Advances in therapy in Diffuse Large Cell B cell and Follicular Lymphoma

1
Advances in therapy inDiffuse Large Cell B cell
and Follicular Lymphoma

• Dr Robert Marcus
• Kings College Hospital
• London

2
WHO classification of B cell malignancy 2008

• 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

• 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

3
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

Other
ALBCL
PMLBCL
DLBCL
Burkitts lymphoma
MCL
CLL/SLL
Mature T-celllymphoma
FL
MALT lymphoma
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.
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5
Comparison of CHOP with Three Intensive
Chemotherapy Regimens for Advanced NHL
100
CHOP
m-BACOD
80
ProMACE-CytaBOM
MACOP-B
60
Patients ()
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.
6
CHOP 14 superior to CHOP 21
7
Metaanalysis of First Line ASCT Aggressive NHL
No Proof of benefit
Strehl J, et al. Haematologica. 2003 88 1304 -
1315
8
Hybridoma technology (Koehler and Milstein 1975)
Myeloma cellno antibody production, can be
cultured indefinitely
B-cellproduces antibodies, cannot be
cultured long term
Immunisation or infection
Immune-reaction production of antibodies
Hybridoma cellproduces antibodies, can be
cultured indefinitely
9
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
10
Potential effects ofanti-CD20 on tumour cells
ADCC
CR3
Complement fixation
FcgR
Active signalling
CD20 on malignant cell surface
11
GELA-LNH 98.5 CHOP vs Rituximab CHOP in
Previously Untreated DLBCL
GELA phase III trial
Cyclophosphamide 750 mg/m² Doxorubicin 50
mg/m² Vincristine 1.4 mg/m² Prednisolone 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 346235243
12
10-year follow-up of the GELA LNH-98.5 study
(R-CHOP vs CHOP in DLBCL) EFS
1.0
0.8
0.6
R-CHOP 34
Event-free rate
0.4
0.2
CHOP 19
p lt 0.0001
0.0
0
2
4
6
8
10
Time (years)
Coiffier et al. Blood 2009 114 Abstract 3741.
13
Interim Results of R-CHOP14 vs. R-CHOP21 in
Elderly Patients With DLBCL LNH03-6B GELA
Darbepoetin alfa
R-CHOP21 CHOP21 x 8 cycles Rituximab x 8
cycles (n 103)
RANDOMI ZE
Standard intervention for anemia

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

Darbepoetin alfa
R-CHOP14 CHOP14 x 8 cycles Rituximab x 8
cycles (n 98)
Standard intervention for anemia
(n 202)

• Primary endpoint event-free survival
• Secondary endpoints OS, PFS, DFS, ORR
• Median follow-up 24 months

Delarue et al. ASH 2009 abstract 406.
14
Event-free survival

• Median EFS
• 22 months (R-CHOP14) vs NR (R-CHOP21)
• 2-year EFS
• 48 (R-CHOP14) vs 61 (R-CHOP21)

15
Revised IPI in the rituximab era
Risk group No of IPI factors Patients 4-year PFS 4-year OS
Standard IPI
Low 01 28 85 82
Lowintermed 2 27 80 81
Highintermed 3 21 57 49
High 45 24 51 59
Revised IPI
Very good 0 10 94 94
Good 12 45 80 79
Poor 35 45 53 55
Sehn LH, et al. Blood 2007 10918571861.
16
RICOVER-60 Trial (n1222) PFS according to Sex
and Rituximab
1
0.9
0.8
0.7
0.6
Proportion
Female with Rituximab
0.5
(n285) 3 year rate 75
0.4
Male with Rituximab
(n325) 3 year rate 68
0.3
Female without Rituximab
0.2
(n287) 3 year rate 60
0.1
Male without Rituximab
(n325) 3 year rate 55
0
0
10
20
30
40
50
60
70
80
M o n t h s
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19
DSHNHL R-MegaCHOEP vs R-CHOEP
PBSC
PBSC
PBSC
mCHOEP II CYC 4500 ADR 70 VCR 2ETO 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
mCHOEP I CYC 1500 ADR 70 VCR 2 ETO 600 PRD 500
R
days
1
CHOEP-14 CYC 750 ADR 50 VCR 2 ETO 300 PRD 500
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
PRD and VCR doses are absolute, all others are
per m²
Rituximab (375mg/m²)
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DSHNHL 2002-1 -- MegaCHOEP Event-free survival
1
p0.050
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
50
60
70
Months
21
Survival in NHL by age
22
Age range of recent NHL trials
23
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
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.
24
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 ( ! )

25
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 108Abstract 2766.
26
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
• gt90 fatality in 2 months
• 
  Carson et al Blood May
  2009

27
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

28
Standard of care in relapsed NHL Auto BMT/PBSCT
is based on what ?
100 80 60 40 20 0
Chemo-sensitive respondersORR 58, CR 25
ABMT (n55)
Event-free survival ()
DHAP (n54)
p0.002
0 15 30 45 60 75 90
Months from inclusion
Updated from Blay JY, et al. Blood
19989235623568
29
CORAL Trial of RICE v DHAP

• Which salvage regimen is the best?

R A N D O M I Z E
SD/POD ? Off
R-ICE x 3
?
CD20 DLBCL Relapsed/Refractory
R A N D O M I Z E
R x 6
PR/CR ?
R-DHAP x 3
N400
Obs
Orlando ASCO May 2009 / Coral study C.
Gisselbrecht
30
64
PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE
FROM DIAGNOSIS (INDUCTION ITT)
N160
N228
31
62
N147
PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR
RITUXIMAB (INDUCTION ITT)
N241
30
Orlando ASCO May 2009 / Coral study C.
Gisselbrecht
31
EVENT-FREE SURVIVAL BY PRIOR RITUXIMAB - INDUCTION ITT
Failure from diagnosis gt 12 months
Failure from diagnosis gt 12 months
N 106
N 54
N 41
Failure from diagnosis lt 12 months
Standard salvage regimen does not overcome poor
prognosis of early relapse
N 187
32
Management of DLBCL
R-CHOP or R-CHOP-like
Not in CR
CR
Second-line therapy
Relapse
Cure
CR/PR
NR
Second-line therapy
Investigational or BSC
CR/PR
NR
Investigational or BSC
HDT/ASCT
33
Signposts for the future

• Most patients are gt 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

34
Follicular Lymphoma
35
Natural history of FL
Barts data Johnson et al, JCO,
1995
36
Follicular Lymphoma International Prognostic
Index (FLIPI)
1.0
Nodal regions gt 4 Elevated LDH Age gt 60 Stage
III/IV Haemoglobin lt 12 g/dl
0.8
0.6
Probability of survival
0.4
Good
Intermediate
0.2
p lt 0.0001
Poor
0
0
0
12
24
36
84
48
60
72
Months
Risk group Factors (n) Patients () 5-year OS 10-year OS
Low 01 36 90.6 70.7
Intermediate 2 37 77.8 50.9
High 35 27 52.5 35.5
Solal-Celigny P, et al. Blood 2004 10412581265.
37
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 gt 7cm
• B symptoms
• Raised B2-microglobulin /LDH  
• Involvement of 3 nodal sites (gt3 cm)
• Splenic enlargement
• Compression syndrome
• Pleural/peritoneal effusion

38
Watch and wait in Follicular Lymphoma
n Not Treated TTT (months) ORR CR OS (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 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.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
Including 23 Spont. remissions
39
Therapy in the pre-antibody era

• No proven benefit for first line
• anthracyclines
• PBSCT
• Possible benefit for
• interferon with anthracyclines

40
Intergroup randomised Watch and Wait trial in
asymptomatic FL
Watch and Wait
FL Asymptomatic Non bulk No critical organ
failure
Rituximab 4 weeks standard course
Randomisation
Rituximab 4 weeks standard course followed by
maintenance 1 dose every 2 months for 2 years
41
Trial 1 R-CVP versus CVP study design
R A N D O M I S E

• Follicular NHL (IWF B, C, D)
• Stage III-IV
• ? 18 years
• No prior Rx
• Measurable disease
• Central histology review

R E S T A G E
R-CVP x 4 cycles (q3wk)
R-CVP x 4 cycles (q3wk)
CR, PR
CVP x 4 cycles (q3wk)
CVP x 4 cycles (q3wk)
SD PD off-study
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
Marcus R, et al Blood 2005 10514171423.
42

Rituximab-based induction therapy significantly
improves time to progression
Median follow up of 53 months
R-CVP Median 34 months
CVP Median 15 months
p lt 0.0001
Marcus R, et al. JCO 2008
43
CVP rituximab in previously untreated FL
disease-free survival (DFS)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Median follow-up 53 months
R-CVP median not reached
Event-free probability
CVP median 21 months
p 0.0001
0 6 12 18 24 30 36 42 48 54 60 66 72
Study month
Patients at riskCVP 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
Marcus R, et al. Blood (ASH Annual Meeting
Abstracts) 2006108481
44
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, Blood04
- / 42 / 46 R-CHOP R-Benda III 540 91.3 30 PFS 46.7m(FL) PFS n.r. Rummel, ASH09
7 / 37 / 56 R-MCP-gtIFN 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 R-CHVPIFN III 358 85 34 PFS n.r. (5y 53) Salles, Blood08
45
Phase III Study of First-line Bendamustine/Rituxim
ab (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

RANDOMIZE
1
29
113
57
85
141
Days
R-CHOP
1
22
85
43
64
106
Days
Rummel et al. ASH 2009 abstract 405.
46
Phase III Study of First-line Bendamustine/Rituxim
ab (B-R) Versus R-CHOP in Indolent NHL Efficacy
B-R (n 260) R-CHOP (n 253) P Value HR
Overall Response Rate 93 91
Complete response 40 30 .0262
Median Progression-Free Survival 54.9 months 34.8 months .00012 0.57
Median Time to Next Treatment Not reached 37.5 months .00002 0.52
Rummel et al. ASH 2009 abstract 405.
47
Overall survival improvement with rituximab in FL
1.0
GLSG study NHL 2000
0.8
0.6
GLSG study NHL 1996
Survival probability
0.4
0.2
p lt 0.0001
0.0
24
0
12
36
48
60
72
84
96
108
120
Time (months)
Number of patients at risk
NHL 1996
538
485
457
419
386
332
242
125
46
0
NHL 2000
794
621
440
250
108
8
0
Hiddemann W, et al. Blood 2006 108Abstract 483.
48
PRIMA Study Final Design
Maintenance (SAKK) 1 dose every 8 weeks for 24
months
CR/PR
Indolent NHL stages IIIIV, untreated
CHEMO x 6-8 R x 8
Observation
PDs/SDs off study
49

• HDS versus
  R-chemotherapy
• in 134 previously untreated patients with
  Follicular Lymphoma
• Trial Design

Ladetto, M. et al. Blood 20081114004-4013
50
PBSCT versus R-chemotherapy in 134 previously
untreated patients with Follicular Lymphoma
Ladetto, M. et al. Blood 20081114004-4013
51
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 gt 90 in FCR arm ( higher in patients
  treated with oral FC !)
• 24 month FU EFS 90
• Minimal toxicity

Marin Niebla et al Haematologica 2009
94suppl.2397 abs. 0985
52
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
53
EORTC 20981 Rituximab maintenance in
relapsed/resistant follicular non-Hodgkins
lymphoma
R A N D O M I S E
R A N D O M I S E
Observation (re-treatment as necessary)
CHOP every21 days(maximum 6 cycles)
CRPR
R-CHOP every21 days(maximum 6 cycles)
Rituximab maintenance (375 mg/m2 every 3 months
until relapse or for a maximum of 2 years)
van Oers MH, et al. Blood 2006 10832953301.
54
EORTC 20981 - van Oers JCO 2010 in Press
Progression free survival after R-CHOP induction
Progression free survival after CHOP induction
R maintenance median 4.4 yrs
R maintenance median 3.1 yrs
Observation median 1.0 yr
Observation Median 1.9 yrs
HR 0.69
HR 0.37
55
Role of transplantation

• ?No prospective randomised trials in second CR in
  post Rituximab era
• PFS in 1st CR now likely to be gt 4 years
• Transplant confined to early recurrence
  transformation ?
• New approaches needed

56
Barts/DFCI Autograft Data 2007
Rohatiner et al , J Clin Onc 2007
57
W Ingram et al , Brit J Haem 2008
58
GA101 induces high ADCC andcell death
Mechanisms of action of GA101 (a type II
antibody) versus type I antibodies (e.g.,
rituximab, 2H7)

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

CD20
B cell
Complement
Effector cell
Fc-?RIIIa

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

1. Increased ADCCvia increased affinity to the
   'ADCC receptor' Fc-?RIIIA

59
Tumour response in evaluable patients at the end
of induction (13-week assessment)
100
80
60
40
20
Change in indicator lesions ()
-20
NHL CLL
-40
-60
-80
Patient (N20)
60
BO21000 Study Design
Screening
Relapsed / Refractory CD20 Follicular NHL
CHOP
FC
IVRS
As determined by investigator As determined
by investigator and confirmed by Sponsor
CR Complete ResponsePR Partial ResponseSD
Stable DiseasePD Progessive Disease
Total approx. 56 eligible patients
61
CD22-Targeted Chemotherapy, CMC-544
Inotuzumab Ozogamicin
Humanized IgG4 anti-CD22
AcBut linker
O
O
NH
O
Me
Me
O
H
O
NHN
S
Me
N
H
C
H
O
S
O
3
C
H
3
O
I
O
C
H
S
3
O
C
H
3
O
H
H
N
O
C
H
O
O
H
O
3
H
O
O
C
H
O
O
C
H
3
3
E
t
H
O
O
N
CH3
O
H
O
C
H
3
O
C
H
3
NAc-gamma Calicheamicin DMH
O
62
Phase I/II Trial of Inotuzumab Ozogamicin Plus
Rituximab Results

• 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

• Dang et al. ASH 2009 abstract 584.

63
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)
Total 28 4 3 21 86 (75)

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

CRuunconfirmed 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.
64
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 gt 5 years
• Can we afford to make progress ?