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
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