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Rituximab in relapsed indolent
lymphoma
MHJ van Oers
Department of Haematology, Academic Medical Centre
Amsterdam, The Netherlands
Rituximab in relapsed indolent
lymphoma
Rituximab monotherapy
– Pivotal trial McLaughlin et al JCO 1998
– Schedule/dose varation
Piro et al Ann Oncol 1999
Ghielmini et al Blood 2004
– Re-treatment Davis et al JCO 2000
Combination with chemotherapy
– Phase II Czuczman et al JCO 1999; ASH 2003 abstr 1493
– Phase III - GLSG Dreyling et al. ASH 2003 abstr 351
- EORTC 20981 Intergroup study
GLSG = German low-grade lymphoma study group
EORTC = European Organization for Research and Treatment of Cancer
Rituximab pivotal trial
Multicentre, open-label, phase II trial
166 patients with relapsed indolent non-Hodgkin’s
lymphoma (NHL)
2
Rituximab 375mg/m weekly x 4
Favourable safety profile (fever, chills)
Host antibody responses (HACA) rare
B-cell depletion; no increase in infections
McLaughlin P, et al. J Clin Oncol 1998;16:2825–33
Rituximab pivotal trial:
overall response
Median DR 11.6 months
100
80
Patients (%)
60
PR
CR
40
20
0
Intent-to-treat Evaluable patients
McLaughlin P, et al. J Clin Oncol 1998;16:2825–33
Rituximab weekly x 8 in relapsed
indolent lymphoma: response
Patients (%)
(n=35)*
ORR 60
CR 14
PR 46
*Evaluable patients Piro LD, et al. Ann Oncol 1999;10:655–61
Prolonged rituximab in follicular lymphoma
a phase III randomised trial
202 patients, 64 previously untreated
Design: – rituximab 375 mg/m weekly x 4
2
– at week 12 CR/PR : randomised between
observation and prolonged rituximab
2
(375 mg/m every 2 months, x4)
Results in previously treated patients (128 evaluable)
– ORR 46%, 8% CR
– Response duration 12.7 vs. 24.7 months (p=0.065)
Ghielmini et al Blood 2004; 103: 4416
Rituximab retreatment for relapse after prior
response to rituximab: time to progression
ORR: 40% CR: 11% PR: 29% (n=57)
Rituximab regimen
Prior
Current
0 2 4 6 8 10 12 14 16 18 20
Months
Davis TA, et al. J Clin Oncol 2000;18:3135–43
Phase II: R-CHOP in indolent
lymphoma – 9 years follow-up
Response Naive patients Previously treated patients
variable (n=29) (n=9)
CR rate (%)* 59 56
PR rate (%)* 41 44
TTP (months) 84.9+ 47.4
(4.5, 105.6+) (6.8, 95.5+)
DR (months) 83.5+ 46.1
(2.9, 105.1+) (4.1, 94+)
*Response rates based on protocol-defined criteria
Czuczman MS, et al. Blood 2003;102:411a (Abstract 1493)
Update on patients bcl-2 [t(14;18)]
positive at baseline
Baseline Post-treatment
One remained positive
• Progressed at 76 months
Eight patients: R-CHOP Three converted to and remain negative
bcl-2 positive • All are CRs at 85+, 98+, and 99+ months
Four converted to negative and then
reverted to positive*
• Two are CRs at 100+ and 101+ months
• Two progressed at 31 and 85 months †
*In these four patients, pre- and post-treatment Bcl-2 positive
specimens are being analysed by nucleotide sequencing
†
Patients retreated with rituximab 4, achieved molecular CR,
currently ongoing response at 59+ months
Czuczman MS, et al. Blood 2003;102:411a (Abstract 1493)
Phase II: R-CHOP in indolent lymphoma –
conclusions
R-CHOP results in excellent efficacy in indolent NHL
– 100% ORR
– prolonged TTP: median of 82.3+ months
– 16 patients ongoing at 77.3+ to 105.6+ months
Combination therapy is safe and does not cause
significant added toxicity
Conversion of bcl-2 from positive to negative in blood and
bone marrow indicates clearance of microscopic disease
(i.e. ‘better quality’ remission)
This trial provides a foundation for further studies of
chemoimmunotherapy in indolent lymphoma
FCM ± rituximab in relapsed
lymphoma (GLSG)
N=126: 65 follicular lymphoma, 48 mantle
cell lymphoma 13, other indolent NHL
Relapse after CHOP etc.
Randomised between 4 x FCM or 4 x R-FCM
– fludarabine 25mg/m days 1–3,
2
– cyclophosphamide 200mg/m days 1–3 2
– mitoxantrone 8mg/m day 1) 2
Dreyling MH et al. Blood 2003;102:103a (Abstract 351);
Forstpointner R, et al. Blood 2004 (epub ahead of print)
FCM ± rituximab in relapsed
follicular lymphoma: results
Rituximab
FCM + FCM
(%) (%) p value
Completed induction 28/30 32/35
ORR 21 (75) 30 (94) 0.047
CR 7 (25) 14 (44) 0.106
PR 14 (50) 16 (50)
MR 2 (7) 0
SD 0 0
PD 5 (18) 1 (3)
Excluded 0 1 (3)
Dreyling MH et al. Blood 2003;102:103a (Abstract 351);
Forstpointner R, et al. Blood 2004 (epub ahead of print)
FCM ± rituximab in relapsed follicular
lymphoma: progression-free survival
1.00
Proportion progression-free
0.75
Rituximab + FCM (25/35)
0.50
0.25 FCM (14/30)
p=0.0134
0
0 1 2 3 4
Years
Dreyling MH et al. Blood 2003;102:103a (Abstract 351);
Forstpointner R, et al. Blood 2004 (epub ahead of print)
FCM ± rituximab in relapsed
follicular lymphoma: overall survival
1.00
Rituximab + FCM (32/36)
Proportion surviving
0.75 FCM (23/31)
0.50
0.25
p=0.0964
0
0 1 2 3 4
Years
Dreyling MH et al. Blood 2003;102:103a (Abstract 351);
Forstpointner R, et al. Blood 2004 (epub ahead of print)
E20981 intergroup study
Rituximab in remission induction and
maintenance treatment
of relapsed follicular NHL:
a phase III randomised clinical trial
Interim analysis report
10 March, 2004
Cut off date: 27 February, 2004
EORTC 20981 phase III trial:
eligibility criteria
Follicular NHL (at initial diagnosis) after a maximum
of two non-anthracycline-containing systemic regimens
– either remission (complete remission or partial
remission), no change, or progression on first or
second regimen
– prior treatment included at least 2 months of
single-agent therapy and/or at least two consecutive
cycles of polychemotherapy or purine analogues
Age 18 years
Ann Arbor stage II–IV
CD20+
EORTC 20981 phase III trial:
R-CHOP versus CHOP: study design
R R
CHOP every
A 21 days
A
N maximum six N Observation
D cycles D
O O
M Rituximab + M
I CHOP every I
21 days Rituximab
S S maintenance*
maximum six
E cycles
E
D D
2
*375mg/m every 3 months for 2 years or until relapse
EORTC 20981 phase III trial:
objectives
To establish in a prospective, randomised clinical trial
in relapsed/resistant follicular lymphoma
– the effect of addition of rituximab to CHOP
chemotherapy on the response rate and quality
(partial remission, complete remission and
molecular complete remission)
– the effect of rituximab maintenance treatment on
progression-free survival of follicular lymphoma in
remission after CHOP with or without rituximab
Accrual by group
Randomised Randomised
Group for induction (%) for maintenance (%)
NCIC 104 (22.6) 68 (21.3)
BNLI 101 (21.9) 68 (21.3)
HOVON 75 (16.3) 43 (13.5)
ALLG 65 (14.1) 50 (15.7)
EORTC LYG 61 (13.2) 45 (14.1)
NLG 44 (9.5) 36 (11.3)
SA NH 9 (2) 7 (2.2)
SAKK 2 (0.4) 2 (0.6)
Total 461 319
Evaluable 369 268
EORTC 20981 phase III trial: conclusions
from second interim analysis IDMC
Both original study questions have been answered
Superiority of R-CHOP induction in terms of
(complete) response rate and progression-free
survival
Superiority of rituximab maintenance in terms
of progression-free survival
Proposal
Close the initial randomisation
Continue the study with the maintenance
randomisation after R-CHOP (200 new patients)
Conclusion
Combined immunochemotherapy represents
the new standard approach in relapsed
follicular lymphoma
