ARZ0310/063/1
The opinions and views expressed in the slide decks are those of the author and do not
necessarily constitute the opinions or recommendations of GlaxoSmithKline. Dosages,
indications and methods of use for medicinal products referred to by the author may
reflect their research or clinical experience, or may be derived from professional literature
or other sources. Such dosages, indications and methods of use might not reflect the
prescribing information for such medicinal products and are not recommended by
GlaxoSmithKline. Prescribers should consult the prescribing information approved for use
in their country before the prescription of any medicinal product.
What’s Lacking in Our Current Management
of Chronic Lymphocytic Leukemia (CLL)?
Stephan Stilgenbauer, MD
University of Ulm
Ulm, Germany
ARZ0310/063/1
Chronic Lymphocytic Leukemia (CLL)
• Most common leukemia in adults
• Diagnosis straightforward
– CD19+/CD5+/CD23+ lymphocytosis
• Molecular pathogenesis unresolved
– Microenvironmental stimulation
– B-cell receptor signalling (antigenic drive)
– Genomic aberrations, mutations, epigenetics
• Clinical course highly variable
– Survival times ranging from months to decades
– Wide range of treatments (watch & wait – SCT)
1. Grever MR, et al. In: Abeloff MD, et al, eds. Abeloff’s Clinical Oncology. 4th edition. Philadelphia, PA: Churchill
Ligingston; 2008:2293-2308.
Primary Treatment of Advanced Stage CLL
Fludarabine (F) vs Chlorambucil (Clb)
Overall Survival
Remission Duration
100
80
80
60
60
40
40
20
20
0
0
0
1
2
3
4
5
6
7
Years
Rai KR, et al. N Engl J Med. 2000;343(24):1750-1757.
F
Clb
F+Clb
100
F
Clb
8
0
1
2
3
4
Years
5
6
7
8
Primary Treatment of Advanced CLL
UK CLL4: Clb vs F vs FC
Patients Events
194
387
196
80
149
311
102
O/E
100
1.1
1.3
0.5
80
Survival, %
Progression-Free Survival, %
100
60
40
F
Clb
FC
20
60
40
Patients Events
F
Clb
FC
20
0
194
387
196
O/E
71
116
67
1.1
0.9
1.0
0
0
1
2
3
4
Time, years
Catovsky D, et al. Lancet. 2007;370(9583):230-239.
5
0
1
2
3
Time, years
4
5
FC + Rituximab (FCR)
M. D. Anderson, Historical Comparison
Outcome
1.0
n
6-Year OS
F
190
54%
F±M/C
140
59%
P = .37
R-FC
300
77%
P ≤.001
Probability
0.8
0.6
0.4
0.2
0
0
12
24
36
48
60
72
Time, months
Tam CS, et al. Blood. 2008;112(4):975-980.
84
96
108
P Value
FCR (M. D. Anderson): Survival by Response
PFS
1.0
P=.03
P=.28
P<.01
CR (n = 217)
PR-nod (n = 31)
PR-i (n = 21)
PR-d (n = 16)
OS
1.0
.8
.8
.6
.6
.4
.4
.2
.2
0
0
0 12 24 36 48 60 72 84 96 108
Months
Tam CS, et al. Blood. 2008;112(4):975-980.
P=.12
P<.01
P=.16
P=.10
CR (n = 217)
PR-nod (n = 31)
PR-i (n = 21)
PR-d (n = 16)
Fail (n = 15)
0 12 24 36 48 60 72 84 96 108
Months
International CLL8 Trial (n = 817)
First-Line Treatment
Fludarabine + Cyclophosphamide
(FC)
R
FC + Rituximab (Anti-CD20)
(FCR)
Hallek M, et al. Blood. 2009;114: Abstract 535.
CLL8: Progression-Free Survival (PFS)
(Median Follow-Up 25.5 Months)
1.0
FC
FCR
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
P<.001
0
6
12
18
24
Months
Hallek M, et al. Blood. 2009;114: Abstract 535.
30
36
42
48
54
CLL8: Overall Survival (OS) Update 2009
(Median follow-up 37.6 months)
“FCR improves
response rates,
progression-free,
and overall survival
in untreated patients
with CLL”
1.0
FC
FCR
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
HR 0.664
P = .012
0
6
12 18 24 30 36 42 48 54 60 66
OS Months
Hallek M, et al. Blood. 2009;114: Abstract 535.
CLL8: Genomics and Treatment Effect (OS)
1.0
17p11q+12q
13q- single
normal
0.9
0.8
0.7
0.6
0.5
11q-
0.4
0.3
0.2
FC
FCR
0.1
0.0
0
6
12
18
24
30 36 42 48 54 60
OS Months
Hallek M, et al. Blood. 2009;114: Abstract 535.
66
Refractory CLL – A Great Unmet Medical Need
Long-term Outcome following Treatment
Failure of First-line FCR in CLL
• 114 patients received first salvage therapy between 01/2000 and 09/2009
• Most commonly used was FCR-like regimens (33 patients)
• ORR after first salvage therapy was 61% (15% CR and 45% PR)
N
CR
nPR
ORR
FCR ± Other
36
14%
14%
83%
Rituximab ± Other
27
4%
4%
41%
Alemtuzumab ± Rituximab
15
33%
13%
67%
CFAR
9
44%
22%
89%
Keating MJ, et al. ASH 2009; Abstract 2381.
Refractory CLL – A Great Unmet Medical Need
Prognosis of CLL Refractory to
Conventional Therapy
Total Died
609
129
327
167
794
548
233
158
Overall Survival, %
100
80
Subgroup
Initial diagnosis
1st therapy
1st fludarabine salvage
Fludarabine refractory
60
40
Failed alkylating agents
20
Failed fludarabine
0
0
24
48
72
Time, months
Keating MJ, et al. Leuk Lymph. 2002;43(9):1755-1762.
96
120
144
Frontline Bendamustine plus Rituximab
Therapy (CLL2M trial) : Patient Characteristics
Number of Patients
N
%
Total
117
100
Male
84
71.8
Female
33
28.2
Age
Years
Median
64
Age Categories
N
%
<65 years
60
51.3
≥65 <70 years
27
23.1
≥70 years
30
25.6
Fischer K, et al. Blood. 2009;114: Abstract 205.
CLL2M: Response by Genetics
Response
N
ORR
(%)
CR
(%)
+12
19
17
89.5
3
15.8
11q-
21
19
90.5
9
42.9
17p-
7
3
42.9
-
-
63
56
88.9
25
IGHV
unmutated
Fischer K, et al. Blood. 2009;114: Abstract 205.
39.7
Alemtuzumab in Chemo-Refractory CLL
Response Rate: 33% to 34%
100
CLL2H: Time to treatment failure
Median: 5.6 months
(Keating et al.
After IV: 4.7 months)
75
100
75
50
50
25
25
0
CLL2H: Overall survival
Median: 19.1 months
(Keating et al.
After IV: 16 months)
0
0
6
12
18 24 30 36
Time, months
42
48
0
6
12
18 24 30 36 42
Time, months
Keating M, et al. Blood, 2002;99(10):3554-3561. Stilgenbauer S, et al. J Clin Oncol. 2009; 27(24):3994-4001.
48
54
CLL2H: Alemtuzumab in Refractory CLL
Survival by Genomic Subgroups
OS
100
PFS
17p11qother
75
100
75
50
50
25
25
0
0
0
6
12
18 24
30
36 42
48 54
Time, months
Stilgenbauer S, et al. J Clin Oncol. 2009;27(24):3994-4001.
17p11qother
0
6
12
18
24
30
36
Time, months
42
48
What’s Lacking in Our Current Management
of Chronic Lymphocytic Leukemia (CLL)?
• Majority of patients achieve lasting remissions with current
treatments such as immunochemotherapy
• CLL8 study results are applicable to young medically fit
patients. Elderly or medically non-fit patients?
• Patients with no or only brief (<24 months) response to
immunochemotherapy have poor outcome
• Limited treatments for patients who are fludarabinerefractory (in particular F-combinations)
• Biologic factors such as 17p-, 11q- and TP53 mutation
identify subgroups with poor prognosis
• Novel treatment options beyond classical chemotherapy (ie,
targeting biologic pathomechanisms) needed
ARZ0310/063/1
The opinions and views expressed in the slide decks are those of the author and do not
necessarily constitute the opinions or recommendations of GlaxoSmithKline. Dosages,
indications and methods of use for medicinal products referred to by the author may
reflect their research or clinical experience, or may be derived from professional literature
or other sources. Such dosages, indications and methods of use might not reflect the
prescribing information for such medicinal products and are not recommended by
GlaxoSmithKline. Prescribers should consult the prescribing information approved for use
in their country before the prescription of any medicinal product.
Next Generation of Anti-CD20
Monoclonal Antibodies
John Gribben, MD, DSc, FRCP,
FRCPath, FMedSci
Barts and The London School of Medicine
London, United Kingdom
ARZ0310/063/1
CD20: An Attractive Target for the
Treatment of B-Cell Malignancies
• Expressed:1-3
CD20
Small
loop
– Exclusively on B-cells
Large
loop
– On most malignant B-cells
• Stable on B-cell surface, allowing
sustained mAb binding1-3
• Implicated in B-cell growth, proliferation,
differentiation, and activation1-3
B-cell membrane
– No known ligand
B cell
– Involved in B-cell receptor activation and
signalling
1. Cragg MS, et al. Curr Dir Autoimmun. 2005;8:140-174. 2. Hotta T. Acta Histochem Cytochem. 2002;35(4):275-279.
3. Teeling JL, et al. J Immunol. 2006;177(1):362-371.
CD20: Expressed at Key Stages
of B-Cell Development
CML
Hematopoietic
stem cell
B-cell lymphomas
Precursor
B-cell
acute
leukemias
Lymphoid
stem cell
Myeloma
CLL
CD20+
ProB cell
Pre-B
cell
Immature
B cell
Mature
B cell
Bone
Marrow
Activated
B cell
Memory
B cell
Plasma cell
Blood,
Lymph
CD20 expression begins at early pre-B cell stage, is largely lost during plasma cell differentiation 1-2
 Present on stages that give rise to CLL and B-cell lymphomas
 Not present on hematopoietic stem cells and antibody-producing plasma cells
1. Cragg MS, et al. Curr Dir Autoimmun. 2005;8:140-174. 2. O'Connor OA. Presented at: Optimizing Strategies for Targeting
CD20 in B-Cell Lymphoproliferative Disorders Satellite Symposium; June 7, 2007; held in conjunction with the 12th Annual
Congress of the European Hematology Association; June 7-10, 2007; Vienna, Austria.
Anti-CD20 mAbs May Destroy CD20+
B-Cells by Three Mechanisms
Macrophage
C1q
mAb
CD20
MAC
CDC = complement-dependent cytotoxicity
ADCC = antibody-dependent cellular cytotoxicity
MAC = membrane attack complex
B cell
• CDC1-3
• ADCC1-3
• Apoptosis1-3
1. Bello C, et al. Hematology Am Soc Hematol Educ Program. 2007:233-242. 2. Glennie MJ, et al. Mol Immunol.
2007;44(16):3823-3837. 3.Jazirehi AR, et al. Oncogene. 2005;24(13):2121-2143.
CDC
Membrane Attack Complex
(MAC) and B-Cell Lysis
Inrushing
fluids
MAC
MAC
Complement
mAb
Cell membrane
CD20
MAC
• Sequential activation of
complement components
leads to incorporation into the
MAC1-3
• MAC forms a pore through
target cell membrane, causing
osmotic cell lysis2
1. Bhole D, et al. Crit Care Med. 2003;31(suppl 1):S97-S104. 2. Shernan SK. Anesthesiol Clin North Am. 2003;21(3):465485. 3. Shernan SK, et al. BioDrugs. 2001;15(9):595-607.
ADCC
Anti-CD20 mAbs induce ADCC
 Fc region of CD20-bound mAb binds to
Fc receptor on phagocytic cells, e.g.
natural killer cells, macrophages,
neutrophils1-3
Macrophage
 Effector cells release mediators that
damage and destroy B-cells1-3
 B-cells are phagocytosed1-3
mAb
CD20
B cell
Fc receptor
Cell damage
and
phagocytosis
1Cragg
MS, et al. Curr Dir Autoimmun 2005; 8: 140–174; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;
3Jazirehi AR, Bonavida B. Oncogene 2005; 24(13): 2121–2143
Apoptosis
mAb
Anti-CD20 mAbs May Directly Induce
B-Cell Apoptosis
mAb binding to CD20 may induce transmission of intracellular signals
that trigger cell cycle arrest and apoptosis1,2
CD20
Death signal
1Cragg
MS, et al. Curr Dir Autoimmun 2005; 8: 140–174; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837.
Anti-CD20 mAbs: Two Types
Type I
Type II
Differences between type I and
type II anti-CD20 mAbs1-3
Type I
Type II
CD20 clustering in
B-cell membrane
++
-
Induction of CDC
++
+
Induction of ADCC
++
++
Induction of
apoptosis
+
++
– = no activity; + = some activity; ++ = significant activity
1Cragg
MS, et al. Curr Dir Autoimmun 2005; 8: 140–174; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;
3Teeling JL, et al. Blood 2004; 104(6): 1793–1800.
Rituximab: Currently Available Type I
Anti-CD20 mAb
• The anti-CD20 mAb rituximab is approved
for the treatment of NHL, CLL, and
rheumatoid arthritis
• Studies with rituximab validate CD20 as a
therapeutic target for B-cell malignancies1-3
• Initially introduced as a monotherapy4
• Now most commonly used in combination
with chemotherapy in NHL and CLL5-7
• Rituximab mechanism of action is mainly via
ADCC and minimally via CDC8
1. Cvetković RS, et al. Drugs. 2006;66(6):791-820. 2. Teeling JL, et al. Blood. 2004;104(6):1793-1800. 3. Teeling JL, et al. J Immunol.
2006;177(1):362-371. 4. Czuczman MS, et al. J Clin Oncol. 1999;17(1):268-276. 5. Marcus R, et al. Blood. 2005;105(4):1417-1423. 6.
Hiddemann W, et al. Blood. 2005;106(12):3725-3732. 7. Hiddemann W, et al. Blood. 2005;106(12):3725-3732. 8. Weiner GJ. Semin
Hematol. 2010;47(2):115-123.
Limitations of Rituximab
- Potential Mechanisms
100
• Low CD20 density1,2
% CDC
80
– Rituximab requires high CD20
density for cell killing by CDC
60
– Rituximab’s limited efficacy in
CLL may be due to relatively low
CD20 density
40
20
0
• Complement inhibition3,4
0
CLL
Lymphoma
CD20-ABC*
Lower rituximab-induced CDC
correlates with lower CD20 density†1
*Antibodies bound per cell = number of CD20
molecules per cell
– B-cell over-expression of
complement inhibitory proteins,
e.g CD55 and CD59, may reduce
rituximab-mediated CDC
†Preclinical
(in vitro) study in a
human CD20 cell model
1. van Meerten T, et al. Clin Cancer Res. 2006;12(13):4027-4035. 2. Czuczman MS, et al. Clin Cancer Res. 2008;14(5):15611570. 3. Cillessen SA, et al. Blood. 2007;110: Abstract 2346. 4. Golay J, et al. Blood. 2000;95(12):3900-3908.
Evolution of Anti-CD20 mAbs
Veltuzumab
Ocrelizumab
Murine
Chimeric
1987
1f5 “serotherapy” in 4
pts with refractory Bcell carcinoma
1994
Ofatumumab
Humanized
1997
Fully human
2003
2006
Rituximab: FDA approval for
relapsed or refractory, low
grade, CD20+, B-cell NHL
CD2B: phase I study in pts with
recurrent B-cell lymphoma
Tositumomab: Rituximab:
approved for use approved for
in NHL
first-line use in Bcell lymphomas
AME-133v
GA-101
PRO-131921
Engineered
2009 - 2010
Ofatumumab: approved in
US/EU for CLL refractory to
fludarabine and alemtuzumab
Rituximab: approved in EU for
untreated and relapse/refractory
CLL
1. Press O, et al. Blood. 1987;69(2):584-591. 2. Bello C, et al. Hematology Am Soc Hematol Educ Program. 2007:233242. 3. Lim SH, et al. Haematologica. 2010;95(1):135-143.
Anti-CD20 mAbs in Clinical Development1-4
Antibody
Type
Properties
ADCC
CDC
Apoptosis
Ofatumumab
I
Fully human
++
++++
+
Rituximab
I
Chimeric
++
++
+
Veltuzumab
I
Humanized
++
++
+
Ocrelizumab
I
Humanized
+++
+/-
+
PRO131921
I
Humanized
++++
++
+
AME-133
I
Humanized
++++
++
++
GA-101
II
Humanized
++++
-
++++
mAb 1.5.3
II
Fully human
++
++
+++
1. Adapted in part from Maloney D. Hematology 2007; from the 2007 ASH Education Book. 2. Beers SA, et al. Blood.
2008;112(10):4170-4177. 3. Salles GA, et al. Blood 2008; 112 (11): Abstract 234. 4. www.clinicaltrials.gov. Accessed
April 30, 2010.
GA101: A Type II Anti-CD20 Antibody
• Glyco-engineered, humanized, type II CD20 mAb in
clinical development
• Compared with rituximab, GA101 provides*:
– Enhanced direct cell-death induction1,2
– Enhanced ADCC1,2
• Lower CDC activity
– Due to recognition of type II epitope
*based on preclinical studies
1. Umaña P, et al. Blood. 2006;108: Abstract 229. 2. Umaña P, et al. Ann Oncol. 2008;19(Suppl 4): Abstract 098.
3. Alduaij W, et al. Blood. 2009;114: Abstract 725. 4. Niederfellner G, et al. Blood. 2009;114: Abstract 3726.
Key Features of Ofatumumab
Rituximab
binding site
Ofatumumab
binding site
Small
loop
Large
loop
• Novel, human monoclonal antibody
developed for the treatment of
refractory CLL and NHL1
• Unique mechanism of action that
targets both the small and large loop
epitopes on CD20 2
• Unique small loop epitope binding on
CD20
– Selected for high functional activity
B-cell
membrane
– Produces robust CDC in vitro3
• Exhibits enhanced binding to, and slow
dissociation from, CD20 in vitro1,2
Schematic diagram of the structure of CD20
• Enables CD20-mediated cell lysis in
vitro in cells with low CD20 expression2
or in rituximab-resistant cells1
1. Teeling JL, et al. Blood. 2004;104(6):1793-1800. 2. Teeling JL, et al. J Immunol. 2006;177(1):362-371.
3. Pawluczkowycz A, et al. J Immunol. 2009;183:749-758.
Ofatumumab is Effective in Low CD20
Expressing Cells
100
% CDC
80
60
Ofatumumab 10 µg/mL
40
Rituximab 10 µg/mL
20
0
0
CD20 molecules/cell*
* CEM T cells transduced to express CD20
Ofatumumab- and rituximab-induced CDC correlated
with CD20 density
• In vitro, ofatumumab effectively kills B-CLL cells, which have low CD20 density
• Ofatumumab is more effective than rituximab at all CD20 densities in vitro
Teeling JL, et al. J Immunol. 2006;177(1):362-371.
100
80
60
40
2µg/mL C1q
20
1µg/mL C1q
no C1q
0
% Lysed Cells
Daudi cells*
Ofatumumab
35µg/mL C1q
0 5 10 15 20 25
Time, min
100
80
60
40
20
Rituximab
35µg/mL C1q
2µg/mL C1q
1µg/mL C1q
no C1q
Z138 cells*
% Lysed Cells
Raji cells*
% Lysed Cells
Ofatumumab: Induces More CDC
in vitro than Rituximab
100
80
60
40
20
0
0
0
5 10 15 20 25
Time, min
Pawluczkowycz A, et al. J Immunol. 2009;183:749-758.
0 5 10 15 20 25
Time, min
Ofatumumab Differs from Rituximab
Ofatumumab 10 µg/mL
Ofatumumab
Rituximab 10 µg/mL
Rituximab
7D8
Ofatumumab
Rituximab
50
% CDC
80
60
40
20
0
40
30
20
10
0
0
CD20 molecules/cell*
% Initial Binding
% Lysed Cells
100
100
0
80
60
40
20
10 20 30 40
C1q µg/mL
In vitro, ofatumumab induces
CDC of rituximab-resistant
primary CLL cells*2
0
0
60
120
180
Time, minutes**
*Cells opsonized with 35 µg/mL mAb, ** DOHH
Teeling JL, et al. Blood. 2004;104(6):1793-1780. Pawluczkowycz A, et al. J Immunol. 2009;183(1):749-758.
Conclusions
 Monoclonal antibodies are evolving from original murine to full
human form
 Binding of mAbs to CD20 lead to B-cell destruction by three
mechanisms: CDC, ADCC & Apoptosis
 Now FDA / EMA approved ofatumumab (Arzerra®) has a unique
mechanism of action distinct from other anti-CD20 mAbs:
 Novel small loop binding anti-CD20 mAb
 Induces more potent CDC than rituximab in cells expressing
low levels of CD20 in vitro
 Induces CDC in rituximab-resistant cells in vitro
 Several types of mAbs are in development - their clinical relevance
needs to be further explored
ARZ0310/063/1
The opinions and views expressed in the slide decks are those of the author and do not
necessarily constitute the opinions or recommendations of GlaxoSmithKline. Dosages,
indications and methods of use for medicinal products referred to by the author may
reflect their research or clinical experience, or may be derived from professional literature
or other sources. Such dosages, indications and methods of use might not reflect the
prescribing information for such medicinal products and are not recommended by
GlaxoSmithKline. Prescribers should consult the prescribing information approved for use
in their country before the prescription of any medicinal product.
Refractory CLL:
Improving Outcomes with Novel
Therapeutic Strategies
Anders Österborg, MD, PhD
Karolinska University Hospital
Karolinska Institutet
Stockholm, Sweden
ARZ0310/063/1
Multi-Agent First-Line Therapy May Result in
Difficulties to Choose Optimal Later-Line Therapies
Aim of therapy:
___________
Molecular
remission
mAbs
IMiDS
___________
Palliation
Chlorambucil
__________
Complete
remission
Transplantation
Auto-allo-RIC
CHOP
___________
R-FC
Remission
FCM
Fludarabine
CdAC
CdA
CVP
MIME
Bendamustine DexaBEAM
Cure?
Refractory CLL – A Great Unmet Medical Need
Prognosis of CLL Refractory to
Conventional Therapy
Total Died
609
129
327
167
794
548
233
158
Overall Survival, %
100
80
Subgroup
Initial diagnosis
1st therapy
1st fludarabine salvage
Fludarabine refractory
60
40
Failed alkylating agents
20
Failed fludarabine
0
0
24
48
72
Time, months
Keating MJ, et al. Leuk Lymph. 2002;43(9):1755-1762.
96
120
144
Overall Survival with Salvage Therapy in
Multi-Agent Refractory CLL: MDACC Data
Fludarbine/alemtuzumab
-refractory (N = 54)
1.0
Median survival: 8 months
0.8
Bulky fludarabine
-refractory (N = 41)
0.6
Median survival: 14 months
0.4
0.2
0.0
0
6
12
Months
Tam CS, et al. Leuk Lymphoma. 2007;48(10):1931-1939.
18
24
Salvage Therapy in Refractory CLL
Need for Active Agents
• Poor prognosis for fludarabine-refractory CLL1
– Median OS: 10 months
• No standard treatment option if also refractory to
alemtuzumab, or with bulky lymph nodes2
– Response with any salvage regimen: 20%-26%;
median TTF 2-3 months
– Median OS: 8 months and 14 months, respectively
– Major infections: 60% and 45%, respectively
1. Keating MJ, et al. Leuk Lymph. 2002;43(9):1755-1762. 2. Tam CS, et al. Leuk Lymphoma. 2007;48(10):1931-1939.
Target Antigens in Lymphoid Malignancies
ocrelizumab,GA101
ofatumumab,TRU-015,
rituximab, AME-133v,
PRO131921, tositumab,
veltuzumab
epratuzumab
Lym-1,
apolizumab
TCR
CD4/8
CD22
HLA-DR
CD23
lumiliximab
CD80
galiximab
alemtuzumab
milatuzumab
CD52
CD74
dacetuzumab
CD38?
Ror-1?
TRU-016
(SMIP)
zanolimumab
HuMaxCD4
CD3
B cell
T cell
CD25
CD52
denileukin
diftitox,
daclizumab
alemtuzumab
Clinical Effects of Alemtuzumab
as a Single Agent: Advanced Disease
Study
Tumor
Type
Disease
Phase
No. of
Patients
Response
Rate
PFS
Österborg et al1
B-CLL
Alkylating-agent
refractory
29
42%
12 mo
Keating et al2
B-CLL
F-Refractory
93
33%
9 mo
Rai et al3
B-CLL
F-Refractory
187
43%
Not stated
Lozanski et al4
B-CLL
F-Refractory, 17p-
15
40%
8 mo
Stilgenbauer et al5
B-CLL
F-Refractory, SC
103
34%
8 mo
B-CLL
F-Refractory, SC
30mg frontloading
20
75%
20 mo
Karlsson et al6
1. Österborg A, et al. J Clin Oncol.1997;15(4):1567-1574.
3. Rai K, et al. Blood. 2002;100: Abstract 772.
5. Stilgenbauer S, et al. J Clin Oncol. 2009;27(24):3994-4001.
2. Keating M, et al. Blood. 2002;99(10):3554-3561.
4. Lozanski G, et al. Blood. 2004;103(9):3278-3281.
6. Karlsson C, et al. Br J Haematol. 2009;144(1):78-85.
Selection of Patients: Pre-Existing Cytopenias
CLL-Related Thrombocytopenia Is an Indication,
Not a Contraindication for Alemtuzumab
250
Time kinetics of blood lymphocytes ()
and platelets () in one CLL patient
during 12 weeks of alemtuzumab
treatment
200
150
100
50
0
0
2
4
Österborg A, et al. J Clin Oncol. 1997;15(4):1567-1574.
6
8
10
12
Selection of Patients: Autoimmune Complications
Alemtuzumab to Treat Refractory
Autoimmune Hemolytic Anemia (AIHA)
• 6 B-CLL patients with severe, transfusion-dependent
AIHA refractory to conventional therapy (steroids,
rituximab, chemotherapy, etc)
• 5/6 patients responded (Hb increase >2 g/dL, no
transfusions) after a median at 4 weeks (range 3–8)
• Median Hb conc. increased from 7.8 g/dL to 12.2 g/dL
• No further AIHA episodes during follow-up
Karlsson C, et al. Leukemia. 2007;21(3):511-514.
Selection of Patients: Performance Status
Alemtuzumab: Response Rate and Infections
in Relation to Performance Status (PS)
PS 0 or 1
(n = 125†)
PS 2 or 3*
(n = 125†)
P Value
Response rate
38%
0%
<.001
Any infection
57%
71%
NS
Grade 3 or 4 infection
26%
28%
NS
*Only 1 patient had PS grade 3
†Data combined from studies CAM211, 005 and 009
Note: When salvage therapy is needed,
don’t wait until the patient is getting worse!
Österborg A. Cutting Edge. 2006;11:3-6.
Lymphadenopathy Predicts Poor Response
to Alemtuzumab in Refractory CLL
Partial
response
No
response
Complete
response
Reason why lymph nodes are less sensitive remains unclear
Phase II Study of Alemtuzumab + High-Dose
Prednisone (CAM-PRED) in 17p- CLL:
NCRI CLL206 Trial
• 39 patients, relapsed of first-line, all were 17p-
• Alemtuzumab 30 mg tiw for 16 wks
• IV methylprednisone 1 g/m2 d 15, wk 1, 5, 8 and 13
• ORR 86% (24% CR). (first-line: 100% and 37%)
• Median PFS 15 months
• 21% went on to allo-SCT
• CMV reactivation and hematologic toxicity similar to
alemtuzumab alone, but 41% grade 3-4 other infections
Pettitt R, et al. Haematologica. 2009;94 (Suppl 2): Abstract 0351.
Rituximab + High-Dose Prednisone
in Relapsed CLL
• Castro JE, et al1: n = 13, fludarabine-refractory, high-risk
disease. Rituximab 375 mg/m2 weekly x 4 +
methylprednisolone 1 g/m2 d 15
– ORR 93% (36% CR). Well-tolerated and SAEs were rare
• Bowen DA, et al2: n = 37, relapsed, high-risk
– ORR 78% (22% CR) but 1/3 delevoped infections within 1 month
• Explored also as first-line therapy with 40% reduced
steroid dose: 96% ORR with 32% CR (Castro JE, et al)3
– To be used preferentially in patients with pre-existing cytopenia?
1. Castro JE, et al. Leukemia. 2008;22(11):2048-2053. 2. Bowen DA, et al. Leuk Lymph. 2007;48:2412-2417.
3. Castro JE, et al. Leukemia. 2009;23(10):1779-1789.
CLL2M (Bendamustine + Rituximab): How Effective
Is Bendamustine in FC-Refractory CLL?
Response
Fludarabine sensitive
Fludarabine refractory
N
41
9
ORR
29
7
Cross-resistance vs FC or not ???
Fisher K, et al. Blood. 2008;112: Abstract 330.
CR
4
-
Effects of Lenalidomide on CLL Cells
and Their Microenvironment
Chanan-Khan AA, et al. J Clin Oncol. 2008;26(9):1544-1552.
Phase II Trials of Lenalidomide Monotherapy
in Recurrent and Refractory CLL
Response (intent-to-treat analysis)
Ferrajoli et al1
(n = 44)
Chanan-Khan et al2
(n = 45†)
Increased up to
10-15-(25) mg/day,
days 1–28
25 mg/day,
days 1–21
of a 28-day cycle
Response
Complete response, %
Partial response, %
7
25
9
38
Stable disease, %*
25
18
Lenalidomide dose
* Continued lenalidomide treatment; †32 patients evaluable
Note: 10 mg/day was identified as a safe and tolerable dose in the Ferrajoli trial
1. Ferrajoli A, et al. Blood. 208;111(11):5291-5297.
2. Chanan-Khan AA, et al. J Clin Oncol. 2006;24(34):5343-5349.
Safety of Lenalidomide at
Higher Doses in CLL
• Lenalidomide at 25 mg/day in relapsed CLL associated
with unacceptable adverse events
• Tumor flare reaction and tumor lysis syndrome (TLS)
– Chanan-Khan et al1:
• Tumor flare reaction occurred in 58% of patients
(Grades 1 or 2 in 50%; grade 3 or 4 in 8%)
• TLS (grade 3) in 5% of patients
– Ferrajoli et al2:
• Tumor flare reaction in 37% of patients
(Grades 1 or 2 in 30%; grades 3 or 4 in 7%)
• No TLS
– Moutouh-de Parseval et al3:
• Review of all reports until July 2007: 7 of 260 (2.7%) patients treated
with lenalidomide had tumor lysis syndrome
1. Ferrajoli A, et al. Blood. 2008;111(11):5291-5297;
2. Chanan-Khan AA, et al. J Clin Oncol. 2006;24(34):5343-5349;
3. Moutouh-de Parseval LA, et al. J Clin Oncol. 2007;25(31):5047.
Anti-CD20 mAbs in Clinical Development1-4
Antibody
Type
ADCC
CDC
Apoptosis
Stage of Development
Ofatumumab
I
++
++++
+
Phase 2/3 in CLL, NHL &
autoimmune conditions
Veltuzumab
I
++
++
+
Phase 1/2 in NHL & ITP
Ocrelizumab
I
+++
+/-
+
Phase 3 in NHL &
autoimmune conditions
PRO131921
I
++++
++
+
Phase 1/2 in CLL & NHL
AME-133
I
++++
++
++
Phase 1/2 in relapsed NHL
GA-101
II
+++++
-
++++
Phase 2/3 in NHL, DLBCL,
CLL
mAb 1.5.3
II
++
++
+++
Preclinical
1. Adapted in part from Maloney D. Hematology 2007; from the 2007 ASH Education Book. 2. Beers SA, et al.
Blood. 2008;112(10):4170-4177. 3. Salles GA, et al. Blood 2008; 112 (11): Abstract 234. 4. www.clinicaltrials.gov.
Accessed April 30, 2010.
GA101: Response Rate* and Safety
in Patients with Relapsed CLL (Phase I Study)
Cohort
CR
400/800 mg (n = 3)
800/1200mg (n = 3)
1
PR
SD
2
1
1
1
1200/2000 mg (n = 4)
4
1000/1000 mg (n = 3)
1
2
8
4
TOTAL (n = 13)
1
• 11/13 patients responded
• Response assessment included CT scans
PD
0
*Preliminary data 06/09
• Grade 3/4 hematologic toxicities:
– Transient neutropenia (n = 9)
– Febrile neutropenia (n = 1)
– Transient thrombocytopenia (n = 1)
• 10 patients had infections (17 episodes with only three being grade 3)
Morschhauser F, et al. Blood. 2009;114: Abstract 884.
Ofatumumab: Characteristics
• Novel human monoclonal
antibody unlike other CD20
mAbs1-3
Ofatumumab
binding site
Large
loop
Small
loop
• Unique mechanism of action
that binds a small loop
• Potent lysis of B-cells
• More effective in vitro CDC vs
rituximab
B-cell
membrane
Schematic diagram of the structure of CD20
• Promising activity in pilot CLL
Study: ORR of 50% in highdose group (n = 27)
1. Teeling JL, et al. J Immunol. 2006;177(1):362-371. 2. Teeling JL, et al. Blood 2004;104(6):1793-1800. 3. Coiffier B,
et al. Blood 2008;111(3):1094-1100.
Ofatumumab Pivotal Study
Study design: Multinational, open-label, single-arm study: in 154 patients
with fludarabine-refractory CLL
 Cohort A: double-refractory to both fludarabine and alemtuzumab (n=59)
 Cohort B: refractory to fludarabine and inappropriate for alemtuzumab
due to bulky lymph nodes (>5 cm) (n=79)
Week
0
1
2
Ofatumumab*
300 mg
3
4
5
6
Ofatumumab*
2000 mg
Wierda WG, et al. J Clin Oncol 2010; 28: 1749-55.
7
12
16
20
* Patients were pre-medicated with acetaminophen
and cetrizine prior to infusions. Additionally, before
the 1st, 2nd and 9th infusions, patients received
glucocorticoid
24
Baseline Characteristics of DoubleRefractory CLL patients
Patient Characteristics
Median age, years (range)
Fludarabine+AlemtuzumabRefractory Pts (n = 59)
64 (41–86)
Rai stage III/IV, %
54
Binet stage C, %
51
ECOG performance status 1–2, %*
53
Largest lymph node >5 cm, %†
93
Median number of prior therapies (range)
Prior rituximab containing regimens, %
5 (1–14)
59
*One patient had ECOG PS grade 3 at baseline due to elbow surgery unrelated to CLL and was allowed to enrol in the study;
†Lymph node size determined at study entry by palpation or computed tomography (CT) scan
ECOG = Eastern Cooperative Oncology Group
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755.
Ofatumumab in Double-Refractory CLL:
Objective Responses
ORR, %
58%*
99% CI
*P<.0001 versus H0 (twosided exact test)
H0: ORR = 15%
Fludarabine+Alemtuzumab-Refractory Pts
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755. Osterborg A, et al. Haematologica. 2009;95(Suppl. 2):Abstract 0494.
Ofatumumab in Double-Refractory CLL:
Response by Baseline Characteristics
Fludarabine+Alemtuzumab-Refractory Pts
Subgroup
N
ORR, %
Prior rituximab
No prior rituximab
35
24
54
63
Refractory to FCR
Other*
16
43
50
60
Age ≥70 yrs
Age <70 yrs
10
49
60
57
Rai stage III-IV
Rai stage I-II
32
26
56
58
≥5 prior therapies
<5 prior therapies
37
22
65
45
17p del
No 17p del
17
40
41
65
11q del
No 11q del
24
33
63
55
*Patients refractory to a fludarabine-based regimen other than that containing FCR
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755.
Ofatumumab in Double-Refractory CLL:
Time to Response and Duration
100
1.8 mo
80
60
40
20
0
0
2
4
6
8
Months from Start of Treatment
Median duration of response*
(n = 34)
Estimated Probability, %
Estimated Probability, %
Median time to response
(n = 34)
100
80
60
7.1 mo
40
20
0
0
2
4
6
8 10 12 14 16
Months from Onset of Response
Fludarabine+Alemtuzumab-Refractory Pts
*Time from initial response to progression (assessed by IRC) or death.
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755. Osterborg A, et al. Blood 2008;112:Abstract 328. Osterborg A,
et al. Haematologica. 2009;95(Suppl. 2):Abstract 0494.
Association of Pharmacokinetic Parameters with
Progression-Free Survival Outcomes
• At Dose 8 and 12, higher Cmax, Cmin, and AUC, and lower CL were significantly
correlated with longer PFS
• Based on exploratory multivariate analyses, PK parameters were not
independent predictors of ORR or PFS
PK at Infusion 8 (All Patients)
PK at Infusion 12 (All Patients)
PK Parameter
PFS HR
P Value
PFS HR
P Value
Cmax, mg/L
<1.000
.007
0.999
.009
Cmin, mg/L
0.999
.004
0.998
.007
AUC, mg•hr/L
<1.000
.014
<1.000
.015
CL, mL/hr
1.047
.029
1.128
.000
Vss, mL
>1.000
.473
>1.000
.010
t1/2, days
0.999
.057
0.996
.008
Cmax, maximum concentration; Cmim, minimum concentration; AUC, area under the concentration-time curve; CL,
clearance; Vss, volume of distribution at staty state; t1/2, elimination half-life
Österborg A, et al. Blood.2009;114: Abstract 3433.
Ofatumumab in Double-Refractory CLL:
Median Overall Survival by Response
Landmark analysis* at week 12†
Fludarabine+Alemtuzumab-Refractory Pts
not reached
9.8 mo
† Analysis
included patients who were alive at the Week 12 time point.
* Anderson JR, et al. J Clin Oncol. 2008;26:3913-3915. Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755.
Summary of Clinical Improvement
(by physical exam)
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755. Osterborg A, et al. Haematologica. 2009;95(Suppl. 2):Abstract 0494.
Median Hemoglobin Over Time in Patients
with Baseline Anemia
Fludarabine+Alemtuzumab-Refractory
Treatment period
Follow-up
13
Screening
Median Hemoglobin, g/dL
14
12
11
10
9
−2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Weeks from Start of Treatment
Number of patients
DR
27 27 16 13 12
11
11
11
10
10
8
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755; adapted chart.
2
1
Median Platelet Counts Over Time in Patients
with Baseline Thrombocytopenia
Treatment period
150
Follow-up
140
130
120
110
100
Screening
Median Platelet Count, 109/L
Fludarabine+Alemtuzumab-Refractory
90
80
70
60
−2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Weeks from Start of Treatment
Number of patients
DR
29 29 24 22 21
21
18
18
16
13
10
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755; adapted chart.
4
0
Summary of Drug-Related Adverse Events
Related Adverse Events
Hematologic
Fludarabine+Alemtuzumab-Refractory (n = 59)
All Grades
Grade 3–4
n†
%
n†
%
Neutropenia
Anaemia
Non-hematologic
11
2
19
3
8
0
14
0
Infections
Fatigue
Cough
Diarrhea
Dyspnea
Nausea
Rash
Fever
12
3
5
5
5
3
5
5
20
5
8
8
8
5
8
8
7
0
0
0
1
0
0
1
12
0
0
0
2
0
0
2
†Number
of patients who experienced at least one event
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755; adapted chart.
Infusion Reactions
Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755. Osterborg A, et al. Haematologica. 2009;95(Suppl. 2):Abstract 0494.
Efficacy and Safety of Ofatumumab in
Double-Refractory CLL vs Historic Data*
(Ofatumumab)
FA-ref1
(n = 59)
Tam et al*2
FA-ref
(n = 54)
58%
0%
20%
(0%)
Median PFS,
mos
5.7
TTF 2–3
Median OS,
mos
13.7
8
Death within 8
wks
7%
16%
Major
infections
25%
60%
ORR
CR
*Data from retrospective study:
TTF = time to treatment failure
1. Wierda WG, el at. J Clin Oncol. 2010;28(10):1749-1755. 2. Tam CS, et al. Leuk Lymph. 2007;48:1931-1935.
Coming Up…..Small Molecules to Interfere with the
Signal Transduction Machinery?
CLL: Targets and Small Molecule Inhibitors in Pipeline
• CDK inhibition:
flavipiridol, SCH 727965
• Bcl-2 inhibition:
oblimersen, ABT-263
• PKC inhibition:
enzastaurin
• PI3-K inhibition:
MVP-BEZ235, CAL-101
• mTOR inhibition:
siro-, temsiro- and everolimus
• HDAC inhibitors:
vorinostat (SAHA), valproic acid
• HSP 90/ZAP-70 inhibitors:
CNF 2024, SNX7081
• p53 restoration/activation:
Nutlin-3, PRIMA
• PARP (ATM):
AZD2881
• SRC/ABL RTK inhibitor:
dasatinib
• VEGF inhibition:
sorafenib
• Silvestrol (translation inhibitor)
• MTA (microtubule targeting agents):
PBOX-15
• Syk inhibition:
R406 (fostamatinib)
Refractory CLL: Conclusions June 2010
• Unmet need for salvage treatment options exists for
refractory patients with CLL
• Most patients with refractory CLL are elderly, have poor
prognosis, at high risk of infections, and reduced PS; all
this affects tolerability of salvage therapy
• Alemtuzumab is the standard of care if 17p-, when patients
failed purine analogues, unless large lymph nodes are
present. Cam-Pred may be used in high-risk patients?
• Rituximab combined with high-dose steroids, or with
bendamustine?
• Lenalidomide is in development: A safe and effective dose
is being identified in ongoing trials. Combination therapy?
Refractory CLL: Conclusions June 2010
• Ofatumumab (Arzerra®) is approved in fludarabineplus alemtuzumab-refractory CLL, and yields
response rates of 58%
• Effective irrespective of cytogenetic abnormalities (17p-?)
or prior rituximab therapy
• Relief of disease-related constitutional symptoms and
improvements in PS
• Well tolerated with no unexpected adverse events
• In pipeline: Several new antibodies, antibody-like
constructs, and small inhibitory molecules