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MabThera® and Autologous Stem Cell Transplant (ASCT)
ASCT: Protocol
Debulking/MobilizationRegimen
BM/Stem Cell Harvest and “Purging”
High-DoseChemoradiotherapy
Stem CellTransplant
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
Buckstein et al. Semin Oncol. 1999;26(5 suppl 14):115; Mangel et al. Blood. 2000;96(suppl 1):383a. Abstract 1655.
CBVLeukapheresisMabThera G-CSF * Stem cell transplant
Weeks
*
Days
0 8 11 24 27
0
10
20
30
40
In Vivo Purging With MabThera®:Median PB CD34+ Cell Count
Day 5Day 4Baseline
CD
34+
x 1
06 /L No MabThera®
MabThera® purging
Buckstein et al. Semin Oncol. 1999;26:115; Mangel et al. Blood. 2000;96(suppl 1):383a. Abstract 1655.
In Vivo Purging With MabThera®: Response
Clinical 100
CR 38
CRu 63
Molecular* (6 mo post-transplant) 100
% of Patients(N=16)
* Among the 7 patients who presented with the bcl-2 rearrangement.
Response
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
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
% of Patients(N=16)
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
Buckstein et al. Blood. 2002;100:647a. Abstract 2547.
* 3 MU/m2 t.i.w.; †375 mg/m2
Study 1 No purge HDTIFN maintenance* for 2 years
Study 2 HDTMabThera®
maintenance† weekly x 4 at 2 and 6 months
Study 3 HDT
IFN maintenance* for2 years + MabThera® maintenance† weekly x 6 at 3 months
MabThera® in vivo purge†
MabThera® in vivo purge†
MabThera® In Vivo Purging and Maintenance after HDT/ASCT in Relapsed Follicular Lymphoma:
Patient Characteristics
Buckstein et al. Blood. 2002;100:647a. Abstract 2547.
IFN
(n=14) MabThera
®
(n=23)
MabThera®
+ IFN (n=12)
Median age (y) 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)
MabThera® In Vivo Purging and Maintenance after HDT/ASCT in Relapsed Follicular Lymphoma:
Results
Buckstein et al. Blood. 2002;100:647a. Abstract 2547.
* Only 10 evaluable patients
IFN
(n=14) MabThera®
(n=23)
MabThera®
+IFN (n=12)
% CR/CRu pretransplant 7 19 40
% CR/CRu 3-months post-transplant 23 90 70*
% Relapses 71 35 17
Deaths 2 2 0
Median follow-up (months) 59 37 10
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 Maintenanceafter HDT/ASCT in Relapsed Follicular Lymphoma:
Event-free Survival
Buckstein et al. Blood. 2002;100:647a. Abstract 2547.
100
80
60
40
20
0
Pat
ien
ts E
ven
t-fr
ee (
%)
0 12 24 36 48 60Months
Interferon
MabThera®/Interferon
MabThera®
P=0.12
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
Khouri et al. Blood. 2002;100:645a. Abstract 2538.
Schema 1 (n=27)
MabThera®
375 mg/m2
Cyclophosphamide4-7 g/m2
Day
MabThera®
1,000 mg/m2
Day
MabThera®
375 mg/m2
MabThera®
1,000 mg/m2
Ifosfamide 3.33 g/m2
Etoposide 300 mg/m2
Schema 2 (n=15)
GM-CSF 250 µg/m2
G-CSF 10 µg/kg
G-CSF 6 µg/kg b.i.d.
1 2 3 4 5 6 7 8 9 10
1 2 3 4 5 6 7 8 9 10
High-dose MabThera® In Vivo Purge + HDT/ASCT in Relapsed B-Cell Lymphoma:
Eligibility Criteria
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 50% Pulmonary function test 50%
Exclusion Hepatitis HIV-positive
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 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. 2002;100:645a. Abstract 2538.
High-dose MabThera® In Vivo Purge + HDT/ASCT in Relapsed B-Cell Lymphoma: Overall and
Disease-free Survival
91% 1-year disease-free survival
93% 1-year overall survivalKhouri et al. Blood. 2002;100:645a. Abstract 2538.
0 5 10 15 20 25Months Post-transplant
1.0
0.8
0.6
0.4
0.2
0
Cu
mu
lati
veP
rop
ort
ion
Su
rviv
ing
OS
DFS
n=42
High-dose MabThera® In Vivo Purge + HDT/ASCT in Relapsed B-Cell Lymphoma:
Tolerability
Khouri et al. Blood. 2002;100:645a. Abstract 2538.
Number of episodes
Grade 3/4 non-hematologic toxicity 13
Infection
Bacterial infection 12
Viral infection 5
Fungal infection 2
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.
Magni et al. Blood. 2000;96:864.
Cyclophosphamide CytarabineMabThera
Melphalan Mitoxantrone + melphalan
Weeks
0 3 6 9
* * ** Stem cell transplant
In Vivo Purging With MabThera®: Protocol
Magni et al. Blood. 2000;96:864.
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 >10 cm — 30%
Sites of involvement Nodal 93% 100%Extranodal 13% 30%BM 100% 100%PB 40% 30%
HDT(n=10)
M + HDT(n=15)
In Vivo Purging With MabThera®: Patient Characteristics
33
93
20
40
0
20
40
60
80
100
In Vivo Purging With MabThera®: PCR-Negative Harvests
Magni et al. Blood. 2000;96:864.
Post-Cyclophosphamide
Pat
ien
ts W
ith
PC
R-
Neg
ativ
e H
arve
sts
(%)
Post-Cytarabine
(P=0.007)
M + HDT
HDT
Clinical 70 100
Molecular 70 100
% of Patients
ResponseHDT(n=10)
M + HDT(n=14)*
In Vivo Purging With MabThera®: Response
Magni et al. Blood. 2000;96:864.
* Evaluable patients.
In Vivo Purging With MabThera®: Protocol
Flinn et al. Biol Blood Marrow Transplant. 2000;6:628.
Preparative RegimenDay 1: MabThera Day 4: CyclophosphamideDay 5+: G-CSF
LeukapheresisHDTCyclophosphamideTotal body irradiation
Stem Cell Transplant
Post-transplant TherapyMabThera
G-CSF
No. of patients 25
Age (y) Median 51(range) (33-67)
Histology FL (center) 44%MCL 28%CLL/SLL 20%Lymphoplasmacytic 4%Marginal zone 4%
No. of prior Median 1treatments (range) (1-3)
Remission status 1st complete 48% (at baseline) 1st partial 24%
2nd partial 20%3rd partial 8%
In Vivo Purging With MabThera®: Patient Characteristics
Flinn et al. Biol Blood Marrow Transplant. 2000;6:628.
In Vivo Purging With MabThera®: Response
Flinn et al. Biol Blood Marrow Transplant. 2000;6:628.
Successful mobilization 92 (N=25; 2.0 x 106 CD34+ cells/kg)
Clinical* (n=11)
CR 55PR 27Stable disease 18
Molecular† (after in vivo purging; n=7) 86
% of PatientsResponse
* 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.
Gianni et al. Bone Marrow Transplant. 2002;29(suppl 1):10–13.
MabThera® In Vivo Purging in Previously Untreated Mantle Cell Lymphoma: Protocol
Days
0 21 42 70 84
Reinfusion
MabThera®
Cyclophosphamide Cytarabine MelphalanMitoxantrone +
melphalan
Collection1 2 3
No. of patients 28
Age (y) Median 49 Ann Arbor stage III 7%
IV 93%IPI score 1–2 75%
3 14%4–5 11%
Molecular rearrangement bcl-1 46%IgH 36%Probe N/A 18%
B symptoms Yes 38%
Size of mass >10 cm 29%
LDH level Abnormal 36%
MabThera® In Vivo Purging in Previously Untreated Mantle Cell Lymphoma:
Patient Characteristics
Gianni et al. Bone Marrow Transplant. 2002;29(suppl 1):10–13.
Clinical 96(n=27*)
Molecular 100(n=20)
% of PatientsResponse
MabThera® In Vivo Purging in Previously Untreated Mantle Cell Lymphoma: Response
*Evaluable patients
Gianni et al. Bone Marrow Transplant. 2002;29(suppl 1):10–13.
MabThera® In Vivo Purging in Previously Untreated Mantle Cell Lymphoma:
3-Year Survival
0 12 24 3648
0 12 24 3648
OS
MabThera® + sHDT (n=28)
100
Years
Per
cen
t
0
20
40
60
80
100
EFS
Historical controls (n=39)*
OS
*CHOP-like regimenP
erce
nt
80
60
40
20
0
Years
EFS
Gianni et al. Bone Marrow Transplant. 2002;29(suppl 1):10–13.
MabThera® after HDT/ASCT in Follicular and Mantle Cell Lymphoma: Protocol
6 x VACOP-B
VIPE
VIPE
TBI/Cy
12 Gy/120 mg/kg
4 x MabThera®
375 mg/m2/week
CD34+ selection
NR/PDoff study
Or equivalenttreatment (e.g., CHOP)
Week –4 0 8 9 10 11
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
MabThera® after HDT/ASCT in Follicular and Mantle Cell Lymphoma: Patient
Characteristics
No of patients* 30
Age (y) Median 49 (range) (31–59)
Sex Male 53%
Female 47%
Histology Follicular lymphoma 67%
Stage III 45%
Stage IV 55%
Mantle cell lymphoma 33%
Stage III/IV 30%
Stage IV 70%
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
* Evaluable patients
Total 15 7
Lymphopenia 5 6
Thrombocytopenia – 1
Nausea 1 –
Infection 6 –
Neurologic pain 1 –
Thyroiditis 1 –
Other 1 –
Grade 4Grade 3
MabThera® after HDT/ASCT in Follicularand Mantle Cell Lymphoma:
Grade 3/4 Adverse Events
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
Before TBI/Cy 13
After TBI/Cy 47
After MabThera® 50
6 months 59
9 months 74
12 months 91
24 months 91
% of Patients in CR
MabThera® after HDT/ASCT in Follicular and Mantle Cell Lymphoma: Clinical Response
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
MabThera® after HDT/ASCT in Follicular and Mantle Cell Lymphoma: Molecular Response
Brugger et al. Ann Oncol. 2002;13(suppl 2):38. Abstract 113.
0
20
40
60
80
100
PC
R-n
egat
ive
(%)
*
***P=0.0077; **P<0.001
P=0.0116
Pre-HDT Post-HDT Post- 6 months
MabThera®
post-HDT
MabThera® In Vivo Purge + Maintenance with HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma: Protocol
**CBVHDT
CHOPx 4–8
cycles
*R G-CSF
Day
0
Weeks
8–11
Weeks
24–27
CollectionImmunotherapy
(two courses of MabThera®)
*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 6–3
Carmustine 500 mg/m2 day 2
Etoposide 2.4 g/m2 36 hour CI day 7
Mangel et al. Blood. 2001;98(suppl 1):677a. Abstract 2833.
Reinfusion
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) (41–65)
Sex Male 50%Female 50%
ECOG PS 0–1 100%
Stage IV (BM involvement) 86%
Low/low-intermediate IPI score 93%
B Symptoms 21%
LDH (IU/l) Median 195 (range) (144–402)
Cycles induction chemotherapy Median 6 (range) (4–8)
Mangel et al. Blood. 2001;98(suppl 1):677a. Abstract 2833.
% after % after % after
induction ASCT MabThera®*
ORR 100 100 100
CR 43 57 92
CRu 7 43 8
PR 50 0 0
MabThera® In Vivo Purge + Maintenance with HDT/ASCT in Previously Untreated Mantle Cell
Lymphoma: Clinical Response
* 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†
MobilizationESHAP
BEAM
Trneny et al. Blood. 2002;100:804a. Abstract 3176.
Harvest
ASCT*Fludarabine 3 x 25 mg/m2
†Cyclophosphamide 3 x 300 mg/m2
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
* 375 mg/m2 every 2 months x 4, 30 days post-transplant
Patients: relapsed follicular lymphoma in 2nd/3rd CR or VGPR after any treatment
RANDOMIZATION
MOBILIZATION + PBSC COLLECTION HDT: BEAM + PBSC INFUSION
Group B: Observation
Group C: MabThera®
maintenance*
Group D: Observation
Group A: MabThera® in vivo purging
(375 mg/m2 weekly x 4)
Group C:No purging
Group B: MabThera® in vivo purging
(375 mg/m2 weekly x 4)
Group D:No purging
Group A: MabThera®
maintenance*
MabThera® EBMTLYM1 Trial: Eligibility Criteria
Inclusion Relapsed follicular B-cell
lymphoma
WHO PS 0-1
Platelets >100 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 >30% BM
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
Age 1-75 years
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.
Exclusion
CNS involvement
MabThera® for B-PTLD: Patient Characteristics
Choquet et al. Blood. 2002;100:467a. Abstract 1811.
SOT (n=44)
SCT (n=11)
Median age in years (range) 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 transplantSCT = stem cell transplant
MabThera® for B-PTLD: Response
Choquet et al. Blood. 2002;100:467a. Abstract 1811.
SOT (%) (n=44)
SCT (%) (n=11)
All (%) (n=55)
ORR 43 54 45
CR 20 54 27
CRu 7 0 5
PR 16 0 13
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.