Microsoft Word - Mabthera IV_CDS 27.0_0216-MAB-01_all DP sites in license _clean_Current

0216-MAB-01 000928 Solution for IV Infusion (Tumor Lysis Syndrome; TLS) (Severe Mucocutaneous Reactions) B (HBV) (Progressive Multifocal Leukoencephalopathy; PML) () 24 80% ( 2.4 2.6 ) (TLS) TLS ( 2.4 2.6 ) () ( 2.4 2.6 ) B (HBV) B HBV B ( 2.4 ) (PML) JC PML ( 2.4 2.6 ) 1 1.1 / ATC Code: L01XC02 1.2 1.3 (i.v.) 1

1.4 / 1.5 rituximab () 100 /10 500 /50 polysorbate 80 2 2.1 B- CVP ()B CHOP CD20 B methotrexate ( ) (TNF) () methotrexate X () fludarabine cyclophosphamide CD20 (CLL) () / CD20 (Granulomatosis with Polyangiitis, GPA)(Wegener s ) (Microscopic Polyangiitis, MPA) () (glucocorticoids) (GPA ) (MPA) 2.2 () 2

(i.v. push or bolus) ( 4.2 ) (Low-grade or Follicular Non-Hodgkin s Lymphoma (NHL)) () (premedication)/ ( paracetamol) ( diphenhydramine) (glucocorticoids) () () () 375 /(BSA) ( ) () CVP (cyclophosphamide, vincristine and prednisolone) 375 / 8 (21 /) CVP (glucocorticoids) 50 / 30 50 / 400 / () 100 / 30 100 / 400 / () 375 / ( ) () 2 375 / (12 ) /() 3 375 / B (Diffuse Large B-cell NHL) () (premedication)/ ( paracetamol) ( diphenhydramine) 3

(glucocorticoids) () () () CHOP (cyclophosphamide doxorubicin prednisone vincristine) () 375 / 8 CHOP (glucocorticoid) CHOP () 50 / 30 50 / 400 / () 100 / 30 100 / 400 / (Chronic Lymphocytic Leukaemia (CLL)) () (premedication)/ ( paracetamol) ( diphenhydramine) (glucocorticoids) () CLL 48 (uricostatics)>25x10 9 / CLL () prednisone/prednisolone 100 ( ) () / () 1 375 / 1 500 / 28 6 ( 3.1.2 /)() 50 / 30 50 / 400 / () 100 / 30 100 / 400 / (Rheumatoid Arthritis) 4

() (premedication)/ ( paracetamol) ( diphenhydramine) (glucocorticoids) () 30 100 methylprednisolone ( 2.4 ) () 500-1,000 () 500-1,000 2 2 500-1,000 24 DAS28-ESR 2.6 () ( 3.1.2 /) 16 24 28 50 / 30 30 50 / 400 / 4.25 () 100 / 30 100 / 400 / 3.25 ( ) 4 / 250 () 120 30 250 / 90 600 / 120 120 (clinically significant) ( ) () () (GPA)(Wegener s ) (MPA) () (premedication)/ ( paracetamol) ( diphenhydramine) () (GPA) (MPA) 375 / 4 Methylprednisolone 1,000 1-3 prednisone 1 /( 80 ) () () 14 () 5

50 / 30 50 / 400 / () 100 / 30 100 / 400 / (GPA) (MPA) () 6 (Pneumocystis jiroveci pneumonia) 2.2.1 () (>65 ) 2.3 rituximab () 2.4 2.4.1 () (infusion-related reaction) (cytokines) /(chemical mediators) (cytokine release syndrome) () () 30-2 ( 2.6 ) (high tumor burden) (>25 10 9 /) (CLL)(mantle cell lymphoma) diphenhydramine acetaminophen 50% ( 100 50 ) 6

() (>25 10 9 /)(high tumor burden) (CLL)(mantle cell lymphoma) () >25 x 10 9 / / () X 1 2 ( 2.2 ) () CD20 () (tumor lysis syndrome TLS)( ) ((>25 x 10 9 /) CLL <mantle cell lymphoma> ) TLS TLS () () (paraneoplastic pemphigus) - (Stevens-Johnson syndrome) (lichenoid dermatitis) (vesiculobullous dermatitis) (toxic epidermal necrolysis) () 1 () () 7

() 12 () ( ) () () (tumor lysis sydrome) cisplatin () cisplatin () () 6 ( 1-77 ) () 1.5 10 9 // 75 10 9 / () () () CHOP CVP ()( ) (cytomegalovirus) (herpes simplex virus) B19 (parvovirus B19) (varicella zoster virus)(west Nile virus) B C () B (HBV) CD20 ( ()) B B (HBsAg) HBsAg B (anti-hbc) B HBV ( HBsAg anti-hbc B (anti-hbs)) B HBV HBV DNA HBsAg anti-hbc HBsAg B (transaminase) () HBsAg anti-hbc HBV HBV (HBsAg 8

() HBsAg anti-hbc )() B HBV () HBV HBV () 24 HBV () HBV () HBV ()HBV () B (PML) () NHL CLL ( 2.6 2.6.2 ) () NHL CLL PML () () () ( (tetanus recall antigen)(16% vs 81%) (Keyhole Limpet Haemocyanin neoantigen KLH)(4% vs 76% 2 )) (A ) () (Rheumatoid Arthritis)(GPA)(Wegener s ) (MPA) () ()(IRRs) / () (premedication)/ () (glucocorticoids) ( 2.2 2.6 ) RA ( 2.6.2 ) 9

() 1% ( 2.6 ) () () 50% ( 100 / 50 /) GPA MPA RA ( 2.6 (Wegener s ) ) GPA MPA () (glucocorticoids)( 2.2 ) ( RA ) / () () () 12 () ( )( ) () ()() ( CD4 CD8 ) () ( 2.6 ) () B (HBV) CD20 ( ()) B B (HBsAg) HBsAg B (anti-hbc) B HBV ( HBsAg anti-hbc B (anti-hbs)) B HBV HBV DNA HBsAg anti-hbc HBsAg B (transaminase) 10

() HBsAg anti-hbc HBV HBV (HBsAg () HBsAg anti-hbc )() B HBV () HBV HBV () 24 HBV () HBV () HBV ()HBV () B () (paraneoplastic pemphigus) - (Stevens-Johnson syndrome) (lichenoid dermatitis) (vesiculobullous dermatitis) (toxic epidermal necrolysis) () 1 () () (PML) ()( ) () PML () PML PML () () B () RA () () () methotrexate () methotrexate (tetanus recall antigen)(39% vs 42%) (pneumococcal polysaccharide vaccine)(43% vs 82% ) (Keyhole Limpet Haemocyanin neoantigen)(34% vs 80%)() () 11

() Methotrexate(MTX) methotrexate () 2.4.2 () 2.4.3 () (CLL) () fludarabine cyclophosphamide fludarabine cyclophosphamide () methotrexate () (human anti-mouse antibody-hama) (human anti-chimeric antibody-haca) RA 373 () DMARDs 240 DMARD ()( DMARD ) 6.1 / DMARD 4.9 / 2.5 2.5.1 IgG cynomolgus () B () B rituximab B () () 12 2.5.2 12

Rituximab IgG () 2.5.3 ()() (hypogammaglobulinaemia) B 2.6 2.6.1 ()(ADRs) 2% 1/10 1/100 < 1/10 1/1,000 < 1/100 ()/ 356 () ( 3.1.2 /) 671 R-CHOP R-CVP R-FCM () 2 ( 3.1.2 /)() 12 () 1 1 ()(N=356) () (N=671) ( 10%) ( 1% - < 10%) ( 0.1% - < 1%) + + + + (LDH) 13

+ + + + + + + + + IgG ( )+ ( 3 NCI ) () NHL CLL () /( ) 202 R-CHOP B (DLBCL) 234 162 R-CHOP R-CVP 397 () fludarabine cyclophosphamide(r-fc) CLL 274 / CLL ( 3.1.2 /) 2 R-CHOP DLBCL (N=202) R-CHOP (N=234) R-CVP (N=162) R-FC (N=397) / (N=274) ( 10%) ( 1% - < 10%) B * # * R-FC / CLL ( 3 NCI ) 14

# / R-FC / ()( <2%) () ( MCP CHVP-IFN) () CVP CHOP FC 4 50% () ( ) 2 (NHL) 41% ( ) 7% () <1% ( R-CVP NHL R-CHOP DLBCL R-FC CLL) rituximab 12% 1% 4 () 70% 80% B 356 30.3% 3.9% ( 3 4 ) 2 (NHL) 1 4 25% () 45% 3% 11% () ( 3/4 ) () 1% (2%) (2%)(1%) (1%) ( ) 15

( 2%() 10%) ( 7% () 11%) ( 2%() 4%) 2 NHL (PML)(2.4 ) ( R-CVPNHLR-CHOPDLBCLR-FCCLL) R-CVP 28 (R-CVP 33% CVP 32%) R-CVP 12.3% CVP 16.4% R-CVP 4.3% CVP 4.4% R-CHOP R-CHOP 2 4 45.5% CHOP 42.3% 24 R-CHOP (4.5% CHOP 2.6%) R-CHOP 2 4 (4.5%) CHOP (1.5%) R-CHOP 2 4 ( ) 55.4% CHOP 51.5% ( ) R-CHOP 20.8% CHOP 15.3% CLL (R-FC 18% FC 17%)/ (R-FC 19% FC 18%) 28 3 4 3 4 B ( ) R-FC 2% FC 0% 4 4.2% ( 3 4 ) 1.1% 1.7% 2 (NHL) () 3-4 ( 2%() 5%) 3-4 ( 4%() 10%) 3 4 ( 1% () <1%)() B 12 B ( R-CVP NHL R-CHOP DLBCL R-FC CLL) () 3/4 (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%)(R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19%) ( R-FC 3% vs. FC 1%) 16

() / (CLL) () FC 3/4 CLL R-FC 4% 3/4 FC 7% R-FC 7% 3/4 FC 10%/ CLL R-FC 12% 3/4 FC 13% 3/4 R-FC 11% FC 9% 4 18.8% () 3 4 ( ) 2 (NHL) 3 4 <1% () 3% (1%) (1%)(<1%) (<1%) ( R-CVP NHL R-CHOP DLBCL R-FC CLL) R-CHOP R-CHOP 3 4 ( /)(6.9% ) CHOP (1.5% )() ( 2.4 ) 3 4 R-CHOP CHOP CLL 3 4 (R-FC 4% FC 3%) / (R-FC 4% FC 4%) IgG 2 (NHL) () IgG (LLN)(<7 /) IgG LLN ()() IgG LLN 2 60% (2 36%) ( R-CVP NHL R-CHOP DLBCL R-FC CLL) R-CHOP 2% CHOP 1.5% 17

CLL 3 4 (R-FC 4% FC 4%) / (R-FC 3% FC 3%) 4 ( 65 ) 3 4 ( 88.3% 92.0% 3 4 ADR 16.0% 18.1%) ( 65 ) 3/4 / CLL ( 65 ) 3 4 ( 25.6% 15.4%) ( 92.3% 89.2%) () 3 4 3 4 ( 95.0% 89.7% 3 4 13.3% 14.8%) () RA 30006 5 719823002 3 RA ()methotrexate(mtx) RAMTX (MTX-IR)TNF (TNF-IR) ( 3.1.2/) methotrexate(10-25/ ) 2 1000 2 500 () 2 2 ( 2.2 )3 2% 2% 3( 1/10) ( 1/100 <1/10)( 1/1,000 <1/100) 3 () 18

/ ( ( / () 2% 6 () 3095 () 1077 (35%) CTC 1 2 1% (14/3095 ) () CTC 4 ( 2.6.2 ) CTC 3 3 () 720/3095 (23%) (/ ) ( 2.4 ) 120 () 24 120 () 19

( 3.1.2 /) () (patient year) 97 () 4 3 1.9% ()( 0.8 ) (GPA)(Wegener s ) (MPA) (Wegener s )(GPA) (MPA) 99 ()(375 / 4 ) ( 3.1.2 /) () 10% ( 1/10) 4 (GPA) (MPA) () 6 * ( 10%) Rituximab Cyclophosphamide N=99 N=98 n (%) n (%) a 61 (61.6%) 46 (46.9%) 18 (18.2%) 17 (17.2%) 20 (20.4%) 12 (12.2%) 17 (17.2%) 19 (19.4%) 17 (17.2%) 13 (13.1%) 16 (16.2%) 10 (10.1%) 16 (16.2%) 13 (13.1%) 15 (15.3%) 9 (9.2%) 20 (20.4%) 26 (26.5%) 6 (6.1%) 21 (21.4%) 14 (14.1%) 12 (12.2%) ALT 13 (13.1%) 15 (15.3%) 20

13 (13.1%) 11 (11.1%) 10 (10.1%) 11 (11.2%) 6 (6.1%) 11 (11.2%) 12 (12.1%) 5 (5.1%) b 12 (12.1%) 11 (11.2%) 10 (10.1%) 17 (17.3%) * 13 6 2. a Rituximab b Rituximab (GPA) (MPA) 24 () 99 12% CTC 1 2 () (glucocorticoid) () 99 210 (95% 173-256) 25 () 4% () 2.05 (standardized incidence ratios) (GPA) (MPA) 2.6.1.1 () (hypogammaglobulinaemia; IgG IgM ) IgG IgM () () 0.94% (13/1382) rituximab 0.27% (2/731) (3 4 ) 1.06 0.53 21

0.97 0.88 rituximab (GPA)(Wegener s ) (MPA) () GPA MPA (hypogammaglobulinaemia IgA IgG IgM ) () 6 27% IgA 58% IgG 51% IgM cyclophosphamide 6 25% IgA 50% IgG 46% IgM IgA IgG IgM rituximab GPA MPA 24% rituximab () 23% cyclophosphamide CTC 3 rituximab GPA MPA rituximab 2.6.2 () () ( 2.4 ) () / ( )(leukocytoclastic vasculitis) /( 2.4 ) - (PRES)/ (RPLS) PRES/RPLS PRES/RPLS/ 22

() B rituximab ( 2.4 ) rituximab rituximab rituximab ( (CMV) ) JC ((PML) 2.4 ) C Kaposi ()Kaposi HIV () (GPA)(Wegener s ) (MPA) () (PML) B - (PRES)/ (RPLS) PRES/RPLS PRES/RPLS / ( 2.6.1 ) 2.6.2.1 () Waldenstrom rituximab IgM IgM 4 23

2.7 5000 (2250 / ) B 3. 3.1 3.1.1 Rituximab (chimeric) /(transmembrane) CD20 pre-b B pro-b 95% B-(NHLs) CD20 CD20 Rituximab B CD20 B- (CDC) (ADCC)(apoptosis) rituximab B- () B 6 B 12 ( 2.6.1 ) rituximab B rituximab 2 CD19 20 cells/μl B 6 B B (~4%) () B 3 3 (GPA) (MPA) rituximab CD19 B- 10 cells/μl (84%) 6 (81%) 12 B >10 cells/μl 18 (87%) B >10 cells/μl (human anti-mouse antibody HAMA) 67 356 (human anti-chimeric antibody HACA) 1.1% (4 ) 3.1.2 / 1 4 24

166 B NHL 375 / () 1 4 (intent-to-treat ITT) (overall response rate ORR) 48% (95% 41%-56%)(complete response CR) 6% (partial response PR) 42% (time to progression TTP) 13 ORR IWF B C D IWF A (58% 12%) < 5 > 7 (53% 38%) (< 3 )(50% 22%) (autologous bone marrow transplant ABMT) ORR 78% ABMT ORR 43% LDH (extranodal disease)()( (Fisher s exact test)) 40% 59% (p=0.0186) (stepwise logistic regression) bc1-2 1 8 37 B NHL 375 /() 1 8 ORR 57% (95% 41 73% CR 14% PR 43%) TTP 19.4 ( 5.3 38.9 ) (bulky disease) 1 4 39 ( 10 ) B NHL 375 / () 1 4 ORR 36% (95% 21 51% CR 3% PR 33%) TTP 9.6 ( 4.5 26.8 ) 1 4 58 B- NHL 375 / () 1 4 () 60 ORR 38% (95% 26-51% CR 10% PR 28%) TTP 17.8 ( 5.4-26.6 ) TTP () (12.4 ) CVP 25

322 3 8 CVP ( cyclophosphamide 750 / vincristine 1.4 /( 2 ) 1-5 prednisolone 40 /) () 375 / CVP (R-CVP)() 321 (R-CVP 162 CVP 159 ) 53 () R-CVP CVP ( 27 6.6 p<0.0001 (log-rank test)) R-CVP (CR CRu PR) (80.9%) CVP (57.2%)(p<0.0001 (Chi-Square test)) CVP R-CVP (R-CVP 33.6 CVP 14.7 p<0.0001 (log-rank test)) R-CVP 37.7 CVP 13.5 (p<0.0001 ) (p=0.029 ) 53 R-CVP 80.9% CVP 71.1% 5 () CVP M39021 ORR CR TTP OS n ( ) % % ( ) % TTP 53 CVP 159 57 10 53 14.7 71.1 R-CVP 162 81 41 33.6 80.9 p<0.0001 p=0.029 TTP OS 1193 R-CHOP (n=881) R-CVP (n=268) R-FCM (n=44) 1078 1018 () (n=505)(n=513) () 2 375 /() 2 25 () (PFS)( 6) PFS (independent review committee; IRC) ( 6) () (event-free survival; EFS) (time to next 26

anti-lymphoma treatment; TNLT) (time to next chemotherapy; TNCT) (overall response rate; ORR)( 6) 73 ( 6) 6 ()(25 73 ) a b (N=513) (N=505) (N=513) (N=505) (PFS c ) ( ) NR NR 49 NR p () p < 0.0001 p < 0.0001 HR [95%] () 0.50 [0.39;0.64] 0.58 [0.48;0.69] (OS) ( ) NR NR NR NR p () p = 0.7246 p = 0.8959 HR [95%] () 0.89 [0.45;1.74] 1.02 [0.71;1.47] / 398 389 509 500 (CR/Cru, PR) 219/398(55%) 288/389(74%) 309/509(61%) 395/500(79%) p ( 2 ) p < 0.0001 p < 0.0001 179/398(45%) 101/389(26%) 200/509(39%) 105/500(21%) (CR/CRu) 190(48%) 260(67%) 268(53%) 361(72%) (PR) 29(7%) 28(7%) 41(8%) 34(7%) (SD) 1(<1%) 0(0%) 1(<1%) 1(<1%) (PD) 162(41%) 79(20%) 181(36%) 86(17%) (EFS) ( ) 38 NR 48 NR p () p < 0.0001 p < 0.0001 HR [95%] () 0.54 [0.43;0.69] 0.61[0.51;0.72] (TNLT) ( ) NR NR 71 NR p () p = 0.0003 p < 0.0001 HR [95%] () 0.61 [0.46;0.80] 0.63 [0.52;0.76] (TNCT) ( ) NR NR 85 NR p () p = 0.0011 p = 0.0006 HR [95%] () 0.60 [0.44;0.82] 0.70 [0.57;0.86] (Transformation rate) 27

173 91 278 186 19/513(4%) 11/505(2%) 24/513(5%) 16/505(3%) HRNR 1 = 30.4375 ( 365.25 /12 ) p HR Cox p 2 ( ) a 2009/01/1425.5 b 2013/01/3173 c (CR PR)( ) (<60 60 ) FLIPI ( 1 2 3) (R-CHOP R-CVP R-FCM)() / 465 / NHL CHOP (cyclophosphamide doxorubicin vincristine prednisolone n=231)() CHOP (R-CHOP n=234) 334 () (n=167)(n=167)() 3 375 /() 2 31 CHOP R-CHOP / NHL ( 7) 7 CHOP R-CHOP ( 31 ) CHOP R-CHOP p 1) ORR 2) 74% 87% 0.0003 NA CR 2) 16% 29% 0.0005 NA PR 2) 58% 58% 0.9449 NA OS( ) NR NR 0.0508 32% PFS( ) 19.4 mo. 33.2 mo. 0.0001 38% 1) (hazard ratios) 2) CR PR (trend test) (p < 0.0001) NA NRmo ORR CRPR OS PFS 28 () PFS ( ) (p<0.0001 )() PFS 42.2 14.3 Cox () 28

61% (95% CI 45%-72%) 12 () Kaplan-Meier 78% 57% () (p=0.0039 ) () 56% (95% CI 22%-75%) () ( 38.8 20.1 p<0.0001 ) 50% (95% CI 30%-64%) CR/Cru ( )() (DFS)( 53.7 16.5 p=0.0003 )( 8) 67% (95% CI 39%-82%) 8 () ( 28 ) Kaplan-Meier ( ) (N=167) (N=167) p (PFS) 14.3 42.2 <0.0001 61% NR NR 0.0039 56% 20.1 38.8 <0.0001 50% a 16.5 53.7 0.0003 67% PFS CHOP R-CHOP CR PR 11.6 22.1 14.3 14.3 37.5 51.9 52.8 37.8 <0.0001 0.0071 0.0008 <0.0001 71% 46% 64% 54% OS CHOP R-CHOP NR NR NR NR NR a CR 0.0348 0.0482 55% 56% () (CHOP R-CHOP)(CR PR) ( 8)() CHOP (PFS 37.5 11.6 p<0.0001) R-CHOP (PFS 51.9 22.1 p=0.0071) PFS () CHOP R-CHOP (( ) ( 60 >60 ) ( III IV ) WHO (0 >0) B () ( ) IPI (0-2 3-5) FLIPI (0-1 2 3-5) (0-1 >1 )(<5 5 )(1 2 )(CR/PR NC/PD)(<12 g/dl 12 g/dl) 29

β 2 -(<3 / 3 /) LDH())() B 399 B ( 60 80 ) CHOP (cyclophosphamide 750 / doxorubicin 50 / vincristine 1.4 / 2 prednisolone 1-5 40 /) 3 8 () 375 / CHOP (R-CHOP) () (CHOP 197 R-CHOP 202 ) 31 R-CHOP ( )(p=0.0001) Kaplan Meier R-CHOP 35 CHOP 13 41% 24 R-CHOP 68.2% CHOP 57.4% ( 60 ) R-CHOP CHOP (p=0.0071) 32% () R-CHOP CHOP 8 R-CHOP 76.2% CHOP 62.4% (p=0.0028) R-CHOP 46% 51% ( Ann Arbor ECOG β 2 LDH B ) (R-CHOP CHOP) 0.83 0.95 R-CHOP / 817 CLL 522 / CLL 4 6 FC ( 1-3 fludarabine 25 / cyclophosphamide 250 /) () FC (R-FC)() 375 / 1 500 / 810 (R-FC 403 FC 407 )( 9) ( 10) 552 /(R-FC 276 FC 276 )( 11) 20.7 R-FC ( ) 40 FC 32 (p<0.0001 )( 9) R-FC (p=0.0427 ) 48.1 R-FC 55 FC 33 (p<0.0001 ) R-FC FC (p=0.0319 30

) ( Binet A-C ) PFS ( 10) 9 - () FC FC ( 20.7 ) Kaplan-Meier ( ) FC (N=407) R-FC (N=403) p (PFS) 32.2 (32.8)*** 39.8 (55.3)*** <0.0001 (<0.0001)*** 0.56 (0.55)*** NR (NR)*** NR (NR)*** 0.0427 (0.0319)*** 0.64 (0.73)*** 31.1 (31.3)*** 39.8 (51.8)*** <0.0001 (<0.0001)*** 0.55 (0.56)*** (CR npr PR) 72.7% 86.1% <0.0001 n.a. CR 17.2% 36.0% <0.0001 n.a. * 34.7 (36.2)*** 40.2 (57.3)*** 0.0040 (<0.0001)*** (DFS)** NR NR 0.7882 (48.9)*** (60.3)*** (0.0520)*** CLL NR NR 0.0052 (47.2)*** (69.7)*** (<0.0001)*** CR *** 48.1 (ITT : 409 FC, 408 R-FC) NR n.a. * CR npr PR ** CR 0.61 (0.56)*** 0.93 (0.69)*** 0.65 (0.58)*** 10 Binet (ITT) - 20.7 (PFS) FC R-FC (95% CI) p Binet A 22 18 0.13 (0.03; 0.61) 0.0025 (22)* (18)* (0.39 (0.15; 0.98))* (0.0370)* Binet B 257 259 0.45 (0.32; 0.63) <0.0001 (259)* (263)* (0.52 (0.41; 0.66))* (<0.0001)* Binet C 126 125 0.88 (0.58; 1.33) 0.5341 (126)* (126)* (0.68 (0.49; 0.95))* (0.0215)* CI * 48.1 (ITT : 409 FC, 408 R-FC) / R-FC () 30.6 FC 20.6 (p=0.0002 ) PFS R-FC FC 11 / - () FC FC ( 25.3 ) 31

Kaplan-Meier ( ) FC (N=276) R-FC (N=276) Log-Rank p value (PFS) 20.6 30.6 0.0002 35% 51.9 NR 0.2874 17% 19.3 28.7 0.0002 36% (CR npr PR) 58.0% 69.9% 0.0034 n.a. CR 13.0% 24.3% 0.0007 n.a. * 27.6 39.6 0.0252 31% (DFS)** 42.2 39.6 0.8842-6% CLL 34.2 NR 0.0024 35% CR NR n.a. * CR npr PR ** CR ()( CHOP FCM PC PCM bendamustine cladribine) CLL PFS () (ACR) 2 () 2 15 () 100 methylprednisolone methotrexate WA17042 2-7 8-14 glucocorticoid DAS28 (i.e. DAS28-ESR 2.6) 6 (PRN ) /( 8) 16 WA17042 (REFLEX) 517 TNF (TNF-IR) 24 ACR20 2 x 1000 () 24 56 X () PRN WA17045 (SERENE) 511 methotrexate (MTX-IR) 24 ACR20 32

2 x 500 2 x 1000 () 24 () 48 methotrexate () 2 1,000 ACR 20%( 12) MTX (RF / CCP) ACR ( (HAQ) CRP (/)) 12 ACR (ITT ) ACR +MTX Rituximab+MTX (2 x1000 ) WA17042 ( TNF TNF-IR) WA17045 ( methotrexate MTX-IR) 24 N=201 N=298 ACR20 36 (18%) 153 (51%) *** ACR50 11 (5%) 80 (27%) *** ACR70 3 (1%) 37 (12%) *** 24 N=172 N=170 ACR20 40 (23%) 86 (51%) *** ACR50 16 (9%) 44 (26%) *** ACR70 9 (5%) 17 (10%) *** * p <0.05, ** p 0.001, *** p 0.0001 ()(DAS28) methotrexate () EULAR methotrexate ( 13) 13 DAS28-ESR EULAR (ITT ) +MTX Rituximab+MTX 2 1000 WA17042 (TNF-IR) 24 DAS28 EULAR ( 24 ) WA17045 (MTX-IR) 24 DAS28 EULAR ( 24 ) n=201-0.4 n=201 20% 2% n=171-0.8 n=298-1.9*** n=298 50%*** 15%*** n=168-1.7*** 33

n=172 29% 5% *p <0.05, ** p 0.001, *** p 0.0001 n=170 51%*** 12%*** WA17042 WA17047 X Sharp (modified Total Sharp Score; mtss)(erosion score) (joint space narrowing score) WA17042 TNF-IR () methotrexate 56 () methotrexate X () 56 WA17047 MTX (755 8 4 ) ( 2.4.1 ) 2 x 500 2 x 1000 () 24 ()() 104 Sharp +MTX 2 x 1000mg () methotrexate 52 (progression of joint damage; PJD)( 14) WA17042 2 X MTX(2 x 1000 ) MTX 14 WA17042 WA17047 X (MITT ) +MTX Rituximab+MTX 2 1000 WA17042 (TNF-IR) n=184 n=273 Sharp 2.30 1.01* 1.32 0.60* 0.98 0.41** X 46% 53% NS 52% 60% NS WA17047 (MTX-naive) n=232 n=244 Sharp 1.079 0.359** 0.738 0.233*** 0.341 0.126 X 53% 64%* 55% 67% WA17047 52 WA17042 56 X 34

WA17042 150 +MTX RTX+MTX * p <0.05, ** p 0.001, *** p 0.0001, NS(Non Significant) () (HAQ-DI FACIT-Fatigue SF-36 ) methotrexate ()(HAQ-DI) (FACIT-Fatigue) SF-36 15 HAQ-DI FACIT Fatigue +MTX 1 RTX+MTX 1 WA17042 (TNF-IR) - 24 HAQ a - 24 HAQ MCID - 24 FACIT-Fatigue b WA17045 (MTX-IR) - 24 HAQ a - 24 HAQ MCID - 24 FACIT-Fatigue b N=201-0.1 20% -0.5 N=172 a (170) b -0.21 48% 2.7 (2 x 1000 ) N=298-0.4*** 51% -9.1*** N=170 a (168) b -0.42*** 58%* 6.4*** MCID= 6.33 5.42 a (HAQ) b (FACIT-Fatigue) * p <0.05, ** p 0.001, *** p 0.0001 ( CMH ANOVA ) 16 (SF-36) +MTX RTX+MTX (2 x 1000 ) WA17042 (TNF-IR) N=197 N=294-24 - 24 MCID - 24-24 MCID 0.9 13% 1.3 20% 5.8*** 48%*** 4.7** 38%** WA17045 (MTX-IR) N=147 N=155-24 - 24 MCID 2.7 31% 5.9*** 48% 2.1 4.4** - 24 24% 35%* - 24 MCID MCID= 6.33 5.42 (N) * p <0.05, ** p 0.001, *** p 0.0001 ( CMH ANOVA ) 35

10% HACA HACA HACA B 3 (RF)() ( 45-64% 1) 1 1 RF (ITT RF ) 60 weeks 0 4 16 24 40 20 RF % % change in RF 0-20 -40-60 -80 Rit+MTX (%change) MTX (%change) () 4 IgG () 24 rituximab rituximab ( 6 C A S100 A8 A9 ) (RF anti-cyclic citrullinated peptide )( (osteocalcin) procollagen 1 N terminal peptide (P1NP)) 24 methotrexate ()( methotrexate cyclophophamide ) methotrexate rituximab ( P1NP) 36

(Treatment to Remission) (PRN)( )() ( 2) 2 ACRn (MTX-IR )) 120 (ML25641) 351 TNF methotrexate () ()(n = 306) 6-9 1-2 rituximab (n = 45) 2 x1000mg () methotrexate () 1 15 168 182 ( 1 ) 4.25 ( 15 ) ( 168 182 ) 120 () 120 15 6.5% (95% CI [4.1%-9.7%]) 168 182 (120 ) 37

( 2.6.1 ) (GPA)(Wegener s ) (MPA) 197 (GPA) (MPA)[(ANCA) ] 6 12 15 Chapel Hill Consensus 75%(Wegener s ) 24% (MPA) 1% (BVAS/GPA) 3 BVAS/GPA 96 (49%) 101 (51%) 14 (pulse) methylprednisolone 1000 mg 1 3 6 1 1 () 375 / 4 cyclophosphamide (2mg/kg) 3 6 () acetaminophen (premedication) prednisone (1 mg/kg/day 80 mg) 6 cyclophosphamide azathioprine () GPA MPA 6 (BVAS/GPA) 0 20%() 6 cyclophosphamide ( 17) 17 (ITT ) 6 () Cyclophosphamide (n=99) (n=98) ( Cyclophosphamide) 64% 53% 11% 95.1% b (54%, 73%) (43%, 63%) ( 3%, 24%) a a (-3% > -20%) b 95.1% 0.001 α 12 18 () 44% 6 12 38% 6 12 18 cyclophosphamide ( azathioprine ) 38% 6 12 31% 6 12 18 () () 8 17 15 () GPA MPA () 38

3.2 3.2.1 298 CHOP NHL B (CL 1 )(CL 2 ) (V 1 ) 0.14 /0.59 / 2.7 Rituximab 22 ( 6.1 52 ) 161 4 1 375 / CD19 rituximab CL 2 CD19 CL 2 CD19 CL 2 V 1 (BSA) CHOP BSA (1.53 2.32 ) CHOP V 1 (27.1% 19.0%) WHO rituximab rituximab 203 NHL 1 4 375 / C max 486 /( 77.5 996.6 /) Rituximab CD19 B International Working Formulation (IWF) B C D A 3-6 rituximab 37 NHL 1 8 375 / C max 243 /( 16-582 /) 550 /( 171-1177 / ) Rituximab 6 CHOP 6 375 / rituximab CLL 375 /( ) () 500 / fludarabine cyclophosphamide 500 / C max (N=15) 408 /(97-764 /) 1,000 2 2 rituximab 20.8 ( 8.58 35.9 ) 0.23 / ( 0.091 0.67 / ) 4.6 ( 1.7 7.51 ) 0.26 / 20.4 BSA 39

BSA Rituximab 500 1000 rituximab rituximab C max 157-171 /( 2 x 500 ) 298-341 /( 2 x 1000 ) C max 183-198 /( 2 x 500 ) 355-404 /( 2 x 1000 ) 15-16.5 ( 2 x 500 ) 17-21 ( 2 x 1000 ) C max 16-19% rituximab 500 1000 rituximab C max 170-175 /( 2 x 500 ) 317-370 /( 2 x 1000 )C max 207 /( 2 x 500 ) 377 386 /( 2 x 1000 ) 19 ( 2 x 500 ) 21-22 ( 2 x 1000 ) rituximab TNF (2 x 1000 ) ( 369 / 19.2 ) (GPA)(Wegener s ) (MPA) 97 (GPA) (MPA) rituximab 375 / 4 23 ( 9-49 ) Rituximab 0.312 L/day ( 0.115-0.728 L/day) 4.50 L ( 2.21-7.52 L) HACA HACA 3.2.2 3.2.1 3.2.3 4. 4.1 (EXP) 2 8 () 2-8 24 40

4.2 () 0.9% 5% rituximab 1-4 / () 2 8 24 12 () (polyvinyl chloride)(polyethylene) / ( ) 4.3 10 50 100 2015 2 CDS 27.0 04.15-MAB-3B01 000928 F. Hoffmann-La Roche Ltd. Grenzacherstrasse 124, CH-4070, Basel, Switzerland Roche Diagnostics GmbH Sandhoferstrasse 116, D-68305, Mannheim, Germany Genentech Inc. 4625 NW Brookwood Parkway, Hillsboro, OR 97124, USA F. Hoffmann-La Roche Ltd. 41

Wurmisweg, CH-4303, Kaiseraugst, Switzerland 3 134 9 42