Rituximab maintenance therapy
after rituximab induction
Michele Ghielmini
Swiss Group for Clinical Cancer Research (SAKK)
Oncology Institute of Southern Switzerland
Bellinzona, Switzerland
Rituximab maintenance after induction
therapy
Induction Maintenance
Chemo
… … … … …
R-Chemo
… … … … …
R
… … … … …
= Chemo
=R
Maintenance is effective: why debate?
Treatment
– has side effects
– is expensive
– modifies the target (resistance)?
Is maintenance cost-effective?
Depends on how you measure:
COSTS EFFECT
Money Response rate (RR)
Toxicity Event-free survival (EFS)
Inconvenience Overall survival (OS)
Social costs Time without chemotherapy
Quality of life
The two most common
maintenance schedules
SAKK
USA
6 months
USA maintenance schedule:
progression-free survival
100
Progression-free survival (%)
80
Follicular/small cleaved
Median PFS = 52.1 months
60
40
20
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Months
Updated from Hainsworth J et al. J Clin Oncol 2002;20:4261–7
Rituximab maintenance versus
retreatment: protocol
Weeks 1–4 Week 6 Off study
No response
Induction
Restage
therapy
(Rituximab Maintenance therapy
CR (identical to induction course)
375mg/m2 PR
i.v. weekly every 6 months
SD (months 6, 12, 18)
x 4)
Randomise
Retreatment at time of disease
progression
(identical to induction course)
Hainsworth JD, et al. Blood 2003;102:69a (Abstract 231)
Rituximab maintenance versus
retreatment: progression-free survival
100
Progression-free survival (%)
80
60
Maintenance
40
20
Retreatment
p=0.0066
0
0 12 24 36 48 60
Months
Hainsworth JD, et al. Blood 2003;102:69a (Abstract 231)
Rituximab maintenance versus
retreatment: efficacy
Maintenance Retreatment
(n=44) (n=46) p value
ORR (%) 52 35 0.14
CR (%) 27 4 0.007
In continuous remission (%) 45 24 0.05
Remaining in CR (%) 23 2 0.03
Median PFS (months) 31.7 7.4 0.007
Median duration of rituximab
benefit (months) 31.7 27.4 0.94
ORR = overall response rate
CR = complete response
Hainsworth JD, et al. Blood 2003;102:69a (Abstract 231)
Rationale for testing prolonged
rituximab therapy
Rituximab 375mg/m weekly x 4:
2
– CR (5–10%) compared to ORR (50–60%)
– relatively short response duration
– correlation drug exposure – response rate
– other treatments usually given for 4–8 months
SAKK 35/98 study design
FL = 202 FL = 151
MCL = 104 MCL = 61 Observation
R
Rituximab Prolonged
SD,PR,CR
375mg/m²
weekly x 4 Rituximab 375mg/m² every 2 months x 4
PD off study
Response to induction therapy
Response rate 52% (8% CR)
Prognostic factors for response in a multivariate
analysis on 273 evaluable patients
– diameter <5cm p=0.0006
– follicular histology p=0.003
– normal Hb p=0.003
Submitted for publication
SAKK 35/98: event-free survival
1.0
0.8 FL + MCL (n=306)
0.6
0.4 Prolonged treatment: median 15 months
0.2
p=0.005
Observation: median 9 months
0.0
0 1 2 3 4 5 6
Time (years)
SAKK 35/98: overall survival
FL + MCL (n=306)
1.0
Prolonged treatment: median=NR
0.8
0.6
Observation: median=NR
0.4
0.2
p=0.37
0
0 1 2 3 4 5 6
Time (years)
Prognostic factors for event-free survival
Multivariate analysis on 162 evaluable and
randomised FL + MCL patients
Parameter Hazard ratio P
Response to induction
response vs 2 <0.0001
SD or PD
Stage
≤III vs 2 <0.0001
IV
Fc receptor status
VF/FF vs 2 0.02
VV
SAKK 35/98: B-cells and IgM profile
Median values of B cell counts Median values of IgM ratios to baseline
200 1.1
Observation
Ratio to baseline
150 1.0
Observation
E6/I
100 0.9
50 0.8
Prolonged treatment Prolonged treatment
0 0.7
8–12 20 36 52 78 104 0 12 28 52
Weeks since treatment start Weeks since treatment start
Toxicity
(SAE possibly or probably related)
No of patients
Infections 13
Cardiac 6
Intestinal 5
Other 11
Second tumours 16
Equally distributed in the two arms
Single-agent rituximab
Single-agent rituximab is a valid treatment
for patients with
– follicular lymphoma
– low tumour burden
– normal Hb
– (VV152 Fc phenotype)
If they respond, prolonging treatment is
recommended
New SAKK 35/03 study design
Short
maintenance
Rituximab 375mg/m² every 2 months x 4
R
Rituximab PR,CR
375 mg/m²
weekly x 4 Rituximab 375mg/m² every 2 months
until relapse
PD, SD off study Long
maintenance
Conclusions
Single-agent rituximab is a good treatment
for indolent NHL
Rituximab works better if given for longer
than 6 months
Long-term maintenance remains investigational