MabThera

1
MabThera for Chronic Lymphocytic Leukemia (CLL)
2
Chronic Lymphocytic Leukemia

• Staging
• CLL Characteristics
• Therapy Options
• MabThera in combination with chemotherapy for CLL
• MabThera monotherapy for CLL

3
Rai Staging of Chronic Lymphocytic Leukemia

• Stage
• Criteria 0 I II III IV
• Lymphocytosis (gt15,000/mm3) ? ? ? ? ?
• Lymphadenopathy ? ? ? ?
• Splenomegaly ? ? ?
• Hepatomegaly ? ? ?
• Anemia (hemoglobin lt11 g/dL) ? ?
• Thrombocytopenia (lt100,000/mm3) ?

? ? /-
4
CLL Characteristics

• B-cell lineage 95
• Immunophenotype CD5 CD19 CD20 CD23 CD52
• Cytogenetic abnormalities Deletions at
  13q14 Trisomy 12

5
Therapeutic Options for CLL

• Chemotherapy
• Single-agent chlorambucil, fludarabine
• Combination FC, CVP
• MoAbs
• MabThera
• Campath-1H
• SCT
• Allogeneic
• Mini-allogeneic
• Autologous
• Radiation (localized)

6

• MabThera in combination with chemotherapy for CLL

7

• MabThera fludarabine for previously untreated
  CLL
• Byrd et al
• Blood 2003

8
MabThera fludarabine for previously untreated
CLL protocol
Fludarabine 25mg/m2
MabThera 375mg/m2
Concurrent
R A N D O M I S E D
Consolidation therapy Patients with CR, PR, or
stable disease received MabThera
(375mg/m2 weekly x 4)
1
5
9
13
17
21
(2 months)
Weeks
Sequential
1
5
9
13
17
21
Weeks
Byrd JC, et al. Blood 2003101614
9
MabThera fludarabine for previously untreated
CLL patient characteristics
Byrd JC, et al. Blood 2003101614
10
MabThera fludarabine for previously untreated
CLL response
Byrd JC, et al. Blood 2003101614
11
MabThera fludarabine in previously untreated
CLL progression-free survival
100 80 60 40 20 0
Sequential arm
Percentageprogression-free survival
Concurrent arm
0 10 20 30 40 50
Months
Byrd JC, et al. Blood 2003101614
12
MabThera fludarabine in previously untreated
CLL overall survival
Byrd JC, et al. Blood 2003101614
13
MabThera fludarabine for previously untreated
CLL grade 3/4 adverse events

• Consolidation therapy well tolerated in both
  treatment arms

Byrd JC, et al. Blood 2003101614
14
MabThera fludarabine for previously untreated
CLL comparison with fludarabine only
Similar patient eligibility criteria
Combined sequential/concurrent arms
Byrd JC, et al. Blood 200310273a (Abstract 245)
15
MabThera fludarabine for previously untreated
CLL summary

• Higher ORR and CR rate in the concurrent arm (90
  and 47, respectively) than in the sequential arm
  (77 and 28, respectively)
• Response rates increased after consolidation
  therapy with MabThera
• MabThera consolidation therapy well tolerated
• There is a significant advantage for treatment
  with MabThera fludarabine compared with
  fludarabine alone

Byrd JC, et al. Blood 2003101614 Byrd JC, et
al. Blood 200310273a (Abstract 245)
16

• MabThera Fludarabine/Cyclophosphamide (FCR)
  for Previously Untreated CLL
• Wierda et al
• Ann Oncol 2003

17
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Untreated CLL Protocol
Start cycle 2
Cycle 1
MabThera 375 mg/m2 (cycle 1) or 500 mg/m2
(cycles 26)
1 2 3 4
8
15
22
29
Days
Fludarabine 25 mg/m2
Cyclophosphamide 250 mg/m2
Cycle repeats
Cycles 26
1 2 3
8
15
22
29
Days
Wierda et al. Ann Oncol. 200213(suppl 2)3.
Abstract 008.
18
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Untreated CLL Patient
Characteristics
No. of patients 135 Age (y) Median 57 (range) (
2486) Sex Male 67 Female 33 Rai
stage 0II 63 IIIIV 37 Median
b2-microglobulin (mg/dl) 3.9 Median WBC
(x103/µl) 9.2
Wierda et al. Ann Oncol. 200213(suppl 2)3.
Abstract 008.
19
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Untreated CLL Response

• of Patients (n135)
• ORR 95
• CR 63
• PR 17
• Nodular PR 15
• No response 4
• Early death 1

Wierda et al. Ann Oncol. 200213(suppl 2)3.
Abstract 008.
20
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Untreated CLL Response

• of Patients
• MabThera FC Fludarabine FC
• (n135) (n82) (n53)
• ORR 95 85 91
• CR 63 35 43
• PR 32 50 48
• Historical controls

Wierda et al. Ann Oncol. 200213(suppl 2)3.
Abstract 008.
21
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Untreated CLL Molecular Response

• PCR-negative
• CR (n55) 56
• PR (n10) 60
• Nodular PR (n8) 38

Wierda et al. Ann Oncol. 200213(suppl 2)3.
Abstract 008.
22
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Untreated CLL Tolerability
of Cycles (n721) Hematologic (grade
3/4) Neutropenia 60 Thrombocytopenia
7 Non-hematologic (all grades) Nausea
20 Vomiting 6 Infections 14 Tumor
lysis 1
Wierda et al. Ann Oncol. 200213(suppl 2)3.
Abstract 008.
23
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Untreated CLL Summary

• ORR and CR rate of 95 and 63, respectively
• CRs substantially higher after six versus three
  courses
• MabThera does not increase apparent toxicity of
  FC

Wierda et al. Ann Oncol. 200213(suppl 2)3.
Abstract 008. Keating et al. Blood. 200096(suppl
1)514a. Abstract 2214.
24

• Fludarabine, cyclophosphamide and MabThera in
  relapsed/refractory CLL
• Wierda et al
• Blood 2003

25
Fludarabine, cyclophosphamide and MabThera in
relapsed/refractory CLL treatment protocol
Allopurinol 300mg/day
Wierda W, et al. Blood 2003102110a (Abstract
373)
26
Fludarabine, cyclophosphamide and MabThera in
relapsed/refractory CLL response
(72)
Wierda W, et al. Blood 2003102110a (Abstract
373)
27
Fludarabine, cyclophosphamide and MabThera in
relapsed/refractory CLL survival by response
1.0 0.8 0.6 0.4 0.2 0
CR (median not reached)
Nodular PR (median not reached)
PR (median 41 months)
Proportion surviving
No response (median 18 months)
Early death (median 2 months)
0 1 2 3 4
Years
Wierda W, et al. Blood 2003102110a (Abstract
373)
28
Fludarabine, cyclophosphamide and MabThera in
relapsed/refractory CLL response by treatment
regimen
59
67
72
Historical controls
Wierda W, et al. Blood 2003102110a (Abstract
373)
29
Fludarabine, cyclophosphamide and MabThera in
relapsed/refractory CLL overall survival by
treatment regimen
Wierda W, et al. Blood 2003102110a (Abstract
373)
30
Fludarabine, cyclophosphamide and MabThera in
relapsed/refractory CLL conclusions

• FC plus MabThera is well tolerated and produces
  the highest CR rate in previously treated
  patients to date
• Improved survival with FC plus MabThera compared
  with historical F P and FC treated patients

Wierda W, et al. Blood 2003102110a (Abstract
373)
31

• MabThera Fludarabine/Cyclophosphamide (FCR)
  for Previously Treated CLL
• Garcia-Manero et al
• Blood 2001

32
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Treated CLL Eligibility Criteria

• Performance status ?3
• Rai stage III with active disease (e.g., weight
  loss gt10, fever, fatigue)
• Rai stage IIIIV
• Normal organ function

Garcia-Manero et al. Blood. 200198(suppl
1)633a. Abstract 2650.
33
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Treated CLL Patient
Characteristics
No. of patients 136 Age (y) Median 59 (range)
(3681) Stage IV 38 Other 62 Performance
status ?1 79 No. of prior treatments Median 2.5 P
rior treatment status Alkylating agents
only 15 Fludarabine sensitive 62 Fludarabine
refractory 23
Evaluable patients
Garcia-Manero et al. Blood. 200198(suppl
1)633a. Abstract 2650.
34
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Treated CLL Response
of Patients (n136) ORR
71 CR 21 PR 37 Nodular PR 13
Evaluable patients

• Median follow-up 5 months

Garcia-Manero et al. Blood. 200198(suppl
1)633a. Abstract 2650.
35
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Treated CLL Response by Prior
Therapy
of Patients Alkylators Fludarabine
Fludarabine only sensitive resistant (n20) (
n85) (n31) ORR 60 78 56 CR 15 27
6 PR 30 37 41 Nodular PR 15 14 9
Garcia-Manero et al. Blood. 200198(suppl
1)633a. Abstract 2650.
36
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Treated CLL Tolerability
of Courses (n554) Hematologic Neutropenia 4
6 Febrile neutropenia 2 Thrombocytopenia
5 Non-hematologic Nausea 19 Vomiting
5 Pneumonia 2
Garcia-Manero et al. Blood. 200198(suppl
1)633a. Abstract 2650.
37
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Treated CLLSurvival Compared
with Historical Controls
Garcia-Manero et al. Blood. 200198(suppl
1)633a. Abstract 2650.
38
MabThera Fludarabine/Cyclophosphamide (FCR)
for Previously Treated CLL Summary

• ORR of 71
• 21 CR
• 37 PR
• 13 nodular PR
• Survival advantage of MabThera FC versus FC
  alone demonstrated at 13 months median follow-up
  (Plt0.01)
• MabThera does not increase the apparent toxicity
  of FC

Garcia-Manero et al. Blood. 200198(suppl
1)633a. Abstract 2650.
39

• Sequential fludarabine, high-dose
  cyclophosphamide and MabThera in CLL
• Lamanna et al
• Blood 2003

40
Sequential fludarabine, high-dose
cyclophosphamide and MabThera in CLL protocol
Fludarabine (25mg/m2/day x 5 days every 4 weeks x
6 cycles)
High-dose cyclophosphamide (3g/m2 every 23 weeks
x 3 cycles)
MabThera (375mg/m2/week x 4)
Lamanna N, et al. Blood 2003102440a (Abstract
1603)
41
Sequential fludarabine, high-dose
cyclophosphamide and MabThera in CLL patient
characteristics
Lamanna N, et al. Blood 2003102440a (Abstract
1603)
42
Sequential fludarabine, high-dose
cyclophosphamide and MabThera in CLL response
Lamanna N, et al. Blood 2003102440a (Abstract
1603)
43
Sequential fludarabine, high-dose
cyclophosphamide and MabThera in CLL grade 3/4
adverse events
There were no treatment-related deaths
Lamanna N, et al. Blood 2003102440a (Abstract
1603)
44
Sequential fludarabine, high-dose
cyclophosphamide and MabThera in CLL summary

• Consolidation therapy with high-dose
  cyclophosphamide improves quality of response
  over induction with fludarabine
• A second consolidation with MabThera further
  improves quality of response in a significant
  proportion of patients

Lamanna N, et al. Blood 2003102440a (Abstract
1603)
45

• MabThera Fludarabine in CLL
• Schulz et al
• Blood 2001

46
MabThera Fludarabine in CLL Protocol
MabThera 375 mg/m2/week i.v., weeks 9, 13, 17,
21 Fludarabine 25 mg/m2/day i.v. days 15, weeks
1, 5, 9, 13
1 5 9
13 17
21
Week
Schulz et al. Blood. 200198(suppl 1)364a.
Abstract 1534.
47
MabThera Fludarabine in CLLPatient
Characteristics
No. of patients 30 Age (y) Median 59 (range) (30
70) Sex Male 70 Female 30 Binet
stage B 70 C 30 B symptoms 50 Prior
therapy None 63 Chlorambucil/prednisone 37
Schulz et al. Blood. 200198(suppl 1)364a.
Abstract 1534.
48
MabThera Fludarabine in CLL Tolerability
of Patients (n30) Grade 3/4
Hematologic Neutropenia 37 Leukopenia 27 Th
rombocytopenia 10 Anemia 10 Non-hematologic Infe
ctions 13 Fever 3 Pain 3 Arrhythmia 3
Nine patients (30) experienced grade I/II
infections
Schulz et al. Blood. 200198(suppl 1)364a.
Abstract 1534.
49
MabThera Fludarabine in CLL Response
of Patients All Untreated Relapsed Stage
B Stage C (n29) (n18) (n11) (n21) (n8) O
RR 90 89 90 91 87 CR 24 22 27 29 12 CRu 10
6 18 14 PR 55 61 45 48 75 SD 3 9 5
Schulz et al. Blood. 200198(suppl 1)364a.
Abstract 1534.
50
MabThera Fludarabine in CLLTime to
Progression
1.0 0.8 0.6 0.4 0.2 0
Five progressions (n30). Median not reached
Rate with progression
0 3 6 9 12 15 18 21
Months
Schulz et al. Blood. 200198(suppl 1)364a.
Abstract 1534.
51

• MabThera Monotherapy for CLL

52

• Standard Dose MabThera in SLL (CLL-Type)
• McLaughlin et al
• J Clin Onc 1998

53
Standard Dose MabThera in SLL (CLL-Type)
P0.01
ORR ()
Patients
McLaughlin et al. J Clin Oncol. 1998162825.
54
Low ORRs With MabThera in Patients With CLL
Possible Explanations

• Reduced CD20 expression
• Rapid MabThera clearance/low serum levels
• High lymphocyte counts

55
MabThera Serum Concentrations Correlate With
Response
800 600 400 200 0
Responders (CRs) Non-responders
MabThera Serum Levels (?g/mL)
0 500 1000 1500
Infusion
Hours
Adapted from McLaughlin et al. J Clin Oncol.
1998162825.
56
Strategies for Enhancing MabThera Efficacy in
CLL

• Modify dosing regimen
• Increase dose intensity (weekly x 4 with dose
  escalation)
• Increase dose density (thrice weekly x 4)
• Combine with chemotherapy
• fludarabine /- cyclophosphamide

57

• Dose Escalation of MabThera for CLL
• OBrien et al
• J Clin Onc 2001

58
Dose Escalation of MabThera for CLL Protocol

• Dose 1 Doses 2-4Cohorts
  n (mg/m2) (mg/m2)
• A 19 375 500
• B 4 375 650
• C 3 375 825
• D 4 375 1000
• E 5 375 1500
• F 12 375 2250

OBrien et al. J Clin Oncol. 2001192165.
59
Dose Escalation of MabThera for CLL
Eligibility Criteria

• CLL or other mature B-cell leukemias
• PS ?3 (Zubrod)
• Rai stage III-IV
• Rai stage I-II with evidence of active disease
  (eg, weight loss, fever, fatigue)
• Normal renal and hepatic function

OBrien et al. J Clin Oncol. 2001192165.
60
Dose Escalation of MabThera for CLL Patient
Characteristics
No. of patients 50 Age (y) Median 66 (range)
(44-87) Histology CLL 80 MCL 8 MZL 8 PLL
4 Stage I-II 20 III-IV 80 No. of prior
treatments Median 2 (range) (0-6) Patients
refractory to fludarabine 53 Alkylating
agents 43 Both 33
OBrien et al. J Clin Oncol. 2001192165.
61
Dose Escalation of MabThera for CLL Response
in Patients With CLL
Response Rate ()
(n24)
(n7)
(n9)
(n39)
MabThera (mg/m2)
Evaluable patients.
OBrien et al. J Clin Oncol. 2001192165.
62
Dose Escalation of MabThera for CLL Response
Characteristic Histology CLL 36 MCL 25 MZL 75
PLL 100 Stage I-II 60 III-IV 35 Prior
fludarabine Sensitive 56 response Refractory 20
of Patients
P0.06
P0.02
OBrien et al. J Clin Oncol. 2001192165.
63
Dose Escalation of MabThera for CLL TTP in
Responders
1.0
0.8
0.6
Proportion in Remission
0.4
0.2
0
2
0
4
6
8
10
12
14
16
Months
Adapted from OBrien et al. J Clin Oncol.
2001192165.
64
Dose Escalation of MabThera for CLL Toxicity
of Patients (N50)
Grade 3/4 toxicity (1st infusion) 12 CLL
(n40) 3 Other (n10) 50 Myelosuppression Neu
trophil count lt109/L 27 Neutrophil count lt0.5
x 109/L 11 Tumor lysis 2 Infection 10
P0.001
OBrien et al. J Clin Oncol. 2001192165.
65
Dose Escalation of MabThera for CLL Summary

• Dose-response relationship
• ORRs up to 75 with 2250 mg/m2 MabThera
• Higher ORRs in patients with early-stage disease
  and fludarabine?-sensitive patients
• Elevated MabThera doses well tolerated

OBrien et al. J Clin Oncol. 2001192165.
66

• MabThera Thrice Weekly for CLL
• Byrd et al
• J Clin Onc 2001

67
MabThera Thrice Weekly for CLLProtocol

• 1st dose (all cohorts) 100 mg over 4 hours

No. of Patients
Subsequent Doses (mg/m2)
Infusion Schedule
Cohort

• I 3 250 4 h, thrice weekly x 4
• II 7 375 4 h, thrice weekly x 4
• III 23 375 4 h (infusions 1 and 2) ? 1 h
  thrice weekly x 4

Byrd et al. J Clin Oncol. 2001192153.
68
MabThera Thrice Weekly for CLL Eligibility
Criteria

• Histologically confirmed CLL or SLL
• Failed ?1 prior therapy or were previously
  untreated with positive antiglobulin test,
  history of autoimmune anemia, autoimmune
  thrombocytopenia, or were not candidates for
  chemotherapy based on comorbid illnesses
• Recovered from toxicity of prior therapy
• Performance status ?3 (ECOG)
• Life expectancy ?3 months
• CD20
• Creatinine level ?3.0 mg/dL
• No infection requiring IV or PO antibiotics
• Not pregnant
• No previous allergic reaction to MabThera

Byrd et al. J Clin Oncol. 2001192153.
69
MabThera Thrice Weekly for CLL Patient
Characteristics
No. of patients 33 Age (y) Median 66 (range)
(50-80) Histology CLL 79 SLL 21 Stage I-II 27
III-IV 73 No. of prior treatments
Median 2 (range) (0-6) Prior
therapy None 18 Alkylator/purine
analog 30 fludarabine refractory 52
Byrd et al. J Clin Oncol. 2001192153.
70
MabThera Thrice Weekly for CLL Response
of Patients Response (n29)
ORR 52 CR 3 PR 48
Evaluable patients.
Byrd et al. J Clin Oncol. 2001192153.
71
MabThera Thrice Weekly for CLL Response (contd)

• Characteristic n ORR
• Histology SLL 7 43 CLL 26 46
• Stage I-II 9 56 III-IV 24 42
• Prior therapy None 6 83 Alkylator/fludarabine 1
  0 30 fludarabine refractory 17 41

Byrd et al. J Clin Oncol. 2001192153.
72
MabThera Thrice Weekly for CLL Median
Progression-Free Survival
100
Responders
All patients
80
60
Patients ()
40
20
0
2
0
4
6
8
10
12
14
16
18
20
Months
Adapted from Byrd et al. J Clin Oncol.
2001192153.
73
MabThera Thrice Weekly for CLL MabThera Serum
Concentrations
Concentration(µg/mL)
StandardDeviation
Infusion
Evaluation

• 1 Before 0 0 After 17.4 12.5
• 2 Before 7.7 10.7 After 245.3 91.3
• 3 Before 159.5 144.7 After 401.1 271.1
• 6 Before 418.8 259.1 After 676.3 263.5
• 12 Before 686.4 283.7 After 891.0 332.2

Byrd et al. J Clin Oncol. 2001192153.
74
MabThera Thrice Weekly for CLL Toxicity
Byrd et al. J Clin Oncol. 2001192153.
75
MabThera Thrice Weekly for CLL Summary

• ORR of 52
• Higher ORR in previously untreated patients
• Median duration of response of 10 months
• MabThera serum levels continued to accumulate
  after dose 3
• No patients experienced rapid clearance of
  MabThera
• Toxicity generally mild and transient

Byrd et al. J Clin Oncol. 2001192153.
76

• MabThera first-line and maintenance therapy for
  CLL and SLL
• Hainsworth et al
• J Clin Onc 2003

77
MabThera first-line and maintenance therapy for
CLL and SLL protocol
Patients with PD off study
MabThera (375mg/m2 weekly x 4)
Evaluation (week 6)
Patients with OR or SD MabThera maintenance
therapy (375mg/m2 weekly x 4, every 6 months for
up to four courses)
Hainsworth J, et al. J Clin Oncol 200321174651
78
MabThera first-line and maintenance therapy for
CLL and SLL patient characteristics
Hainsworth J, et al. J Clin Oncol 200321174651
79
MabThera first-line and maintenance therapy for
CLL and SLL response
Evaluable patients
Hainsworth J, et al. J Clin Oncol 200321174651
80
MabThera first-line and maintenance therapy for
CLL and SLL PFS
100 80 60 40 20 0
PFS ()
0 3 6 9 12 15 18 21 24 27 30
Months

• Median survival 19 months at 24-month follow-up
• Actuarial PFS 62 at 1 year and 49 at 2 years

Hainsworth J, et al. J Clin Oncol
200321174651 Hainsworth J, et al. Proc Am Soc
Clin Oncol 200320564 (Abstract 2332)
81
MabThera first-line and maintenance therapy for
CLL and SLL safety

• No grade 34 adverse events during maintenance
  MabThera courses
• No patient withdrew from treatment due to toxicity

Hainsworth J, et al. J Clin Oncol 200321174651
82
MabThera first-line and maintenance therapy for
CLL and SLL summary

• Mabthera is an effective first-line treatment for
  patients with CLL/SLL
• ORR of 51 (4 CR) increased to 58 (9 CR) after
  28 patients had begun MabThera maintenance
  therapy
• Treatment was well tolerated

Hainsworth J, et al. J Clin Oncol 200321174651
83

• MabThera consolidation in CLL for older patients
  in remission after first-line chemotherapy
• Mauro et al
• Blood 2003

84
MabThera consolidation in CLL for older patients
in remission after first-line chemotherapy
protocol
Chlorambucil (10mg/m2/day x 5) Prednisone (25mg/m
2/day x 5) every 28 days x 6 cycles
CR, PR
MabThera (375mg/m2/week x 4)
Mauro FR, et al. Blood 2003102674a (Abstract
2497)
85
MabThera consolidation in CLL for older patients
in remission after first-line chemotherapy
patient characteristics
Mauro FR, et al. Blood 2003102674a (Abstract
2497)
86
MabThera consolidation in CLL for older patients
in remission after first-line chemotherapy
response
Mauro FR, et al. Blood 2003102674a (Abstract
2497)
87
MabThera consolidation in CLL for older patients
in remission after first-line chemotherapy time
to second-line therapy
Mauro FR, et al. Blood 2003102674a (Abstract
2497)
88
MabThera consolidation in CLL for older patients
in remission after first-line chemotherapy
summary

• MabThera given as post-remission therapyin older
  patients with CLL achieves improved responses in
  many patients with a partial response to
  chlorambucil/prednisone
• Post-remission MabThera is well tolerated

Mauro FR, et al. Blood 2003102674a (Abstract
2497)