Transcript Slide 1

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
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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
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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
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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 ~
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
2%
Burkitt’s lymphoma 2%
12%
31%
3%
MCL
CLL/SLL
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
80
ProMACE-CytaBOM
Patients (%)
MACOP-B
225
223
233
218
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
 Expressed on most B-cell
1
2
3
4
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/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; 346:235–243
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 %
0–1
28
85
82
Low–intermed
2
27
80
81
High–
intermed
3
21
57
49
4–5
24
51
59
0
10
94
94
Good
1–2
45
80
79
Poor
3–5
45
53
55
Risk group
Standard IPI
Low
High
Revised IPI
Very good
Sehn LH, et al. Blood 2007; 109:1857–1861.
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
1
14
PBSC
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
R
1
15
29
43
57
71
85
CHOEP-14
CYC 750
ADR 50
VCR 2
ETO 300
PRD 500
PRD and VCR doses are
absolute, all others are per m²
Rituximab (375mg/m²)
99
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;92:3562–3568
CORAL Trial of RICE v DHAP
Which salvage regimen is the best?
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R
A
N
→
D
CD20+ DLBCL
Relapsed/Refractory
O
M
I
Z
N=400
E
SD/POD → Off
R-ICE x 3
AB
SE
CA
TM
R-DHAP x 3
R
A
Rx6
N
D
PR/CR →
O
M
I
Z
Obs
E
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
64%
N=160
31%
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
Failure from diagnosis =>=
12 months ITT
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
0–1
36
90.6%
70.7%
2
37
77.8%
50.9%
3–5
27
52.5%
35.5%
Solal-Celigny P, et al. Blood 2004; 104:1258–1265.
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 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
O’Brien3
ww
56
21
33
NA
6.3
Young 4
ww
44
17#
34
NA/43
Both
83 % (4yrs)
PromaceMopp/
TNI
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 O’Brien 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 III−IV
•  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 1–5
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; 105:1417–1423.
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
p = 0.0001
0
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/H
R)
Regimen
Phase
Pts
ORR
CR
Duration
Ref
14 / 41 / 45
R-CHOP
III
428
96%
17%
TTF: (2y 85%)
Hiddemann,
Blood’04
- / 42 / 46
R-CHOP
R-Benda
III
540
91.3
%
30%
PFS: 46.7m(FL)
PFS: n.r.
Rummel,
ASH’09*
III
201
92%
50%
PFS: n.r. (4y71%)
Herold,
JCO’07
7 / 37 / 56
R-MCP>IFN
19 / 41 / 40
R-CVP
III
331
81%
41%
TTP: 34 mo
Marcus,
Blood’05
19 / 35 / 46
RCHVP+IFN
III
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
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
I
Z
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
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
Overall survival improvement with
rituximab in FL
1.0
Survival probability
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 III–IV,
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-Hodgkin’s 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; 108:3295–3301.
Observation
(re-treatment as
necessary)
Rituximab
maintenance
(375 mg/m2 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
70
60
60
R maintenance
median 3.1 yrs
50
R maintenance
median 4.4 yrs
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
Effector
cell
Fc-γRIIIa
3. Lower CDC activity
unlike rituximab (type I epitope)
due to recognition of type II epitope
2. Increased ADCC
via increased affinity to the
'ADCC receptor' Fc-γRIIIA
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)
IVRS
PD
(maintenance
only)
Total: approx. 56 eligible patients
* As determined by investigator
** As determined by investigator
and
confirmed
by Sponsor
CR
= Complete
Response
PR = Partial Response
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
CHOP*
Treatment
CD22-Targeted Chemotherapy, CMC-544
Inotuzumab
Humanized
IgG4 anti-CD22
Ozogamicin
AcBut linker
O
O
NH
O Me
Me
CH 3 O
O
CH 3
HO
O
OCH 3 OH
CH 3
S
O
HO
S
NHN
I
Me
NH
S
O
O
CH 3
HN
HO
OCH 3 OH
OCH 3
Et
N
CH3
O
OCH 3
O
O
H
O
O
OCH 3
O
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
OS Rate
 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
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%)
Total
28
4
3
21
86% (75%)
 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 ?