Other%20B-Cell%20Malignancies

1
Other B-Cell Malignancies

• Mantle Cell Lymphoma
• MALT
• HIV-associated DLCL
• Burkitts Lymphoma
• Waldenstroms Macroglobulinemia
• Hodgkins Disease
• Autoimmune Disorders

2
MabThera for Other B-Cell Disorders

• Mantle Cell Lymphoma (MCL)

3
Mantle Cell Lymphoma (MCL) Background

• Classified as unique entity in 1992
• Accounts for approximately 5 of all NHLs in US
• Characterized by t(1114) translocation involving
  bcl-1
• Overexpression of Cyclin D1
• Strong male predominance (21 to 41)
• Clinical presentation Advanced-stage
• High rate of extranodal disease
• Median age 55
• Represents a particularly treatment-refractory
  subset of NHL

4
MCL Prognostic Factors

• Improved Prognosis Age lt65
• Good PS
• Limited-stage disease
• Normal LDH, normal ?2-M
• Low IPI
• Poor Prognosis Blastoid transformation
• High mitotic rate
• B symptoms
• Splenomegaly, blood involvement
• Low albumin

5

• MabThera Single-Agent Therapy for MCL
• Foran et al
• J Clin Oncol 2000

6
MabThera Single-Agent Therapy for MCL Protocol
MabThera (375 mg/m2)
Restage
Restage


8
12
1
2
3
4
Weeks
Foran et al. J Clin Oncol. 200018317.
7
MabThera Single-Agent Therapy for MCL Patient
Characteristics
MCL1 (n34)
MCL2 (n40)
IMC (n28)
SLL (n29)
Age (y) Median 57 63 59 58 (range)
(33-83) (49-83) (31-73) (34-80) PS
(WHO) 0 76 48 54 41 1 18 38 29 52 2 6 1
5 18 7 No. of previous treatments
Median N/A 3 3 3 (range) (1-7) (1-7) (1-9) Pri
or therapy Alkylator N/A 58 86 76 Anthracycli
ne N/A 55 64 55 fludarabine
N/A 25 46 48 HDT N/A 18 14 0 Other (?1)
N/A 60 39 52
Foran et al. J Clin Oncol. 200018317.
8
MabThera Single-Agent Therapy for MCL
Eligibility Criteria

• Exclusion
• Active hepatitis
• HIV
• CNS

• Inclusion
• Diagnosis
• Previously untreated MCL (MCL1)
• Previously treated MCL (MCL2), IMC, or SLL
• Prior therapy completed ?1 month before MabThera
  initiation
• ?18 years
• PS ?2
• CD20

Foran et al. J Clin Oncol. 200018317.
9
MabThera Single-Agent Therapy for MCL Response
of Patients
MCL1 (n32)
MCL2 (n35)
IMC (n25)
SLL (n28)
ORR 38 37 28 14 CR 16 14 0 0 PR 22 23 28 14
Evaluable patients.
Foran et al. J Clin Oncol. 200018317.
10
MabThera Single-Agent Therapy for MCL Duration
of Response (Responders With MCL)
100
80
60
Patients ()
(n25)
40
20
0
0.5
1.0
1.5
0
Years
Adapted from Foran et al. J Clin Oncol.
200018317.
11
MabThera Single-Agent Therapy for MCL Toxicity
of Patients (N131)
Hematologic (grade 3/4) Thrombocytopenia
6 Leukopenia 5 Neutropenia 3 Anemia 2 Nonhema
tologic (all grades) Fever 49 Rigors 28 Infecti
ons 24 Arrhythmia 8 Ophthalmologic 7
Most cases normalized after therapy.
Foran et al. J Clin Oncol. 200018317.
12
MabThera Single-Agent Therapy for MCL Summary

• ORR of 38 in previously untreated and heavily
  pretreated patients with MCL
• Infusions well tolerated
• Most grade 3/4 hematologic toxicity transient

Foran et al. J Clin Oncol. 200018317.
13

• MabThera HyperCVAD/M-A for Previously
  Untreated Mantle Cell Lymphoma
• Romaguera et al
• Blood 2001

14
MabThera HyperCVAD/M-A for Previously
Untreated Mantle Cell Lymphoma Protocol
M-A methotrexate cytosine arabinoside
Romaguera et al. Blood. 200198(suppl 1)726a.
Abstract 3030.
15
MabThera HyperCVAD/M-A for Previously
Untreated Mantle Cell Lymphoma Patient
Characteristics

• No. of patients 77
• Age (y) Median 62
• Stage IV 100
• Organ involvement Spleen 39
• Bone marrow 92
• Peripheral blood 47
• GI tract 90
• Diffuse histology 72
• (Blastic variant) (17)

M-A methotrexate cytosine arabinoside
Romaguera et al. Blood. 200198(suppl 1)726a.
Abstract 3030.
16
MabThera HyperCVAD/M-A for Previously
Untreated Mantle Cell Lymphoma Response
of Patients (n56)
CR 89 2-year FFS 72 2-year OS 90
Median 14 month follow-up Evaluable patients.
M-A methotrexate cytosine arabinoside
Romaguera et al. Blood. 200198(suppl 1)726a.
Abstract 3030.
17
MabThera HyperCVAD/M-A for Previously
Untreated Mantle Cell Lymphoma Response Versus
Historical Controls
of Patients of Patients of Patients of Patients of Patients
lt66 years lt66 years gt65 years gt65 years
R-HyperCVAD/M-A(n46) HyperCVAD/M-A/ASCT(n26) R-HyperCVADM-A(n29) HyperCVAD/M-A(n22)
CR 89 100 90 70
2-year FFS 84 75 60 41
2-year OS 87 96 96 77
M-A methotrexate cytosine arabinoside
18 of 26 potentially eligible patients
underwent SCT
Romaguera et al. Blood. 200198(suppl 1)726a.
Abstract 3030.
18
MabThera HyperCVAD/M-A for Previously
Untreated Mantle Cell Lymphoma Summary

• High CR rate of 89
• Addition of MabThera to HyperCVAD/M-A without
  SCT appears equivalent to HyperCVAD/M-A alone in
  patients lt66 years
• Trend for improved outcome with MabThera
  HyperCVAD/M-A in patients gt65 years
• CR 90 vs 70
• 2-year FFS 60 vs 41
• 2-year OS 96 vs 77
• Toxicity
• grade 4 hematological toxicity (60)
• grade 3 infections (14)

M-A methotrexate cytosine arabinoside
Romaguera et al. Blood. 200198(suppl 1)726a.
Abstract 3030.
19

• MabThera FCM Versus FCM in Relapsed Follicular
  and Mantle Cell Lymphoma
• Hiddemann et al
• ICML 2002

20
MabThera FCM Versus FCM in Relapsed Follicular
and Mantle Cell Lymphoma Protocol
Month 3
Month 9
R a n d o m i z a t i o n
4 x FCM MabThera
R a n d o m i z a t i o n
4 x MabThera
4 x MabThera
CR, PR
4 x FCM
Observation only
CR, PR
Hiddemann et al. ICML 2002 Satellite Symposium
(Lugano)
21
MabThera FCM Versus FCM in Relapsed Follicular
and Mantle Cell Lymphoma Patient Characteristics
MabThera FCM FCM No. of
patients 51 53 Age (y) Median 64 62 lt60
32 37 ³60 68 63 Male 57 57 Female 43 43
Histology Follicular lymphoma 53 49 Mantle
cell lymphoma 37 36 Other 10 15
Evaluable patients
Hiddemann et al. ICML 2002 Satellite Symposium
(Lugano)
22
MabThera FCM Versus FCM in Relapsed Follicular
and Mantle Cell Lymphoma Response

• of Patients (n104)
• MabThera FCM FCM (n51) (n53)
• ORR 83 58
• CR 35 13
• PR 48 46
• PD 15 31
• Evaluable patients

Hiddemann et al. ICML 2002 Satellite Symposium
(Lugano)
23
MabThera FCM Versus FCM in Relapsed Follicular
and Mantle Cell Lymphoma Response by Histology
of Patients of Patients of Patients of Patients of Patients
Follicular lymphoma Follicular lymphoma Mantle cell lymphoma Mantle cell lymphoma
MabThera FCM(n27) FCM(n26) MabThera FCM(n19) FCM(n19)
ORR 89 100 90 70
CR 84 75 60 41
PR 87 96 96 77
Hiddemann et al. ICML 2002 Satellite Symposium
(Lugano)
24
MabThera FCM Versus FCM in Relapsed Follicular
and Mantle Cell Lymphoma Summary

• Significantly higher responses with MabThera
  FCM (ORR 83, CR 35) versus FCM alone (ORR 58,
  CR 13)
• Improved response with no increase in toxicity
• Superiority of MabThera FCM seen in all
  histological subgroups but most striking in
  mantle cell lymphoma
• follicular lymphoma (ORR 92 vs 75, CR 40 vs
  21)
• mantle cell lymphoma (ORR 65 vs 33, CR 35 vs
  0)

Hiddemann et al. ICML 2002 Satellite Symposium
(Lugano)
25

• MabThera for MALT Lymphoma
• Conconi et al
• Proc Am Soc Clin Onc 2002

26
MabThera for MALT LymphomaPatient
Characteristics

• No. of patients 35
• Age (y) Median 57 (range) (2785)
• Histology Primary gastric MALT 43
• Primary non-gastric 57
• Ann Arbor stage I 34
• II 9
• IV 57
• Bone marrow involvement 26
• B symptoms 6
• Elevated LDH 9

Conconi et al. Proc Am Soc Clin Oncol.
200221267a. Abstract 1067.
27
MabThera for MALT Lymphoma Response

• of Patients
• ORR 71
• CR 43
• PR 29

Evaluable patients at median 12-month follow-up

• Median time to best response was 2.2 months
• Three patients had PD after treatment (three
  relapsed after CR, two after PR)
• Favorable tolerability profile

Conconi et al. Proc Am Soc Clin Oncol.
200221267a. Abstract 1067.
28
MabThera CHOP for HIV-associated Aggressive
Lymphoma

• Boue et al
• Blood 2002

29
MabThera CHOP for HIV-associated Aggressive
Lymphoma Protocol
Cyclophosphamide Doxorubicin Vincristine
MabThera
Prednisone
Repeat cycle (6 cycles total)
0 1 2 3 4 5 6 7 14 21
Days
Boué et al. Blood. 2002100470a. Abstract 1824.
30
MabThera CHOP for HIV-associated Aggressive
Lymphoma Eligibility Criteria

• Inclusion
• HIV with aggressive stage I-IV untreated NHL
• CD20
• Age 18-75 years
• Good/intermediate prognosis no more than one of
  CD4 lt100/µL, Karnofsky index lt60, ECOG gt2,
  history of opportunistic infection

• Exclusion
• Active viral hepatitis

Boué et al. Blood. 2002100470a. Abstract 1824.
31
MabThera CHOP for HIV-associated Aggressive
Lymphoma Patient Characteristics
Boué et al. Blood. 2002100470a. Abstract 1824.
32
MabThera CHOP for HIV-associated Aggressive
Lymphoma Response
Evaluable patients
Boué et al. Blood. 2002100470a. Abstract 1824.
33
MabThera CHOP for HIV-associated Aggressive
Lymphoma Relapse-free Survival
1.0 0.8 0.6 0.4 0.2 0
Relapse-free Survival
0 12 24 36 48
Months
Boué et al. Blood. 2002100470a. Abstract 1824.
34
MabThera CHOP for HIV-associated Aggressive
Lymphoma Overall Survival
1.0 0.8 0.6 0.4 0.2 0
Overall Survival
0 12 24 36
Months
Boué et al. Blood. 2002100470a. Abstract 1824.
35
MabThera CHOP for HIV-associated Aggressive
Lymphoma Tolerability
Boué et al. Blood. 2002100470a. Abstract 1824.
36
MabThera CHOP for HIV-associated Aggressive
Lymphoma Summary

• 77 CR/CRu comparable to CR/CRu in DLCL in GELA
  LNH 98.5 trial (76)
• Relapse-free and overall survival appear better
  than those reported in previous cohorts
• Well-tolerated therapy with moderate hematologic
  toxicity
• Adding MabThera to CHOP does not increase the
  risk of infection

Boué et al. Blood. 2002100470a. Abstract 1824.
37

• MabThera Hyper-CVAD as First-line Treatment in
  Burkitts Lymphoma
• Thomas et al
• Blood 2002

38
MabThera Hyper-CVAD as First-line Treatment in
Burkitts Lymphoma Protocol
Methotrexate/cytarabine

• Hyper-CVAD
• MabThera (days 1 11 of hyper-CVAD, days 1 8
  of methotrexate/cytarabine)

0 2 4 6 8
Courses
Thomas et al. Blood. 2002100763a. Abstract 3022.
39
MabThera Hyper-CVAD as First-line Treatment
in Burkitts Lymphoma Patient Characteristics
Thomas et al. Blood. 2002100763a. Abstract 3022.
40
MabThera Hyper-CVAD as First-line Treatment in
Burkitts Lymphoma Response

• 89 CR in 19 evaluable patients
• No induction deaths
• 86 of non-HIV patients disease-free at a median
  follow-up of 12 months
• MabThera did not add significantly to the
  toxicity of the hyper-CVAD regimen

Thomas et al. Blood. 2002100763a. Abstract 3022.
41
MabThera Hyper-CVAD as First-line Treatment in
Burkitts Lymphoma Summary

• The combination of MabThera and hyper-CVAD is a
  feasible treatment for Burkitts lymphoma
• Durable CR observed
• Tolerability and toxicity profile similar to
  hyper-CVAD alone

Thomas et al. Blood. 2002100763a. Abstract 3022.
42
MabThera for Other B-Cell Disorders

• Other B-Cell Lymphoproliferative Disorders

43
MabThera for Other Lymphoproliferative
Disorders Candidates

• Post-transplant lymphoproliferative disorder
  (PTLD)
• Waldenströms macroglobulinemia (WM)
• Hodgkins disease (HD)
• Multiple myeloma (MM)

44
Other Lymphoproliferative Disorders Common
Treatment Modalities

• Conventional therapy
• Chemotherapy
• Myeloablative chemotherapy SCT
• Limitations
• Moderate efficacy
• High rate of relapse
• Toxicity common

Treon and Anderson. Semin Oncol. 20002779
Dimopoulos et al. J Clin Oncol. 200018214.
45
MabThera for Other Lymphoproliferative
Disorders Rationale

• CD20 expression detected in
• 75 to 100 of patients with WM
• 20 of patients with MM CD20 MM patients
  appear to have a more aggressive phenotype than
  those who are CD20-
• Re-treatment with MabThera is generally safe and
  associated with increased/prolonged efficacy in
  lymphoma
• Low toxicity with MabThera vs chemotherapy
  regimens

Treon and Anderson. Semin Oncol. 20002779
Treon et al. Semin Oncol. 200027598.
46
MabThera for WM Patient Characteristics

• MabThera 375 mg/m2 weekly x 4-8 weeks

No. of patients 7 Age (y) Median 60 (range)
(50-75) PS Median 1 (range) (1-3) IgM Mean
(g/dL) 2.9 Leukocyte count Mean
(/cm3) 5.1 Hemoglobin count Mean (g/dL)
10.5 Platelet count Mean (/cm3) 219 No. of
prior treatments Median 3 (range) (1-4) Prior
treatment status Alkylator 100 fludarabine 57 R
efractory to last treatment 71
Byrd et al. Ann Oncol. 1999101525.
47
MabThera for WM Response
(N7)
PR (no. of patients) 3 Median PFS (mo)
6.6 (range) (2.2-29) Duration of response (mo)
2-29
Byrd et al. Ann Oncol. 1999101525.
48
MabThera for WM Protocol/Patient
Characteristics

• MabThera 375 mg/m2 weekly x 4-8 weeks

No. of patients 30 Age (y) Median 60 (range)
(32-83) IgM ?3000 mg/dL 40 Hematocrit
?30 47 Platelet count (PLT) ?100,000/
µL 40 Dependence PRBC, PLT, or 23 erythropoietin
No. of prior treatments Median 1 (range)
(0-6) Prior treatment status None 23 Nucleoside
analog 47 Transplant 3
Treon et al. J Immunother. 200124272.
49
MabThera for WM Response
of Patients Response (N30) PR
27 MR 33 Stable Disease 30 Decreased IgM levels
(Plt0.001) 80 TTF Responders (PR, MR) 8
mo Patients with Stable Disease 5 mo
Treon et al. J Immunother. 200124272.
50
MabThera for WM Summary

• MabThera is an active agent for WM
• Hematologic recovery was seen
• Toxicity
• Transient
• Mild to moderate

51
Extended MabThera Dosing in Waldenstroms
Macroglobulinemia Protocol
PD off study
MabThera (375 mg/m2 weekly x 4)
Evaluation (week 12)
PD off study
SD, PR, CR MabThera (375 mg/m2 weekly x 4)
Evaluation (week 24)
Every 2-monthfollow-upfor 2 yearsor until
offstudy
Treon et al. Proc Am Soc Clin Oncol.
200221(suppl 1)268a. Abstract 1068.
52
Extended MabThera Dosing in Waldenstroms
MacroglobulinemiaPatient Characteristics
No. of patients 29 Age (y) Median 65 (range)
(4390) Prior therapies Median 1 (range) (02)
No prior therapy 38 IgM gt3,000
mg/dl 66 Hematocrit lt30 35 Platelets
lt100,000 µl 28
22 evaluable patients
Treon et al. Proc Am Soc Clin Oncol.
200221(suppl 1)268a. Abstract 1068.
53
Extended MabThera Dosing in Waldenstroms
Macroglobulinemia Response

• Partial response in 11 of 22 evaluable patients
  (50)
• Minor response in five patients (23)
• Stable disease in three patients (14)
• Median TTTF not reached after median
  12-monthfollow-up
• Reduction in incidence of anemia (35 vs 5) and
  thrombocytopenia (28 vs 9) following MabThera
• Expression of complement resistance antigens on
  tumor cells does not correlate with MabThera
  clinical activity

Treon et al. Proc Am Soc Clin Oncol.
200221(suppl 1)268a. Abstract 1068.
54
MabThera Fludarabine in Waldenströms
Macroglobulinemia Protocol
MabThera (375 mg/m2 weekly) Weeks 1-4
Fludarabine (25 mg/m2 x 5 days) Week 13
SD, PR, CR
MabThera (375 mg/m2 weekly)Weeks 17 18
Fludarabine (25 mg/m2 x 5 days) Weeks 5 9
Evaluation (week 12)
Fludarabine (25 mg/m2 x 5 days) Weeks 19 23 27
PD off study
MabThera (375 mg/m2 weekly) Weeks 30 31
Fludarabine dose modification and delay G-CSF
use permitted based on hematologic toxicities
Treon et al. Blood. 2002100211a. Abstract 794.
55
MabThera Fludarabine in Waldenströms
Macroglobulinemia Patient Characteristics
Treon et al. Blood. 2002100211a. Abstract 794.
56
MabThera Fludarabine in WaldenströmsMacroglob
ulinemia Response

• Response duration 3-18 months

Evaluable patients
Treon et al. Blood. 2002100211a. Abstract 794.
57
MabThera Fludarabine in Waldenströms
Macroglobulinemia Tolerability

• Grade III/IV neutropenia in 44 of patients
  mostly asymptomatic
• 4 deaths
• 2 possibly due to immunosuppression of protocol
  therapy and/or disease
• 1 unrelated to protocol therapy
• 1 in patient off study due to complications
  associated with abrupt spike in serum IgM and
  viscosity

Treon et al. Blood. 2002100211a. Abstract 794.
58
MabThera Fludarabine in Waldenströms
Macroglobulinemia Summary

• Combination therapy with MabThera and
  fludarabine is highly active (ORR 76)
• Therapy appears tolerable
• Impact on response duration remains to be
  established

Treon et al. Blood. 2002100211a. Abstract 794.
59
MabThera in Previously Untreated Waldenstroms
Macroglobulinemia Protocol
MabThera 375 mg/m2 i.v.
If no evidence ofPD after 3 months, repeat
4-weekcourse of MabThera
1 2 3 4
Weeks
Dimopoulos et al. Blood. 200198(suppl 1)367a.
Abstract 1547.
60
MabThera in Previously Untreated Waldenstroms
MacroglobulinemiaPatient Characteristics
No. of patients 17 Age (y) Median 74 (range) (3
984) Sex Male 82 Female 18 Lymphadenopathy
47 Splenomegaly 18 Hemoglobin lt10
g/dl 53 Serum peak ³4 mg/dl 41 b2-microglobuli
n ³4 mg/l 47 BM lymphocytes ³50 65
Dimopoulos et al. Blood. 200198(suppl 1)367a.
Abstract 1547.
61
MabThera in Previously Untreated Waldenstroms
Macroglobulinemia Response
of Patients (n17)
ORR 35 CR 0 PR 35 SD 47 PD 18 TTR
(months) Median 3 (range) (28) TTP
(months) Median 15 (range) (330)
Dimopoulos et al. Blood. 200198(suppl 1)367a.
Abstract 1547.
62
MabThera in Previously Untreated Waldenstroms
MacroglobulinemiaTime to Progression
1.0 0.8 0.6 0.4 0.2 0
Progression-free
0 10 20 30 40
Months
Dimopoulos et al. Blood. 200198(suppl 1)367a.
Abstract 1547.
63
MabThera in Previously Untreated Waldenstroms
Macroglobulinemia Summary

• MabThera in previously untreated Waldenstroms
  Macroglobulinemia
• Is a very well tolerated treatment
• Achieves objective responses in 35 of patients
• Has a 15-month median TTP
• Some patients with SD had a clinical benefit and
  did not require further treatment for several
  months

Dimopoulos et al. Blood. 200198(suppl 1)367a.
Abstract 1547.
64
MabThera for Other B-Cell Disorders

• Hodgkins Disease

65
MabThera for Previously Treated Hodgkins
Disease Patient Characteristics
No. of patients 14 Age (y) Median 41 (range)
(1851) Stage I 21 II 29 III 7 IV 43 No.
of prior treatments Median 2 Time from diagnosis
(y) Median 9
Schulz et al. Ann Oncol. 200213(suppl 2)63.
Abstract 210.
66
MabThera for Previously Treated Hodgkins
Disease Response
of Patients (n12) ORR 86 CR 57 PR 29
PD 14

• Median follow-up 12 months

Schulz et al. Ann Oncol. 200213(suppl 2)63.
Abstract 210.
67
MabThera for Previously Treated Hodgkins
Disease Duration of Response
1.0 0.8 0.6 0.4 0.2 0
responding
Mean 20 months 95 CI 15.025.1
0 12 24 36
Months
Schulz et al. Ann Oncol. 200213(suppl 2)63.
Abstract 210.
68
MabThera for Previously Treated Hodgkins
Disease Tolerability

• Infusion-related reactions in 11/14 (79) of
  patients
• Majority mild-moderate (94), transient and
  resolved after first infusion
• No grade 3/4 hematologic toxicity
• One patient experienced grade 3 non-hematologic
  toxicity (chills and hypertension) on first
  infusion

Schulz et al. Ann Oncol. 200213(suppl 2)63.
Abstract 210.
69
MabThera for Previously Treated Hodgkins
Disease Summary

• ORR of 86
• 57 CR
• 29 PR
• Nine of 12 (75) responders in remission at
  median 12-month follow-up
• Median duration of response not reached at 20
  months follow-up
• MabThera therapy well-tolerated

Garcia-Manero et al. Blood. 200198(suppl
1)633a. Abstract 2650.
70
MabThera in Relapsed Hodgkins Disease Patient
Characteristics
No. of patients 22 Age Median 35 (range) 1766
Sex Male 68 Female 32 Nodular sclerosis
histology 100 Nodal disease only
41 Extranodal disease 59 B symptoms
32 Prior treatments Median 4 (range) 212 Prio
r stem cell transplant 82 CD20 expression on
H/RS cells Positive 27 Negative 68 Unknown
5
Younes et al. Blood. 200198(suppl 1)132a.
Abstract 555.
71
MabThera in Relapsed Hodgkins Disease Response
of Patients All CD20 CD20- patients H/R
S cells H/RS cells (n22) (n6) (n16) ORR 23 33
19 CR 5 0 6 PR 18 33 13 SD 36 50 31 6/7
patients (86) had resolution of B symptoms
Younes et al. Blood. 200198(suppl 1)132a.
Abstract 555.
72
MabThera in Relapsed Hodgkins Disease Response
by Site of Disease
of Patients Nodal disease only
Extranodal disease (n9) (n13) ORR 55
0 CR 11 0 PR 44 0 SD 33 38
Younes et al. Blood. 200198(suppl 1)132a.
Abstract 555.
73
MabThera ABVD for previously untreated
classical Hodgkins disease protocol
MabThera 375mg/m2 i.v. day 1 ABVD Doxorubicin
25mg/m2 i.v. Bleomycin 10mg/m2 i.v. Vinblastine
6mg/m2 i.v. Dacarbazine 375mg/m2 i.v.
Week
1 2 3 4 5 6 7 8 9 10 11 12
Restage
ABVD was given on day 2 of weeks 1, 3 and 5
(day after MabThera) and on day 1 of weeks 7,
9, 11
Younes A, et al. Blood 200310227a (Abstract 83)
74
MabThera ABVD for previously untreated
classical Hodgkins disease patient
characteristics
Younes A, et al. Blood 200310227a (Abstract 83)
75
MabThera ABVD for previously untreated
classical Hodgkins disease severe toxicities
Younes A, et al. Blood 200310227a (Abstract 83)
76
MabThera ABVD for previously untreated
classical Hodgkins disease results
Median follow-up 21 months
Younes A, et al. Blood 200310227a (Abstract 83)
77
MabThera ABVD for previously untreated
classical Hodgkins disease event-free survival
100 75 50 25 0
Percentage event-free survival
0 12 24 36
Months
Younes A, et al. Blood 200310227a (Abstract 83)
78
MabThera ABVD for previously untreated
classical Hodgkins disease summary

• MabThera ABVD is the first regimen for the
  treatment of classical Hodgkins disease that
  combines chemotherapy with a selective targeted
  therapy of the microenvironment
• MabThera ABVD is feasible and well tolerated
• Preliminary analysis shows promising results

Younes A, et al. Blood 200310227a (Abstract 83)
79
MabThera for Other B-Cell Disorders

• Autoimmune Disorders

80
MabThera for Autoimmune Disorders Candidates

• Autoimmune hemolytic anemia (AIHA)
• Idiopathic thrombocytopenic purpura (ITP)
• Rheumatoid arthritis (RA)
• IgM polyneuropathies

81
Autoimmune Disorders Common Treatment Modalities

• Immunosuppression
• Chemotherapy
• Corticosteroids
• Splenectomy
• Limitations
• Moderate efficacy
• High rate of relapse
• Sustained maintenance therapy required
• Significant toxicity

82
MabThera for Autoimmune Disorders Rationale

• Autoimmune disorders are dependent on the
  production of autoantibodies by B lymphocytes
• Depletion of antibody-producing B cells by
  MabThera may reduce autoantibody titers
• Re-treatment with MabThera is generally safe
  and associated with increased/prolonged efficacy
  in lymphoma
• Low toxicity with MabThera vs chemotherapy
  regimens

83
MabThera for ITP Patient Characteristics
No. of patients 25 Age (y) Median 46 (range)
(22-74) ITP duration (prior to MabThera) Median
(mo) 22 (range) (9-56) Baseline platelet count
Median (x 109/L) 13 (range) (3-25) Prior
treatments Prednisone 100 IV IgM 100 High-dose
dexamethasone 44 Splenectomy 32 Coombs test
Positive 0
Stasi et al. Blood. 200198952.
84
MabThera for ITP Response
Response of Patients (N25) ORR
52 CR 20 PR 20 MR 12 Duration of response ?6 mo

Stasi et al. Blood. 200198952.
85
MabThera for primary chronic cold agglutinin
disease protocol
MabThera (375mg/m2 weekly x 4)
Responders
Followed for at least 6 months
Non-responders
After 3 months MabThera (375mg/m2 weekly x 4)
IFN-? (5 MU, t.i.w.)
Berentsen S, et al. Hematol J 20034(Suppl.
2)878
86
MabThera for primary chronic cold agglutinin
disease patient characteristics
Berentsen S, et al. Hematol J 20034(Suppl.
2)878
87
MabThera for primary chronic cold agglutinin
disease response

• 18 patients received 22 courses of therapy
• Median Hb increase 2.7g/dL
• Median IgM decrease 2.9g/L

Berentsen S, et al. Hematol J 20034(Suppl.
2)878
88
MabThera for primary chronic cold agglutinin
disease summary

• MabThera is an efficient therapy for cold
  agglutinin disease
• The duration of response has yet to be determined
• Only five patients have received IFN-a, whichdid
  not improve the response

Berentsen S, et al. Hematol J 20034(Suppl.
2)878
89
MabThera for AIHA Patient Characteristics
No. of patients 6 Age (y) Median 64 (range)
(22-83) AIHA type Warm 50 Cold 50 AIHA
duration (prior to MabThera) Range
(mo) 3-240 Prior treatments Steroids 100 Chemother
apy 33 Splenectomy 33 Plasmapheresis 17 Steroid
-dependent 50
All in patients with cold AIHA.
All in patients with warm AIHA.
Lee et al. Blood. 200096(suppl 1)596a. Abstract
2560.
90
MabThera for AIHA Response
of Patients Response (n5) CR
100 Recurrent hemolysis 0 Duration of
response 4 mo-2.7 y
Evaluable patients.
Lee et al. Blood. 200096(suppl 1)596a. Abstract
2560.
91
MabThera for CLL-associated AIHA Protocol
MabThera 375 mg/m2 i.v. day 1 Cyclophosphamide
7501,000 mg/m2 i.v. day 2 Dexamethasone 12
mg/day i.v. days 1 and 2 orally days 37
Cycles repeat to best response
1 2 3 4 5 6 7 8 9 10 11 12 13 14
23 24 25 26 27 28 29
Days

• Appropriate prophylaxis for tumor lysis syndrome
  with allupurinol and i.v. fluids was also given

AIHA autoimmune hemolytic anemia
Gupta et al. Blood. 200198(suppl 1)363a.
Abstract 1529.
92
MabThera for CLL-associated AIHAPatient
Characteristics
No. of patients 8 Age (y) Median 60 (range) 46
70 Sex Male 88 Female 12 Rai stage
III 50 IV 50 Splenomegaly 63 Hemoglobin
(g/dl) Median 8.3 (range) (59.9) Platelet
count (µl) Median 110,000 (range)
(9,000259,000) Absolute lymphocyte count (µl)
Median 190,000 (range) (20,000310,000) Positiv
e Coombs test 100 Prior therapies Median 2
(range) (04)
Gupta et al. Blood. 200198(suppl 1)363a.
Abstract 1529.
93
MabThera CLL-associated AIHA Initial Response

• All eight patients responded to therapy
• Hemoglobin levels improved from a pretreatment
  median of 8.3 g/dl to 13.5 g/dl after therapy
• Five of eight patients (63) converted to
  Coombstest negative
• Median duration of response was 13 months
• Five patients relapsed and were retreated

Gupta et al. Blood. 200198(suppl 1)363a.
Abstract 1529.
94
MabThera for CLL-associated AIHA Tolerability

• Adverse events were minimal and tolerable
• Majority of the side effects were related to
  first infusion of MabThera
• Grade IV neutropenia was seen in one patient
• None of the patients required any dose
  modification
• No opportunistic infections were observed

Gupta et al. Blood. 200198(suppl 1)363a.
Abstract 1529.
95
MabThera for CLL-associated AIHARetreatment
Response
Hemoglobin levels (g/dl)
No. of DRPatient cycles Pre-Tx Post-Tx
(months) 5 1 8.1 14.3 20 8 3 8.2 13.4
9 3 2 6.1 14.5 7 4 2 8.0 12.5
6 6 3 7.2 12.2 3
Gupta et al. Blood. 200198(suppl 1)363a.
Abstract 1529.
96
MabThera for Refractory AIHA in Children
Patient Characteristics
Zecca et al. Blood. 2002100444a. Abstract 1722.
97
MabThera for Refractory AIHA in Children
Response
16 12 8 4 0
Hemoglobin(g/dL)
Pre-treatment 2 months
800 600 400 200 0
Reticulocytes(x109/L)
Pre-treatment 2 months

• 77 of patients had normal Hb and reticulocyte
  counts without immunosuppression at 11 months
  follow-up

Zecca et al. Blood. 2002100444a. Abstract 1722.
98
MabThera for Refractory AIHA in Children
Tolerability and Status

• Generally well tolerated 3 children with
  moderate events during infusion
• All adverse events resolved following appropriate
  therapy
• 3 responders were retreated and achieved a second
  remission 1 retreated twice more and responded
  each time
• Remaining 10 responders alive with normal Hb and
  reticulocyte levels at median 11 months
  post-treatment (range 9-25 months)

Zecca et al. Blood. 2002100444a. Abstract 1722.
99
MabThera for Refractory AIHA in Children Summary

• MabThera is effective in reducing/abolishing
  hemolysis in pediatric patients with AIHA
• MabThera is generally well tolerated without
  theside-effects of traditional AIHA therapies
• The efficacy of MabThera is maintained with
  retreatment

Zecca et al. Blood. 2002100444a. Abstract 1722.
100
MabThera for RA Protocol
MabThera (300-600 mg)
Prednisolone
Cyclophosphamide
1
2
3
4
5
6
7
14
21
8
10
11
12
13
16
17
18
19
20
9
15
22
Days
Edwards and Cambridge. Rheumatology. 200140205.
101
MabThera for RA Patient Characteristics
No. of patients 5 Age (y) Median 55 (range)
(42-69) Duration of RA (y) Median 23 (range)
(11-40) Treatment failure Gold 100 Azathioprine
100 Sulphasalazine 100 Methotrexate
100 Penicillamine 80 Prednisolone 40 Hydroxychl
oroquine 20
Edwards and Cambridge. Rheumatology. 200140205.
102
MabThera for RA Response
Improvement Over Baseline

Swollen Joint Count
Pain VAS
Morning Stiffness
ACR Grade
Patient
CRP
ESR

• 1 70 94 73 75 88 100
• 2 70 92 96 71 74 94
• 3 70 100 66 42 77 100
• 4 70 83 89 74 70 50
• 5 70 79 86 67 82 100

After re-treatment with MabThera.
Edwards and Cambridge. Rheumatology. 200140205.
103
MabThera for IgM Polyneurophathies Patient
Characteristics
No. of patients 5 Age (y) Median 53 (range)
(44-68) Duration of IgM neuropathy (y) Median
10 (range) (4-14) Antibody target GM1
80 MAG 20 Prior treatment Plasma
exchange 100 Cyclophosphamide 100 IV
Ig 80 Steroids 20
Levine and Pestronk. Neurology. 1999521701.
104
MabThera for IgM Polyneurophathies Response
Total IgM (mg)
IgM Titer

Strength Change
Follow-up (mo)
Patient
Before
After
Before
After

• 1 16 154 97 60,500 38,000 6
• 2 18 446 423 23,000 11,000 6
• 3 22 261 1030 700 3
• 4 19 59 51 3000 2500 3
• 5 37 631 322 261,000 130,000 6

Levine and Pestronk. Neurology. 1999521701.
105
MabThera for Autoimmune DisordersSummary

• CR rate of 100 in patients with AIHA
• ORR of 52 in heavily pretreated, chronic ITP
• 100 of patients with RA achieved ACR70 criteria
• MabThera reduced IgM autoantibody titers and
  increased strength by ?16 in patients with IgM
  polyneurophathies
• Toxicity was transient and mild for all disorders