1314
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Cance Medicine. 2021;10:1314–1326.
wileyonlinelib a y.com/jou nal/cam4
Recei ed: 28 Ap il 2020
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Re ised: 30 No embe 2020
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Accep ed: 24 Decembe 2020
DOI: 10.1002/cam4.3730
ORIGINAL RESEARCH
R-COMP e sus R-CHOP as i s -line he apy o di use la ge
B-cell lymphoma in pa ien s ≥60yea s: Resul s o a andomized
phase 2 s udy om he Spanish GELTAMO g oup
Juan-ManuelSancho1
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RubénFe nández-Al a ez2
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F anciscoGual-Capllonch3
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Es he González-Ga cía2
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Ca losG ande4
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No maGu ié ez5
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Ma ía-JesúsPeña ubia6
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AnaBa lle-López7
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E aGonzález-Ba ca8
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José-Ma íaGuinea9
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E aGimeno10
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F ancisco-Ja ie Peñal e 11
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MiguelFue es12
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Ma ianaBas os13
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José-
ÁngelHe nández-Ri as14
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José-Ma íaMo aleda15
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OlgaGa cía1
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Ma cSo igué1
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Alejand oMa in5
1Hema ology Depa men , ICO-IJC-Hospi al Ge mans T ias i Pujol, Badalona, Spain
2Hema ology Depa men , Hospi al de Cabueñes, Gijón, Spain
3Ca diology Depa men o Hospi al Ge mans T ias i Pujol, Badalona, Spain
4Hema ology Depa men , Hospi al Doce de Oc ub e, Mad id, Spain
5Hema ology Depa men , Hospi al Uni e si a io de Salamanca, IBSAL, CIBERONC, Salamanca, Spain
6Hema ology Depa men , Hospi al Clínico de Valladolid, Valladolid, Spain
7Hema ology Depa men , Hospi al Ma qués de Valdecilla, San ande , Spain
8Hema ology Depa men , ICO-Hospi al Du án i Reynals (Hospi ale de Llob ega , Ba celona, Spain
9Hema ology Depa men , Hospi al Uni e si a io de A aba, Vi o ia, Spain
10Hema ology Depa men , Hospi al del Ma , Ba celona, Spain
11Hema ology Depa men , Hospi al Uni e si a io Fundación de Alco cón, Mad id, Spain
12Hema ology Depa men , Hospi al Clínico Lozano Blesa, Za agoza, Spain
13Hema ology Depa men , Hospi al G ego io Ma añón, Mad id, Spain
14Hema ology Depa men , Hospi al Uni e si a io In an a Leono , Mad id, Spain
15Hema ology Depa men , Hospi al Vi gen de la A ixaca, Mu cia, Spain
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion and ep oduc ion in any medium, p o ided he o iginal
wo k is p ope ly ci ed.
© 2021 The Au ho s. Cance Medicine published by John Wiley & Sons L d.
Co espondence
D Juan-Manuel Sancho, Hema ology
Depa men , ICO-IJC-Hospi al Ge mans
T ias i Pujol, Uni e si a Au ònoma
de Ba celona, C/Canye S/N, 08916
Badalona Ba celona, Spain.
Email: [email p o ec ed]
Funding in o ma ion
Te a Pha maceu ical Indus ies
Abs ac
The use o non-pegyla ed liposomal doxo ubicin (Myoce ®) in di use la ge B-cell
lymphoma (DLBCL) has been in es iga ed in e ospec i e and single-a m p ospec-
i e s udies. This was a p ospec i e phase 2 ial o DLBCL pa ien s ≥60yea s old
wi h le en icula ejec ion ac ion (LVEF) ≥55% andomized o s anda d R-CHOP
o in es iga ional R-COMP (wi h Myoce ® ins ead o con en ional doxo ubicin). The
p ima y end poin was o e alua e he di e ences in subclinical ca dio oxici y, de-
ined as dec ease in LVEF o <55% a he end o ea men . Seconda y objec i es
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1315
SANCHO e Al.
1
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INTRODUCTION
The combina ion o he monoclonal an i-CD20 an ibody i -
uximab plus chemo he apy wi h cyclophosphamide, doxo u-
bicin, inc is ine, and p ednisone (R-CHOP) s ill cons i u es
he s anda d i s -line egimen o pa ien s wi h di use la ge
B-cell lymphoma (DLBCL).1 Howe e , i s use is limi ed es-
pecially in elde ly pa ien s due, among o he easons, o ca -
dio oxici y de i ed om doxo ubicin. Doxo ubicin-induced
ca dio oxici y is caused by he binding o he d ug and he
e ic ion, p oducing he o ma ion o ee adicals ha p o-
ides lipid pe oxida ion and p og essi e myocy e damage.2
The cumula i e dose o doxo ubicin appea s o be he main
ac o in ol ed in he de elopmen o ca dio oxici y, and al-
hough a h eshold o 500mg/m2 has been es ablished as a
isk dose, some s udies ha e desc ibed ea ly ca dio oxici y
wi h doses o only 200mg/m2.3,4
In addi ion o clinical symp oms, de e mina ion o he le
en icula ejec ion ac ion (LVEF) by echoca diog aphy o
ca diac scin ig aphy (mul i-ga ed acquisi ion [MUGA]) scan is
he mos equen pa ame e employed o e alua e ca dio oxic-
i y, and usually a dec ease in LVEF p ecedes he de elopmen
o conges i e hea ailu e.3 In ecen yea s, he measu emen o
ca diac bioma ke s, especially oponin and N- e minal p o-B-
ype na iu e ic pep ide (NT-p oBNP), has been p oposed as a
me hod o de ec ea ly ca dio oxici y, and se e al s udies ha e
shown a ela ion be ween aised le els o ca diac bioma ke s
and le en icula dys unc ion, in pa icula wi h a dec ease in
LVEF, and he de elopmen o hea ailu e.4-9
Se e al s a egies ha e been p oposed o dec ease ca dio-
oxici y p o oked by an h acyclines in elde ly popula ions.
These include he adminis a ion o educed doses o slow
in usions o doxo ubicin, use o ca diop o ec i e agen s o
subs i u ion by o he an ineoplas ic agen s o by o he less
ca dio oxic an hacyclines, such as mi oxan one, epi ubicin,
o liposomal o mula ions o doxo ubicin.10-14 Myoce ® is a
non-pegyla ed liposomal doxo ubicin ha demons a ed o
be less ca dio oxic—wi h simila an i umo al ac i i y— han
con en ional doxo ubicin in a phase 3 ial in pa ien s wi h
me as a ic b eas cance .2 Due o i s pha macokine ic and
pha macodynamics p o iles, i has also been associa ed wi h
less myelosupp ession and mucosi is.14 Howe e , i s ac i i y
in lymphoma pa ien s has mainly been in es iga ed in e o-
spec i e and single-a m p ospec i e s udies.15-20
Taking in o accoun his backg ound, we designed a clin-
ical ial o pa ien s ≥60yea s old diagnosed wi h DLBCL
o g ade 3b ollicula lymphoma (FL) wi h no mal ca diac
unc ion, wi h he main objec i e o e alua ing he possible
bene i s in e ms o ca diac oxici y, o he subs i u ion o
con en ional doxo ubicin by non-pegyla ed liposomal doxo-
ubicin (Myoce ®, R-COMP a m) as pa o R-CHOP he apy.
2
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MATERIALS AND METHODS
P ospec i e andomized phase 2 ial (ClinicalT ials.go
Iden i ie : NCT02012088) o newly diagnosed pa ien s
≥60yea s old wi h non-localized DLBCL o g ade 3b FL
we e e icacy, sa e y, and a ia ions o oponin and N- e minal p o-B- ype na iu e ic
pep ide (NT-p oBNP) and LVEF along ollow-up.
Nine y pa ien s we e included, 45 in each g oup. No di e ences we e obse ed in he pe cen -
age o pa ien s wi h LVEF <55% a end o ea men (11% in R-CHOP a m s. 7% in R-COMP
a m, p=0.697) o a 4mon hs (10% s. 6%, espec i ely, p=0.667) and 12mon hs (8% s. 7%,
espec i ely, p=1). Howe e , a highe pe cen age o R-CHOP compa ed wi h R-COMP pa ien s
showed inc eased oponin le els in cycle 6 (100% s. 63%, p=0.001) and a 1mon h a e ea -
men (88% s. 56%, espec i ely, p=0.015). Ca dio ascula ad e se e en s we e seen in i e
R-CHOP pa ien s (nine episodes, ou g ade ≥3) and in ou R-COMP pa ien s ( i e episodes, all
g ade 1–2). No signi ican di e ences in e icacy we e obse ed.
In conclusion, R-COMP is a easible immunochemo he apy schedule o DLBCL pa ien s
≥60yea s, wi h simila e icacy o R-CHOP. Howe e , he use o non-pegyla ed doxo ubicin
ins ead o con en ional doxo ubicin was no associa ed wi h less ea ly ca dio oxici y, al hough
some educed ca diac sa e y signals we e obse ed.
T ial egis a ion: ClinicalT ials.go Iden i ie : NCT02012088.
KEYWORDS
ca dio oxici y, di use la ge B-cell lymphoma, liposomal doxo ubicin, N- e minal p o-B- ype
na iu e ic pep ide, oponin
1316
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SANCHO e Al.
wi h a baseline LVEF ≥55%. The ial was conduc ed ac-
co ding o Good Clinical P ac ice Guidelines and he 2008
e ision o he Decla a ion o Helsinki. All pa ien s p o ided
w i en in o med consen be o e pa icipa ion in his s udy.
The equi emen s o he pa ien s o be included we e: age
≥60yea s, newly diagnosed non-localized DLBCL o g ade
3b FL ( hose wi h localized lymphoma we e included in he
p esence o bulky disease) wi h a leas one measu able lesion,
Eas e n Coope a i e Oncology G oup (ECOG) pe o mance
s a us o 0–2, adequa e hema ological, enal and hepa ic pa-
ame e s (unless seconda y o lymphoma in ol emen ), and
a baseline LVEF ≥55%. Pa ien s wi h localized lymphoma,
his o y o ans o med lymphoma, cen al ne ous sys em
(CNS) in ol emen , o posi i i y o hepa i is B o C i-
uses o human immunode iciency i us we e excluded, as
we e hose wi h clinically signi ican ca dio ascula disease,
such as non-con olled a e ial hype ension, non-con olled
en icula o sup a en icula a hy hmias, symp oma ic
ischemic hea disease (class II o highe acco ding o he
Canadian Ca dio ascula Socie y c i e ia), pas o p esen
his o y o conges i e hea ailu e, LVEF <55%, mode a e
o se ious le en icula hype ophy, and signi ican al e
abno mali ies. In addi ion, pa ien s wi h no adequa e window
o de e mine LVEF by echoca diog aphy we e also excluded.
Physical examina ion, s anda d blood es s, ho acic and
abdominal compu ed omog aphy (CT) scan (and ce ical
i clinically indica ed) plus posi on emission omog aphy
(PET) o combined PET/CT scan, and bone ma ow biopsy
we e pe o med a baseline and a he end o ea men . Fo
he ca diac e alua ion, an elec oca diog am (ECG) and
de e mina ion o he ca diac bioma ke s oponin and NT-
p oBNP in se um we e pe o med a baseline, 48–72h a e
he hi d and six h cycles o chemo he apy and a he end
o ea men (1mon h a e he las cycle o chemo he apy),
and in he ollow-up isi s pe o med 4 and 12mon hs la e
in each pa icipan ins i u ion acco ding o local p ocedu es.
The LVEF was measu ed by echoca diog apy a baseline, a
he end o ea men (1mon h a e he las cycle o chemo-
he apy), and 4 and 12mon hs la e . Fo LVEF de e mina-
ion, he biplane Simpson's me hod om he apical acous ic
window was used,21 and he inal esul o he LVEF a each
e alua ion poin was he mean o h ee measu emen s.
2.1
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T ea men
Pa ien s we e andomized 1:1 o ecei e R-CHOP ( i uximab
375 mg/m2 [day 1], cyclophosphamide 750 mg/m2 [day 1],
doxo ubicin 50mg/m2 [day 1], inc is ine 1.4mg/m2 [day 1,
capped a a maximum o 2mg], and p ednisone 60mg/m2 [days
1–5]) o R-COMP (wi h he same d ugs excep o con en ional
doxo ubicin being eplaced by non-pegyla ed liposomal doxo-
ubicin, Myoce ®, a doses o 50mg/m2 [day 1]), adminis e ed
in bo h a ms e e y 21days o a o al o six cycles. I he delay
in he adminis a ion o subsequen cycles was g ea e han
2 weeks due o oxici y, he pa ien was wi hd awn om he
s udy. Reduc ions o 25% and 50% in he doses o cyclophos-
phamide and doxo ubicin (in R-CHOP a m) o in he doses o
cyclophosphamide and non-pegyla ed liposomal doxo ubicin
(in R-COMP a m) we e manda o y o pa ien s wi hou hema-
ological eco e y (minimum neu ophil coun o 1×109/L and
pla ele coun o 75×109/L), a e 1 o 2weeks, espec i ely, o
he 21-day pe iod o he p e ious cycle. In he case o g ade 3–4
neu opa hy, discon inua ion o inc is ine was manda o y, bu
he pa ien s we e allowed o con inue o pa icipa e in he ial
and ecei e he emaining d ugs o he chemo he apy schedule.
P ima y p ophylaxis o eb ile neu openia wi h g anulocy e
colony-s imula ing ac o was allowed acco ding o he clinical
p ac ice. CNS p ophylaxis wi h in a hecal chemo he apy (ac-
co ding o clinical p ac ice in he hospi al) was ecommended
wi h each cycle o chemo he apy in he p esence o inc eased
se um lac a e dehyd ogenase plus in ol emen o mo e han
one ex anodal si e, o in pa ien s wi h a high In e na ional
P ognos ic Index (IPI) o in hose wi h in ol emen o , a leas ,
one o he ollowing in ol ed si es: pa anasal sinus, Waldeye 's
ing, epidu al space, b eas , kidney, o es es. Radio he apy a e
chemo he apy on esidual mass in pa ien s wi h baseline bulky
disease was also allowed acco ding o he physician's decision.
2.2
|
P ima y and seconda y end poin s
The p ima y end poin o he s udy was o e alua e he di e ences
in subclinical ca dio oxici y, de ined by a dec ease in LVEF o
<55% a he end o ea men (measu ed by echoca diog aphy
a 1 mon h a e he apy), in pa ien s ecei ing he s anda d
R-CHOP egimen compa ed wi h hose ea ed wi h R-COMP.
Conside ing a non-supe io i y hypo hesis es o wo independ-
en samples wi h a s a is ical powe o 80%, a signi icance le el
o 5% and assuming a p opo ion o subclinical ca diac oxic-
i y in he e e ence and expe imen al g oups o app oxima ely
15%22,23 and 5%,22,23 espec i ely, wi h 5% d opou s, 45 pa ien s
in each ea men a m we e necessa y o be ec ui ed.
Seconda y end poin s we e e icacy in e ms o o e all
and comple e esponse a es (ORR and CR) in all andomized
pa ien s, e en - ee su i al (EFS), p og ession- ee su i al
(PFS), o e all su i al (OS), and sa e y. Response o ea -
men was e alua ed acco ding o clinical, labo a o y esul s
and he e alua ion o imaging echniques acco ding o he
c i e ia de ined by Cheson e al.24 EFS was de ined as he
ime om inclusion o he pa ien s in he ial un il ea men
ailu e, including disease p og ession, ea men discon inua-
ion, o dea h by any cause. PFS was de ined as he ime om
inclusion in o he ial un il p og ession/ elapse o dea h by
any cause. OS was de ined as ime om s udy inclusion o
dea h by any cause.
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1317
SANCHO e Al.
Sa e y, wi h special a en ion o ca dio ascula oxici y,
was e alua ed acco ding o clinical signs and labo a o y pa-
ame e s, and assessmen o ad e se e en s (AE) using e -
sion 4.0 o he NCI-CTCAE scale o g ading oxici y, as
well as he a ia ions in ca diac bioma ke s oponin and NT-
p oBNP in bo h a ms h oughou he s udy.
The p ima y end poin analysis was ca ied ou in pa-
ien s who ecei ed six cycles o ea men and in whom
pos - ea men e alua ion o LVEF was pe o med. E icacy
analyses we e ca ied ou on an in en ion- o- ea (ITT)
popula ion, de ined as all andomized pa ien s, and in he
e aluable popula ion, de ined as ITT popula ion excluding
pa ien s who wi hd ew he ial wi hou a esponse e alua-
ion. The sa e y analysis was ca ied ou in a sa e y popu-
la ion, which included all pa ien s ha ecei ed a leas one
cycle o chemo he apy.
2.3
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S a is ical analysis
Baseline demog aphic and clinical cha ac e is ics we e
desc ibed as equency and pe cen age o ca ego ical
a iables, and median and ange o quan i a i e a iables.
Compa isons o ca ego ical a iables be ween ea men
g oups we e s udied using he Chi-squa e es o Fishe 's
exac es , when necessa y, while he median es was used o
compa e con inuous a iables.
Fo he p ima y end poin (e alua ion o di e ences in
subclinical ca dio oxici y), he pe cen age o pa ien s in
whom he LVEF dec eased o <55% a he end o ea men
in each ea men g oup was compa ed using he Chi-squa e
es o Fishe 's exac es , when necessa y. The median LVEF
a he end o ea men , as well as a 4 and 12mon hs la e ,
and he median o he di e ences be ween baseline and end
o ea men LVEF measu es we e compa ed by he nonpa a-
me ic median es . Compa ison o pa ien s wi h a ia ions in
ca diac bioma ke s h oughou he s udy was made by Chi-
squa e es o Fishe 's exac es , when necessa y.
Rega ding e icacy, OR and CR a es we e compa ed
using he Chi-squa e es o Fishe 's exac es , whe eas
EFS, PFS, and OS cu es we e plo ed by he Kaplan–Meie
me hod25 and compa ed by he log- ank es .26
A desc ip i e analysis o he epo ed AE ( equency
and pe cen age) was pe o med, and compa ison be ween
R-CHOP a m
(n=45)
R-COMP a m
(n=45) p alue
O e all se ies
(n=90)
Male, n (%) 17/45 (38%) 24/45 (53%) 0.138 41/90 (46%)
Age (yea s), median
( ange)
74 (60–84) 74 (60–86) 1 74 (60–86)
Baseline LVEF (%),
median ( ange)
63 (55–81.4) 65 (55–87.1) 0.204 64 (55–87.1)
Hype ension, n (%) 26/45 (58%) 17/44 (39%) 0.071 43/89 (48%)
Diabe es, n (%) 7/45 (16%) 8/44 (18%) 0.741 15/89 (17%)
Dyslipemia, n (%) 21/45 (47%) 15/44 (34%) 0.227 36/89 (40%)
ECOG <2, n (%) 37/45 (82%) 38/45 (84%) 0.777 75/90 (83%)
B symp oms, n (%) 20/45 (44%) 19/44 (43%) 0.904 39/89 (44%)
Inc eased LDH le el,
n (%)
29/45 (64%) 23/45 (51%) 0.2 52/90 (58%)
Ex anodal
in ol emen , n (%)
26/45 (58%) 26/45 (58%) 1 52/90 (58%)
>1 ex anodal si e
in ol ed, n (%)
12/45 (27%) 13/45 (29%) 0.814 25/90 (28%)
BM in ol emen , n (%) 11/44 (25%) 12/45 (27%) 0.857 23/89 (26%)
Bulky disease, n (%) 11/44 (25%) 12/45 (27%) 0.857 23/89 (26%)
Ann-A bo s age, n (%)
I–II 9/45 (20%) 10/45 (22%) 0.796 19/90 (21%)
III–IV 36/45 (80%) 35/45 (78%) 71/90 (79%)
IPI, (n %)
0–2 25/44 (57%) 26/44 (59%) 0.829 51/88 (58%)
3–5 19/44 (43%) 18/44 (41%) 37/88 (42%)
Abb e ia ions: BM, bone ma ow; ECOG, Eas e n Coope a i e Oncology G oup; IPI, In e na ional P ognos ic
Index; LDH, lac a e dehyd ogenase; LVEF, le en icula ejec ion ac ion; WBC, whi e blood cells.
TABLE 1 Baseline cha ac e is ics o
he o e all se ies and di ided by ea men
a m
1318
|
SANCHO e Al.
ea men g oups was made using he Chi-squa e es o
Fishe 's exac es .
No impu a ion me hod was used o missing da a. Two-
sided p alues <0.05 we e conside ed as s a is ically signi -
ican . All analyses we e pe o med wi h SPSS 24 (SPSS
Inc.).
3
|
RESULTS
F om Oc obe 2013 o Feb ua y 2016, a o al o 90 pa ien s
wi h DLBCL om 15 hospi als belonging o he Spanish
GELTAMO g oup we e p ospec i ely included. O hese, 45
we e andomized o he R-CHOP a m and 45 o he R-COMP
a m, wi hou signi ican di e ences be ween he wo a ms
ega ding baseline cha ac e is ics (Table1). The median age
o he en i e se ies was 74yea s ( ange 60–86), wi h ECOG
<2 in 83%; 79% o pa ien s we e in ad anced s age and 42%
had an in e media e o high IPI. The median LVEF a s udy
en y was 64% ( ange 55–87.1), and almos hal o pa ien s
had a p e ious his o y o hype ension. Figu e1 shows he
low cha o he pa ien s along he s udy. Thi y-eigh ou
o 45 pa ien s (84%) and 42/45 (93%) ecei ed six cycles o
R-CHOP and R-COMP, espec i ely, (p=0.130) and we e
included in he analysis o he p ima y end poin .
3.1
|
Subclinical ca dio oxici y: LVEF and
ca diac bioma ke s
Rega ding he p ima y end poin , no signi ican di e ences
we e obse ed be ween he R-CHOP and R-COMP a ms in
he numbe o pa ien s wi h a LVEF <55% de e mined a he
end (1mon h) o ea men (11% [n=4/36] in he R-CHOP
a m s. 7% [3/42] in he R-COMP a m, p = 0.697), o a
4mon hs (10% [n=3/31] in he R-CHOP a m s. 6% [2/33] in
he R-COMP a m, p=0.667) o a 12mon hs (8% [n=2/24]
in he R-CHOP a m s. 7% [2/28] in he R-COMP a m, p=1)
a e he apy (Table2). Fu he mo e, no di e ences we e ob-
se ed in an explo a o y analysis compa ing pa ien s wi h a
dec ease in LVEF below 50% a he end o ea men o du -
ing ollow-up (da a no shown), as well as in he numbe o
FIGURE 1 Flowcha o pa ien s
En olled
n= 98
Excluded: 8
Randomized
n= 90
R-COMP
n= 45
R-CHOP
n= 45
Wi hd awal by AE: 3 (suba achnoidhemo hage, enal
ailu e, a ial ib illaon)
Dea h by AE: 3 (gas oin esnal hemo hage, sepc
shock, wo seninggene al condion)
P og ession: 2
Remo alconsen : 1
Wi hd awal by AE: 1 (wo sening gene al condion)
Dea hbyAE: 2 (sepc shock, abdominal
hemo hage)
FINISHED TREATMENT
n= 36
FINISHED TREATMENT
n= 42
(Reasons o exclusion: 3 due o o he
lymphoma sub ype, 2 due o localizeddisease,
1 due ono adequa e window o de e mine
LVEF, 2 due o physician c i e ia)

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1319
SANCHO e Al.
pa ien s wi h LVEF d op ≥10% a 1, 4, o 12 mon hs a e
ea men compa ed o baseline LVEF. Simila ly, he e we e
also no signi ican di e ences be ween he wo g oups in he
median LVEF de e mined a he end o ea men and a 4 and
12 mon hs, o in he a ia ions in LVEF de e mined a di e -
en imes compa ed o he baseline LVEF (Table2). Finally,
no di e ences we e de ec ed in he p ima y end poin (LVEF
<55% a 1 mon h o ea men ) conside ing all andomized
pa ien s (9% [n=4/45] in he R-CHOP a m s. 7% [3/45] in
he R-COMP a m, p=1).
Wi h espec o he ca diac bioma ke s oponin and NT-
p oBNP, a highe pe cen age o pa ien s showed inc eased
oponin le els (compa ed o baseline alues) measu ed in
cycle 6 (24/24 [100%] in he R-CHOP a m s. 17/27 [63%]
in he R-COMP a m, p=0.001) and a 1mon h a e he
end o ea men (21/24 [88%] in he R-CHOP a m s.
14/25 [56%] in he R-COMP a m, p=0.015), bu no a e
cycles 3 o a 4 and 12mon hs a e ea men (Table3).
Rega ding NT-p oBNP, no di e ences we e obse ed in
he pe cen age o pa ien s wi h inc eased le els along he
ea men pe iod (in cycles 3 and 6) and ollow-up (1, 4,
and 12mon hs a e he apy) compa ed o he baseline le -
els (Table3).
3.2
|
E icacy e alua ion
OR and CR we e obse ed in 77 (85.5%) and 56 (62%) ou
o he 90 andomized pa ien s, wi h no di e ences be ween
ea men g oups (OR and CR in he R-CHOP a m in 36
R-CHOP a m
(n=45)
R-COMP a m
(n=45) p alue
LVEF <55% a he end o ea men
(1mon h), numbe o pa ien s (%)
4/36 (11%) 3/42 (7%) 0.697
LVEF <55% a 4mon hs o he end o
ea men , numbe o pa ien s (%)
3/31 (10%) 2/33 (6%) 0.667
LVEF <55% a 12mon hs o he end o
ea men , numbe o pa ien s (%)
2/24 (8%) 2/28 (7%) 1
Va ia ion (di e ence) ≥10% in baseline
LVEF (%) compa ed wi h LVEF
1mon h a e he end o ea men :
5/36 (14%) 4/42 (10%) 0.725
Va ia ion (di e ence) ≥10% in baseline
LVEF (%) compa ed wi h LVEF
4mon hs a e he end o ea men :
4/31 (13%) 4/33 (12%) 1
Va ia ion (di e ence) ≥10% in baseline
LEVF (%) compa ed wi h LVEF
12mon hs a e he end o ea men :
3/24 (12%) 2/28 (7%) 0.652
LVEF (%) a he end o ea men
(1mon h), median ( ange)
61 (41–84.6) 63.9 (49–74) 0.820
LVEF (%) a 4mon hs o he end o
ea men , median ( ange)
61 (41–76) 63.7 (53.3–80) 0.129
LVEF (%) a 12mon hs o he end o
ea men , median ( ange)
60.5 (43.2–84) 65 (52–80) 0.091
Va ia ion (di e ence) in baseline LVEF (%) compa ed wi h LVEF 1mon h a e he end o
ea men :
Mean (SD) 1.6 (9.3) 2.3 (7.4) 0.793
Median ( ange) 2 (−23.6 o 24.7) 2.3 (−16.4 o 24.4)
Va ia ion (di e ence) in baseline LVEF (%) compa ed wi h LVEF 4mon hs a e he end o
ea men :
Mean (SD) 3.7 (6.9) 1.6 (7.5) 0.841
Median ( ange) 3 (−13 o 28) 2 (−16.7 o 19.4)
Va ia ion (di e ence) in baseline LEVF (%) compa ed wi h LVEF 12mon hs a e he end o
ea men :
Mean (SD) 1.3 (8.4) 0.4 (6.8) 0.592
Median ( ange) 3 (−20.3 o 16) 0.5 (−14 o 13)
Abb e ia ions: LVEF, le en icula ejec ion ac ion; SD, s anda d de ia ion.
TABLE 2 Subclinical ca dio oxici y
(LVEF) in bo h ea men a ms h oughou
he ea men
1320
|
SANCHO e Al.
[80%] and 28 [62%] pa ien s, espec i ely; OR and CR in
he R-COMP a m in 41 [91%] and 28 [62%] pa ien s, e-
spec i ely). We pe o med an addi ional e icacy analysis
including only he 80 pa ien s e aluable o e icacy; 38
in he R-CHOP a m (3 we e excluded due o AE, 3 due o
dea h om AE, and he emaining pa ien due o wi hd awal
o consen ) and 42 in he R-COMP a m (2 we e excluded
due o dea h om AE and he hi d pa ien due o AE). OR
and CR we e obse ed in 77 (96%) and 56 (70%) ou o 80
e aluable pa ien s, espec i ely, again wi hou di e ences
be ween he R-CHOP and R-COMP g oups (ORR o 95%
s. 98%, p=0.498, and CR a e o 74% s. 67%, p=0.494,
espec i ely).
Wi h a median ollow-up o 42mon hs ( ange 2.1–61.2)
o pa ien s ali e a he ime o analysis, 15 pa ien s in he
R-CHOP g oup had died (6 by lymphoma) and 14 in he
R-COMP a m (10 by lymphoma).The 2-yea EFS and PFS
p obabili ies o he en i e se ies we e 54% (95% con i-
dence in e al [CI] 44%–64%) and 61% (95% CI 51%–71%)
(Figu e2), espec i ely, wi hou di e ences be ween he wo
g oups (2-yea EFS o 46% [95% CI 31%–61%] s. 62% [95%
CI 48%–76%] o R-CHOP and R-COMP pa ien s, espec-
i ely, p=0.083, and 2-yea PFS o 59% [95% CI 44%–74%]
and 62% [95% CI 48%–76%] o RCHOP and R-COMP
pa ien s, espec i ely, p=0.505) (Figu e3).The 2-yea OS
p obabili y o he en i e se ies was 74% (95% CI 65%–83%)
(Figu e2), bu again wi hou signi ican di e ences be ween
he wo g oups (75% [95% CI 62%–88%] o R-CHOP pa-
ien s s. 73% [95% CI 60%–86%] o R-COMP pa ien s,
p=0.751) (Figu e3).
3.3
|
Sa e y
The main AEs epo ed by >5% o he pa ien s a e lis ed in
Table 4. O e all, he mos equen non-hema ologic AEs
we e pain (53% o pa ien s), a igue (51%), in ec ion (49%),
pe iphe al neu opa hy (31%), cons ipa ion (29%). and py-
exia (28%), wi h no di e ences be ween bo h a ms. Non-
hema ological g ade 3–4 oxici y was also simila in bo h
g oups, being in ec ion he mos equen ( i e pa ien s
[11%] in he R-CHOP g oup and se en pa ien s [16%] in he
R-CHOP a m
(n=45)
R-COMP a m
(n=45) p alue
T oponin
Inc eased oponin le els a cycle 3,
numbe o pa ien s (%)
13/23 (57%) 12/26 (46%) 0.469
Inc eased oponin le els a cycle 6,
numbe o pa ien s (%)
24/24 (100%) 17/27 (63%) 0.001
Inc eased oponin le els a end o
ea men (1mon h), numbe o
pa ien s (%)
21/24 (88%) 14/25 (56%) 0.015
Inc eased oponin le els a 4mon hs
a e ea men , numbe o pa ien s
(%)
16/21 (76%) 16/22 (73%) 0.795
Inc eased oponin le els a 12mon hs
a e ea men , numbe o pa ien s
(%)
10/15 (67%) 10/15 (67%) 1
NT-p oBNP
Inc eased NT-p oBNP le els a cycle 3,
numbe o pa ien s (%)
25/29 (86%) 32/34 (94%) 0.401
Inc eased NT-p oBNP le els a cycle 6,
numbe o pa ien s (%)
27/29 (93%) 23/28 (82%) 0.253
Inc eased NT-p oBNP le els a end
o ea men (1mon h), numbe o
pa ien s (%)
14/29 (48%) 14/33 (42%) 0.644
Inc eased NT-p oBNP le els a
4mon hs a e ea men , numbe o
pa ien s (%)
14/25 (56%) 12/27 (44%) 0.405
Inc eased NT-p oBNP le els a
12mon hs a e ea men , numbe o
pa ien s (%)
12/18 (67%) 6/17 (35%) 0.063
Abb e ia ion: NT-p o-BNP, N- e minal p o B- ype na iu e ic pep ide.
TABLE 3 Ca diac bioma ke s ( oponin
and NT-p oBNP) in bo h ea men a ms
h oughou he ea men
|
1321
SANCHO e Al.
R-COMP g oup). Rega ding g ade 3–4 hema ological oxic-
i y, neu openia was obse ed mo e equen ly in R-CHOP
pa ien s (49% s. 29%), bu his was no ansla ed in o mo e
incidence o eb ile neu openia, while h ombocy openia
and anemia we e iden ical (Table4).
Ca dio ascula oxici y is desc ibed in Table5. Fou een
ca dio ascula AEs we e obse ed in nine pa ien s, nine AEs
in i e pa ien s who ecei ed R-CHOP, and i e AEs in ou
pa ien s ea ed wi h R-COMP. Fou ca dio ascula AEs we e
o g ade ≥3 ( wo cases o a ial ib illa ion, one hea ailu e,
and one myoca dial in a c ion), all o hem in he R-CHOP
g oup.
A o al o 67 se ious ad e se e en s (SAEs) we e epo ed
in 39 pa ien s (26 in 18 pa ien s om he R-CHOP g oup
and 41 in 21 pa ien s om he R-COMP g oup), including
16 episodes o eb ile neu openia (6 in R-CHOP and 10 in
R-COMP), 14 in ec ions (7 in each g oup), 6 episodes o
bleeding (2 in R-CHOP and 4 in R-COMP), and 4 episodes o
py exia (all in he R-COMP a m). Ca dio ascula SAEs we e
epo ed in only i e pa ien s: sup a en icula achyca dia
(n=2, R-CHOP g oup), a ial ib illa ion (n=1, R-COMP
g oup), myoca dial in a c ion (n=1, R-CHOP g oup), and
hea ailu e (n=1, R-CHOP g oup).
4
|
DISCUSSION
This s udy demons a es ha non-pegyla ed doxo ubicin in-
s ead o con en ional doxo ubicin as pa o he R-CHOP
egimen did no dec ease he incidence o LVEF d op below
55% a he end o chemo he apy in pa ien s ≥60yea s old di-
agnosed wi h DLBCL wi h no mal baseline ca diac unc ion.
Mo eo e , in his se ies, R-COMP was a easible immuno-
chemo he apy schedule o pa ien s ≥60yea s o age wi h de
no o DLBCL, wi h simila e icacy o R-CHOP.
The main esul s o his s udy a e conco dan wi h a sim-
ila p e ious phase 3 ial by he Aus ian AGMT g oup23
ha compa ed R-CHOP and R-COMP in 79 adul pa ien s
wi h DLBCL and no mal ca diac unc ion. In he ci ed
s udy, a low- a e o ca dio oxici y was desc ibed in R-CHOP
and R-COMP pa ien s. Howe e , while in he p esen s udy
no signi ican di e ences we e obse ed in he pe cen age
FIGURE 2 E en - ee su i al (EFS), p og ession- ee su i al (PFS), and o e all su i al (OS) p obabili ies o he o e all se ies
1322
|
SANCHO e Al.
o pa ien s wi h LVEF <55% a he end o ea men (wi h
only 11% and 7% o pa ien s wi h a LVEF below <55% a
he end o he s udy in R-CHOP and R-COMP pa ien s,
espec i ely), he Aus ian g oup epo ed highe measu e-
men s o LVEF <50% h oughou he s udy in R-CHOP
pa ien s compa ed o he R-COMP g oup (15.8% s. 4.6%,
espec i ely, p < 0.001), despi e simila baseline LVEF
alues in bo h g oups, a su p isingly inding since ha
younge pa ien s we e included in he Aus ian (median age
o 65yea s and 38% o pa ien s <60yea s) compa ed o ou
s udy (median age o 74yea s and all pa ien s o e 60yea s
old), and age is a well ecognized isk ac o o ca dio-
oxici y. Howe e , as in he p esen s udy, no di e ences
we e obse ed in LVEF alues a he end o ea men in
he R-CHOP compa ed o he R-COMP g oup, sugges -
ing ha he subs i u ion o con en ional doxo ubicin by
non-pegyla ed doxo ubicin does no seem o p o ec agains
an h acycline-de i ed subclinical ca dio oxici y, a leas in
e ms o LVEF dec ease in DLBCL pa ien s. Simila e-
sul s ega ding LVEF a ia ions we e desc ibed p e iously
in ano he phase 2 ial o 75 pa ien s wi h DLBCL ea ed
wi h 8 cycles o R-COMP20; al hough LVEF measu emen s
dec eased a mos ime poin s, he di e ences we e no sig-
ni ican , wi h a mean change om baseline o he end o
ea men o −2.6%, e y simila o ha ound in ou s udy
(Table2). In addi ion, despi e he lowe numbe o mea-
su emen s, he p esen s udy also sugges s a lack o bene i
in mid- e m subclinical ca dio oxici y, wi h simila LVEF
measu emen s a 4 o a 12mon hs compa ed o baseline
LVEF in he R-CHOP and R-COMP a ms.
Ca diac bioma ke s ha e been used as a complemen a y
me hod o de ec subclinical ca diac oxici y.5-9 T oponin and
NT-p oBNP a e ela ed o ea ly ca diac inju y and hea ail-
u e, espec i ely. In he p esen s udy, only oponin le els
mo e equen ly inc eased in R-CHOP compa ed o R-COMP
pa ien s, al hough his inc ease was only de ec able in cycle 6
and 1mon h a e he comple ion o ea men , bu no a he
o he measu emen imes. This inding sugges s he highe
ea ly ca dio oxici y in he R-CHOP a m wi h he cumula-
i e doses o con en ional doxo ubicin, bu he absence o
FIGURE 3 E en - ee su i al (EFS), p og ession- ee su i al (PFS), and o e all su i al (OS) p obabili ies by ea men g oup (RCHOP
and R-COMP g oups ep esen ed in he con inuous and dashed lines, espec i ely)