Other B-Cell Malignancies Mantle Cell Lymphoma MALT HIV-associated DLCL Burkitt’s Lymphoma Waldenstrom’s Macroglobulinemia Hodgkin’s Disease Autoimmune.

Other B-Cell Malignancies

Mantle Cell LymphomaMALTHIV-associated DLCLBurkitt’s LymphomaWaldenstrom’s MacroglobulinemiaHodgkin’s Disease

Autoimmune Disorders

MabThera® for Other B-Cell Disorders

Mantle Cell Lymphoma (MCL)

Mantle Cell Lymphoma (MCL) Background

Classified as unique entity in 1992 Accounts for approximately 5% of all NHLs in US Characterized by t(11;14) translocation involving

bcl-1 Overexpression of Cyclin D1 Strong male predominance (2:1 to 4:1) Clinical presentation: Advanced-stage

High rate of extranodal disease

Median age = 55

Represents a particularly treatment-refractory subset of NHL

MCL – Prognostic Factors

Improved Prognosis: Age <65

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

MabThera® Single-Agent Therapy for MCL

Foran et al

J Clin Oncol 2000

MabThera® Single-Agent Therapy for MCL: Protocol

Foran et al. J Clin Oncol. 2000;18:317.

Weeks

1 2 3 4 8 12

Restage Restage

MabThera® (375 mg/m2)

* *

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% 15% 18% 7%

No. of previous treatments Median N/A 3 3 3

(range) (1-7) (1-7) (1-9)

Prior therapy Alkylator N/A 58% 86% 76%Anthracycline N/A 55% 64% 55%fludarabine® N/A 25% 46% 48%HDT N/A 18% 14% 0%Other (1) N/A 60% 39% 52%

MabThera® Single-Agent Therapy for MCL: Patient Characteristics

MCL1(n=34)

MCL2(n=40)

IMC(n=28)

SLL(n=29)


Exclusion

Active hepatitis HIV+

CNS+

MabThera® Single-Agent Therapy for MCL: Eligibility Criteria

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+


MabThera® Single-Agent Therapy for MCL: Response

ORR 38 37 28 14

CR 16 14 0 0

PR 22 23 28 14

MCL1(n=32)*

MCL2(n=35)*

IMC(n=25)*

SLL(n=28)*

* Evaluable patients.

% of Patients


MabThera® Single-Agent Therapy for MCL: Duration of Response

(Responders With MCL)

Adapted from Foran et al. J Clin Oncol. 2000;18:317.

Years

0.5 1.0 1.5

Pat

ien

ts (

%)

(n=25)

00

20

40

60

80

100

MabThera® Single-Agent Therapy for MCL: Toxicity

Hematologic (grade 3/4)*Thrombocytopenia 6Leukopenia 5Neutropenia 3Anemia 2

Nonhematologic (all grades)Fever 49Rigors 28Infections 24Arrhythmia 8Ophthalmologic 7

% of Patients(N=131)

* Most cases normalized after therapy.


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


MabThera® + HyperCVAD/M-A* for Previously Untreated Mantle Cell Lymphoma

Romaguera et al

Blood 2001

MabThera® + HyperCVAD/M-A* for Previously Untreated Mantle Cell Lymphoma: Protocol

Romaguera et al. Blood. 2001;98(suppl 1):726a. Abstract 3030.

MabThera® M-A*HyperCVAD

Weeks

1 4 7 10 13 16 19 22

* M-A = methotrexate + cytosine arabinoside

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%)



CR 89

2-year FFS 72

2-year OS 90

MabThera® + HyperCVAD/M-A* for Previously Untreated Mantle Cell

Lymphoma: Response

% of Patients (n=56)*

Median 14 month follow-up* Evaluable patients.


*M-A = methotrexate + cytosine arabinoside

MabThera® + HyperCVAD/M-A* for Previously Untreated Mantle Cell Lymphoma:

Response Versus Historical Controls

# 18 of 26 potentially eligible patients underwent SCT



% of Patients

<66 years >65 years

R-HyperCVAD/M-A*(n=46)

HyperCVAD/M-A*/ASCT

(n=26*)

R-HyperCVADM-A*(n=29)

HyperCVAD/M-A*(n=22)

CR 89 100 90 70

2-year FFS 84 75 60 41

2-year OS 87 96 96 77

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 <66 years

Trend for improved outcome with MabThera® + HyperCVAD/M-A* in patients >65 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%)



MabThera + FCM Versus FCM in Relapsed Follicular and Mantle Cell

Lymphoma

Hiddemann et al

ICML 2002

Randomization

4 x FCM

4 x FCM +

MabThera®

Randomization

CR, PR

CR, PR

4 xMabThera®

4 xMabThera®

Observation only

Hiddemann et al. ICML 2002 Satellite Symposium (Lugano)

MabThera® + FCM Versus FCM in Relapsed Follicular and Mantle Cell Lymphoma:

Protocol

Month 3 Month 9


Patient Characteristics

MabThera®

+ FCM FCM

No. of patients* 51 53

Age (y) Median 64 62

<60 32% 37%

60 68% 63%

Male 57% 57%

Female 43% 43%

Histology Follicular lymphoma 53% 49%Mantle cell lymphoma 37% 36%

Other 10% 15%* Evaluable patients



Response


MabThera® + FCM FCM(n=51) (n=53)

ORR 83 58

CR 35 13

PR 48 46

PD 15 31

* Evaluable patients


MabThera® + FCM Versus FCM in Relapsed Follicular and Mantle Cell Lymphoma: Response by

Histology


% of Patients

Follicular lymphoma Mantle cell lymphoma

MabThera ® + FCM

(n=27)FCM(n=26)

MabThera ® + FCM

(n=19)FCM(n=19)

ORR 89 100 90 70

CR 84 75 60 41

PR 87 96 96 77


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%)


MabThera® for MALT Lymphoma

Conconi et al

Proc Am Soc Clin Onc 2002

MabThera® for MALT Lymphoma:Patient Characteristics

No. of patients 35

Age (y) Median 57(range) (27–85)

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. 2002;21:267a. Abstract 1067.

MabThera® for MALT Lymphoma: Response

% of Patients*

ORR 71

CR 43

PR 29

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

*Evaluable patients at median 12-month follow-up

Conconi et al. Proc Am Soc Clin Oncol. 2002;21:267a. Abstract 1067.

MabThera® + CHOP for HIV-associated Aggressive Lymphoma

Boue et al

Blood 2002

MabThera® + CHOP for HIV-associated Aggressive Lymphoma: Protocol

Days

MabThera®

CyclophosphamideDoxorubicinVincristine

Prednisone

Boué et al. Blood. 2002;100:470a. Abstract 1824.

0 1 2 3 4 5 6 7 14 21

Repeat cycle(6 cycles total)

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 <100/µL, Karnofsky index <60%, ECOG >2, history of opportunistic infection

Exclusion Active viral hepatitis


MabThera® + CHOP for HIV-associated Aggressive Lymphoma: Patient

Characteristics

All Patients (n=61)

Evaluable Patients (n=52)

Median age in years 41 40

Males/females 55/6 49/3

CD4 at inclusion 172/µL 180/µL

CDC stage at inclusion (A/B/C) 33/13/13 32/11/9

IPI score (0-1/2/3) 31/27/1 28/23/0

LDH >2 x normal 39 32

Histology Burkitt’s lymphoma 6 6 DLBCL 42 36 Burkitt-like lymphoma 10 9 Immunoblastic lymphoma 2 1 Other 1 0



ORR CR CRu PR

87 67 10 10

Progression 13

Stable disease 0

MabThera® + CHOP for HIV-associated Aggressive Lymphoma: Response



MabThera® + CHOP for HIV-associated Aggressive Lymphoma: Relapse-free

Survival

1.0

0.8

0.6

0.4

0.2

0

Rel

apse

-fre

e S

urv

ival

0 12 24 36 48

Months


MabThera® + CHOP for HIV-associated Aggressive Lymphoma: Overall Survival

1.0

0.8

0.6

0.4

0.2

0

Ove

rall

Su

rviv

al

0 12 24 36

Months


MabThera® + CHOP for HIV-associated Aggressive Lymphoma: Tolerability

% of Patients (n=60)

Hematologic (grade 3/4) Anemia Febrile neutropenia Thrombocytopenia

27 15

8

AIDS-related adverse events HIV encephalitis CMV disease

2 2

Infection Bacterial Opportunistic

34

5


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


MabThera® + Hyper-CVAD as First-line

Treatment in Burkitt’s Lymphoma

Thomas et al

Blood 2002

MabThera® + Hyper-CVAD as First-line Treatment in Burkitt’s Lymphoma: Protocol

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. 2002;100:763a. Abstract 3022.

Methotrexate/cytarabine

MabThera® + Hyper-CVAD as First-line Treatment in Burkitt’s Lymphoma: Patient

Characteristics


No. of patients 20

Median age in years (range) 52 (27-77)

Males/females 18/2

HIV-positive 6

Median WBC count (x109/L) 6.4

Stage III/IV 80%

CNS involvement 17%

MabThera® + Hyper-CVAD as First-line Treatment in Burkitt’s 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


MabThera® + Hyper-CVAD as First-line Treatment in Burkitt’s Lymphoma: Summary

The combination of MabThera® and hyper-CVAD is a feasible treatment for Burkitt’s lymphoma

Durable CR observed

Tolerability and toxicity profile similar to hyper-CVAD alone



Other B-Cell Lymphoproliferative Disorders

MabThera® for Other Lymphoproliferative Disorders: Candidates

Post-transplant lymphoproliferative disorder (PTLD)

Waldenström’s macroglobulinemia (WM)

Hodgkin’s disease (HD)

Multiple myeloma (MM)

“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. 2000;27:79; Dimopoulos et al. J Clin Oncol. 2000;18:214.

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. 2000;27:79; Treon et al. Semin Oncol. 2000;27:598.

MabThera® for WM: Patient Characteristics

MabThera® 375 mg/m2 weekly x 4-8 weeksNo. 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% Refractory to last treatment71%

Byrd et al. Ann Oncol. 1999;10:1525.

MabThera® for WM: Response

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. 1999;10:1525.

(N=7)

MabThera® for WM: Protocol/Patient Characteristics

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

No. of patients 30


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. 2001;24:272.

% of Patients Response (N=30)

PR 27

MR33

Stable Disease 30

Decreased IgM levels (P<0.001) 80

TTF

Responders (PR, MR) 8 mo

Patients with Stable Disease 5 mo

MabThera® for WM: Response

Treon et al. J Immunother. 2001;24:272.

MabThera® for WM: Summary

MabThera® is an active agent for WM

Hematologic recovery was seen

Toxicity – Transient

– Mild to moderate

Extended MabThera® Dosing in Waldenstrom’s Macroglobulinemia: Protocol

Treon et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):268a. Abstract 1068.

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)

PD: off study

Every 2-monthfollow-up

for 2 yearsor until off

study

Extended MabThera® Dosing in Waldenstrom’s Macroglobulinemia:


No. of patients 29*


Prior therapies Median 1(range) (0–2)

No prior therapy 38%

IgM >3,000 mg/dl 66%

Hematocrit <30% 35%

Platelets <100,000 µl 28%*22 evaluable patients


Extended MabThera® Dosing in Waldenstrom’s 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


MabThera® + Fludarabine in Waldenström’s Macroglobulinemia: Protocol

Fludarabine dose modification and delay + G-CSF use permitted based on hematologic toxicities

Treon et al. Blood. 2002;100:211a. Abstract 794.

PD: off study

Fludarabine(25 mg/m2 x 5 days)Week 13

MabThera®

(375 mg/m2 weekly)Weeks 17 + 18

Fludarabine(25 mg/m2 x 5 days)Weeks 19 + 23 + 27

MabThera®

(375 mg/m2 weekly)Weeks 30 + 31

SD, PR, CR

Evaluation(week 12)

MabThera®

(375 mg/m2 weekly)Weeks 1-4

Fludarabine(25 mg/m2 x 5 days)Weeks 5 + 9

MabThera® + Fludarabine in Waldenström’s Macroglobulinemia: Patient Characteristics


No. of patients 28

Median age in years (range) 61 (55-76)

No prior therapy 75%

IgM >3,000 mg/dL 60%

Hematocrit <30% 53%

Platelets <100,000/µL 12%

MabThera® + Fludarabine in Waldenström’sMacroglobulinemia: Response

Response duration: 3-18+ months




ORR 76

CR 14

PR (50% IgM) 61

Minor response (25% IgM) 14

MabThera® + Fludarabine in Waldenström’s 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


MabThera® + Fludarabine in Waldenström’s Macroglobulinemia: Summary

Combination therapy with MabThera® and fludarabine is highly active (ORR 76%)

Therapy appears tolerable

Impact on response duration remains to be established


MabThera® in Previously Untreated Waldenstrom’s Macroglobulinemia: Protocol

MabThera® 375 mg/m2 i.v.

1 2 3 4Weeks

If no evidence ofPD after 3 months, repeat 4-weekcourse of MabThera®

Dimopoulos et al. Blood. 2001;98(suppl 1);367a. Abstract 1547.

MabThera® in Previously Untreated Waldenstrom’s Macroglobulinemia:


No. of patients 17


Sex Male 82%Female 18%

Lymphadenopathy 47%

Splenomegaly 18%

Hemoglobin <10 g/dl 53%

Serum peak 4 mg/dl 41%

2-microglobulin 4 mg/l 47%

BM lymphocytes 50% 65%

Dimopoulos et al. Blood. 2001;98(suppl 1):367a. Abstract 1547.

MabThera® in Previously Untreated Waldenstrom’s Macroglobulinemia: Response

ORR 35

CR 0

PR 35

SD 47

PD 18

TTR (months) Median 3(range) (2–8)

TTP (months) Median 15(range) (3–30+)



MabThera® in Previously Untreated Waldenstrom’s Macroglobulinemia:

Time to Progression%

Pro

gre

ssio

n-f

ree

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Months


MabThera® in Previously Untreated Waldenstrom’s Macroglobulinemia: Summary

MabThera® in previously untreated Waldenstrom’s 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



Hodgkin’s Disease

No. of patients 14


Stage I 21%II 29%III 7%IV 43%

No. of prior treatments Median 2

Time from diagnosis (y) Median 9

MabThera® for Previously Treated Hodgkin’s Disease: Patient Characteristics

Schulz et al. Ann Oncol. 2002;13(suppl 2):63. Abstract 210.


ORR 86

CR 57

PR 29

PD 14

Median follow-up = 12 months

MabThera® for Previously Treated Hodgkin’s Disease: Response


MabThera® for Previously Treated Hodgkin’s Disease: Duration of Response

% r

esp

on

din

g

1.0

0.8

0.6

0.4

0.2

00 12 24 36

Months

Mean 20 months95% CI 15.0–25.1


MabThera® for Previously Treated Hodgkin’s 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


MabThera® for Previously Treated Hodgkin’s 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. 2001;98(suppl 1):633a. Abstract 2650.

MabThera® in Relapsed Hodgkin’s Disease: Patient Characteristics

No. of patients 22Age Median 35

(range) 17–66Sex Male 68%

Female 32%Nodular sclerosis histology 100%Nodal disease only 41%Extranodal disease 59%B symptoms 32%Prior treatments Median 4

(range) 2–12Prior stem cell transplant 82%CD20 expression on H/RS cells Positive 27%

Negative 68%Unknown 5%

Younes et al. Blood. 2001;98(suppl 1):132a. Abstract 555.

MabThera® in Relapsed Hodgkin’s Disease: Response

% of Patients

All CD20+ CD20-patients H/RS cells H/RS cells

(n=22) (n=6) (n=16)

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


MabThera® in Relapsed Hodgkin’s Disease: Response by Site of Disease

% of Patients

Nodal disease only Extranodal disease(n=9) (n=13)

ORR 55 0

CR 11 0

PR 44 0

SD 33 38


MabThera + ABVD for previously untreated classical Hodgkin’s disease: protocol

Younes A, et al. Blood 2003;102:27a (Abstract 83)

Week

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.

Restage

1 2 3 4 5 6 7 8 9 10 11 12

* ABVD was given on day 2 of weeks 1, 3 and 5 (day after MabThera) and on day 1 of weeks 7, 9, 11

MabThera + ABVD for previously untreated classical Hodgkin’s disease: patient

characteristics


Percentage of patients (n=41)

Median age in years (range) 32 (18–62) Stage I II IV

50 32 18

Histology Nodular sclerosis Mixed cellularity

88 12

CD20 negative RS cells 83 2-microglobulin >2.5mg/L 38 Elevated LDH 28 Lesion 5cm 78 Prognostic score 2 53

MabThera + ABVD for previously untreated classical Hodgkin’s disease: severe toxicities

No. of cases (%) (n=40)

Pneumocystis carinii pneumonia 1 (3)

Neutropenic fever 2 (5)


MabThera + ABVD for previously untreated classical Hodgkin’s disease: results

* Median follow-up = 21 months

Percentage of patients (n=36)

Objective response 100

Primary refractory disease 0

Event-free survival* 83


MabThera + ABVD for previously untreated classical Hodgkin’s disease: event-free

survival


100

75

50

25

00 12 24 36

Months

Per

cen

tag

e ev

ent-

free

su

rviv

al

MabThera + ABVD for previously untreated classical Hodgkin’s disease: summary

MabThera + ABVD is the first regimen for the treatment of classical Hodgkin’s disease that combines chemotherapy with a selective targeted therapy of the microenvironment

MabThera + ABVD is feasible and well tolerated

Preliminary analysis shows promising results



Autoimmune Disorders

MabThera® for Autoimmune Disorders: Candidates

Autoimmune hemolytic anemia (AIHA)

Idiopathic thrombocytopenic purpura (ITP)

Rheumatoid arthritis (RA)

IgM polyneuropathies

Autoimmune Disorders: Common Treatment Modalities

Immunosuppression– Chemotherapy

– Corticosteroids

– Splenectomy

Limitations– Moderate efficacy

– High rate of relapse

– Sustained maintenance therapy required

– Significant toxicity

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

MabThera® for ITP: Patient Characteristics

No. of patients 25


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. 2001;98:952.

MabThera® for ITP: Response

Stasi et al. Blood. 2001;98:952.

Response % of Patients (N=25)

ORR 52

CR 20

PR 20

MR 12

Duration of response 6 mo

MabThera(375mg/m2

weekly x 4)

MabThera for primary chronic cold agglutinin disease: protocol

Responders Followed for atleast 6 months

Non-responders

After 3 monthsMabThera (375mg/m2 weekly x 4)

+ IFN- (5 MU, t.i.w.)

Berentsen S, et al. Hematol J 2003;4(Suppl. 2):87–8

MabThera for primary chronic cold agglutinin disease: patient characteristics


No. of patients (n=18)

Male/female 5/13

Type of B-cell proliferation

Lymphoplasmacytic 9

Small lymphocytic 3

Marginal zone 1

Unclassified 3

None detected 1

Median Hb 8.0g/dL

Median IgM 4.5g/L

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

Percentage of courses (n=22)

ORR 63

PR 45

MR 18


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-, whichdid not improve the response


MabThera® for AIHA: Patient Characteristics

No. of patients 6


AIHA type Warm 50%Cold 50%

AIHA duration (prior to MabThera®) Range (mo) 3-240

Prior treatments Steroids 100Chemotherapy* 33Splenectomy* 33Plasmapheresis* 17Steroid-dependent† 50

Lee et al. Blood. 2000;96(suppl 1):596a. Abstract 2560.

* All in patients with cold AIHA.† All in patients with warm AIHA.

MabThera® for AIHA: Response

% of PatientsResponse (n=5)*

CR 100

Recurrent hemolysis 0

Duration of response 4 mo-2.7 y

* Evaluable patients.

Lee et al. Blood. 2000;96(suppl 1):596a. Abstract 2560.

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

1 2 3 4 5 6 7 8 9 10 11 12 13 14 23 24 25 26 27 28 29

MabThera® for CLL-associated AIHA: Protocol

MabThera® 375 mg/m2 i.v. day 1

Cyclophosphamide 750–1,000 mg/m2 i.v. day 2

Dexamethasone 12 mg/day* i.v. days 1 and 2; orally days 3–7

Cycles repeatto best response

Days

Gupta et al. Blood. 2001;98(suppl 1):363a. Abstract 1529.

AIHA = autoimmune hemolytic anemia

MabThera® for CLL-associated AIHA:Patient Characteristics

No. of patients 8Age (y) Median 60

(range) 46–70Sex Male 88%

Female 12%Rai stage III 50%

IV 50%Splenomegaly 63%Hemoglobin (g/dl) Median 8.3

(range) (5–9.9)Platelet count (µl) Median 110,000

(range) (9,000–259,000)Absolute lymphocyte count (µl) Median 190,000

(range) (20,000–310,000)Positive Coombs test 100%Prior therapies Median 2

(range) (0–4)Gupta et al. Blood. 2001;98(suppl 1):363a. Abstract 1529.

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


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


MabThera® for CLL-associated AIHA:Retreatment Response

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

Hemoglobin levels (g/dl)


MabThera® for Refractory AIHA in Children: Patient Characteristics

Zecca et al. Blood. 2002;100:444a. Abstract 1722.

No. of patients 15

Median age in years (range)

2 (0.3-14)

Diagnosis AIHA Evans’ syndrome

10 5

AIHA type

Warm (IgE) Cold (IgM) DAT negative

12 1 1

2 prior courses of immunosuppression

15

Splenectomy 2

MabThera® for Refractory AIHA in Children: Response

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


Pre-treatment +2 months

Pre-treatment +2 months

16

12

8

4

0

800

600

400

200

0

Ret

icu

locy

tes

(x10

9 /L)

Hem

og

lob

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/dL

)

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)


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


MabThera® for RA: Protocol

Edwards and Cambridge. Rheumatology. 2001;40:205.

1 2 3 4 5 6 7 14 21

Days

8 10 11 12 13 16 17 18 19 209 15

MabThera®

(300-600 mg)PrednisoloneCyclophosphamide

22

MabThera® for RA: Patient Characteristics

No. of patients 5


Duration of RA (y) Median 23(range) (11-40)

Treatment failure Gold 100%Azathioprine 100%Sulphasalazine 100%Methotrexate 100%Penicillamine 80%Prednisolone 40%Hydroxychloroquine 20%


MabThera® for RA: Response

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

Patient

SwollenJoint Count CRP ESR

PainVAS

MorningStiffness

ACRGrade

% Improvement Over Baseline

* After re-treatment with MabThera®.


MabThera® for IgM Polyneurophathies: Patient Characteristics

No. of patients 5


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. 1999;52:1701.

MabThera® for IgM Polyneurophathies: Response

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

Patient Before After Before After

StrengthChange

Total IgM (mg)Follow-up

(mo)

IgM Titer

Levine and Pestronk. Neurology. 1999;52:1701.

MabThera® for Autoimmune Disorders:Summary

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

Other B-Cell Malignancies Mantle Cell Lymphoma MALT HIV-associated DLCL Burkitt’s Lymphoma Waldenstrom’s Macroglobulinemia Hodgkin’s Disease Autoimmune.

Documents

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