O iginal A icle
Real-Wo ld Cha ac e is ics and Ou come o
Pa ien s T ea ed Wi h Single-Agen Ib u inib o
Ch onic Lymphocy ic Leukemia in Spain
(IBRORS-LLC S udy)
Pau Ab isque a,
1
Ja ie Losce ales,
2
Ma ia José Te ol,
3
Ángel Ramí ez Paye ,
4
Maca ena O iz,
5
Inmaculada Pé ez,
6
Ca olina Cuella -Ga cía,
7
Ma ga i a Fe nández de la Ma a,
8
Alicia Rod íguez,
9
Ana La io,
10
Julio Delgado,
11
Ana Godoy,
12
José M ªA guiñano Pé ez,
13
M ªJosé Be uezo,
14
Ana Oli ei a,
15
José-Ángel He nández-Ri as,
16
Ma ia Dolo es Ga cía Malo,
17
Ángeles Medina,
18
Paloma Ga cía Ma in,
19
San iago Oso io,
20
Pa icia Bal asa ,
21
Miguel Fe nández-Za zoso,
22
Fe nando Ma co,
23
M ªJesús Vidal Manceñido,
24
Alicia Smucle Simono ich,
25
Mon se a López Rubio,
26
Isid o Ja que,
27
Alexia Sua ez,
28
Rubén Fe nández Ál a ez,
29
Aima Lancha o Anchel,
30
Edua do Ríos,
31
Ma ía del Ca men Losada Cas illo,
32
E nes o Pé ez Pe sona,
33
Rica do Ga cía Muñoz,
34
Ra ael Ramos,
35
Luc ecia Yáñez,
36
José Luis Bello,
37
C is ina Lo ien e,
38
Daniel Acha,
38
Miguel Villanue a
38
Abb e ia ions: AE, ad e se e en ; BR, bendamus ine plus i uximab; Clb, chlo ambucil;
CLL, ch onic lymphocy ic leukemia; CI, con idence in e al; CIT, chemoimmuno he -
apy; CR, comple e esponse; CT, compu ed omog aphy; ECOG, Eas e n Coope a i e
Oncology G oup; FCR, luda abine, cyclophosphamide, and i uximab; HR, haza d
a io; IgA, immunoglobulin A; IGHV, immunoglobulin hea y chain; NCI-CTCAE,
Na ional Cance Ins i u e Common Te minology C i e ia o ad e se e en s; NR, no
eached; OR, Odds a io; ORR, o e all esponse a e; OS, o e all su i al; PD, p og es-
si e disease; PFS, p og ession- ee su i al; PR, pa ial esponse; PR-L, pa ial emission
wi h lymphocy osis; R/R, elapsed/ e ac o y; TN, ea men naï e.
1
Hospi al Uni e si a io Vall d
´
Heb on, Ba celona, Spain
2
Hospi al Uni e si a io La P incesa, IIS-IP, Mad id, Spain
3
Hospi al Clínico Uni e si a io de Valencia, Valencia, Spain
4
Hospi al Uni e si a io Cen al de As u ias, O iedo, Spain
5
Hospi al Regional Uni e si a io de Málaga, Malaga, Spain
6
Hospi al Vi gen de la Vic o ia, Málaga, Spain
7
Hospi al de la San a C eu i San Pau, Ba celona, Spain
8
Hospi al Uni e si a io Reina So ía, Có doba, Spain
9
Hospi al Uni e si a io Vi gen Maca ena, Se illa, Spain
10
Hospi al Uni e si a io Ramón y Cajal, Mad id, Spain
11
Hospi al Clinic i P o incial, Ba celona, Spain
12
Hospi al Uni e si a io Miguel Se e , Za agoza, Spain
13
Complejo Hospi ala io de Na a a, Pamplona, Spain
14
Hospi al Uni e si a io de Je ez, Cádiz, Spain
15
ICO L’Hospi ale , L’Hospi ale de Llob ega , Spain
16
Hospi al Uni e si a io In an a Leono , Mad id, Spain
17
Hospi al Gene al Uni e si a io Mo ales Mesegue , Mu cia, Spain
18
Hospi al Cos a del Sol, Málaga, Spain
19
Hospi al Uni e si a io Vi gen de las Nie es, G anada, Spain
20
Hospi al Gene al Uni e si a io G ego io Ma añón, Mad id, Spain
21
Hospi al Uni e si a io La Paz, Mad id, Spain
22
Hospi al Uni e si a io D . Pese , Valencia, Spain
23
Hospi al Uni e si a io de Basu o, Bilbo, Bizkaia, Spain
24
Hospi al Uni e si a io de León, León, Spain
25
Hospi al Uni e si a io El Bie zo, Pon e ada, León, Spain
26
Hospi al Uni e si a io P incipe de As u ias, Alcalá De Hena es, Mad id, Spain
27
Hospi al Uni e si a io La Fe, Valencia, Spain
28
Hospi al Uni e si a io de G an Cana ia Doc o Neg ín, Las Palmas, Spain
29
Hospi al de Cabueñes, Gijón, Spain
30
Hospi al Gene al Uni e si a io de Cas ellón, Cas ellón, Spain
31
Hospi al Uni e si a io Vi gen de Valme, Se illa, Spain
32
Hospi al Uni e si a io Insula de G an Cana ias, Las Palmas de G an Cana ia, Las
Palmas, Spain
33
Hospi al Txago i xu, Vi o ia-Gas eiz, Spain
34
Hospi al San Ped o, Log oño, Spain
35
Hospi al Uni e si a io de Badajoz, Badajoz, Spain
36
Hospi al Uni e si a io Ma qués de Valdecilla, San ande , Spain
37
Hospi al Clínico Uni e si a io de San iago-CHUS, San iago de Compos ela, A
Co uña, Spain
38
Medical Depa men -Hema ology Janssen-Cilag, S.A., Mad id, Spain
Submi ed: May 21, 2021; Re ised: Jul 16, 2021; Accep ed: Jul 19, 2021; Epub: 3
Augus 2021
Add ess o co espondence: Pau Ab isque a, MD, PhD. Depa men o Hema ology,
Hospi al Uni e si a io Vall d
´
Heb on, Passeig de la Vall d’Heb on, 119-129, 08035
Ba celona, Spain.
E-mail con ac : [email p o ec ed]
2152-2650/$ - see on ma e © 2021 The Au ho (s). Published by Else ie Inc. This is an open
access a icle unde he CC BY license ( h p://c ea i ecommons.o g/licenses/by/4.0/ )
h ps://doi.o g/10.1016/j.clml.2021.07.022 Clinical Lymphoma, Myeloma and Leukemia Decembe 2021 e985
Real-Wo ld-E idence o Ib u inib o CLL ea men
Abs ac
Ib u inib demons a ed obus e ficacy, ega dless o high- isk ea u es, in p e iously un ea ed o
elapsed/ e ac o y ch onic lymphocy ic leukemia (CLL). The IBRORS-CLL s udy suppo s he e ec i eness
and he manageable sa e y p ofile o single-agen ib u inib, which was no ad e sely a ec ed by high- isk
cha ac e is ics in eal-wo ld CLL pa ien s in Spain. We also ound a high molecula es ing a e o del(17p)/TP53
mu a ion and IGHV mu a ion s a us.
Backg ound: Ib u inib demons a ed ema kable e ficacy and a o able ole abili y in pa ien s wi h un ea ed o
elapsed/ e ac o y (R/R) ch onic lymphocy ic leukemia (CLL), including hose wi h high- isk gene ic al e a ions. The
IBRORS-CLL s udy assessed he cha ac e is ics, clinical managemen and ou come o CLL pa ien s ecei ing ib u i-
nib in ou ine clinical p ac ice in Spain.Pa ien s: Obse a ional, e ospec i e, mul icen e s udy in CLL pa ien s who
s a ed single-agen ib u inib as fi s -line ea men o a fi s o second elapse be ween Janua y 2016 and Janua y
2019. Resul s: A o al o 269 pa ien s we e included (median age: 70.9 yea s; ca dio ascula como bidi y: 55.4%,
including hype ension [47.6%] and a ial fib illa ion [AF] [7.1%]). O e all, 96.7% and 69% o pa ien s unde wen molec-
ula es ing o del(17p)/TP53 mu a ion and IGHV mu a ion s a us. High- isk gene ic ea u es included unmu a ed IGHV
(79%) and del(17p)/TP53 mu a ion (fi s -line: 66.3%; second-line: 23.1%). O e all, 84 (31.2%) pa ien s ecei ed ib u inib
as fi s -line ea men , and i was used as second- and hi d-line he apy in 121 (45.0%) and 64 (23.8%) pa ien s. The
median p og ession- ee su i al and o e all su i al we e no eached i espec i e o del(17p)/TP53, o unmu a ed
IGHV. Common g ade ≥3 ad e se e en s we e in ec ions (12.2%) and bleeding (3%). G ade ≥3 AF occu ed in 1. 5 % o
pa ien s. Conclusion: This eal-wo ld s udy shows ha single-agen ib u inib is an e ec i e he apy o CLL, ega dless
o age and high- isk molecula ea u es, consis en wi h clinical ials. Addi ionally, single-agen ib u inib was well ole -
a ed, wi h a low a e o ca dio ascula e en s. This s udy also emphasized a high molecula es ing a e o del(17p)/TP53
mu a ion and IGHV mu a ion s a us in clinical p ac ice acco ding o guideline ecommenda ions.
Clinical Lymphoma, Myeloma and Leukemia, Vol. 21, No. 12, e985–e999 © 2021 The Au ho (s). Published by Else ie Inc.
This is an open access a icle unde he CC BY license ( h p://c ea i ecommons.o g/licenses/by/4.0/ )
Keywo ds: Ch onic lymphocy ic leukemia (CLL), E ec i eness, Fi s -line, Ib u inib, Real-wo ld, Relapsed/ e ac o y (R/R)
In oduc ion
Ch onic lymphocy ic leukemia (CLL) is cha ac e ized by a
ma ked immune dys unc ion
1 and a he e ogeneous clinical
ou come mainly de e mined by he pa ien
´
s clinical ea u es, cy oge-
ne ic al e a ions and gene mu a ions.
2 , 3 Dele ions in ch omo-
some 17p [del(17p)] and mu a ion in TP53 gene, dele ion o 11q
[del(11q)], and unmu a ed immunoglobulin hea y chain a iable
(IGHV) egion gene s a us is associa ed wi h poo esponse and
ou come o chemoimmuno he apy (CIT).
4-9
Tes ing o hese al e -
a ions is he e o e o pa amoun impo ance o guiding ea men
decisions in ou ine clinical p ac ice in CLL.
10-12
Addi ional analy-
sis as complex ka yo ype (i.e., ≥3 ch omosomal abno mali ies), ha
ha e an ad e se p ognos ic signi icance, a e s ill conside ed in es i-
ga ional.
10 , 11 , 13
Ib u inib is a i s -in-class, o al once-daily, co alen inhibi o o
B u on
´
s y osine kinase (BTK), which has demons a ed highe
e icacy and a o able ole abili y p o ile compa ed o he mos
e ec i e CIT egimens in bo h elapsed/ e ac o y (R/R)
14 , 15 and
ea men -naï e (TN)
16-19 pa ien s. The e o e, he e icacy and
sa e y seen in clinical ials suppo he use o ib u inib o all CLL
pa ien p o iles which equi e ea men .
The bene i demons a ed wi h ib u inib in clinical ials has also
been obse ed in he eal-wo ld se ing.
20-31 Howe e , mos eal-
wo ld e idence came om s udies in R/R CLL,
20 , 25-27 , 30 , 31
includ-
ing epo s whe e ib u inib was used in compassiona e use p og ams
24 , 27 , 30 , 31 and om single-si e expe ience.
22 , 26 Addi ionally, eal-
wo ld da a om di e en heal hca e sys ems ac oss coun ies may
be he e ogeneous due o di e gences in clinical p ac ice, and na ion-
wide expe iences a e o pa icula in e es .
This eal-wo ld s udy aimed o explo e he clinical, gene ic,
and molecula cha ac e is ics o CLL pa ien s ecei ing single-agen
ib u inib in ea lie lines o he apy in Spain. We also assessed he
e ec i eness o ib u inib in e ms o esponse and clinical ou come
and he sa e y and ole abili y p o ile o his agen when used unde
ou ine clinical p ac ice condi ions.
Pa ien s and Me hods
S udy Design and Pa ien s
The IBRORS-LLC was a mul icen e , e ospec i e, obse a ional
s udy o explo e he cha ac e is ics and clinical ou come o pa ien s
ea ed wi h single-agen ib u inib in ea lie he apy lines in he eal-
wo ld se ing in Spain.
The s udy included pa ien s aged ≥18 yea s diagnosed wi h CLL
equi ing ea men who s a ed single-agen ib u inib as i s -line
ea men o a i s o second elapse om Janua y 2016 (s a o
ib u inib comme cializa ion in Spain) o Janua y 2019 (a leas 6
mon hs be o e s udy en y) unde ou ine clinical p ac ice condi-
ions. Pa ien s we e excluded i hey had pa icipa ed in an in e en-
ional s udy while ecei ing ib u inib.
The p ima y s udy endpoin was he demog aphic, clinical,
gene ic and molecula cha ac e iza ion o pa ien s a diagnosis
and ib u inib ea men ini ia ion. Fo his pu pose, a e ospec-
i e cha e iew was pe o med o collec da a on como bidi ies,
concomi an he apies, disease cha ac e is ics such as he s age o
e986 Clinical Lymphoma, Myeloma and Leukemia Decembe 2021
Pau Ab isque a e al
he disease, common ch omosomal abe a ions, namely del(13q),
isomy 12, del(11q), and del(17p), and molecula al e a ions
including del(17p)/TP53 mu a ion, IGHV mu a ion s a us and
complex ka yo ype. Seconda y endpoin s included o e all esponse
a e (ORR), OS, PFS, ime o esponse, ime o subsequen CLL
he apy, and immune econs i u ion based on immunoglobulin
A (IgA) le els and CD4/CD8 a io. Single-agen ib u inib sa e y
p o ile and managemen (dose educ ion and in e up ion, discon-
inua ion), and pos -ib u inib he apy o CLL we e also assessed.
Independen e hics commi ees app o ed he s udy, which was
ca ied ou in acco dance wi h he Decla a ion o Helsinki and
Good Clinical P ac ice Guidelines and applicable egula o y equi e-
men s. W i en in o med consen was ob ained om all pa ien s
be o e hei inclusion in he s udy, excep o hose deceased a he
ime o s udy ini ia ion, in which case he equi emen o in o med
consen was wai ed o e ospec i e collec ion o da a om medical
cha s. Cen alized moni o ing ( emo e e alua ion o he s udy da a)
was ca ied ou o ensu e s udy da a quali y.
S a is ical Analysis
A desc ip i e s a is ical analysis was pe o med o desc ibe he
demog aphic, clinical, gene ic and molecula cha ac e is ics o
pa ien s ecei ing single-agen ib u inib. The analysis ocused on
he o e all popula ion (ib u inib adminis e ed a any ea men line)
and in he i s - and second-line se ing.
Measu es o cen al endency and dispe sion (mean ±s anda d
de ia ion, median and in e qua ile ange [IQR]) we e used o
desc ibe quan i a i e a iables and coun s and pe cen ages we e
applied o epo quali a i e a iables. Compa isons be ween
ca ego ical a iables we e pe o med using he Chi-squa ed o he
Fische exac es , and con inuous a iables we e compa ed using
he Mann-Whi ney U es o he K uskal-Wallis es .
The ORR was de ined as he p opo ion o pa ien s achie ing a
comple e esponse (CR), noncon i med CR, pa ial esponse (PR),
and pa ial emission wi h lymphocy osis (PR-L). The bes esponse
o ea men was de ined based on he clinical desc ip ion and
biochemis y
10 as bone ma ow biopsy and compu ed omog a-
phy (CT) scan a e no manda o y in clinical p ac ice o e alua e
esponse. OS was calcula ed om ib u inib ea men ini ia ion o
dea h om any cause. PFS was calcula ed om ib u inib ea men
ini ia ion o disease p og ession o dea h om any cause. Time o
subsequen CLL he apy was measu ed om ea men ini ia ion o
he adminis a ion o a new CLL he apy o dea h, whiche e was
i s . Time- o-e en a iables we e es ima ed by using he Kaplan-
Meie me hod, and g oups we e compa ed wi h he Log- ank es .
Pos -hoc analyses we e conduc ed o assess ORR and he ou come
in e ms o PFS and OS acco ding o age ( ≤65 yea s s. > 65 yea s)
and ca dio ascula como bidi ies (hype ension, diabe es melli us
[DM], a ial ib illa ion [AF], o he a hy hmias, and/o s oke).
Addi ionally, he impac o del(11q), del(17p)/TP53 mu a ion,
IGHV mu a ional s a us, and complex ka yo ype on he esponse,
PFS and OS, was also assessed.
A mul i a ia e COX eg ession analysis o po en ial ac o s associ-
a ed wi h PFS was ca ied ou . Va iables wi h s a is ical signi i-
cance P < .2 in he uni a ia e analysis we e included in a mul i-
a ia e model using a s epwise selec ion me hod. Haza d a io (HR)
and 95% con idence in e als (CI) we e calcula ed. The co a ia es
assessed as po en ial independen ac o s o PFS in he uni a ia e
analysis included age, disease s age (based on Rai and Bine ), β2-
mic oglobulin le el, and cy ogene ic and molecula al e a ions a
diagnosis ( isomy 12, del(11q), del(17p)/TP53 mu a ion, IGHV
mu a ion s a us, and complex ka yo ype).
Ad e se e en s (AEs) occu ing du ing single-agen ib u inib
ea men ( ega dless o a ibu ion) we e desc ibed and g aded
acco ding o he Na ional Cance Ins i u e Common Te minology
C i e ia o AEs (NCI-CTCAE) e sion 4.0.
S a is ical analyses we e pe o med using he S a is ical Package
o he Social Sciences e sion 18.0, wi h a signi icance le el o 0.05.
Resul s
Pa ien Cha ac e is ics
Be ween Decembe 2018 and Augus 2019, 286 pa ien s we e
en olled in he s udy a 37 Spanish hospi als. Se en een pa ien s
we e excluded due o non-compliance wi h eligibili y c i e ia. Thus,
269 pa ien s we e included in he s udy and e aluable o e ec i e-
ness and sa e y analyses.
O e all, 84 (31.2%) pa ien s ecei ed single-agen ib u inib as
i s -line ea men o CLL, and i was used as second- and hi d-
line he apy in 121 (45.0%) pa ien s and 64 (23.8%) pa ien s,
espec i ely.
Table 1 shows he baseline demog aphic, clinical, and gene ic
cha ac e is ics o he o e all popula ion and acco ding o he line in
which ib u inib was ecei ed. The median age o pa ien s a ea -
men ini ia ion was 70.9 yea s, wi h 46.8% o pa ien s being olde
han 65 yea s. Mos pa ien s had an ECOG pe o mance s a us o
0 o 1 (94.9%). O e all, 50.8% o pa ien s p esen ed Rai Bine
s age B/C. The mos common como bidi y be o e ib u inib ea -
men ini ia ion was ca dio ascula disease, mos commonly a e ial
hype ension (47.6%), dyslipidemia (26.8%), DM (19%), and
AF (7.1%). Acco dingly, concomi an ea men mainly included
an ihype ensi es (41.6%), an ipla ele (11.5%), and an icoagulan
he apy (7.8%). O e all, 10 (3.7%) and 6 (2.2%) pa ien s we e
ecei ing i amin K an agonis s (VKAs) and di ec o al an icoagu-
lan s (DOACs) (apixaban), espec i ely, a ib u inib ea men ini i-
a ion ( Table 1 ).
Del(11q) and del(13q) we e de ec ed in 17.7% (45/254) and in
38.1% (98/257) o pa ien s, espec i ely. T isomy 12 was epo ed
in 16.5% (43/261) o pa ien s. The p esence o del(17p)/TP53
mu a ion was e alua ed in mos pa ien s (96.7%; 260/269), and
IGHV mu a ion s a us was assessed in 69% (186/269) o pa ien s a
diagnosis. Del(17p)/TP53 mu a ion was de ec ed in 66.3% (55/83)
and 23.1% (27/117) o pa ien s who ecei ed ib u inib in he i s -
and he second-line se ing, espec i ely. Unmu a ed IGHV was
epo ed in 79% (147/186) o pa ien s. Complex ka yo ype was
p esen in 7.9% (18/227) o pa ien s. ( Table 1 ).
P eib u inib The apy o CLL
The CLL he apies used as i s - and second-line ea men be o e
ib u inib ea men ini ia ion a e desc ibed in Table 2 . A o al o 185
pa ien s had p e iously ecei ed CLL ea men , wi h 121 and 64
pa ien s ecei ing one and wo p e ious lines o he apy, espec i ely.
O e all, 144 (77.8%) pa ien s ecei ing ib u inib in he R/R se ing
Clinical Lymphoma, Myeloma and Leukemia Decembe 2021 e987
Real-Wo ld-E idence o Ib u inib o CLL ea men
Table 1 Demog aphic, Clinical, and Gene ic Cha ac e is ics o Pa ien s Recei ing Single-Agen Ib u inib in he O e all Popula ion
and in he Fi s - and he Second-Line Se ing
Va iable Fi s Line Second Line O e all Popula ion
(N = 84) (N = 121) (N = 269)
Median age ( ange), yea s
a 71.3 (63-77) 70.1 (62.2-78.5) 70.9 (63.1-77.4)
> 65 y, n (%) 50 (59.5) 53 (43.8) 126 (46.8)
Gende , male, n (%) 52 (61.9) 84 (69.4) 178 (66.2)
ECOG pe o mance s a us, n (%)
0 44/70 (62.9) 78/110 (70.9) 158/234 (67.5)
1 25/70 (35.7) 25/110 (22.7) 64/234 (27.4)
2 1/70 (1.4) 7/110 (6.4) 10/234 (4.3)
4 0 (0.0) 0 (0.0) 2/234 (0.9)
Como bidi ies, n (%)
b
Ca dio ascula isk ac o s
Hype ension 46 (54.8) 50 (41.3) 128 (47.6)
Diabe es melli us 17 (20.2) 24 (19.8) 51 (19.0)
Ca dio ascula diso de s
Dyslipidemia 27 (32.1) 31 (25.6) 72 (26.8)
A ial fib illa ion 6 (7.1) 6 (5.0) 19 (7.1)
Ischemic hea disease 4 (4.8) 7 (5.8) 13 (4.8)
S oke 1 (1.2) 4 (3.3) 7 (2.6)
Hea ailu e 2 (2.4) 2 (1.7) 6 (2.2)
O he a y hmias 2 (1.7) 2 (1.7) 4 (1.5)
O he como bidi ies
Respi a o y disease 17 (20.2) 22 (18.2) 51 (19.0)
Gas oin es inal disease 15 (17.9) 15 (12.4) 43 (16.0)
Concomi an ea men , n (%)
b
An ihype ensi es 42 (50.0) 42 (34.7) 112 (41.6)
An icoagulan s 8 (9.5) 6 (5.0) 21 (7.8)
VKAs 4 (4.7) 5 (4.1) 10 (3.7)
DOACs 1 (1.2) 1 (1.2) 6 (2.2)
LMWH 3 (3.6) 0 (0.0) 5 (1.9)
An ipla ele s 10 (11.9) 14 (11.6) 31 (11.5)
An ibio ic/an i i al/an i ungal he apy, n (%) 8 (9.5) 26 (21.5) 55 (20.4)
Rai-Bine s age, n (%)
Rai s age 0 - Bine s age A 36/83 (43.4) 64/118 (54.2) 128/260 (49.2)
Rai s age I o II - Bine s age B 29/83 (34.9) 39/118 (33.1) 90/260 (34.6)
Rai s age III o IV - Bine s age C 18/83 (21.7) 15/118 (12.7) 42/260 (16.2)
Labo a o y pa ame e s
c
Median β2-mic oglobulin le el ( ange), mg/L 3.8 (2.5-5.5) 3.3 (2.4-4.6) 3.3 (2.4-4.6)
Median hemoglobin ( ange), g/dL 13.3 (12.0-14.6) 13.3 (11.6-14.6) 13.4 (11.9-14.6)
Median pla ele s ( ange), x10
3
/μL 175.5 (139.3-226.3) 155.0 (112.5-208.0) 164.0 (117.0-214.0)
C ea inine (mg/dL) 0.9 (0.8-1.1) 0.9 (0.8-1.1) 0.9 (0.8-1.1)
Genomic abe a ions, n (%)
c
Del(11q) dele ion 11/80 (13.8) 22/114 (19.3) 45/254 (17.7)
Del(17p)/TP53 mu a ion 55/83 (66.3) 27/117 (23.1) 95/260 (36.5)
IGHV, n (%)
Unmu a ed 45/58 (77.6) 63/82 (76.8) 147/186 (79.0)
Mu a ed 13/58 (22.4) 19/82 (23.2) 39/186 (21.0)
( con inued on nex page )
e988 Clinical Lymphoma, Myeloma and Leukemia Decembe 2021
Pau Ab isque a e al
Table 1 ( con inued )
Va iable Fi s Line Second Line O e all Popula ion
(N = 84) (N = 121) (N = 269)
Complex ka yo ype, n (%)
d 4/67 (6.0) 13/102 (12.7) 18/227 (7.9)
Molecula high- isk, n (%)
e 74 (88.1) 80 (66.1) 199 (74.0)
DOACs: di ec o al an icoagulan s; ECOG: Eas e n Coope a i e G oup; IGHV = immunoglobulin hea y a iable chain; LMWH = low-molecula -weigh hepa in; VKA = i amin K an agonis s;
a
Age a ea men ini ia ion;
b
A ib u inib ea men ini ia ion;
c
A diagnosis;
d
Complex ka yo ype: ≥3 ch omosomal abno mali ies;
e
Unmu a ed IGHV, del(17p)/TP53 dis up ion, o complex ka yo ype.
Table 2 P io The apy o CLL in he Fi s - and he Second-
Line Se ing
T ea men Fi s Line Second Line
N (%) N (%)
(N = 185) (N = 64)
Chemoimmuno he apy
a 144 (77.8) 48 (75.0)
FCR 75 (40.5) 6 (9.3)
BR 29 (15.7) 28 (43.8)
Clb-R 16 (8.6) 6 (9.3)
R 8 (4.3) 2 (3.1)
R-CHOP 7 (3.8) –
G-Clb 5 (2.7) 0 (0.0)
G-benda 2 (1.1) 4 (6.25)
R-FCM 2 (1.1) 0 (0.0)
R-CVP 2 (1.1) 0 (0.0)
Chemo he apy
b 38 (20.5) 11 (17.2)
Clb 18 (9.7) 2 (3.1)
FC 11 (5.9) 2 (3.1)
Bendamus ine 8 (4.3) 2 (3.1)
Fluda abine 3 (1.6) 0 (0.0)
Ta ge ed agen s 4 (2.2) 3 (4.7)
Idelalisib-R 4 (2.2) 1 (1.5)
Idelalisib 0 (0.0) 2 (3.1)
O he he apies
c 8 (4.3) 4 (6.3)
Benda = bendamus ine; BR = bendamus ine plus i uximab; CHOP = cyclophos-
phamide, doxo ubicin, inc is ine, and p ednisolone; Clb = chlo ambucil; FC = fluda abine-
cyclophosphamide; CVP = cyclophosphamide, inc is ine, and p ednisone; FCM = fluda a-
bine, cyclophosphamide, and mi oxan one; G = obinu uzumab; R = i uximab
a
Chemoimmuno he apy egimens used in > 1 pa ien each;
b
Chemo he apy egimens used in > 1 pa ien each;
c
O he he apies used in one pa ien each
had p e iously ecei ed CIT as i s -line ea men , mos commonly
FCR (40.5%) and BR (15.7%). Fo y-eigh (75%) pa ien s ecei -
ing ib u inib as hi d-line ea men had been ea ed wi h CIT in
he second line, mos equen ly BR (43.8%). Idelalisib was used in
4 and 3 pa ien s in he i s - and he second-line se ing, espec i ely.
Ib u inib T ea men
Pa ien s ini ia ed ea men wi h single-agen ib u inib be ween
June 2016 and Janua y 2019. The median ime om diagnosis o
ib u inib ea men ini ia ion was 21 (IQR: 3.4-48.6) mon hs. The
median du a ion o ib u inib ea men was 18.4 (IQR: 12.5-26.6)
mon hs (up o 40 mon hs). A da a cu -o , 220 (82.8%) pa ien s
emained on ib u inib ea men while 49 (18.2%) pa ien s had
discon inued ib u inib. The main easons o ea men discon in-
ua ion we e disease p og ession (16/269; 5.9%) and AEs (16/269;
5.9%). Fou (4.8%) and 6 (4.9%) pa ien s discon inued ib u inib
ea men due o AEs in he i s - and second-line se ings. Discon-
inua ion due o disease p og ession occu ed in 6 (7.1%) i s -line
pa ien s and in 9 (7.4%) pa ien s ecei ing ib u inib in he second-
line se ing ( Table 3 ). The p opo ion o pa ien s discon inuing
ea men due o disease p og ession ( ≤65 yea s: 30.0%; > 65 yea s:
34.5%) and AEs ( ≤65 yea s: 30.0%; > 65 yea s: 34.5%) was no
signi ican ly di e en be ween pa ien s aged ≤65 yea s and pa ien s
olde han 65 yea s ( P = .811).
Ou he 16 pa ien s who discon inued ib u inib ea men due o
disease p og ession ( i s -line: n = 6; second-line: n = 9), 9 (56.3%)
pa ien s ha bo ed del(17p)/TP53 mu a ion ( i s -line: n = 5;
second-line: n = 4), 2 (13.3%) pa ien s had del(11q) (second-line:
n = 2), and 7 (77.8%) pa ien s ca ied unmu a ed IGHV ( i s -line:
n = 3; second-line: n = 3).
Dose educ ion was equi ed in 53 (19.7%) pa ien s, and o
hese, only 7 pa ien s (13.2%) needed a u he dose educ ion.
The occu ence o AEs was he eason o dose educ ion in 31
(11.5%; 31/269) pa ien s. O e all, 13 (4.8%) and 18 (6.7%)
pa ien s equi ed dose educ ions due o hema ological and non-
hema ological AEs, espec i ely. Eigh (9.5%) and 14 (11.6%)
pa ien s equi ed dose educ ions due o AEs du ing i s - and
second-line ib u inib ea men , espec i ely ( P = .819) ( Table 3 ).
Ib u inib dose was inc eased o 420 mg in 25 (47.2%) pa ien s
in whom dose educ ions had p e iously been necessa y (n = 53).
Ib u inib was empo a ily in e up ed in 107 (39.8%) pa ien s, wi h
66 (61.7%) pa ien s equi ing one ea men in e up ion only. O
he ea men in e up ions (n = 168), 25% (42/168) we e due
o majo and/o mino su gical p ocedu es. Tempo a y in e up-
ion o i s - and second-line ib u inib occu ed in 27 (32.1%) and
52 (42.9%) pa ien s, espec i ely. We obse ed a end owa d a
highe a e o ea men in e up ions due o AEs in he second
line (21.5%) compa ed wi h he on line se ing (10.7%) ( P =
.058) ( Table 3 ). Median ime o ea men e-ini ia ion a e empo-
a y in e up ion was 11 (6.2-21.3) days. Single-agen ib u inib
ea men was ein oduced a he s anda d dose o 420 mg in
Clinical Lymphoma, Myeloma and Leukemia Decembe 2021 e989

Real-Wo ld-E idence o Ib u inib o CLL ea men
Table 3 Ib u inib T ea men Modi ica ion and Discon inua ion
T ea men modi ica ion Fi s Line Second Line O e all Popula ion
N (%) N (%) N (%)
(N = 84) (N = 121) (N = 269)
Dose educ ion 17 (20.2) 22 (18.2) 53 (19.7)
Pa ien s wi h a leas one dose educ ion due o oxici y
a 8 (9.5) 14 (11.6) 31 (11.5)
To al numbe o dose educ ions 18 24 60
Dose educ ions due o oxici y
b 8 (44.4) 16 (66.7) 34 (56.7)
Hema ological oxici y 4 (22.2) 7 (29.2) 16 (26.7)
Non-hema ological oxici y 4 (22.2) 9 (37.5) 18 (30.0)
Dose inc ease a e educ ion
b 7 (38.9) 12 (50.0) 33 (55.0)
Tempo al ea men in e up ion 27 (32.1) 52 (43.0) 107 (39.8)
Pa ien s wi h a leas one in e up ion due o oxici y
a 9 (10.7) 26 (21.5) 31 (11.5)
To al numbe o ea men in e up ions 39 87 168
T ea men in e up ions due o oxici y
c 11 (28.2) 38 (43.7) 63 (37.5)
Hema ological oxici y 10 (25.6) 13 (14.9) 19 (11.3)
Non-hema ological oxici y 2 (5.1) 25 (28.7) 46 (27.4)
T ea men discon inua ion 15 (17.8) 21 (17.3) 49 (18.2)
Reasons o ea men discon inua ion
a
Disease p og ession 6 (7.1) 9 (7.4) 16 (5.9)
Ad e se e en s 4 (4.8)
d 6 (4.9)
e 16 (5.9)
Dea h 1 (1.2) 2 (1.7) 6 (2.2)
Pa ien decision 0 (0.0) 1 (0.8) 1 (0.4)
O he easons 4 (4.8) 3 (2.5) 10 (3.7)
a
Pe cen ages calcula ed o e he o al numbe o pa ien s ecei ing ib u inib in he o e all popula ion (n = 269), in he fi s line (n = 84) and he second-line se ing (n = 121);
b
Pe cen ages calcula ed o e o al numbe o dose educ ions;
c
Pe cen ages calcula ed o e o al numbe o in e up ions;
d
Pancy openia (n = 1), in ec ion (UTI) (n = 1), esophagi is (n = 1), and ischemic ce eb o ascula acciden (n = 1);
e
gas oin es inal bleeding (n = 2), pneumonia (n = 1), in ec ion (n = 1), and pleu al e usion (n = 1).
84 (78.5%) pa ien s whose ea men was empo a ily in e up ed
(n = 107).
Response o T ea men and Ou come
ORR wi h single-agen ib u inib was 79.2% (95% CI: 73.7%-
83.8%) (CR: 14.1%). ORR was 79.8% (CR: 16.7%) in he i s
line and 76.9% (CR: 13.2%) in he second line ( Table 4 ).
Wi h a median ( ange) ollow-up o 19.2 (12.8-26.9) mon hs (up
o 40 mon hs), he median PFS was no eached ( Figu e 1 A) in
ei he he i s -line o second-line (Supplemen a y Figu e 1), and
es ima ed PFS a e a 24 mon hs was 84.7% (95% CI: 79.2%-
90.1%). Simila ly, median OS was no eached ( Figu e 1 B), i espec-
i e o he line in which ib u inib was used (Supplemen a y Figu e
1). A he ime o analysis, 30 pa ien s had died. Ele en (4.1%)
pa ien s died due o disease p og ession, and second neoplasia was
he eason o dea h in wo pa ien s. Median ime o subsequen
CLL ea men was no eached.
The age o pa ien s a ib u inib ea men ( ≤65 s. > 65 yea s) did
no ha e a signi ican impac ei he on PFS (p = 0.285) o OS ( P =
.055), and he median PFS and OS we e no eached, i espec i e o
he age o pa ien s. Simila ly, ORR was compa able be ween pa ien s
aged ≤65 yea s (95.9%) and pa ien s olde han 65 yea s (94.1%)
( P = .538) (Supplemen a y Table 1).
Median PFS and OS we e no eached ega dless o whe he
pa ien s had any ca dio ascula diso de (hype ension, DM, AF,
o he a hy hmias, and/o s oke) be o e ib u inib ea men ini i-
a ion (n = 149) (Supplemen a y Table 2). ORR was no a ec ed
ei he by he p esence o any ca dio ascula diso de (a ec ing > 5
pa ien s) (Supplemen a y Table 3).
Subg oup analyses ega ding high- isk gene ic ac o s showed ha
o e all esponse was no a ec ed by ei he del(17p)/TP53 mu a ion
( P = .816) o unmu a ed IGHV ( P = .205). Simila ly, he p esence
o del(11q) did no un a o ably a ec ea men esponse ( P =
.298) (Supplemen a y Table 4). The p esence o complex ka yo ype
(n = 18) did no impac esponse o ea men ei he ( P = .308)
(Da a no shown).
Median PFS was no eached wi h single-agen ib u inib, i espec-
i e o he p esence o del(17p)/TP53 mu a ion (p = 0.439),
del(11q) ( P = .826), o unmu a ed IGHV ( P = .282). Simila ly,
none o hese gene ic al e a ions ad e sely a ec ed OS, which was
no eached in all subg oups ( Figu e 2 ). Median PFS o pa ien s
wi hou complex ka yo ype (n = 209) was no eached (95% CI:
no eached [NR]-NR), while i was 28 mon hs (95% CI: 17.4-
e990 Clinical Lymphoma, Myeloma and Leukemia Decembe 2021
Pau Ab isque a e al
Table 4 Summa y o Response o Single-Agen Ib u inib in he O e all Popula ion and he Fi s - and he Second-Line Se ing
Va iable Fi s -Line Second-Line O e all Popula ion
N (%) N (%) N (%)
(N = 84) (N = 121) (N = 269)
Response
CR 14 (16.7) 16 (13.2) 38 (14.1)
PR 27 (32.1) 30 (24.8) 85 (31.6)
PR + lymphocy osis 12 (14.3) 17 (14.0) 33 (12.3)
SD 1 (1.2) 3 (2.5) 5 (1.9)
PD 0 (0.0) 4 (3.3) 4 (1.5)
Re ac o iness 0 (0.0) 2 (1.7) 2 (0.7)
No e alua ed 13 (15.5) 17 (14.0) 40 (14.9)
Dea h 3 (3.6)
a 2 (1.7)
b 5 (1.9)
c
Non-confi med CR
d 14 (16.7) 30 (24.8) 57 (21.2)
ORR
e 79.8 76.9 79.2
95% CI 69.6-87.8 68.3-84.0 73.7-83.8
CI = confidence in e al; CR = comple e esponse; ORR = o e all esponse a e; PD = p og essi e disease; PR = pa ial esponse; SD = s able disease.
a
Due o disease p og ession in one pa ien
b
Due o disease p og ession in pa ien s
c
Due o disease p og ession in 4 pa ien s
d
No confi med by bone ma ow biopsy o imaging (CT)
e
Including CR, non-confi med CR, PR, and PR + lymphocy osis.
Figu e 1 Kaplan-Meie cu es o p og ession- ee su i al (A) and o e all su i al (B) wi h single-agen ib u inib.
CI = con idence in e al, NR = no eached. Pa ien s we e censo ed a he da e o he las a ailable ollow up i s ill
ali e o wi hou disease p og ession a he ime o he analysis.
Clinical Lymphoma, Myeloma and Leukemia Decembe 2021 e991
Real-Wo ld-E idence o Ib u inib o CLL ea men
Figu e 2 Kaplan-Meie cu es o p og ession- ee su i al acco ding o he p esence/absence o del(17p)/TP53 mu a ion (A)
and del(11q) (C), and IGHV mu a ion s a us (E). Kaplan-Meie cu es o o e all su i al acco ding o he
p esence/absence o del(17p)/TP53 mu a ion (B) and del(11q) (D), and IGHV mu a ion s a us (F). CI = con idence
in e al, NR = no eached. Pa ien s we e censo ed a he da e o he las a ailable ollow up i s ill ali e o wi hou
disease p og ession a he ime o he analysis.
e992 Clinical Lymphoma, Myeloma and Leukemia Decembe 2021
Pau Ab isque a e al
40.0) o pa ien s wi h a complex ka yo ype (n = 18), wi h no
signi ican di e ences be ween hese subg oups ( P = .174). The
p esence o complex ka yo ype did no ha e an ad e se impac on
OS ei he (NR [95% CI: NR-NR] s. 31.3 [95% CI: 30.4-32.2],
P = .127).
Uni a ia e COX eg ession analysis showed ha none o he
co a ia es assessed we e signi ican ly associa ed wi h PFS, ega d-
less o he line in which ib u inib was used. None o he a iables
achie ing a s a is ical signi icance P < .2 in he uni a ia e analysis
we e iden i ied as independen ac o s ad e sely a ec ing PFS wi h
single-agen ib u inib in he mul i a ia e analysis (Supplemen a y
Table 5).
Among pa ien s who expe ienced disease p og ession on ib u i-
nib ea men (n = 19), 11 (57.9%) pa ien s ca ied del(17p)/TP53
mu a ion, 4 (23.5%) pa ien s had del(11q), and 3 (27.3%) pa ien s
ha bo ed unmu a ed IGHV. A mul i a ia e logis ic eg ession
analysis was pe o med o assess po en ial ac o s associa ed wi h
disease p og ession, in which age, line o he apy, and cy oge-
ne ic cha ac e is ics (del(11q), del(17p)/TP53 mu a ion, and IGHV
mu a ion s a us) we e assessed. The mul i a ia e analysis iden i ied
del(17p)/TP53 mu a ion as he only independen ac o associa ed
wi h disease p og ession (OR: 2.570, 95% CI: 0.995-6.635; P =
.05), which was associa ed wi h a highe isk o disease p og ession
(da a no shown).
Immune Recons i u ion
Mean IgA le els inc eased om 133.0 ±285 mg/dL a ib u i-
nib ea men ini ia ion (n = 212) o 143.0 ±230.7 mg/dL a he
end o ea men (n = 178). When pai ed analysis was pe o med
(n = 165), we ound ha mean IgA le els signi ican ly inc eased
om he ini ia ion o single-agen ib u inib o he end o ea -
men (124.1 s. 146.6 mg/dL, espec i ely; P < .001). The mean
CD4/CD8 a io was 1.6 a ib u inib ea men ini ia ion (n = 80),
and 1.4 a he end o ea men (n = 42). O e all, 37 pa ien s had
a ailable da a o pai ed analysis, showing ha he CD4/CD8 a io
did no change om ib u inib ea men ini ia ion o he end o
ea men (1.3 s. 1.2 espec i ely; p = 0.100).
Pos ib u inib T ea men o R/R CLL
Six een (5.9%) pa ien s ecei ed a u he line o he apy o
CLL a e ib u inib ea men discon inua ion. The he apies (CIT,
chemo he apy, and a ge ed agen s) used a e discon inua ion o
i s - and second-line ib u inib ea men a e desc ibed in Supple-
men a y Table 6.
Sa e y
A o al o 188 (69.9%) pa ien s expe ienced a leas one AE
du ing ib u inib ea men . The mos equen AEs (any g ade)
( epo ed in > 10%) we e in ec ions (28.3%), bleeding (20.8%),
dia hea (14.9%), and a h algia/myalgia (11.2%). AF and o he
a hy hmias o any g ade occu ed in 8 (3%) and 7 (2.6%) pa ien s,
espec i ely. Hype ension occu ed in 11 (4.1%) pa ien s. O e all,
83 (30.9%) pa ien s expe ienced a leas one g ade 3 o highe AE,
wi h in ec ions (12.2%), neu openia (7.0%), and bleeding (3.0%)
being he mos common ( epo ed in ≥3%) ( Table 5 ).
O e all, 67.9% (57/84) and 71.9% (87/121) o pa ien s expe i-
enced a leas one AE du ing i s - and second-line ib u inib ea -
men , espec i ely. The mos common g ade 3-4 AEs ( epo ed
in > 2%) we e in ec ions ( i s -line: 7.2%; second-line: 11.6%),
and bleeding ( i s -line: 2.4%; second-line: 2.5%). G ade ≥3 AF
was epo ed in one pa ien (1.2%) and 2 pa ien s (1.7%) du ing
i s - and second-line ib u inib, espec i ely. None o he pa ien s
expe ienced o he a hy hmias o g ade ≥3. G ade ≥3 hype ension
occu ed in one pa ien ecei ing second-line ib u inib ( Table 5 ).
Rich e ans o ma ion was no epo ed in any pa ien .
O he 149 (55.4%) pa ien s wi h baseline ca dio ascula como -
bidi y (hype ension, DM, AF, o he a hy hmias, and/o s oke), 6
(4%) pa ien s de eloped AF (any g ade) du ing ib u inib ea men .
The incidence o new-onse AF du ing ib u inib ea men was no
signi ican ly associa ed wi h he p esence o ca dio ascula como -
bidi y a ea men ini ia ion (p = 0.305) (da a no shown).
O e all, 56 (20.8%) pa ien s expe ienced bleeding du ing ib u i-
nib he apy, mainly mino bleeding (g ade 1 o 2) (17.5%). Majo
bleeding (g ade ≥3) was epo ed in 7 (2.6%) pa ien s. Mino bleed-
ing occu ed be o e majo bleeding in 2 pa ien s. The use o an ico-
agulan s and/o an ipla ele s was associa ed nei he wi h he occu -
ence o bleeding ( P = .137) no wi h he ype o bleeding ( P =
.579) (Supplemen a y Table 7). O e all, 66 pa ien s we e ecei -
ing an icoagulan and/o an ipla ele he apy du ing ib u inib ea -
men , wi h 39 (14.5%) pa ien s being ea ed wi h DOACs (apixa-
ban: n = 17; dabiga an: n = 3; edoxaban: n = 2; i a oxaban:
n = 2). Th ee pa ien s who we e ecei ing VKAs (n = 1) and
DOACs (n = 2) expe ienced majo bleeding. O hese, one pa ien
was ea ed wi h acenocouma ol, and one pa ien was gi en dabiga-
an while ecei ing i s - and second-line ib u inib ea men ,
espec i ely.
A o al o 167 in ec ions (any g ade) (in ec ions: n = 131; espi-
a o y in ec ions; n = 36) occu ed in 93 (34.6%) pa ien s. O
he 131 in ec ions de ec ed, 98 (77.2%) we e bac e ial in ec ions,
mainly pneumonia (32.3%) and in ec ions a ec ing he u ina y
ac (12.6%). O e all, 20.5% o in ec ions epo ed we e i al
in ec ions, mos commonly in luenza (6.2%) and he pes zos e
(3.9%). Se en ungal in ec ions we e epo ed (nonin asi e candidi-
asis: n = 5; in asi e aspe gillosis (IA): n = 1; muco mycosis: n = 1).
Two (0.7%) pa ien s expe ienced oppo unis ic in ec ions (IA and
muco mycosis), bo h epo ed in pa ien s in he R/R se ing. An
oppo unis ic in ec ion (IA) was epo ed in one pa ien ecei ing
second-line ib u inib who had been p e iously ea ed wi h high-
dose co icos e oids and alem uzumab (Supplemen a y Table 8). O
no e, he occu ence o in ec ions was no signi ican ly associa ed
wi h he e olu ion o IgA le els om ib u inib ea men ini ia-
ion o ea men end (dec ease, main enance, inc ease) ( P = 0.301)
(Da a no shown).
G ade ≥3 in ec ions (any ype o in ec ion, including lowe
and uppe espi a o y ac in ec ion) we e epo ed in 37 (13.8%)
pa ien s ( i s -line: 8 [9.5%]; second-line: 15 [12.4%]; hi d-line:
14 [21.9%]). O hese, 14 (37.8%) pa ien s ca ied del(17p)/TP53
mu a ion, 7 (19.4%) pa ien s had del(11q), and 4 (17.4%) pa ien s
had unmu a ed IGHV. A mul i a ia e logis ic eg ession analysis
whe e he ea men line and he abo emen ioned gene ic cha ac-
e is ics we e assessed showed ha he line in which ib u inib was
Clinical Lymphoma, Myeloma and Leukemia Decembe 2021 e993