Advances in therapy in

Diffuse Large Cell B cell and Follicular Lymphoma

Dr Robert MarcusKings 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      Waldenström 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 HHV8-

associated 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 ~ 60m), there are 8,450 new NHL cases/year1

Across the EU (population ~ 490m) this equates to an incidence of 69,000 new NHL cases/year

ALBCL

Other

DLBCL

FLMALT lymphoma

Mature T-celllymphoma

CLL/SLL

MCL

PMLBCLBurkitt’s lymphoma

3%2%

2%

12%

8%

31%

22%8%

7%

6%

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

Fisher RI, et al, N Engl J Med. 1993; 328: 1002-1006.

Pat

ien

ts (

%)

Years

100

80

60

40

20

00 1 2 3 4 5 6

CHOP

m-BACOD

ProMACE-CytaBOM

MACOP-B

Patients at risk

Deaths

3-year estimate (%)

225 88 54

223 93 52

233 97 50

218 93 50

p=0.90

Overall survival

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 culturedlong 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

Physiologic function uncertain

Knockout phenotype normal

Expressed on most B-cell malignancies

Resistant to internalisation or shedding after ligation by antibody

Associates with CD40, CD53, MHC class II, CD81

Extracellular

1 2 3 4

Complement fixation

Active signalling

ADCC

FcgR

CR3

CD20on malignantcell surface

Potential effects ofanti-CD20 on tumour cells

GELA-LNH 98.5: CHOP vs Rituximab + CHOP in Previously Untreated DLBCL

Cyclophosphamide 750 mg/m²Doxorubicin 50 mg/m²Vincristine 1.4 mg/m²Prednisolone 40 mg/m²/day x 5 days

3 weeks 8 cycles

Rituximab + CHOP 375 mg/m²

Coiffier B, et al. N Engl J Med 2002; 346:235–243

GELA phase III trial

10-year follow-up of the GELA LNH-98.5 study (R-CHOP vs CHOP in DLBCL): EFS

Time (years)

0 2 4 6 8 100.0

0.2

0.4

0.6

0.8

1.0

CHOP 19%

R-CHOP 34%

p < 0.0001

Ev

ent-

fre

e r

ate

Coiffier et al. Blood 2009 114: Abstract 3741.

Eligibility criteria:•Diffuse large B-cell lymphoma•Previously untreated •Aged 60-80 years •Age-adjusted IPI 1-3

R-CHOP14CHOP14 x 8 cycles

Rituximab x 8 cycles(n = 98)(n = 202)

RANDOMIZE

Interim Results of R-CHOP14 vs. R-CHOP21 in Elderly Patients With DLBCL: LNH03-6B

GELA

Primary endpoint : event-free survivalSecondary endpoints: OS, PFS, DFS, ORR

Median follow-up: 24 months

Delarue et al. ASH 2009; abstract 406.

Darbepoetin alfa

Standard interventionfor anemia

Darbepoetin alfa

R-CHOP21CHOP21 x 8 cycles

Rituximab x 8 cycles(n = 103)

Standard interventionfor anemia

Event-free survivalEvent-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

Risk groupNo of IPI factors

Patients%

4-year PFS % 4-year OS %

Standard IPI

Low 0–1 28 85 82

Low–intermed 2 27 80 81

High–intermed 3 21 57 49

High 4–5 24 51 59

Revised IPI

Very good 0 10 94 94

Good 1–2 45 80 79

Poor 3–5 45 53 55

Sehn LH, et al. Blood 2007; 109:1857–1861.

M o n t h s

0 10 20 30 40 50 60 70 80

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Male without Rituximab(n=325); 3 year rate: 55%

Male with Rituximab(n=325); 3 year rate: 68%

Female without Rituximab(n=287); 3 year rate: 60%

Female with Rituximab(n=285); 3 year rate: 75%

Pro

po

rtio

n

RICOVER-60 Trial (n=1222)

PFS according to Sex and Rituximab

R

Rituximab (375mg/m²)

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

1 15 29 43 57 71 85 99

PBSC PBSCPBSC

mCHOEP IICYC 4500ADR 70VCR 2ETO 960PRD 500

43 64221 77 9814 36 56

mCHOEP IIICYC 4500ADR 70VCR 2ETO 960PRD 500

mCHOEP IVCYC 6000ADR 70VCR 2ETO 1480PRD 500

DSHNHL : R-MegaCHOEP vs R-CHOEP

mCHOEP ICYC 1500ADR 70VCR 2ETO 600PRD 500

CHOEP-14CYC 750ADR 50VCR 2ETO 300PRD 500

PRD and VCR doses are absolute, all others are per m²

days

DSHNHL 2002-1 -- MegaCHOEPEvent-free survival

Months

0 10 20 30 40 50 60 70

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

R-CHOEP-14

R-MegaCHOEP

p=0.050

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

R-CEOP

(n = 81)

R-CHOP

(n = 162)P Value

Deaths 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

Moccia et al. ASH 2009; abstract 408.

Reason for anthracycline contraindication:• Cardiac contraindication: 87%• Prior anthracycline exposure: 9%

Median follow-up: 28 months

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

Months from inclusion

Eve

nt-

free

su

rviv

al (

%)

ABMT (n=55)

DHAP (n=54)

Standard of care in relapsed NHL – Auto BMT/PBSCT is based on what ?

100

80

60

40

20

00 15 30 45 60 75 90

Chemo-sensitive responders:ORR 58%, CR 25%

p=0.002

Updated from Blay JY, et al. Blood 1998;92:3562–3568

CORAL Trial of RICE v DHAP

CD20+ DLBCL

Relapsed/Refractory

R-ICE x 3

R-DHAP x 3

R

A

N

D

O

M

I

Z

E

R

A

N

D

O

M

I

Z

E

SD/POD → Off

PR/CR →

→A BS EC AT M

R x 6

Obs

N=400

Which salvage regimen is the best?

Orlando ASCO May 2009 / Coral study C. Gisselbrecht

PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT)

PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT)

Orlando ASCO May 2009 / Coral study C. Gisselbrecht

N=160

N=228

N=147

N=241

31%

64%

30%

62%

Failure from diagnosis =>= 12 months

EVENT-FREE SURVIVAL BY PRIOR RITUXIMAB - INDUCTION ITT

Failure from diagnosis > 12 months

Standard salvage regimen does not overcome poor prognosis of early relapse

Failure from diagnosis =< 12 months

N= 106

N= 54

N= 41

N= 187

Management of DLBCL

Not in CR

RelapseSecond-line

therapy

Second-line therapy

Investigationalor BSC HDT/ASCT

Investigationalor BSC

CR/PR

CR/PR NR

NR

R-CHOP or R-CHOP-like

CR

Cure

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

Years

Pati

en

ts in

rem

ssio

n

1 rel

2 rel 3 rel 4 rel

Barts data Johnson et al, JCO, 1995

Overall Survival

5 10 15 20 25 30 35

20

40

60

80

100

Years

N= 387

Follicular Lymphoma International Prognostic Index (FLIPI)

Risk group Factors (n) Patients (%) 5-year OS 10-year OS

Low 0–1 36 90.6% 70.7%

Intermediate 2 37 77.8% 50.9%

High 3–5 27 52.5% 35.5%

Solal-Celigny P, et al. Blood 2004; 104:1258–1265.

Nodal regions > 4

Elevated LDH

Age > 60

Stage III/IV

Haemoglobin < 12 g/dl

1.0

00

0.4

0.2

0.8

0.6

0 12 24 36 8448 60 72

p < 0.0001

Pro

bab

ilit

y o

f su

rviv

al

Good

Intermediate

Poor

Months

Criteria for commencing therapy in FL

BNLI

Life threatening organ involvement

“B” symptoms

Bone marrow failure

Rapidly progressive disease over any 3–6 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 Lymphoman % Not

TreatedTTT

(months)

% ORR

CR

OS (yrs)

Portlock 1 ww 44 43 31 NA 10.1

Horning 2 ww 83 38 * 36 NA 11

O’Brien3 ww 56 21 33 NA 6.3

Young 4 ww

PromaceMopp/TNI

44

60

17#

--

34

--

NA/43

NA/78

Both

83 % (4yrs)

Brice 5 ww

Prmust/IF

66

127

20

--

24

--

70

78/70

78 %(5yrs)

70/84 %

Ardeshna 6 ww

Chloramb

151

158

19 (at 10yrs )

--

31.2

--

76/27

90/63

6.7

5.9

1 Portlock et al. Ann Intern Med 1979 4 Young et al. Semin Hematol.19882 Horning et al. N.Engl.J.Med 1984 5 Brice et al. J Clin Oncol 19973 O’Brien et al. Q J Med 1991 6 Ardeshna et al. Lancet 2003

* Including 23% Spont. remissions

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

FLAsymptomatic

Non bulkNo critical

organ failure

FLAsymptomatic

Non bulkNo critical

organ failure

Watch and WaitWatch and Wait

Rituximab 4 weeks standard course followed by maintenance

1 dose every 2 months for 2 years

Rituximab 4 weeks standard course followed by maintenance

1 dose every 2 months for 2 years

RandomisationRandomisationRituximab

4 weeks standard courseRituximab

4 weeks standard course

Trial 1: R-CVP versus CVP study design

• Follicular NHL (IWF B, C, D)

• Stage III−IV 18 years• No prior Rx• Measurable

disease• Central

histology review

RANDOMISE

CVP x 4 cycles(q3wk)

R-CVP x 4 cycles (q3wk)

CVP x 4 cycles(q3wk)

R-CVP x 4 cycles (q3wk)

SD PD

off-study

CR, PR

Rituximab 375 mg/m2 iv day 1Cyclophosphamide 750 mg/m2 iv day 1Vincristine 1.4 mg/m2 iv day 1Prednisone 40 mg/m2 po days 1–5

RESTAGE

Marcus R, et al Blood 2005; 105:1417–1423.

Rituximab-based induction therapy significantly improves time to progression

R-CVP: Median 34 months

CVP: Median 15 months

p < 0.0001

Time (months)

Eve

nt

free

pro

bab

ilit

y

06 12 18 24 30 36 42 48 540 60

0.2

0.4

0.6

0.8

1.0

66 72

Median follow up of 53 months

Marcus R, et al. JCO 2008

CVP ± rituximab in previously untreated FL: disease-free survival (DFS)

R-CVP: median not reached

CVP: median 21 months

Study month

Eve

nt-

free

pro

bab

ility

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 6 12 18 24 30 36 42 48 54 60 66 72

p = 0.0001

Patients at risk:CVP 18 16 14 11 7 6 6 3 3 1 0 0 0R-CVP 66 65 60 57 47 44 38 32 23 9 1 0 0

Median follow-up: 53 months

Marcus R, et al. Blood (ASH Annual Meeting Abstracts) 2006;108:481

First line FL: Phase III trials

FLIPI (LR/IR/HR

)Regimen Phase Pts ORR CR Duration Ref

14 / 41 / 45 R-CHOP III 428 96% 17% TTF: (2y 85%)Hiddemann,

Blood’04

- / 42 / 46R-CHOP

R-BendaIII 540

91.3% 30% PFS: 46.7m(FL)

PFS: n.r.Rummel, ASH’09*

7 / 37 / 56R-MCP-

>IFNIII 201 92% 50% PFS: n.r. (4y71%)

Herold, JCO’07

19 / 41 / 40 R-CVP III 331 81% 41% TTP: 34 moMarcus, Blood’05

19 / 35 / 46R-

CHVP+IFNIII 358 85% 34% PFS: n.r. (5y 53%)

Salles, Blood’08

Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP in Indolent NHL: Final Results

1 29 113

141

Days57 85

Key Eligibility Criteria:

•CD20+ FL (grade 1/2), MCL, MZL, WM, SLL, other LPL

•Stage III/IV

•No prior therapy

•Age ≥ 18 years

1 22 85 106

43 64Days

RANDOMIZE

B-R

R-CHOP

RituximabBendamustineCHOP

Rummel et al. ASH 2009; abstract 405.

Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP in Indolent NHL: Efficacy

Rummel et al. ASH 2009; abstract 405.

24

Hiddemann W, et al. Blood 2006; 108:Abstract 483.

Su

rviv

al p

rob

abil

ity

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 12 36 48 60 72

p < 0.0001

Number of patients at risk:NHL 1996NHL 2000

538 485 457 419 386 332794 621 440 250 108 8

2420

125 46 0

84 96 108 120

GLSG study NHL 2000

GLSG study NHL 1996

Overall survival improvement with rituximab in FL

PRIMA Study : Final Design

PDs/SDsoff study

Indolent NHLstages III–IV,

untreated

Maintenance (SAKK)1 dose every 8 weeks

for 24 months

Observation

CHEMO x 6-8R x 8

R

CR/PR

Ladetto, M. et al. Blood 2008;111:4004-4013

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

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 diagramAdvanced stage FL

Age 60 or over or anthracycline not appropriate

Randomize

R-CVP x 8(3-weekly)

R-FC x 4 then R x 4(3-weekly)

R maintenance every 2 months for 2 years

CT/BM

CT/BM

CT/BM

RANDOMISE

RANDOMISE

CHOP every21 days

(maximum 6 cycles)

CHOP every21 days

(maximum 6 cycles)

R-CHOP every21 days

(maximum 6 cycles)

R-CHOP every21 days

(maximum 6 cycles)

EORTC 20981 Rituximab maintenance in relapsed/resistant

follicular non-Hodgkin’s lymphoma

RANDOMISE

RANDOMISE

Observation (re-treatment as

necessary)

Observation (re-treatment as

necessary)

Rituximab maintenance

(375 mg/m2 every 3 months until relapse or for a

maximum of 2 years)

Rituximab maintenance

(375 mg/m2 every 3 months until relapse or for a

maximum of 2 years)

CRPR

van Oers MH, et al. Blood 2006; 108:3295–3301.

0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :62 69 32 16 10 9 5 0 0

49 76 61 50 39 30 18 8 3

Logrank test: p<0.0001

0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :65 98 64 47 37 29 21 10 1

51 91 70 61 56 45 28 13 4

Logrank test: p=0.043

Progression free survival after CHOP induction

Progression free survival after R-CHOP induction

R maintenance median 3.1 yrs

Observationmedian 1.0 yr

R maintenance median 4.4 yrs

ObservationMedian 1.9 yrs

EORTC 20981 - van Oers JCO 2010 in Press

HR 0.37 HR 0.69

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 andcell death

Mechanisms of action of GA101 (a type II antibody) versus type I antibodies (e.g., rituximab, 2H7)

CD20

B cell

1. Increased direct cell death(type II epitope, elbow-hinge modification)

Fc-γRIIIa

2. Increased ADCCvia increased affinity to the 'ADCC receptor' Fc-γRIIIA

Complement

3. Lower CDC activityunlike rituximab (type I epitope)due to recognition of type II epitope

Effector cell

Tumour response in evaluable patients at the end of induction (13-week

assessment)C

han

ge

in

in

dic

ato

r l

esio

ns

(%)

NHLCLL

100

Patient (N=20)

80

60

40

20

-20

-40

-60

-80

BO21000 Study Design

Rela

pse

d / R

efractory C

D20+

F

ollicu

lar NH

L

CHOP*

FC*

* As determined by investigator** As determined by investigator

and confirmed by Sponsor

Screening

IVRS

CR = Complete ResponsePR = Partial ResponseSD = Stable DiseasePD = Progessive Disease

Ran

do

mizatio

nR

and

om

ization

RO5072759 (400 mg) + CHOP (400 mg: all infusions)

(up to 8 cycles, ~14 patients)

RO5072759 (1600/800 mg) + CHOP (1600 mg: cycle 1 days 1 and 8800 mg subsequent infusions)(up to 8 cycles, ~14 patients)

RO5072759 (400 mg) + FC (400 mg: all infusions)

(up to 6 cycles, ~14 patients)

RO5072759 (1600/800 mg) + FC (1600 mg: cycle 1 days 1 and 8800 mg subsequent infusions)(up to 6 cycles, ~14 patients)

Treatment

CR

, PR

, SD

or P

D

Response

Su

rviv

al (every 6 m

on

ths)

CR or PR: RO5072759

Maintenance**(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)

+ 2-year Follow-up

(no maintenance)

PD

(maintenance only)

Total: approx. 56 eligible patients

CD22-Targeted Chemotherapy, CMC-544

HumanizedIgG4 anti-CD22

NAc-gamma Calicheamicin

DMH

OOCCHHOO

33

MeMe

OO

OO

NHNH OO

NHNNHN

MeMe MeMe

SS

HH

HHOOOO

OOCCHH33

NNHH OO

OO

OOCCHH33

NNEE ttOO

OOHHHH33

CCHH

OOCCHH33HHNN

HHOO

OOOO

OOHH

CCHH33SS

CCHH33

OOCCHH33

OOCCHH33

II

OO

OO

OOOO

SS

OO

CH3CH3

AcBut linkerAcBut linker

Inotuzumab Ozogamicin

Phase I/II Trial of Inotuzumab Ozogamicin Plus Rituximab: Results

Dang et al. ASH 2009; abstract 584.

Efficacy of CMC-544 MTD

Adverse events

− 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

FL (n = 38) DLBCL (n = 40)Refractory

(n = 28)

ORR 32 (84%) 32 (80%) 5 (18%)

CR 23 (60.5%) 20 (50%) Not reported

1-Year OS Rate 97% 79% Not reached

a

Frontline Therapy With Lenalidomide + Rituximab is Clinically Active in Patients With

Indolent NHL

28 patients received at least 1 post-baseline tumor assessment and were evaluable for response

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%)

Total 28 4 3 21 86% (75%)

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 ?