly a ec ed he ou come, bu he cu -o alue o 1- 3 e sus 4 o mo e o gans in ol ed had a be e p edic i e alue. Thus, cGVHD-RM was 8% e sus 18% o pa ien s wi h 1-2 e sus 3 o mo e o gans in ol ed (P=0.04) while hese igu es we e 9% e sus 24% o pa ien s wi h 1-3 e sus 4 o mo e o gans in ol ed (P=0.01). Also, pla ele coun a he ime o cGVHD diagnosis signi ican ly in lu- enced cGVHD-RM o a cu -o alue o 100¥109/L. Finally, pa ien s wi h o e lap synd ome had a signi ican ly highe mo ali y compa ed o hose wi hou (23% s. 8% cGVHD-RM o pa ien s wi h and wi hou o e lap syn- d ome, espec i ely; P=0.01). In mul i a ia e analysis, he de elopmen o se e e cGVHD acco ding o NIH signi i- can ly in luenced ou come (HR=4.4 (95% CI: 1.3-14.6), P=0.01). When he a iables included in he NIH sco e sys em we e en e ed in he mul i a ia e analysis, pe o m- ance s a us a he ime o cGVHD diagnosis [HR=7.9 (3.4- 19), P<0.001] and pla ele coun [HR=5.1 (1.9-14), P=0.01], oge he wi h se e e gu in ol emen [HR=6.2 (1.8-22), P=0.01] signi ican ly in luenced mo ali y (Figu e 1). Based on hese indings, a new a iable was de eloped wi h a sco e o 0 o 1 o pla ele s o e o below 100¥109/L plus sco e 0, 1 o 2 o ECOG 0, 1 o 2 o o e . A sco e o 3 was gi en o se e e gu in ol emen i espec i e o pla ele s and ECOG. This a iable allowed di e en subg oups o pa ien s o be di e en ia ed in e ms o cGVHD ela ed mo ali y (Figu e 2). Fu he mo e, when his a iable was included in mul i a ia e analysis i had a highe impac on ou come (sco e 2: HR=6.9 (95% CI: 2-24), P=0.002; sco e 3: HR=26.3 (95% CI 7.4-93) P<0.001 o sco e 3. In ac , he same pa ien s wi h he poo es ou come (sco e 3) could be iden i ied by jus combining ECOG plus pla ele s. P ognos ic ac o s o OS-cGVHD The cu -o alue o 1-2 e sus 3 o mo e o gans in ol ed did no signi ican ly a ec su i al while he cu -o alue o 4 e ained a signi ican in luence in uni a ia e analysis (Figu e 3). Conce ning OS-cGVHD (Table 5), he same a iables a ec ing cGVHD-RM signi ican ly a ec ed he ou come (Figu e 4). In addi ion, delayed acu e GVHD did no in luence su i al while pa ien s wi h o e lap syn- d ome displayed a poo e su i al as compa ed o hose wi h classic cGVHD (Figu e 3). In mul i a ia e analysis, again NIH classi ica ion signi ican ly a ec ed su i al (HR=2.48 (95% CI: 1.38-4.45), P=0.002) o hose pa ien s J.a. Pé ez-simón e al. 1190 haema ologica | 2012; 97(8) Table 2. Ch onic GVHD o gan in ol emen . Cha ac e is ics N=336 (%) Pe o mance s a us sco e ECOG 0 71 (36) ECOG 1 85 (44) ECOG ≥ 2 40 (20) O al mucosa No 104 (35) Mild 100 (33) Mode a e 92 (31) Se e e 3 (1) Li e No 133 (44) Mild 66 (22) Mode a e 65 (22) Se e e 35 (12) Skin No 140 (45) Mild 69 (22) Mode a e 50 (16) Se e e 51 (17) Ocula in ol emen No 214 (71.5) Mild 39 (13) Mode a e 44 (15) Se e e 2 (0.5) Gas oin es inal ac in ol emen No 220 (74) Mild 40 (13) Mode a e 35 (12) Se e e 4 (1) Lung No 244 (82) Mild 26 (9) Mode a e 21 (7) Se e e 7 (2) Musculoskele al in ol emen No 288 (96) Mild 3 (1) Mode a e 8 (3) Se e e N. o o gans in ol ed 1 o 2 145 (49) 3 o 4 122 (41) 5 o mo e 30 (10) Table 3. Cha ac e is ics o cGVHD among pa ien s wi h classic e sus o e lap synd ome. Cha ac e is ics Classic O e lap P cGVHD synd ome N=336 N=227 N=61 Type o onse (%) 0.001 De no o 46.5 14 Quiescen 46 39 P og essi e 7.5* 46 N. o o gans in ol ed a onse (%) 0.19 1 o 2 49 55 3 o mo e 5 45 Limi ed / ex ensi e cGVHD (%) 0.087 Limi ed 58 57 Ex ensi e 42 43 NIH sco e (%) 0.11 Mild 33 36 Mode a e 36 28 Se e e 31 36 Pla ele coun (%) 0.2 Mean x 109/L (SD) 79 (112) 104 (85) ©Fe a a S o i Founda ion wi h ea u es o mild o mode a e e sus se e e cGVHD. In o de o analyze which a iables had an impac on su - i al wi hin hose included in he NIH sco e, we included he di e en o gans in ol ed in mul i a ia e analysis. Acco ding o his, ECOG (ECOG 1: HR=2.08 (1.11-3.87), P<0.001; ECOG 2 o mo e: HR=4.1 (2.14-7.83), P=0.005) and a pla ele coun less han 100¥109/L (HR=2.75 (1.71- 4.42), P<0.001) a he ime o cGVHD diagnosis, oge he wi h gu in ol emen (HR=24.06 (4.21-137.4), P<0.001) signi ican ly a ec ed ou come. Va iables wi h a close co - ela ion o pe o mance s a us we e skin ( =0.16, P=0.012), gu ( =0.25, P<0.001) and lung in ol emen ( =0.29, P<0.001). Finally, we combined ECOG, pla ele s and gas oin es i- nal in ol a iable allowed 4 subg oups o pa ien s o be clea ly iden i ied in e ms o ou come (Figu e 5); o e all su i al was 84% o pa ien s wi h a combined sco e o 0 (n=74), 64% o pa ien s wi h a combined sco e o 1 (n=93), 43% o pa ien s wi h a combined sco e o 2 (n=58) and 0% o pa ien s wi h a combined sco e o 3 o mo e (n=17). Fu he mo e, in mul i a iable in ol emen using he p e iously men ioned sco e sys em and again he new a iable analysis, he a iable ob ained had he highes impac on su i al (sco e 0: HR=15.96 (95% CI: 6.85-37.17), P<0.001; sco e 1: HR=5.47 (95% CI: 2.6-11.5), P<0.001; sco e 2: HR=2.8 (95% CI: 1.32-5.93), P=0.007). As o ansplan ela ed mo ali y, he combina ion o ECOG plus pla ele s also iden i ied he same subg oup o pa ien s wi h he wo s ou come (sco e 3). Fu he mo e, he combined a iable ECOG plus pla ele s also iden i ied di e en subg oups o pa ien s in e ms o su i al wi hin he di e en NIH ca ego ies. The e o e, o pa ien s wi h mild cGVHD, he combined a iable iden i ied pa ien s wi h 90%, 61%, 57% and 25% OS (P<0.001); he co e- sponding alues o pa ien s wi h mode a e cGVHD we e 93%, 65%, 44% and 0% OS (P=0.001), and he espec i e alues o se e e cGVHD we e 66%, 58%, 38% and 0% OS (P<0.001), espec i ely. Discussion Ch onic GVHD (cGVHD) is he majo cause o mo bid- i y and mo ali y in long- e m su i o s a e allogeneic s em cell ansplan a ion (allo HSCT). Howe e , cGVHD is also co ela ed wi h a s ong g a - e sus-malignancy e ec , as p e iously epo ed in di e en hema ologic malignancies.7-9 This complica ed ela ionship be ween inc eased isk o non- elapse mo ali y and dec eased isk o elapse highligh s he impo ance o de ining he g oup Table 4. Uni a ia e and mul i a ia e analysis o cGVHD ela ed mo ali y. Cha ac e is ics cGVHD ela ed P HR (95% CI) P mo ali y* uni a ia e mul i a ia e N=336 Type o onse (%)a<0.001 De no o 4 Quiescen 15 P og essi e 29 O e lap synd ome 0.01 No 8 Yes 23 Limi ed / ex ensi e cGVHD (%) <0.001 Limi ed 4 Ex ensi e 22 NIH sco e (%)b<0.001 0.01 Mild 4 Mode a e 9 Se e e 28 4.4 (1.3-14.6) O gan in ol emen (%) Skin 0/1/2/3 5/16/17/27 0.01 Gu 0/1/2/3c7/11/39/75 0.001 6.2 (1.8-22) 0.01 Li e 0/1/2/3 9/10/19/21 0.007 Lung 0/1/2/3 10/15/27/30 0.04 Pe o mance s a us 4/12/38 < 0.001 7.9 (3.4-19) < 0.001 0 / 1 / ≥ 2d N. o o gans in ol ed a onse (%) 0.01 1 o 3 9 4 o mo e 24 Pla ele coun (x109/L) < 100 35 0.001 5.1 (1.9-14) 0.01 ≥ 100 10 *Landma k analysis om cGVHD onse o dea h. asigni ican di e ences o he compa ison be ween de no o o quiescen e sus p og essi e ype o onse ; bsigni ican di e ences o he compa ison be ween mild o mode a e e sus se e e NIH scale; csigni ican di e ences o he compa ison be ween 0 and 1 e sus 2 e sus 3 in uni a ia e analysis and HR shown o 0, 1 o 2 e sus 3 in mul i a ia e analysis; dsigni ican di e ences o he compa ison o 0 e sus 1 e sus 2 and HR shown o 0 o 1 e sus 2 in mul i a ia e analysis. Table 5. Uni a ia e and mul i a ia e analysis o OS-cGVHD. Cha ac e is ics O e all su i al P HR (95% CI) P 5 yea s a e uni a ia e mul i a ia e N=336 cGVHD onse Type o onse (%)a0.025 De no o 66 Quiescen 57 P og essi e 50 O e lap synd ome 0.02 No 68 Yes 52 Limi ed / ex ensi e 0.008 cGVHD (%) Limi ed 70 Ex ensi e 57 NIH sco e (%)b0.001 Mild 68 Mode a e 66 2.48 (1.38-4.45) 0.002 Se e e 48 O gan in ol emen (%) Skin 0/1/2/3 74/60/52/48 0.003 Gu 0/1/2/3c67/65/33/0 <0.001 29.48 (4.9-175) <0.001 Li e 0/1/2/3 67/64/64/19 0.051 Lung 0/1/2/3 64/59/55/19 0.026 Pe o mance 79/61/33 <0.001 4.1 (2.14-7.83) P =0.005 s a us 0 / 1 / ≥ 2d N. o o gans in ol ed a onse (%) 0.035 1 o 3 65 4 o mo e 54 Pla ele coun (¥109/L) <0.001 < 100 36 ≥ 100 69 2.75 (1.71-4.42) <0.001 aSigni ican di e ences o he compa ison be ween de no o e sus quiescen o p og essi e ype o onse ; bsigni ican di e ences o he compa ison be ween mild o mode a e e sus se e e NIH scale; csigni ican di e ences o he compa ison be ween 0 and 1 e sus 2 e sus 3 in uni a ia e analysis and HR shown o 0, 1 o 2 e sus 3 in mul i a ia e analysis; dsigni ican di e ences o he compa ison o 0 e sus 1 e sus 2 and HR shown o 0 o 1 e sus 2 in mul- i a ia e analysis. P ognos ic ac o s in cGVHD haema ologica | 2012; 97(8) 1191 ©Fe a a S o i Founda ion o pa ien s who may bene i om sys emic immune-sup- p ession e sus hose who may jus equi e opical o local ea men . The i s classi ica ion o cGVHD in o limi ed o ex en- si e o ms was based on 20 pa ien s and was aimed a sep- a a ing pa ien s who needed sys emic a he han local o opical he apy.2Un o una ely, mos pa ien s a e inally ca ego ized as ha ing ex ensi e cGVHD, especially among hose ecei ing pe iphe al blood p ogeni o cells.10 In 2005, he NIH published consensus c i e ia o diagno- sis o cGVHD ha es ablish he diagnosis o acu e o ch onic GVHD on he basis o he clinical mani es a ions and no he ime o onse .4Fu he mo e, he NIH es ab- lished a sco ing sys em in an a emp o iden i y hose pa ien s who may equi e sys emic ea men o hose who may bene i om opical ea men only. Al hough his classi ica ion has been e alua ed in se e al s ud- ies,3,5,6,11 i s p ognos ic alue has no been e alua ed in a mul icen e s udy in a la ge se ies o pa ien s. Fu he mo e, ew s udies ha e e alua ed he p ognos ic alue o he new en i ies, delayed acu e and o e lap syn- d ome, p oposed by he NIH wi h con adic o y esul s.3,6,12 The e o e, we aimed o e alua e he p ognos ic alue o he published NIH consensus c i e ia on cGVHD, ocusing on de eloping a simple sco ing sys em, and e alua ion o he p ognos ic alue o he new en i ies p oposed by he NIH. The incidence o cGVHD in his s udy was 48% which is in line wi h p e ious epo s, al hough he epo ed inci- dence a ies be ween 6% and 80%.1,10,13,14 The easons o his dispa i y a e mul i- ac o ial and include diagnosis, ype o dono ,15 condi ioning egimen, GVHD p ophylax- is,7s em cell sou ce,14 g a manipula ion,16 use o dono leukocy e in usion (DLI),17 e c. In addi ion, he lack o s anda dized diagnos ic c i e ia is also likely o be an impo an eason o his he e ogenei y in he incidence o cGVHD. Ou e ospec i e s udy included pa ien s om 3 di e - J.a. Pé ez-simón e al. 1192 haema ologica | 2012; 97(8) Figu e 1. Landma k plo s illus a ing he impac o (A) he NIH se e i y sco e; (B) he ECOG ≥ 2, 1 and 0 pe - o mance s a us; (C) he pla ele coun <100 and >100x109/L; and (D) he se e i y o gu in ol emen on he incidence o cGVHD- ela ed mo ali y. Figu e 2. Landma k plo illus a ing he impac o he new compos- i e a iable on he incidence o cGVHD- ela ed mo ali y. The com- posi e a iable has a alue o 0 o 3 based on he sum o pla ele coun < 100x109/L (1 poin ) and he ECOG pe o mance s a us (0, 1 o 2 poin s o ECOG o 0, 1 o ≥2). In addi ion, pa ien s wi h se e e gu in ol emen we e assigned 3 poin s i espec i e o pla ele s and ECOG. AB D C Se e e Mode a e Mild ECOG ≥2 ECOG 1 ECOG 0 Gu sco e 3 Gu sco e 2 Gu sco e 1 Gu sco e 0 Pla ele s > 100x109/L Pla ele s < 100x109/L cGVHD- ela ed mo ali y cGVHD- ela ed mo ali y cGVHD- ela ed mo ali y 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 0123 456 78 910 01 234 5 67 8 910 Yea s a e cGVHD onse 01 2345678910 Yea s a e cGVHD onse 012345678910 Yea s a e cGVHD onse 70% 26% 10% 3% 012 34 5678910 ©Fe a a S o i Founda ion en Eu opean cen e s. Medical eco ds o 336 pa ien s who de eloped cGVHD we e e alua ed and o gan in ol emen was ca ego ized acco ding o NIH c i e ia i he medical eco ds con ained documen a ion showing unequi ocal mani es a ions. T ansplan ela ed mo ali y and o e all su i al was simila o all 3 cen e s indica ing a homoge- neous s udy popula ion. As a as he new sub-ca ego ies p oposed by he NIH a e conce ned, we can con i m ha delayed acu e cGVHD has no ad e se e ec on ou come. This is in ag eemen wi h conclusions o Vigo i o e al.5In addi ion o hese da a, in he cu en s udy we we e able o e alua e he ou come o delayed aGVHD and obse ed ha a signi i- can p opo ion o pa ien s subsequen ly de eloped ecu - en delayed acu e o ch onic GVHD. These da a would sugges ha , in e ms o immune supp essi e ea men , hese pa ien s should be ini ially managed as aGVHD bu ea men should be main ained o a longe pe iod o ime. Con a y o delayed aGVHD, o e lap synd ome is an P ognos ic ac o s in cGVHD haema ologica | 2012; 97(8) 1193 Figu e 3. (A) O e all su i al om cGVHD diagnosis o pa ien s wi h 1-3 e sus ≥ 4 o gans in ol ed (B) o pa ien s wi h classic cGVHD e sus o e lap synd ome and (C) o pa ien s wi h delayed aGVHD e sus classic cGVHD. Figu e 4. (A) O e all su i al om cGVHD diagnosis o pa ien s wi h mild, mode a e o se e e cGVHD (B) o pa ien s wi h ECOG 0, 1 and ≥ 2 (C) o pa ien s wi h pla ele s <100 and >100x109/L and (D) o pa ien s wi h gu sco e 3, 2, 1 and 0. AB B A D C C 012345678 Yea s a e cGVHD onse 01 23 4567 8 01 23 4567 8 Yea s a e cGVHD onse 01 23 4567 8 Yea s a e cGVHD onse 01 23 4567 8 1-3 o gans in ol ed ≥ 4 o gans in ol ed Mild Mode a e Se e e Pla ele > 100x109/L Pla ele < 100x109/L Gu sco e 0 Gu sco e 1 Gu sco e 2 Gu sco e 3 O e all su i al ECOG 0 ECOG 1 ECOG ≥ 2 Classic cGVHD O e lap synd ome Delayed acu e Classic cGVHD 012345678 Yea s a e cGVHD onse 012345678 Yea s a e cGVHD onse 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 O e all su i al ©Fe a a S o i Founda ion ad e se p ognos ic ac o . This inding has been epo ed p e iously.11 I is wo h men ioning ha a high pe cen age o pa ien s ca ego ized as ha ing o e lap synd ome had a p og essi e ype o onse so ha bo h a iables we e high- ly co ela ed. In his e ospec i e analysis, we ca e ully ied o di e en ia e be ween pa ien s who had signs o symp oms o aGVHD ha we e esol ing a he momen in which he signs o symp oms o cGVHD appea ed, i.e. classic cGVHD wi h p og essi e ype o onse om hose who de eloped bo h ac i e signs o symp oms o acu e and ch onic GVD, i.e. ue o e lap synd ome. Ne e heless, hese da a mus be con i med in p ospec i e s udies. We con i med ha NIH c i e ia a e he mos impo an a iables in p edic ing ou come in mul i a ia e analysis. Ne e heless, only se e e o ms can be clea ly di e en ia - ed in e ms o ou come while mild and mode a e disease had a he simila ou comes. Among hose a iables included in he NIH, pe o mance s a us acco ding o ECOG sco e and pla ele coun s a he ime o cGVHD had he highes impac on ou come, bo h in e ms o cGVHD-RM and su i al. In addi ion, gas oin es inal in ol emen signi ican ly in luenced ou come in mul i- a ia e analysis while skin, li e and lung in ol emen also a ec ed ou come in uni a ia e analysis. By con as mou h, eyes and musculoskele al in ol emen did no in luence ou come. In ac , skin, li e and lung in ol e- men had a high co ela ion wi h ECOG and, acco dingly, a e esponsible o he pe o mance sco e o he pa ien s a he ime o cGVHD. Acco ding o hese da a we c ea ed a new sco e sys em which, in ac , was much mo e powe ul han NIH in p edic ing ou come and a easie o pe o m. Thus, g ea e ECOG sco e in combina ion wi h a low pla ele coun oge he wi h se e e gas oin es inal in ol emen a e s ong p ognos ic ac o s o cGVHD-RM and OS. In e es ingly, he simple combina ion o ECOG plus pla ele coun allowed us o disc imina e he same sub- g oups o pa ien s sugges ing ha his combina ion has p ognos ic impac and could be applied i espec i e o he o gans in ol ed. La ge s udies wi h a highe numbe o pa ien s wi h se e e in ol emen o skin, li e o lung a e equi ed o con i m hese da a and also o con i m he p ognos ic alue o his sco e wi hin he di e en NIH subg oups. In e es ingly, Lee S e al.18 epo ed ha Ka no sky pe o mance sco e, dia hea, weigh loss, and cu aneous and o al in ol emen a e independen p og- nos ic ac o s among pa ien s wi h cGVHD. While we did no ind cu aneous o o al in ol emen o be inde- penden p ognos ic ac o s, he p ognos ic alue o pe - o mance sco e and gas oin es inal in ol emen (mani- es ed as dia hea and/o weigh loss) a e con i med in he cu en s udy. By con as , we also ound pla ele coun o be an independen p ognos ic ac o , simila o he s udy by Akpek e al.19 which desc ibed ex ensi e skin in ol emen , p og essi e ype o onse and h ombocy- openia as independen p ognos ic ac o s. While we also ound hese a iables o ha e a p ognos ic alue in uni- a ia e analysis, only h ombocy openia was con i med in mul i a ia e analysis. In a ecen la ge e ospec i e s udy, A o a e al.20 de eloped a new sco e sys em among pa ien s wi h cGVHD which, simila o he cu en s udy, also iden i ies pla ele coun and pe o mance s a us as he mos impo an p ognos ic ac o s a he ime o cGVHD diagnosis. In con as o he cu en manusc ip , hei s udy is based on egis y da a so ha no speci ic analysis can be p o ided ega ding ei he he impac o o gan in ol emen o he NIH classi ica ion on ou come. By con as , A ai e al.21 ha e ecen ly epo ed a p ospec- i e s udy which con i ms he impac o he NIH classi i- ca ion on ou come. In e es ingly, he pe cen age o pa ien s diagnosed wi h mild cGVHD is much lowe han he cu en s udy al hough, as discussed by he au ho s, he equi emen o sys emic ea men in o de o en oll he pa ien s in he coho could be a eason why he inci- dence o cGVHD was unde es ima ed. I is wo h men- ioning he simila i ies in e ms o cGVHD ela ed mo - ali y in he di e en NIH subg oups in bo h s udies. By con as , he su i al epo ed by A ai e al. is be e o he di e en NIH subg oups han he cu en s udy. Median ollow up in hei se ies is 18 mon hs while he cu en se ies o pa ien s we e ansplan ed be ween 2000 and 2006; his could a leas in pa jus i y he di - e ence. In e es ingly, NIH p oposed a cu o o in ol emen o 3 o gans in o de o dis inguish mild om mode a e cGVHD4so ha , acco ding o his classi ica ion, sys emic immune supp ession is ecommended o pa ien s wi h in ol emen o 3 o gans. Since ou s is a e ospec i e s udy, we canno d aw any conclusions abou he bes ea men o pa ien s wi h in ol emen o 3 o gans bu , acco ding o ou da a, hese pa ien s had a simila su i al o hose wi h 1-2 o gans in ol ed and a signi ican ly be - e su i al han hose wi h 4 o mo e o gans in ol ed. Thus, u he s udies will be equi ed o con i m he bes cu o o sys emic ea men . In conclusion, we ha e iden i ied a simple p ognos ic ool ha does no ake oo long o iden i y di e en sub- g oups o pa ien s in e ms o cGVHD-RM and su i al. Rega ding he new en i ies p oposed by NIH, delayed acu e GVHD did no in luence ou come while o e lap synd ome did. Finally, in ol emen o 4 o mo e o gans wi h mode a e sco es acco ding o NIH c i e ia is equi ed be o e sys emic immune supp ession should be s a ed. J.a. Pé ez-simón e al. 1194 haema ologica | 2012; 97(8) Figu e 5. O e all su i al om cGVHD diagnosis depending on he a iable which esul ed om combining ECOG, pla ele s and gas- oin es inal in ol emen . The ou g aphs show o e all su i al o pa ien s wi h a sco e o 0 (84%), 1 (64%), 2 (43%) and ≥3 (0%). 01 2 3 4 5 678 Yea s a e cGVHD onse P<0.001 84% 64% 43% 0% O e all su i al 1.0 0.8 0.6 0.4 0.2 0.0 ©Fe a a S o i Founda ion Au ho ship and Disclosu es The in o ma ion p o ided by he au ho s abou con ibu ions om pe sons lis ed as au ho s and in acknowledgmen s is a ailable wi h he ull ex o his pape a www.haema ologica.o g. Financial and o he disclosu es p o ided by he au ho s using he ICMJE (www.icmje.o g) Uni o m Fo ma o Disclosu e o Compe ing In e es s a e also a ailable a www.haema ologica.o g. P ognos ic ac o s in cGVHD haema ologica | 2012; 97(8) 1195 Re e ences 1. Lee S. New app oaches o p e en ing and ea ing ch onic g a - e sus-hos disease. Blood. 2005;105(11):4200-6. 2. Shulman HM, Sulli an KM, Weiden PL, McDonald GB, S ike GE, Sale GE. e al. Ch onic-g a - e sus-hos synd ome in man: a long- e m clinicopa hologic s udy o 20 Sea le pa ien s. Am J Med. 1980;69(2):204- 17. 3. Pé ez Simòn JA, Ecinas C, Sil a F, A cos MJ, Díez-Campelo M, Sánchez-Guijo FM, e al. P ognos ic Fac o s o Ch onic G a - e sus- Hos Disease Following Allogeneic Pe iphe al Blood S em Cell T ansplan a ion: The Na ional Ins i u es Heal h Scale Plus he Type o Onse Can P edic Su i al Ra es and he Du a ion o Immunosupp essi e The apy. Biol Blood Ma ow T ansplan . 2008;14(10): 1163-71. 4. Filipo ich AH, Weisdo D, Pa le ic S, Socie G, Winga d JR, Lee SJ, e al. Na ional Ins i u es o Heal h Consensus De elopmen p ojec on C i e ia o Clinical T ials in Ch onic G a - e sus-Hos Disease: I. Diagnosis and S aging Wo king G oup Repo . Biol Blood Ma ow T ansplan . 2005; 11(12):945-56. 5. Vigo i o AC, Camp eghe PV, S o e BE, Ca pen e PA, Mo a ec CK, Kiem HP, e al. E alua ion o NIH consensus c i e ia o clas- si ica ion o la e acu e and ch onic GVHD. Blood. 2009;114(3):702-8. 6. Cho B-S, Min CK, Eom K-S , Kim YJ, Kim HJ, Lee S, e al. Feasibili y o NIH consensus c i- e ia o ch onic g a - e sus-hos disease. Leukemia. 2009;23(1):78-84. 7. Aschan J, Ringdén O, Sundbe g B, Gah on G, Ljungman P, Winia ski J. Me ho exa e combined wi h cyclospo in A dec eases g a - e sus-hos disease, bu inc eases leukemic elapse compa ed o mono he apy. Bone Ma ow T ansplan a ion. 1991;7(2): 113-9. 8. Weiden PL, Sulli an KM, Fluo noy N, S o b R, Thomas ED. An ileukemic e ec o ch on- ic g a - e sus-hos disease: con ibu ion o imp o ed su i al a e allogeneic ma ow ansplan a ion. N Engl J Med. 1981;304(25): 1529-33. 9. Ho owi z MM, Gale RP, Sondel PM, Goldman JM, Ke sey J, Kolb HJ, e al. G a - e sus-leukemia eac ions a e bone ma ow ansplan a ion. Blood. 1990;75(3):555-62. 10. Ca lens S, Ringdén O, Rembe ge M, Lönnq is B, Hägglund H, Klaesson S, e al. Risk ac o s o ch onic g a - e sus-hos dis- ease a e bone ma ow ansplan a ion: a e - ospec i e single cen e analysis. Bone Ma ow T ansplan . 1998;22(8):755-61. 11. A o a M, Naga aj S, Wi e J, DeFo TE, MacMillan M, Bu ns LJ, e al. New classi ica- ion o ch onic GVHD: added cla i y om he consensus diagnoses. Bone Ma ow T ansplan . 2009;43(2):149-53. 12. Jagasia M, Giglia J, Chin a analab W, Dixon S, Chen H, F angoul H, e al. Incidence and Ou come o Ch onic G a - e sus-hos Disease using Na ional Ins i u es o Heal h Consensus C i e ia. Biol Blood Ma ow T ansplan . 2007;13(10):1207-15. 13. Ra ana ha a ho n V, Ayash L, Laza us HM, Fu J, Ube i JP. Ch onic g a - e sus-hos dis- ease: clinical mani es a ion and he apy. Bone Ma ow T ansplan . 2001;28(2):121-9. 14. Eapen M, Logan BR, Con e DL, Haagenson M, Wagne JE, Weisdo DJ, e al. Pe iphe al Blood g a s om un ela ed dono s a e asso- cia ed wi h inc eased acu e and ch onic g a - e sus-hos disease wi hou imp o ed su - i al. Biol Blood Ma ow T ansplan . 2007; 13(12):1461-8. 15. Rembe ge M, Beleen DW, Fause A, Basa a N, Basu O, Ringdén O. Inc eased isk o ex ensi e ch onic g a - e sus-hos disease a e allogeneic pe iphe al blood s em cell ansplan a ion using un ela ed dono s. Blood. 2005;105(2):548-51. 16. A kinson K, Ho owi z MM, Gale RP, an Bekkum DW, Gluckman E, Good RA, e al. Risk ac o s o ch onic g a - e sus-hos dis- ease a e HLA-iden ical sibling bone ma - ow ansplan a ion. Blood. 1990;75(12): 2459-64. 17. Ringdén O, Paulin T, Lönnq is B, Nilsson B. An analysis o ac o s p edisposing o ch on- ic g a - e sus-hos disease. Exp Hema ol. 1985;13(10):1062-7. 18. Lee SJ, Klein JP, Ba e AJ , Ringden O, An in JH, Cahn JY, e al. Se e i y o ch onic g a - e sus-hos disease: associa ion wi h ea - men - ela ed mo ali y and elapse. Blood. 2002;100(2):406-14. 19. Akpek G, Zahu ak ML, Pian adosi S, Ma golis J, Dohe y J, Da idson R, e al. De elopmen o a p ognos ic model o g ad- ing ch onic g a - e sus-hos disease. Blood. 2001;97(5):1219-26. 20. A o a M, Klein JP, Weisdo DJ, Hasseb oek A, Flowe s ME, Cu le CS, e al. Ch onic GVHD isk sco e: a Cen e o In e na ional Blood and Ma ow T ansplan Resea ch analysis. Blood. 2011;117(24):6714-20. 21. A ai S, Jagasia M, S o e B, Chai X, Pidala J, Cu le CS, e al. Global and o gan-speci ic ch onic g a - e sus-hos disease se e i y acco ding o he 2005 NIH consensus C i e ia. Blood. 2011;118(15):4242-9. ©Fe a a S o i Founda ion