Transcript No Slide Title

MabThera® and Autologous
Stem Cell Transplant (ASCT)
ASCT: Protocol
Debulking/
Mobilization
Regimen
BM/Stem Cell
Harvest and
“Purging”
High-Dose
Chemoradiotherapy
Stem Cell
Transplant
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%
(P=0.004)
 40%-70% relapse rate after ASCT
– Possible explanations


Residual lymphoma in patient
Reintroduction of malignant cells with transplant after ex
vivo purging
MabThera® + HDT/ASCT
for Relapsed NHL: Rationale
 In vivo purging agent
 Ex vivo purging agent
 Combination with conditioning therapy
 Post-transplant adjuvant immunotherapy
In Vivo Purging With MabThera®: Protocol
MabThera
G-CSF
CBVStem cell transplant
Leukapheresis
*
*
0
Days
Buckstein et al. Semin Oncol. 1999;26(5 suppl 14):115;
Mangel et al. Blood. 2000;96(suppl 1):383a. Abstract 1655.
8
11
Weeks
24
27
In Vivo Purging With MabThera®:
Median PB CD34+ Cell Count
CD34+ x 106/L
40
MabThera® purging
No MabThera®
30
20
10
0
Baseline
Day 4
Buckstein et al. Semin Oncol. 1999;26:115;
Mangel et al. Blood. 2000;96(suppl 1):383a. Abstract 1655.
Day 5
In Vivo Purging With MabThera®:
Response
Response
% of Patients
(N=16)
Clinical
100
CR
CRu
38
63
Molecular* (6 mo post-transplant)
100
* Among the 7 patients who presented with the bcl-2 rearrangement.
Buckstein et al. Semin Oncol. 1999;26:115.
Mangel et al. Blood. 2000;96(suppl 1):383a. Abstract 1655.
In Vivo Purging With MabThera®:
Toxicity
% of Patients
(N=16)
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. 1999;26:115;
Mangel et al. Blood. 2000;96(suppl 1):383a. Abstract 1655.
®
MabThera In Vivo Purging and Maintenance after
HDT/ASCT in Relapsed Follicular Lymphoma:
Protocol
Study 1
No purge
Study 2
MabThera
in vivo
†
purge
Study 3
MabThera
in vivo
†
purge
HDT
IFN maintenance* for
2 years
HDT
MabThera maintenance
weekly x 4 at 2 and
6 months
HDT
IFN maintenance* for
®
2 years + MabThera
†
maintenance weekly x 6
at 3 months
®
®
®
* 3 MU/m2 t.i.w.; †375 mg/m2
Buckstein et al. Blood. 2002;100:647a. Abstract 2547.
†
®
MabThera In Vivo Purging and Maintenance after
HDT/ASCT in Relapsed Follicular Lymphoma:
Patient Characteristics
®
MabThera
+ IFN
(n=12)
IFN
(n=14)
MabThera
(n=23)
45
50
45
Years from
initial diagnosis
(range)
3.25 (0.5-16)
1.76 (0.8-8)
2.63 (0.7-5)
Median previous
chemotherapy
cycles (range)
6.5 (3-14)
9 (6-28)
7.5 (5-20)
Median salvage
chemotherapy
cycles (range)
5.5 (2-9)
4 (2-7)
3 (2-8)
Median age (y)
Buckstein et al. Blood. 2002;100:647a. Abstract 2547.
®
®
MabThera In Vivo Purging and Maintenance after
HDT/ASCT in Relapsed Follicular Lymphoma:
Results
IFN
(n=14)
% CR/CRu
pretransplant
MabThera
(n=23)
®
MabThera
+IFN
(n=12)
7
19
40
% CR/CRu
3-months posttransplant
23
90
70*
% Relapses
71
35
17
2
2
0
59
37
10
Deaths
Median follow-up
(months)
* Only 10 evaluable patients
Buckstein et al. Blood. 2002;100:647a. Abstract 2547.
®
®
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. 2002;100:647a. Abstract 2547.
®
®
MabThera In Vivo Purging and Maintenance
after HDT/ASCT in Relapsed Follicular Lymphoma:
Event-free Survival
Interferon
Patients Event-free (%)
100
MabThera®/
Interferon
80
MabThera®
60
40
P=0.12
20
0
0
12
24
36
Months
Buckstein et al. Blood. 2002;100:647a. Abstract 2547.
48
60
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. 2002;100:647a. Abstract 2547.
®
High-dose MabThera In Vivo Purge + HDT/ASCT in
Relapsed B-Cell Lymphoma: Protocol
Schema 1 (n=27)
MabThera
375 mg/m2
®
Day 1
2
MabThera
1,000 mg/m2
®
Cyclophosphamide
4-7 g/m2
3
 GM-CSF 250 µg/m
 G-CSF 10 µg/kg
4
5
6
7
8
9
10
2
Schema 2 (n=15)
®
Day 1
2
MabThera
1,000 mg/m2
®
Ifosfamide 3.33 g/m2
Etoposide 300 mg/m2
MabThera
375 mg/m2
3
4
 G-CSF 6 µg/kg b.i.d.
Khouri et al. Blood. 2002;100:645a. Abstract 2538.
5
6
7
8
9
10
®
High-dose MabThera In Vivo Purge + HDT/ASCT in
Relapsed B-Cell Lymphoma:
Eligibility Criteria
Inclusion
Exclusion
 Age 65 years
 Hepatitis
 CD20+ lymphoid malignancies
beyond first remission
 HIV-positive
 Marrow involvement reduced
to 5% with pretransplant
salvage chemotherapy
 ECOG performance status 0-2
 Left ventricular ejection
fraction 50%
 Pulmonary function test 50%
Khouri et al. Blood. 2002;100:645a. Abstract 2538.
High-dose MabThera® In Vivo Purge +
HDT/ASCT in Relapsed B-Cell Lymphoma:
Patient Characteristics
No. of patients
42
Median age in years
(range)
Histology
51
(20-65)
Aggressive
Follicular
86%
14%
IPI score 0-1
71%
CR post-salvage
chemotherapy
45%
Median prior treatments
Khouri et al. Blood. 2002;100:645a. Abstract 2538.
2
High-dose MabThera® In Vivo Purge + HDT/ASCT
in Relapsed B-Cell Lymphoma: Overall and
Disease-free Survival
Cumulative
Proportion Surviving
1.0
OS
0.8
DFS
0.6
0.4
0.2
n=42
0
0
5
10
15
Months Post-transplant
 91% 1-year disease-free survival
 93% 1-year overall survival
Khouri et al. Blood. 2002;100:645a. Abstract 2538.
20
25
High-dose MabThera® In Vivo Purge +
HDT/ASCT in Relapsed B-Cell Lymphoma:
Tolerability
Number of
episodes
Grade 3/4 non-hematologic toxicity
13
Infection
Bacterial infection
12
Viral infection
5
Fungal infection
2
Khouri et al. Blood. 2002;100:645a. Abstract 2538.
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. 2002;100:645a. Abstract 2538.
®
In Vivo Purging With MabThera®: Protocol
0
MabThera
Cyclophosphamide
Cytarabine
Melphalan
Mitoxantrone
+ melphalan
Stem cell transplant
*
*
*
*
3
6
9
Weeks
Magni et al. Blood. 2000;96:864.
In Vivo Purging With MabThera®:
Patient Characteristics
Age (y)
Median
(range)
Histology
M + HDT
HDT
(n=15)
(n=10)
43
(34-58)
46
(36-53)
FL
MCL
MALT
47%
47%
6%
70%
30%
—
Stage
III
IV
27%
73%
10%
90%
Bulky disease
>10 cm
—
30%
Sites of involvement
Nodal
Extranodal
BM
PB
93%
13%
100%
40%
100%
30%
100%
30%
Magni et al. Blood. 2000;96:864.
In Vivo Purging With MabThera®:
PCR-Negative Harvests
93
Patients With PCRNegative Harvests (%)
100
(P=0.007)
80
M + HDT
HDT
60
40
40
33
20
20
0
PostCytarabine
Magni et al. Blood. 2000;96:864.
PostCyclophosphamide
In Vivo Purging With MabThera :
Response
®
% of Patients
Response
HDT
M + HDT
(n=10)
(n=14)*
Clinical
70
100
Molecular
70
100
* Evaluable patients.
Magni et al. Blood. 2000;96:864.
In Vivo Purging With MabThera®: Protocol
Preparative
Regimen
Day 1: MabThera
Day 4: Cyclophosphamide
Day 5+: G-CSF
Leukapheresis
Post-transplant
Therapy
MabThera
G-CSF
Flinn et al. Biol Blood Marrow Transplant. 2000;6:628.
Stem Cell
Transplant
HDT
Cyclophosphamide
Total body irradiation
In Vivo Purging With MabThera®:
Patient Characteristics
No. of patients
25
Age (y)
Median
(range)
Histology
FL (center)
MCL
CLL/SLL
Lymphoplasmacytic
Marginal zone
44%
28%
20%
4%
4%
No. of prior
treatments
Median
(range)
1
(1-3)
Remission status
(at baseline)
1st complete
1st partial
2nd partial
3rd partial
48%
24%
20%
8%
Flinn et al. Biol Blood Marrow Transplant. 2000;6:628.
51
(33-67)
In Vivo Purging With MabThera®:
Response
Response
Successful mobilization
% of Patients
92
(N=25; 2.0 x 106 CD34+ cells/kg)
Clinical* (n=11)
CR
PR
Stable disease
Molecular† (after in vivo purging; n=7)
55
27
18
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(11:14) or t(14:18) detectable by PCR.
Flinn et al. Biol Blood Marrow Transplant. 2000;6:628.
®
MabThera In Vivo Purging in Previously
Untreated Mantle Cell Lymphoma: Protocol
Cyclophosphamide
Cytarabine
Melphalan
Mitoxantrone +
melphalan
Collection
1
Reinfusion
3
2
MabThera®
0
21
42
Days
Gianni et al. Bone Marrow Transplant. 2002;29(suppl 1):10–13.
70
84
MabThera® In Vivo Purging in Previously
Untreated Mantle Cell Lymphoma:
Patient Characteristics
No. of patients
Age (y)
Ann Arbor stage
28
Median
III
IV
1–2
3
4–5
49
7%
93%
75%
14%
11%
Molecular rearrangement
bcl-1
IgH
Probe N/A
46%
36%
18%
B symptoms
Yes
38%
Size of mass
>10 cm
29%
LDH level
Abnormal
36%
IPI score
Gianni et al. Bone Marrow Transplant. 2002;29(suppl 1):10–13.
MabThera In Vivo Purging in Previously
Untreated Mantle Cell Lymphoma: Response
®
Response
Clinical
% of Patients
96
(n=27*)
Molecular
(n=20)
*Evaluable patients
Gianni et al. Bone Marrow Transplant. 2002;29(suppl 1):10–13.
100
MabThera® In Vivo Purging in Previously
Untreated Mantle Cell Lymphoma:
3-Year Survival
MabThera + sHDT (n=28)
®
Historical controls (n=39)*
100
100
OS
80
EFS
Percent
Percent
80
60
40
60
40
20
20
0
0
0
12
24
36
OS
48
Years
Gianni et al. Bone Marrow Transplant. 2002;29(suppl 1):10–13.
EFS
*CHOP-like regimen
0
12
24
Years
36
48
®
MabThera after HDT/ASCT in Follicular and
Mantle Cell Lymphoma: Protocol
Or equivalent
NR/PD
treatment (e.g., CHOP) off study
6 x VACOP-B
V
I
P
E
V
I
P
E
TBI/Cy
12 Gy/120
mg/kg
4 x MabThera
®
375 mg/m2/week
CD34+
selection
Week
–4
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
0
8
9
10
11
®
MabThera after HDT/ASCT in Follicular and
Mantle Cell Lymphoma: Patient
Characteristics
No of patients*
Age (y)
Sex
Histology
Median
(range)
Male
Female
Follicular lymphoma
Stage III
Stage IV
Mantle cell lymphoma
Stage III/IV
Stage IV
* Evaluable patients
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
30
49
(31–59)
53%
47%
67%
45%
55%
33%
30%
70%
MabThera® after HDT/ASCT in Follicular
and Mantle Cell Lymphoma:
Grade 3/4 Adverse Events
Total
Lymphopenia
Thrombocytopenia
Nausea
Infection
Neurologic pain
Thyroiditis
Other
Grade 3
Grade 4
15
5
–
1
6
1
1
1
7
6
1
–
–
–
–
–
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
®
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
6 months
9 months
12 months
24 months
®
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
50
59
74
91
91
®
MabThera after HDT/ASCT in Follicular and
Mantle Cell Lymphoma: Molecular Response
P=0.0116
100
**
PCR-negative (%)
*P=0.0077; **P<0.001
80
*
60
40
20
0
Pre-HDT
Post-HDT
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
Post®
MabThera
6 months
post-HDT
MabThera® In Vivo Purge + Maintenance with
HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma: Protocol
CHOP
x 4–8
cycles
*R
Day
Weeks
Weeks
0
8–11
24–27
**CBV
HDT
G-CSF
Immunotherapy
Collection
Reinfusion
*In vivo purge (R)
®
®
(two courses of MabThera )
**HDT
2
2
MabThera 375 mg/m day 5
Cyclophosphamide 1, 8 g/m days 6–3
G-CSF 10 µg/kg/day, days 4, 3, 2, 1, 0
Carmustine 500 mg/m day 2
Stem cell collection day 0 (1, 2)
Etoposide 2.4 g/m 36 hour CI day 7
Mangel et al. Blood. 2001;98(suppl 1):677a. Abstract 2833.
2
2
®
MabThera In Vivo Purge + Maintenance with
HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma: Patient Characteristics
No. of patients
14
Age (y)
Median
(range)
52
(41–65)
Sex
Male
Female
50%
50%
ECOG PS 0–1
100%
Stage IV (BM involvement)
86%
Low/low-intermediate IPI score
93%
B Symptoms
21%
LDH (IU/l)
Median
(range)
195
(144–402)
Cycles induction chemotherapy
Median
(range)
6
(4–8)
Mangel et al. Blood. 2001;98(suppl 1):677a. Abstract 2833.
MabThera® In Vivo Purge + Maintenance with
HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma: Clinical Response
% after
induction
% after
ASCT
% after
MabThera®*
ORR
100
100
100
CR
43
57
92
7
43
8
50
0
0
CRu
PR
* Based on ®12 of 14 patients who had completed maintenance
MabThera therapy
15-month median follow-up from transplantation
Mangel et al. Blood. 2001;98(suppl 1):677a. Abstract 2833.
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. 2001;98(suppl 1):677a. Abstract 2833.
®
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
2
ASCT
Trneny et al. Blood. 2002;100:804a. Abstract 3176.
*Fludarabine 3 x 25 mg/m
†
2
Cyclophosphamide 3 x 300 mg/m
®
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. 2002;100:804a. Abstract 3176.
®
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. 2002;100:804a. Abstract 3176.
®
MabThera EBMT LYM1 Trial:
Protocol
Patients: relapsed follicular lymphoma in 2nd/3rd CR or VGPR after any treatment
RANDOMIZATION
Group A: MabThera
in vivo purging
®
(375 mg/m2 weekly x 4)
®
Group B: MabThera
in vivo purging
(375 mg/m2 weekly x 4)
Group C:
No purging
Group D:
No purging
MOBILIZATION + PBSC COLLECTION HDT: BEAM + PBSC INFUSION
Group A:
MabThera
maintenance*
®
2
Group B:
Observation
Group C:
MabThera
maintenance*
®
* 375 mg/m every 2 months x 4, 30 days post-transplant
Group D:
Observation
MabThera® EBMTLYM1 Trial:
Eligibility Criteria
Inclusion
Exclusion
 Relapsed follicular B-cell
lymphoma
 Impaired renal/hepatic/cardiac
and pulmonary function
 WHO PS 0-1
 Histologic transformation to high grade
 Platelets >100 x 109/L after
induction therapy
 Previous radiotherapy to >30% BM
 18 years
 CD20+
 CNS involvement
 >3 chemotherapy regimens
for NHL (including re-induction
chemotherapy)
 Previous transplant
 Pregnant/lactating
 HIV, HepB, and HepC positivity
 Previous malignancy <5 years
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. 2000;6:628.
®
MabThera for B-PTLD: Eligibility Criteria
Inclusion
Exclusion
 Age 1-75 years
 CNS involvement
 Histologically or cytologically
confirmed mono- or
polymorphic PTLD with 10%
CD20+ lymphoma B-cells
 High EBV viral load after SCT
 ECOG performance status 3
Choquet et al. Blood. 2002;100:467a. Abstract 1811.
®
MabThera for B-PTLD: Patient
Characteristics
Median age in years (range)
SOT
(n=44)
SCT
(n=11)
50 (13-73)
15 (5-52)
Male
75%
45%
<1 year from transplant to B-PTLD
32%
100%
1 year from transplant to B-PTLD
64%
0%
ECOG grade 0-1
68%
18%
ECOG grade 2
32%
82%
SOT = solid organ transplant
SCT = stem cell transplant
Choquet et al. Blood. 2002;100:467a. Abstract 1811.
®
MabThera for B-PTLD: Response
SOT (%)
(n=44)
SCT (%)
(n=11)
All (%)
(n=55)
ORR
43
54
45
CR
20
54
27
7
0
5
16
0
13
CRu
PR
Choquet et al. Blood. 2002;100:467a. Abstract 1811.
®
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. 2002;100:467a. Abstract 1811.