MabThera

1
MabThera and Autologous Stem Cell Transplant
(ASCT)

2
ASCT Protocol
Debulking/ Mobilization Regimen
BM/Stem Cell Harvest and Purging
High-Dose Chemoradiotherapy
Stem Cell Transplant
3
ASCT for Relapsed NHL

• Higher response and survival rates than with
  chemotherapy alone
• Aggressive NHL PARMA Study EFS 45 vs 12
• Indolent NHL CUP trial PFS 63 vs 33
• (P0.004)
• 40-70 relapse rate after ASCT
• Possible explanations
• Residual lymphoma in patient
• Reintroduction of malignant cells with transplant
  after ex vivo purging

4
MabThera HDT/ASCT for Relapsed NHL Rationale

• In vivo purging agent
• Ex vivo purging agent
• Combination with conditioning therapy
• Post-transplant adjuvant immunotherapy

5
In Vivo Purging With MabThera Protocol
CBV
Leukapheresis
G-CSF

0
8
11
24
27
Weeks
Days
Buckstein et al. Semin Oncol. 199926(5 suppl
14)115 Mangel et al. Blood. 200096(suppl
1)383a. Abstract 1655.
6
In Vivo Purging With MabTheraMedian PB CD34
Cell Count
MabThera purging
No MabThera
CD34 x 106/L
Day 5
Day 4
Baseline
Buckstein et al. Semin Oncol. 199926115
Mangel et al. Blood. 200096(suppl 1)383a.
Abstract 1655.
7
In Vivo Purging With MabThera Response
of Patients (N16)
Response
Clinical 100 CR 38 CRu 63 Molecular (6
mo post-transplant) 100
Among the 7 patients who presented with the
bcl-2 rearrangement.
Buckstein et al. Semin Oncol. 199926115.
Mangel et al. Blood. 200096(suppl 1)383a.
Abstract 1655.
8
In Vivo Purging With MabThera Toxicity
of Patients (N16)

• Lung toxicity 63
• Interstitial pneumonitis 38
• Symptomatic hypoxia (hospitalization required)
  13
• No significant difference in times to neutrophil
  engraftment or platelet independence between
  MabThera and control groups

Buckstein et al. Semin Oncol. 199926115 Mangel
et al. Blood. 200096(suppl 1)383a. Abstract
1655.
9
MabThera In Vivo Purging and Maintenance after
HDT/ASCT in Relapsed Follicular Lymphoma Protocol
IFN maintenance for 2 years
No purge
HDT
Study 1
MabThera maintenance weekly x 4 at 2 and 6
months
MabThera in vivo purge
HDT
Study 2
IFN maintenance for2 years MabThera
maintenance weekly x 6 at 3 months
MabThera in vivo purge
HDT
Study 3
3 MU/m2 t.i.w. 375 mg/m2
Buckstein et al. Blood. 2002100647a. Abstract
2547.
10
MabThera In Vivo Purging and Maintenance after
HDT/ASCT in Relapsed Follicular Lymphoma Patient
Characteristics
Buckstein et al. Blood. 2002100647a. Abstract
2547.
11
MabThera In Vivo Purging and Maintenance after
HDT/ASCT in Relapsed Follicular Lymphoma Results
Only 10 evaluable patients
Buckstein et al. Blood. 2002100647a. Abstract
2547.
12
MabThera In Vivo Purging and Maintenance after
HDT/ASCT in Relapsed Follicular Lymphoma
Molecular and Clinical Responses

• 10/12 MabThera patients had durable molecular
  remissions at last follow-up (18-34 months)
• Clinical relapse in 6/10 patients was preceded by
  detection of MRD
• Median RFS has not been reached for the MabThera
  and MabThera-IFN cohorts compared with 3.3 years
  for IFN

Buckstein et al. Blood. 2002100647a. Abstract
2547.
13
MabThera In Vivo Purging and Maintenanceafter
HDT/ASCT in Relapsed Follicular Lymphoma
Event-free Survival
Interferon MabThera/Interferon MabThera
100 80 60 40 20 0
Patients Event-free ()
P0.12
0 12 24 36 48 60
Months
Buckstein et al. Blood. 2002100647a. Abstract
2547.
14
MabThera In Vivo Purging and Maintenance after
HDT/ASCT in Relapsed Follicular Lymphoma Summary

• HDT/ASCT with MabThera in vivo purge and
  maintenance
• Produces high rates of complete clinical
  remission of up to 90
• Reduces stem cell graft contamination
• Achieves PCR-negativity in virtually all patients
  by 9 months post-ASCT

Buckstein et al. Blood. 2002100647a. Abstract
2547.
15
High-dose MabThera In Vivo Purge HDT/ASCT in
Relapsed B-Cell Lymphoma Protocol
Schema 1 (n27)
MabThera375 mg/m2
Cyclophosphamide4-7 g/m2
MabThera1,000 mg/m2
Day
1 2 3 4 5 6 7 8 9 10

• GM-CSF 250 µg/m2
• G-CSF 10 µg/kg

Schema 2 (n15)
MabThera1,000 mg/m2
MabThera375 mg/m2
Ifosfamide 3.33 g/m2Etoposide 300 mg/m2
1 2 3 4 5 6 7 8 9 10
Day

• G-CSF 6 µg/kg b.i.d.

Khouri et al. Blood. 2002100645a. Abstract 2538.
16
High-dose MabThera In Vivo Purge HDT/ASCT in
Relapsed B-Cell Lymphoma Eligibility Criteria

• Exclusion
• Hepatitis
• HIV-positive

• Inclusion
• Age 65 years
• CD20 lymphoid malignancies beyond first
  remission
• Marrow involvement reduced to 5 with
  pretransplant salvage chemotherapy
• ECOG performance status 0-2
• Left ventricular ejection fraction ³50
• Pulmonary function test ³50

Khouri et al. Blood. 2002100645a. Abstract 2538.
17
High-dose MabThera In Vivo Purge HDT/ASCT in
Relapsed B-Cell Lymphoma Patient Characteristics

• No. of patients 42
• Median age in years 51 (range) (20-65)
• Histology Aggressive 86 Follicular 14
• IPI score 0-1 71
• CR post-salvage chemotherapy 45
• Median prior treatments 2

Khouri et al. Blood. 2002100645a. Abstract 2538.
18
High-dose MabThera In Vivo Purge HDT/ASCT in
Relapsed B-Cell Lymphoma Overall and
Disease-free Survival
1.0 0.8 0.6 0.4 0.2 0
OS
DFS
CumulativeProportion Surviving
n42
0 5 10 15 20 25
Months Post-transplant

• 91 1-year disease-free survival
• 93 1-year overall survival

Khouri et al. Blood. 2002100645a. Abstract 2538.
19
High-dose MabThera In Vivo Purge HDT/ASCT in
Relapsed B-Cell Lymphoma Tolerability
Khouri et al. Blood. 2002100645a. Abstract 2538.
20
High-dose MabThera In Vivo Purge HDT/ASCT in
Relapsed B-Cell Lymphoma Summary

• MabThera in vivo purging and consolidation
  achieved
• 1-year OS of 93
• 1-year DFS of 91
• No additional risk of toxicity or infection
• Comparison of high-dose vs standard MabThera
  purging is warranted

Khouri et al. Blood. 2002100645a. Abstract 2538.
21
In Vivo Purging With MabThera Protocol
Cytarabine
Cyclophosphamide
MabThera?

Mitoxantrone melphalan
Stem cell transplant
Melphalan



0
3
6
9
Weeks
Magni et al. Blood. 200096864.
22
In Vivo Purging With MabThera Patient
Characteristics
HDT (n10)
M HDT (n15)
Age (y) Median 43 46 (range)
(34-58) (36-53) Histology FL 47 70 MCL
47 30 MALT 6 Stage III 27 10 IV
73 90 Bulky disease gt10 cm 30 Sites of
involvement Nodal 93 100 Extranodal
13 30 BM 100 100 PB 40 30
Magni et al. Blood. 200096864.
23
In Vivo Purging With MabThera PCR-Negative
Harvests
(P0.007)
M HDT
HDT
Patients With PCR- Negative Harvests ()
Post- Cyclophosphamide
Post- Cytarabine
Magni et al. Blood. 200096864.
24
In Vivo Purging With MabThera Response
of Patients
M HDT (n14)
HDT (n10)
Response
Clinical 70 100 Molecular 70 100
Evaluable patients.
Magni et al. Blood. 200096864.
25
In Vivo Purging With MabThera Protocol
Preparative Regimen Day 1 MabThera? Day 4
Cyclophosphamide Day 5 G-CSF
HDT Cyclophosphamide Total body irradiation
Leukapheresis
Post-transplant Therapy MabThera? G-CSF
Stem Cell Transplant
Flinn et al. Biol Blood Marrow Transplant.
20006628.
26
In Vivo Purging With MabThera Patient
Characteristics
No. of patients 25 Age (y) Median
51 (range) (33-67) Histology FL
(center) 44 MCL 28 CLL/SLL 20 Lymphoplas
macytic 4 Marginal zone 4 No. of prior
Median 1 treatments (range)
(1-3) Remission status 1st complete 48
(at baseline) 1st partial 24 2nd
partial 20 3rd partial 8
Flinn et al. Biol Blood Marrow Transplant.
20006628.
27
In Vivo Purging With MabThera Response
of Patients
Response
Successful mobilization 92 (N25 ?2.0 x 106
CD34 cells/kg) Clinical (n11) CR 55 PR
27 Stable disease 18 Molecular (after in vivo
purging n7) 86
Response was evaluated in 11 of the 12 patients
who did not have CRs at trial entry. Prior to
in vivo purging, 7 patients had t(1114) or
t(1418) detectable by PCR.
Flinn et al. Biol Blood Marrow Transplant.
20006628.
28
MabThera In Vivo Purging in Previously Untreated
Mantle Cell Lymphoma Protocol
Mitoxantrone melphalan
Cyclophosphamide
Cytarabine
Melphalan
Collection
1
3
2
Reinfusion
MabThera
0 21 42 70 84
Days
Gianni et al. Bone Marrow Transplant.
200229(suppl 1)1013.
29
MabThera In Vivo Purging in Previously Untreated
Mantle Cell LymphomaPatient Characteristics
No. of patients 28 Age (y) Median 49 Ann
Arbor stage III 7 IV 93 IPI score 12 75 3 14
45 11 Molecular rearrangement bcl-1
46 IgH 36 Probe N/A 18 B symptoms Yes
38 Size of mass gt10 cm 29 LDH level
Abnormal 36
Gianni et al. Bone Marrow Transplant.
200229(suppl 1)1013.
30
MabThera In Vivo Purging in Previously Untreated
Mantle Cell Lymphoma Response
of Patients
Response
Clinical 96 (n27) Molecular 100 (n20)
Evaluable patients
Gianni et al. Bone Marrow Transplant.
200229(suppl 1)1013.
31
MabThera In Vivo Purging in Previously Untreated
Mantle Cell Lymphoma3-Year Survival
MabThera sHDT (n28)
Historical controls (n39)
100
100
OS
80
80
EFS
OS
60
60
Percent
Percent
40
40
EFS
20
20
CHOP-like regimen
0
0
0 12 24 36 48
0 12 24 36 48
Years
Years
Gianni et al. Bone Marrow Transplant.
200229(suppl 1)1013.
32
MabThera after HDT/ASCT in Follicular and Mantle
Cell Lymphoma Protocol
NR/PD off study
Or equivalent treatment (e.g., CHOP)

V I P E
V I P E
TBI/Cy 12 Gy/120 mg/kg
4 x MabThera 375 mg/m2/week
6 x VACOP-B
CD34 selection
10
11
8
9
4
Week
0
Brugger et al. Ann Oncol. 200213(suppl 2)38.
Abstract 113.
33
MabThera after HDT/ASCT in Follicular and Mantle
Cell Lymphoma Patient Characteristics
No of patients 30 Age (y) Median 49
(range) (3159) Sex Male 53 Female 47 Histo
logy Follicular lymphoma 67 Stage III 45
Stage IV 55 Mantle cell lymphoma 33
Stage III/IV 30 Stage IV 70
Evaluable patients
Brugger et al. Ann Oncol. 200213(suppl 2)38.
Abstract 113.
34
MabThera after HDT/ASCT in Follicularand Mantle
Cell Lymphoma Grade 3/4 Adverse Events
Grade 4
Grade 3
Total 15 7 Lymphopenia 5 6 Thrombocytopenia 1
Nausea 1 Infection 6 Neurologic pain
1 Thyroiditis 1 Other 1
Brugger et al. Ann Oncol. 200213(suppl 2)38.
Abstract 113.
35
MabThera after HDT/ASCT in Follicular and Mantle
Cell Lymphoma Clinical Response
of Patients in CR
Before TBI/Cy 13 After TBI/Cy 47 After
MabThera 50 6 months 59 9 months 74 12
months 91 24 months 91
Brugger et al. Ann Oncol. 200213(suppl 2)38.
Abstract 113.
36
MabThera after HDT/ASCT in Follicular and Mantle
Cell Lymphoma Molecular Response
P0.0116

P0.0077 Plt0.001

PCR-negative ()
Pre-HDT Post-HDT Post- 6 months MabThera post
-HDT
Brugger et al. Ann Oncol. 200213(suppl 2)38.
Abstract 113.
37
MabThera In Vivo Purge Maintenance with
HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma Protocol
Weeks 811
Weeks 2427
Day 0

CBV HDT
CHOP x 48 cycles
R G-CSF
Immunotherapy (two courses of MabThera)
Collection
Reinfusion
In vivo purge (R) MabThera 375 mg/m2 day
5 G-CSF 10 µg/kg/day, days 4, 3, 2, 1, 0 Stem
cell collection day 0 (1, 2)
HDT Cyclophosphamide 1, 8 g/m2 days
63 Carmustine 500 mg/m2 day 2 Etoposide 2.4
g/m2 36 hour CI day 7
Mangel et al. Blood. 200198(suppl 1)677a.
Abstract 2833.
38
MabThera In Vivo Purge Maintenance with
HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma Patient Characteristics
No. of patients 14 Age (y) Median 52
(range) (4165) Sex Male 50 Female 50 ECOG
PS 01 100 Stage IV (BM involvement) 86 Low/
low-intermediate IPI score 93 B
Symptoms 21 LDH (IU/l) Median 195 (range)
(144402) Cycles induction chemotherapy Median 6
(range) (48)
Mangel et al. Blood. 200198(suppl 1)677a.
Abstract 2833.
39
MabThera In Vivo Purge Maintenance with
HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma Clinical Response
after after after induction ASCT MabTh
era ORR 100 100 100 CR 43 57 92 CRu
7 43 8 PR 50 0 0
Based on 12 of 14 patients who had completed
maintenance MabThera therapy 15-month median
follow-up from transplantation
Mangel et al. Blood. 200198(suppl 1)677a.
Abstract 2833.
40
MabThera In Vivo Purge Maintenance with
HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma Molecular Response

• Nine patients PCR-informative
• Molecular remission achieved in seven/nine
  patients
• Five patients PCR-negative at last follow-up
• Three of five at 18-month follow-up
• CHOP induction followed by MabThera ASCT
  achieves high CRs in patients with previously
  untreated mantle cell lymphoma
• Molecular remission achieved in majority of
  patients

Mangel et al. Blood. 200198(suppl 1)677a.
Abstract 2833.
41
MabThera In Vivo Purge HDT/ASCT in Chronic
Lymphocytic Leukemia Protocol

• 18 adult patients with relapsed or untreated
  chronic lymphocytic leukemia

4 cycles of MabThera-Flu/Cy
Mobilization ESHAP
Harvest
BEAM
Fludarabine 3 x 25 mg/m2 Cyclophosphamide 3 x
300 mg/m2
ASCT
Trneny et al. Blood. 2002100804a. Abstract 3176.
42
MabThera In Vivo Purge HDT/ASCT in Chronic
Lymphocytic Leukemia Response

• Full protocol completed by 8 patients
• CR achieved in 7 patients (88)
• PCR negativity achieved in 7 patients (88)

Trneny et al. Blood. 2002100804a. Abstract 3176.
43
MabThera In Vivo Purge HDT/ASCT in Chronic
Lymphocytic Leukemia Summary

• Combination of MabThera, in vivo purge and
  HDT/ASCT leads to a high clinical and molecular
  complete remission rate
• MabThera does not add significantly to the
  toxicity of HDT/ASCT

Trneny et al. Blood. 2002100804a. Abstract 3176.
44
MabThera EBMT LYM1 TrialProtocol
375 mg/m2 every 2 months x 4, 30 days
post-transplant
45
MabThera EBMTLYM1 Trial Eligibility Criteria

• Inclusion
• Relapsed follicular B-cell lymphoma
• WHO PS 0-1
• Platelets gt100 x 109/L after induction therapy
• ?18 years
• CD20

• Exclusion
• Impaired renal/hepatic/cardiac and pulmonary
  function
• Histologic transformation to high grade
• Previous radiotherapy to gt30 BM
• CNS involvement
• gt3 chemotherapy regimens for NHL (including
  re-induction chemotherapy)
• Previous transplant
• Pregnant/lactating
• HIV, HepB, and HepC positivity
• Previous malignancy lt5 years

46
MabThera ASCT Summary

• CR and molecular response rates up to 100
• Higher yield of PCR-negative stem cells with
  MabThera HDT vs HDT alone
• Toxicity related to MabThera mild and transient

Flinn et al. Biol Blood Marrow Transplant.
20006628.
47
MabThera for B-PTLD Eligibility Criteria

• Inclusion
• Age 1-75 years
• Histologically or cytologically confirmed mono-
  or polymorphic PTLD with ³10 CD20 lymphoma
  B-cells
• High EBV viral load after SCT
• ECOG performance status 3

• Exclusion
• CNS involvement

Choquet et al. Blood. 2002100467a. Abstract
1811.
48
MabThera for B-PTLD Patient Characteristics

• SOT solid organ transplant
• SCT stem cell transplant

Choquet et al. Blood. 2002100467a. Abstract
1811.
49
MabThera for B-PTLD Response
Choquet et al. Blood. 2002100467a. Abstract
1811.
50
MabThera for B-PTLD Summary

• MabThera was effective (ORR 45) and well
  tolerated
• This study is ongoing, and a longer follow-up is
  awaited

Choquet et al. Blood. 2002100467a. Abstract
1811.