Real-World Characteristics and Outcome of Patients Treated With Single-Agent Ibrutinib for Chronic Lymphocytic Leukemia in Spain (IBRORS-LLC Study)

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