other b-cell malignancies mantle cell lymphoma malt hiv-associated dlcl burkitt’s lymphoma...
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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)
Foran et al. J Clin Oncol. 2000;18:317.
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+
Foran et al. J Clin Oncol. 2000;18:317.
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
Foran et al. J Clin Oncol. 2000;18:317.
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.
Foran et al. J Clin Oncol. 2000;18:317.
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. 2000;18:317.
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%)
Romaguera et al. Blood. 2001;98(suppl 1):726a. Abstract 3030.
* M-A = methotrexate + cytosine arabinoside
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.
Romaguera et al. Blood. 2001;98(suppl 1):726a. Abstract 3030.
*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
Romaguera et al. Blood. 2001;98(suppl 1):726a. Abstract 3030.
* M-A = methotrexate + cytosine arabinoside
% 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%)
Romaguera et al. Blood. 2001;98(suppl 1):726a. Abstract 3030.
* M-A = methotrexate + cytosine arabinoside
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
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
<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
Hiddemann et al. ICML 2002 Satellite Symposium (Lugano)
MabThera® + FCM Versus FCM in Relapsed Follicular and Mantle Cell Lymphoma:
Response
% of Patients (n=104)*
MabThera® + FCM FCM(n=51) (n=53)
ORR 83 58
CR 35 13
PR 48 46
PD 15 31
* Evaluable patients
Hiddemann et al. ICML 2002 Satellite Symposium (Lugano)
MabThera® + FCM Versus FCM in Relapsed Follicular and Mantle Cell Lymphoma: Response by
Histology
Hiddemann et al. ICML 2002 Satellite Symposium (Lugano)
% 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
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)
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
Boué et al. Blood. 2002;100:470a. Abstract 1824.
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
Boué et al. Blood. 2002;100:470a. Abstract 1824.
% of Patients (n=52)*
ORR CR CRu PR
87 67 10 10
Progression 13
Stable disease 0
MabThera® + CHOP for HIV-associated Aggressive Lymphoma: Response
* Evaluable patients
Boué et al. Blood. 2002;100:470a. Abstract 1824.
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
Boué et al. Blood. 2002;100:470a. Abstract 1824.
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
Boué et al. Blood. 2002;100:470a. Abstract 1824.
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
Boué et al. Blood. 2002;100:470a. Abstract 1824.
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. 2002;100:470a. Abstract 1824.
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
Thomas et al. Blood. 2002;100:763a. Abstract 3022.
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
Thomas et al. Blood. 2002;100:763a. Abstract 3022.
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
Thomas et al. Blood. 2002;100:763a. Abstract 3022.
MabThera® for Other B-Cell Disorders
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
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. 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:
Patient Characteristics
No. of patients 29*
Age (y) Median 65(range) (43–90)
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
Treon et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):268a. Abstract 1068.
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
Treon et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):268a. Abstract 1068.
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
Treon et al. Blood. 2002;100:211a. Abstract 794.
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
Treon et al. Blood. 2002;100:211a. Abstract 794.
* Evaluable patients
% of Patients (n=21)*
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
Treon et al. Blood. 2002;100:211a. Abstract 794.
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
Treon et al. Blood. 2002;100:211a. Abstract 794.
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:
Patient Characteristics
No. of patients 17
Age (y) Median 74(range) (39–84)
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+)
% of Patients (n=17)
Dimopoulos et al. Blood. 2001;98(suppl 1):367a. Abstract 1547.
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
Dimopoulos et al. Blood. 2001;98(suppl 1):367a. Abstract 1547.
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
Dimopoulos et al. Blood. 2001;98(suppl 1):367a. Abstract 1547.
MabThera® for Other B-Cell Disorders
Hodgkin’s Disease
No. of patients 14
Age (y) Median 41(range) (18–51)
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.
% of Patients (n=12)
ORR 86
CR 57
PR 29
PD 14
Median follow-up = 12 months
MabThera® for Previously Treated Hodgkin’s Disease: Response
Schulz et al. Ann Oncol. 2002;13(suppl 2):63. Abstract 210.
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
Schulz et al. Ann Oncol. 2002;13(suppl 2):63. Abstract 210.
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
Schulz et al. Ann Oncol. 2002;13(suppl 2):63. Abstract 210.
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
Younes et al. Blood. 2001;98(suppl 1):132a. Abstract 555.
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
Younes et al. Blood. 2001;98(suppl 1):132a. Abstract 555.
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
Younes A, et al. Blood 2003;102:27a (Abstract 83)
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)
Younes A, et al. Blood 2003;102:27a (Abstract 83)
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
Younes A, et al. Blood 2003;102:27a (Abstract 83)
MabThera + ABVD for previously untreated classical Hodgkin’s disease: event-free
survival
Younes A, et al. Blood 2003;102:27a (Abstract 83)
100
75
50
25
00 12 24 36
Months
Per
cen
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free
su
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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
Younes A, et al. Blood 2003;102:27a (Abstract 83)
MabThera® for Other B-Cell Disorders
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
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. 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
Berentsen S, et al. Hematol J 2003;4(Suppl. 2):87–8
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
Berentsen S, et al. Hematol J 2003;4(Suppl. 2):87–8
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
Berentsen S, et al. Hematol J 2003;4(Suppl. 2):87–8
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 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
Gupta et al. Blood. 2001;98(suppl 1):363a. Abstract 1529.
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. 2001;98(suppl 1):363a. Abstract 1529.
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)
Gupta et al. Blood. 2001;98(suppl 1):363a. Abstract 1529.
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
Zecca et al. Blood. 2002;100:444a. Abstract 1722.
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
in(g
/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)
Zecca et al. Blood. 2002;100:444a. Abstract 1722.
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. 2002;100:444a. Abstract 1722.
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
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%Hydroxychloroquine 20%
Edwards and Cambridge. Rheumatology. 2001;40:205.
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®.
Edwards and Cambridge. Rheumatology. 2001;40:205.
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. 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