mabthera ® and autologous stem cell transplant (asct)

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†


Patient Characteristics


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)


Results


* 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


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


MabThera® In Vivo Purging and Maintenanceafter HDT/ASCT in Relapsed Follicular Lymphoma:

Event-free Survival


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


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


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




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


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


Tolerability


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


Magni et al. Blood. 2000;96:864.

Cyclophosphamide CytarabineMabThera

Melphalan Mitoxantrone + melphalan

Weeks

0 3 6 9

* * ** Stem cell transplant



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


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)*



* Evaluable patients.


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




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:



Clinical 96(n=27*)

Molecular 100(n=20)

% of PatientsResponse

MabThera® In Vivo Purging in Previously Untreated Mantle Cell Lymphoma: Response

*Evaluable patients


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


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%


* 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


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


MabThera® after HDT/ASCT in Follicular and Mantle Cell Lymphoma: Molecular Response


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


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)


% after % after % after

induction ASCT MabThera®*

ORR 100 100 100

CR 43 57 92

CRu 7 43 8

PR 50 0 0


Lymphoma: Clinical Response

* Based on 12 of 14 patients who had completed maintenance

MabThera® therapy

15-month median follow-up from transplantation



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


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%)


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


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


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


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


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


mabthera ® and autologous stem cell transplant (asct)

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