Advances in therapy in Diffuse Large Cell B

Advances in therapy in Diffuse Large Cell B

Advances in therapy in Diffuse Large Cell B cell and Follicular Lymphoma Dr Robert Marcus Kings College Hospital London WHO classification of B cell malignancy 2008 Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Splenic lymphoma/leukemia, unclassifiable Splenic diffuse red pulp small B-cell lymphoma* Hairy cell leukemia-variant* Lymphoplasmacytic lymphoma Waldenstrm macroglobulinemia Heavy chain diseases: Alpha heavy chain Gamma heavy chain

Mu heavy chain Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone B-cell lymphoma (MZL) Pediatric type nodal MZL Follicular lymphoma Pediatric type follicular lymphoma Primary cutaneous follicle center lymphoma Mantle cell lymphoma

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified T cell/histiocyte rich large B-cell lymphoma DLBCL associated with chronic inflammation Epstein-Barr virus (EBV)+ DLBCL of the elderly Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma rimary cutaneous DLBCL, leg type ALK+ large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma Large B-cell lymphoma arising in HHV8associated multicentric Castleman disease Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma Distribution of NHL subtypes In the UK (population ~ Other 60m), there are 8,450 new NHL cases/year1 Across the EU ALBCL PMLBCL 2% 2% Burkitts lymphoma 3%

(population ~ 490m) this equates to an incidence of 69,000 new NHL cases/year MCL CLL/SLL 12% 31% DLBCL 6% 7% Mature T-cell 8% lymphoma 8% MALT lymphoma 22% FL 1. Leukaemia Research Foundation 2007; Available at: http://www.lrf.org.uk/en/1/infdispatnhl.html. 2. Jaffe E, et al. (Editors). WHO classification of tumors series, vol. 5 2001. Oxford University Press. Comparison of CHOP with Three Intensive Chemotherapy Regimens for Advanced NHL Patients at risk 100 CHOP

m-BACOD 225 223 ProMACE-CytaBOM 233 MACOP-B 218 Patients (%) 80 3-year Deaths estimate (%) 88 93 97 93 54 52 50 50 p=0.90 60 40 20 Overall survival 0 0 1

2 3 4 5 6 Years Fisher RI, et al, N Engl J Med. 1993; 328: 1002-1006. CHOP 14 superior to CHOP 21 Metaanalysis of First Line ASCT Aggressive NHL No Proof of benefit Strehl J, et al. Haematologica. 2003; 88: 1304 - 1315 Hybridoma technology (Koehler and Milstein 1975) Immunisation or infection: Immune-reaction: production of antibodies B-cell: produces antibodies, cannot be cultured long term Myeloma cell: no antibody production, can be cultured indefinitely

Hybridoma cell: produces antibodies, can be cultured indefinitely The CD20 molecule Transmembrane phosphoprotein Single extracellular loop Natural ligand not identified Extracellular Physiologic function uncertain Knockout phenotype normal 1 2 3 4 Expressed on most B-cell malignancies Resistant to internalisation or shedding after ligation by antibody Associates with CD40, CD53, MHC class II, CD81

Potential effects of anti-CD20 on tumour cells ADCC CR3 Complement fixation FcgR Active signalling CD20 on malignant cell surface GELA-LNH 98.5: CHOP vs Rituximab + CHOP in Previously Untreated DLBCL GELA phase III trial Cyclophosphamide 750 mg/m Doxorubicin 50 mg/m Vincristine 1.4 mg/m Prednisolone 40 mg/m/day x 5 days 3 weeks 8 cycles Rituximab + CHOP 375 mg/m Coiffier B, et al. N Engl J Med 2002; 346:235243 10-year follow-up of the GELA LNH-98.5 study (R-CHOP vs CHOP in DLBCL): EFS 1.0 Event-free rate 0.8

0.6 R-CHOP 34% 0.4 0.2 CHOP 19% p < 0.0001 0.0 0 2 4 6 8 10 Time (years) Coiffier et al. Blood 2009 114: Abstract 3741. Interim Results of R-CHOP14 vs. R-CHOP21 in Elderly Patients With DLBCL: LNH03-6B GELA Eligibility criteria: Diffuse large B-cell lymphoma Previously untreated Aged 60-80 years Age-adjusted IPI 1-3 R A N D O M I Z E (n = 202) R-CHOP21 CHOP21 x 8 cycles Rituximab x 8 cycles (n = 103) R-CHOP14 CHOP14 x 8 cycles Rituximab x 8 cycles (n = 98) Darbepoetin alfa Standard intervention for anemia Darbepoetin alfa Standard intervention for anemia Primary endpoint : event-free survival Secondary endpoints: OS, PFS, DFS, ORR Median follow-up: 24 months Delarue et al. ASH 2009; abstract 406.

Event-free survival Median EFS : - 22 months (R-CHOP14) vs NR (R-CHOP21) 2-year EFS : - 48% (R-CHOP14) vs 61% (R-CHOP21) Revised IPI in the rituximab era No of IPI factors Patients % 4-year PFS % 4-year OS % 01 28 85 82 Lowintermed 2 27 80 81 Highintermed

3 21 57 49 45 24 51 59 0 10 94 94 Good 12 45 80 79 Poor

35 45 53 55 Risk group Standard IPI Low High Revised IPI Very good Sehn LH, et al. Blood 2007; 109:18571861. RICOVER-60 Trial (n=1222) PFS according to Sex and Rituximab 1 0.9 Proportion 0.8 0.7 0.6 Female with Rituximab (n=285); 3 year rate: 75% 0.5 0.4 Male with Rituximab (n=325); 3 year rate: 68%

0.3 Female without Rituximab (n=287); 3 year rate: 60% 0.2 0.1 Male without Rituximab (n=325); 3 year rate: 55% 0 0 10 20 30 40 50 Months 60 70 80 DSHNHL : R-MegaCHOEP vs R-CHOEP mCHOEP I CYC 1500

ADR 70 VCR 2 ETO 600 PRD 500 14 PBSC PBSC mCHOEP II CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mCHOEP III CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mCHOEP IV CYC 6000 ADR 70 VCR 2 ETO 1480 PRD 500 22 36 43

56 64 77 98 days PRD and VCR doses are absolute, all others are per m Rituximab (375mg/m) 99 CHOEP-14 85 71 CHOEP-14 57 CHOEP-14 43 CHOEP-14 29 CHOEP-14

CHOEP-14 CYC 750 ADR 50 VCR 2 ETO 300 PRD 500 15 CHOEP-14 1 CHOEP-14 R 1 PBSC DSHNHL 2002-1 -- MegaCHOEP Event-free survival 1 p=0.050 0.9 0.8 0.7 0.6 0.5 0.4 R-CHOEP-14 0.3

R-MegaCHOEP 0.2 0.1 0 0 10 20 30 40 Months 50 60 70 Survival in NHL by age Age range of recent NHL trials Replacement of Doxorubicin by Etoposide (R-CEOP) in Patients With Contraindication to Anthracyclines: Retrospective Analysis Reason for anthracycline contraindication: Cardiac contraindication: 87% Prior anthracycline exposure: 9% Median follow-up: 28 months R-CEOP (n = 81)

R-CHOP (n = 162) P Value 33 (41%) 48 (30%) - 5-Year Time to Progression 57% 62% .21 5-Year Overall Survival 49% 64% .02 5-Year Disease-Specific Survival 64% 68% .17 Deaths

Moccia et al. ASH 2009; abstract 408. Acute Hepatitis B ...in a Patient with Receiving Rituximab Dervite et al NEJM January 2001 ( letter ) Reactivation of Hepatitis B in heavily pretreated 69 year old patient with FL after Rituximab therapy Rise in ALT , Bilirubin HBV DNA Spontaneous recovery ( ! ) Incidence of Hepatitis B reactivation with rituximab Out of 456 patients, 32 were Hep B positive 14 received rituximab monotherapy 18 received rituximab plus chemotherapy Group Patients (n) HBsAg HBsAb HBcAb Liver event (%) A 12 +

+ 3 (25) B 6 + 2 (33) C 8 Not available + 2 (25) D 6 + Variable

Variable 4 (66) A total of 5 patients developed liver failure (15%) Hanbali A, et al. Blood 2006; 108:Abstract 2766. Progressive Multifocal Leukoencephalopathy after Rituximab therapy in HIV-negative patients: 57 cases R A D E R Project PML described in 57 patients treated with Rituximab ( 52 with Lymphoma or other lymphoproliferative disorders Purine analogs in 26 , Alkylating agents in 39 Time from R to onset of symptoms 5 months >90 % fatality in 2 months Carson et al Blood May 2009 Precautions with Rituximab Hepatitis B reactivation : check and offer Lamivudine to patients at risk PML very rare complication , usually in heavily pretreated patients only 57 cases world wide high fatality rate Other viruses ( CMV , adeno ) : isolated case reports only Standard of care in relapsed NHL Auto BMT/PBSCT is based on what ? Event-free survival (%) 100

Chemo-sensitive responders: ORR 58%, CR 25% 80 60 ABMT (n=55) 40 DHAP (n=54) 20 p=0.002 0 0 15 30 45 60 Months from inclusion 75 90 Updated from Blay JY, et al. Blood 1998;92:35623568 CORAL Trial of RICE v DHAP Which salvage regimen is the best? R A N

CD20+ DLBCL Relapsed/Refractory D O M I Z N=400 E SD/POD Off R-ICE x 3 AB SE CA TM R-DHAP x 3 R A N Rx6 D PR/CR O M

I Z Obs E Orlando ASCO May 2009 / Coral study C. Gisselbrecht 64% 31% N=160 N=228 PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT) 62% N=147 30% N=241 PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) Orlando ASCO May 2009 / Coral study C. Gisselbrecht

EVENT-FREE SURVIVAL BY PRIOR RITUXIMAB - INDUCTION ITT Failure from diagnosis =>= 12 months Failure from diagnosis > 12 months N= 106 N= 54 Failure from diagnosis =< 12 months Standard salvage regimen does not overcome poor prognosis of early relapse N= 41 N= 187 Management of DLBCL R-CHOP or R-CHOP-like CR Cure Not in CR Second-line therapy Relapse CR/PR Second-line therapy

NR Investigational or BSC CR/PR HDT/ASCT NR Investigational or BSC Signposts for the future Most patients are > 60 years of age how to tailor therapy for this age group Early levels of R determine response new trials to exploit this Can we utilise the signalling pathways in ABC subtype to design new rational therapy Newer MoAbs ( GA-101 , Ofatumomab ) to be explored on DLBCL Follicular Lymphoma Natural history of FL 100 Overall Survival 60 40

20 N= 387 Patients in remssion 80 1 rel 4 rel 5 10 15 20 25 30 3 rel 2 rel 35 Years Years Barts data Johnson et al, JCO, 1995 Nodal regions > 4

Elevated LDH Age > 60 Stage III/IV Haemoglobin < 12 g/dl Risk group Low Intermediate High Probability of survival Follicular Lymphoma International Prognostic Index (FLIPI) 1.0 0.8 0.6 0.4 Good Intermediate Poor 0.2 0 0 p < 0.0001 12 24 36 48 60 72 84 Months Factors (n) Patients (%) 5-year OS 10-year OS 01 36 90.6% 70.7% 2 37 77.8% 50.9% 35 27 52.5% 35.5% Solal-Celigny P, et al. Blood 2004; 104:12581265. Criteria for commencing therapy in FL BNLI Life threatening organ involvement B symptoms

Bone marrow failure Rapidly progressive disease over any 36 month period GELA Bulky disease : nodal/ extranodal mass > 7cm B symptoms Raised B2-microglobulin /LDH Involvement of 3 nodal sites (>3 cm) Splenic enlargement Compression syndrome Pleural/peritoneal effusion Watch and wait in Follicular Lymphoma n % Not Treated TTT OS

(months) % ORR CR (yrs) Portlock 1 ww 44 43 31 NA 10.1 Horning 2 ww 83 38 * 36 NA 11 OBrien3

ww 56 21 33 NA 6.3 Young 4 ww 44 17# 34 NA/43 PromaceMopp/ TNI Both 83 % (4yrs) 60 -- --

NA/78 ww 66 20 24 70 Brice 5 78 % (5yrs) Ardeshna 6 Prmust/IF 127 -- -- 78/70 70/84 % ww 151 19

31.2 76/27 6.7 -- 90/63 5.9 (at 10yrs ) Chloramb * Including 23% Spont. remissions 158 -- 1 Portlock et al. Ann Intern Med 1979 4 Young et al. Semin Hematol.1988 2 Horning et al. N.Engl.J.Med 1984 5 Brice et al. J Clin Oncol 1997 3 OBrien et al. Q J Med 1991 6 Ardeshna et al. Lancet 2003 Therapy in the pre-antibody era No proven benefit for first line: anthracyclines PBSCT Possible benefit for: interferon with anthracyclines

Intergroup randomised Watch and Wait trial in asymptomatic FL Watch and Wait FL Asymptomatic Non bulk No critical organ failure Randomisation Rituximab 4 weeks standard course Rituximab 4 weeks standard course followed by maintenance 1 dose every 2 months for 2 years Trial 1: R-CVP versus CVP study design Follicular NHL (IWF B, C, D) Stage IIIIV 18 years No prior Rx Measurable disease Central histology review R A N D

O M I S E R-CVP x 4 cycles (q3wk) CVP x 4 cycles (q3wk) Rituximab 375 mg/m2 iv day 1 Cyclophosphamide 750 mg/m2 iv day 1 Vincristine 1.4 mg/m2 iv day 1 Prednisone 40 mg/m2 po days 15 R E S T A G E R-CVP x 4 cycles (q3wk) CR, PR CVP x 4 cycles (q3wk) SD PD off-study Marcus R, et al Blood 2005; 105:14171423. Rituximab-based induction therapy

significantly improves time to progression Median follow up of 53 months Event free probability 1.0 0.8 0.6 R-CVP: Median 34 months 0.4 CVP: Median 15 months 0.2 p < 0.0001 0 0 6 12 18 24 30 36 42 48

54 60 66 72 Time (months) Marcus R, et al. JCO 2008 CVP rituximab in previously untreated FL: disease-free survival (DFS) 1.0 Median follow-up: 53 months Event-free probability 0.9 0.8 0.7 R-CVP: median not reached 0.6 0.5 0.4 0.3 CVP: median 21 months 0.2 0.1 0 p = 0.0001

0 6 12 18 24 48 54 60 66 72 Patients at risk: CVP 18 16 R-CVP 66 65 30 36 42 Study month 14 60 11 57

7 47 6 44 3 23 1 9 0 1 0 0 0 0 6 38 3 32 Marcus R, et al. Blood (ASH Annual Meeting Abstracts) 2006;108:481 First line FL: Phase III trials FLIPI (LR/IR/HR ) Regimen

Phase 14 / 41 / 45 R-CHOP III - / 42 / 46 R-CHOP R-Benda 7 / 37 / 56 R-MCP>IFN Pts ORR CR Duration Ref 428 96% 17% TTF: (2y 85%) Hiddemann, Blood04

III 540 91.3 % 30% PFS: 46.7m(FL) PFS: n.r. Rummel, ASH09* III 201 92% 50% PFS: n.r. (4y71%) Herold, JCO07 19 / 41 / 40 R-CVP III 331

81% 41% TTP: 34 mo Marcus, Blood05 19 / 35 / 46 RCHVP+IFN III 358 85% 34% PFS: n.r. (5y 53%) Salles, Blood08 Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP in Indolent NHL: Final Results B-R Key Eligibility Criteria: CD20+ FL (grade 1/2), MCL, MZL, WM, SLL, other LPL Stage III/IV No prior therapy Age 18 years

Rituximab Bendamustine CHOP R A N D O M IZ E 1 29 57 85 11 3 14 Days 1 22 43 64 85 10

6 R-CHOP 1 Days Rummel et al. ASH 2009; abstract Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP in Indolent NHL: Efficacy Rummel et al. ASH 2009; abstract Overall survival improvement with rituximab in FL Survival probability 1.0 GLSG study NHL 2000 0.8 0.6 GLSG study NHL 1996 0.4 0.2 p < 0.0001 0.0 0 12 24 36 48 538 794 485 621 72 84 96 108 120 Time (months) Number of patients at risk: NHL 1996 NHL 2000 60 457 440 419 250 386

108 332 8 242 0 125 46 0 Hiddemann W, et al. Blood 2006; 108:Abstract 483. PRIMA Study : Final Design CR/PR Indolent NHL stages IIIIV, untreated CHEMO x 6-8 Rx8 Maintenance (SAKK) 1 dose every 8 weeks for 24 months R Observation PDs/SDs off study

HDS versus R-chemotherapy in 134 previously untreated patients with Follicular Lymphoma Trial Design Ladetto, M. et al. Blood 2008;111:4004-4013 PBSCT versus R-chemotherapy in 134 previously untreated patients with Follicular Lymphoma Ladetto, M. et al. Blood 2008;111:4004-4013 Short course FCR as first line therapy in Follicular Lymphoma 81 patients advanced stage FL treated with FC or 4 X FCR + R maintenance ( 46) ORR > 90 % in FCR arm ( higher in patients treated with oral FC !) 24 month FU EFS 90% Minimal toxicity Marin Niebla et al Haematologica 2009; 94[suppl.2]:397 abs. 0985 PACIFICO flow diagram Advanced stage FL Age 60 or over or anthracycline not appropriate CT/BM Randomize R-CVP x 8 (3-weekly) R-FC x 4 then R x 4 (3-weekly)

CT/BM R maintenance every 2 months for 2 years CT/BM EORTC 20981 Rituximab maintenance in relapsed/resistant follicular non-Hodgkins lymphoma R A N D O M I S E CHOP every 21 days (maximum 6 cycles) R-CHOP every 21 days (maximum 6 cycles) CR PR R A N D O M I S

E van Oers MH, et al. Blood 2006; 108:32953301. Observation (re-treatment as necessary) Rituximab maintenance (375 mg/m22 every 3 months until relapse or for a maximum of 2 years) EORTC 20981 - van Oers JCO 2010 in Press Progression free survival after R-CHOP induction Progression free survival after CHOP induction 100 100 90 90 80 80 70

R maintenance median 4.4 yrs 70 60 60 R maintenance median 3.1 yrs 50 50 40 40 30 30 20 Observation median 1.0 yr HR 0.37 Logrank test: p<0.0001 10 0 HR 0.69 Logrank test: p=0.043 20 10 Observation Median 1.9 yrs 0 0 O N 62 69 49 76 1 2 3 4 Number of patients at risk : 32 16 10 9 61 50 39 30

5 6 7 5 0 0 18 8 3 8 0 O N 65 98 51 91 1 2 3 4 Number of patients at risk : 64 47

37 29 70 61 56 45 5 6 7 21 28 10 13 1 4 8 Role of transplantation ?No prospective randomised trials in second CR in post Rituximab era PFS in 1st CR now likely to be > 4 years Transplant confined to early recurrence transformation ? New approaches needed Barts/DFCI Autograft Data 2007 Rohatiner et al , J Clin Onc 2007

W Ingram et al , Brit J Haem 2008 GA101 induces high ADCC and cell death Mechanisms of action of GA101 (a type II antibody) versus type I antibodies (e.g., rituximab, 2H7) CD20 1. Increased direct cell death (type II epitope, elbow-hinge modification) B cell Complement Fc-RIIIa 3. Lower CDC activity unlike rituximab (type I epitope) due to recognition of type II epitope Effector cell 2. Increased ADCC via increased affinity to the 'ADCC receptor' Fc-RIIIA Tumour response in evaluable patients at the end of induction (13-week assessment) 100 Change in indicator lesions (%) 80

60 40 20 -20 NHL CLL -40 -60 -80 Patient (N=20) BO21000 Study Design Screening Response RO5072759 (400 mg) + CHOP RO5072759 (1600/800 mg) + CHOP (1600 mg: cycle 1 days 1 and 8 800 mg subsequent infusions) (up to 8 cycles, ~14 patients) RO5072759 (400 mg) + FC (400 mg: all infusions) (up to 6 cycles, ~14 patients) (every 3 mo for 2 y) CR, PR or SD: 2-year Follow-up (no maintenance **) (+ 6-monthly extended FU,

if CR/PR after 2 years) RO5072759 (1600/800 mg) + FC (1600 mg: cycle 1 days 1 and 8 800 mg subsequent infusions) (up to 6 cycles, ~14 patients) PD (maintenance only) * As determined by investigator ** As determined by investigator and confirmed by Sponsor CR = Complete Response PR = Partial Response Total: approx. 56 eligible patients SD = Stable Disease PD = Progessive Disease Survival (every 6 months) CR or PR: + 2-year RO5072759 Follow-up Maintenance**(no maintenance) (400 mg: all infusions) (up to 8 cycles, ~14 patients)

CR, PR, SD or PD Randomization FC* Randomization Relapsed / Refractory CD20+ Follicular NHL IVRS CHOP* Treatment CD22-Targeted Chemotherapy, CMC-544 Inotuzumab Humanized IgG4 anti-CD22 Ozogamicin AcBut linker O O NH O Me NHN I CH 3 HO Me

CH 3 O S CH 3 O O CH 3 O H OCH 3 OCH 3 OH CH3 O O Me NH S O CH 3 O HN HO O Et O N OCH 3 O

O HO S O O CH 3 O H NAc-gamma Calicheamicin DMH Phase I/II Trial of Inotuzumab Ozogamicin Plus Rituximab: Results Efficacy of CMC-544 MTD ORR CR FL (n = 38) DLBCL (n = 40) Refractory (n = 28) 32 (84%) 32 (80%) 5 (18%)

23 (60.5%) 20 (50%) Not reported 97% 79% Not reached a 1-Year Adverse events OS Rate Grade 3/4 thrombocytopenia (30%) and neutropenia (12%) Common toxicities (all grades) included AST/ALT increases, fatigue, and nausea 19 drug-related SAEs in 12 patients with 2 deaths Dang et al. ASH 2009; abstract 584. Frontline Therapy With Lenalidomide + Rituximab is Clinically Active in Patients With Indolent NHL Tumor subtype n SD PR

CR/CRu ORR (CR/CRu) FL 17 1 0 16 94% (94%) SLL 3 0 2 1 100% (33%) MZL 8 3 1 4

63% (50%) 28 4 3 21 86% (75%) Total 28 patients received at least 1 post-baseline tumor assessment and were evaluable for response CRu=unconfirmed complete response. Fowler et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009; New Orleans, LA. Abstract 1714. Conclusions Addition of Rituximab to chemotherapy has made the largest impact on cure and PFS rates in B cell Lymphoma in past 30 years No improvement with : increased intensity therapy , shortening inter-treatment interval, PBSCT in 1st CR Prospects for patients in relapse post R with DLBCL now very poor . Duration of PFS in FL now likely to be > 5 years Can we afford to make progress ?

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