1
Emanuele Zucca, MDOncology Institute of Southern Switzerland (IOSI)Swiss Group for Clinical Cancer Research (SAKK)
Is there Long-Term Benefit from Maintenance
Rituximab?
Rationale and aim of maintenance
in haematological malignancies
In patients who have responded to initial induction
• Prolong quality and duration of remission
• Prolong overall survival (if possible)
Results of maintenance rituximab trials were not the
same in different B-cell lymphoma subtypes
Maintenance rituximab in DLBCL
• ECOG 4494 trial: no benefit of 2-year maintenance (4xR weekly q6 mos) in elderly pts after R-CHOP
Habermann TM, et al. J Clin Oncol. 2006
• Potential benefit for maintenance rituximab recently reported in a retrospective Chinese study (N = 207)
Huang BT, et al. J Cancer Res Clin Oncol. 2012
• NHL13/NCT00400478 randomized study: maintenance reduced relapse rate but did not prolong EFS nor OS in DLBCL (or FL grade 3) Jaeger at al. Abstr 119, 12-ICML, Lugano 2013
Event Free Survival(ITT population)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Time [months]
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81
p = NS
Rituximab maintenance
Observation
Overall Survival(ITT population)
AA
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Time [months]
0 3 6 9 121518212427303336394245485154576063666972757881848790939699
Rituximabmaintenance
Observation
Jaeger at al., 12-ICML, Hematol Oncol 2013. 31(suppl 1):128, abstr 119
2-yr maintenance rituximab or not after R-CHOP-like regimens for DLBCL
Austrian/Czech study group27 countries, 2004-8 N=683
p = NS
Maintenance rituximab benefit after
R-CHOP but not after R-FC in MCL Among patients who had
a response to R-CHOP, maintenance rituximab significantly improved survival (4-year OS rate, 87%, vs. 63% with IFN-alfa; P=0.005).
Kluin-Nelemans, NEJM 2012
Improvement of FL outcome
What does R-maintenance mean?
From Gribben JG. Blood 2007;109:4617-4626
Rituximab maintenancein relapsed/resistant FL
GLSG study
Forstpointner et al, Blood. 2006;108:4003-8
105 pts
FCM
R-FCM
R-m
aint
enan
cePR/CR
ECOG 1496 – Progression-free survival follicular NHL after CVP
(n = 237)
LR one-sided P = 0.0000003HR 0.4 (0.3–0.6)
Years from maintenance randomisation
Prob
abili
ty
Maintenance (n = 120)Median PFS: 5 yrs
Observation (n = 117)Median PFS: 15 months
0 1 2 3 4 5 60.0
0.2
0.4
0.6
0.8
1.0
Hochster HS, et al. Blood 2005; 106:Abstract 349.
Footer Text
EORTC 20981 Initial Results
van Oers et al. Blood 2006;108:3295-3301
median follow-up from 2nd
randomization, 33 months
R-maintenance vs observation2
Rituximab-based induction and maintenance therapy became the
standard of care for FL
HR for OS (95% CI)
FavoursR-maintenance
Favours observation
p < 0.0003
0.001 0.1 1 10 1000
1.Schulz H et al. J Natl Cancer Inst. 2007;99:706-14 2.Vidal L et al. J Natl Cancer Inst. 2009;101:248-55
R-chemo vs chemo induction1
HR for OS (95% CI)
Favours R-chemo
Favours chemo
p < 0.001
0.2 0.5 1 2
EORTC 20981 Long-Term Outcome
van Oers et al. J Clin Oncol 2010; 28:2853-8
median follow-up from 2nd randomization, 72 months
With long-term follow-up the superior PFS with R-maintenance was confirmed in R/R FL
EORTC 20981 Long-Term Outcome
• The OS improvement did not reach statistical significance, possibly because of the unbalanced use of rituximab at progression.
• R-containing salvage therapy to 59% of patients after CHOP followed by observation, vs. 26% after R-CHOP plus R-maintenance.
van Oers et al. J Clin Oncol 2010; 28:2853-8
• R-maintenance associated with a significant increase in grades 3 to 4 infections: 9.7% vs. 2.4% (P = .01).
Vitolo U et al. JCO 2013;31:3351-3359
R-FND induction phase • Rituximab 375 mg/m2 (d 1)• Fludarabine 25 mg/m2 /d (d
2-4)• Mitoxantrone 10 mg/m2 (d
2)• Dexamethasone 10 mg/d (d
2-4)Monthly x4
RestagingCR/CRuPRSD
consolidation phase • Rituximab 375 mg/m2
Weekly x4
®
Arm A, Maintenance• Rituximab 375 mg/m2
Q 2 months x4
Arm B, Observation
RestagingCR/CruPR
stratifiedby MRD
1:1
FIL phase III Study Design234 patients >60 yro with advanced FL
N=210
N=101
N=101
Vitolo U et al. JCO 2013;31:3351-3359
FIL study: Overall and progression-free survival in elderly patients with advanced
FL
R- maintenance vs. observation in elderly FL patients after induction with 4 R-FND cycles
and consolidation with 4x weekly R 2-year PFS 81% versus 69% HR 0.74 not statistically significant.
No differences between the two arms detected for OS.
Is the maintenance effect the same after any induction regimen in FL?
P = 0.226
Vitolo U et al. JCO 2013;31:3351-3359
MAINTAIN TRIAL (NCT00877214):Significance of Duration of Maintenance Therapy With Rituximab in Non-Hodgkin Lymphomas after Front-Line Therapy with R-BendamustineExperimental Arm• FL: Maintenance rituximab q2 mos for 4 yrs • WM, MZL and MCL: Maintenance rituximab q2
mos for 2 yrs
Standard Arm• FL: Maintenance rituximab q2 mos for 2 yrs • WM, MZL and MCL: Observation
Vs.
Vitolo et al. JCO 2013;31:3351-3359
R- maintenance toxicity in elderly FL
Questions on prolonged rituximab treatment in FL
• When? Front-line or at first relapse?• How long?• Is chemotherapy always needed?
PRIMA study of front line maintenance
Salles G, et al. Lancet. 2011;377:42-51.
Patie
nts
(%)
0
20
40
60
80
100
52%
30%
72%
52%
0
20
40
60
80
100
Patie
nts
(%)
Rituximab maintenance Observation
CR/CRu at end of treatment Conversion from PR to CR/CRu during maintenance/observation
p = 0.0001 p = 0.0001
Rituximab maintenance
3-year PFS
74.9%
57.6%
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 60
PFS (months)
Prob
abili
ty
Observation
p < 0.0001
PRIMA study of front line maintenance
Salles G, et al. Lancet. 2011;377:42-51.
Rituximab maintenance
3-year PFS
74.9%
57.6%
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 60
Prob
abili
ty
Observation
p < 0.0001
But…No significant difference in OS
Rituximab vs. watch & wait in asymptomatic, advanced-stage, non-
bulky FL: PFS
Ardeshna KM, et al. Blood. 2010;116:[abstract 6]
Rx4 + RM: 81%
R vs W + W: p < 0.001R + RM vs W + W: p < 0.001
0.00.10.20.30.40.50.60.70.80.91.0
0 1 2 3 4 5
3-year PFS
PFS (years from randomization)
Prob
abili
ty
W + W: 33%
Rx4: 60%
Median follow-up = 32 months
Rituximab vs. watch & wait in asymptomatic, advanced-stage, non-
bulky FL: OS
Ardeshna KM, et al. Blood. 2010;116:[abstract 6]
Which is the optimal duration of rituximab treatment in FL?
Single-agent rituximab in FL: the SAKK 35/98 study
375 mg/m² every 2 months x 4
FL (n = 151)
PDoff study
n = 202
375 mg/m²weekly x 4
SD, PR, CR(n = 151)
OBSERVATION Standardtreatment
Prolonged treatment
FL pre-treated and untreated in need of treatment
Randomization
Ghielmini M, et al. Blood. 2004; 103(12):4416-23
FL E
vent
-fre
e su
rviv
al (
%)
Prolonged: median 23 mos
Observation: median 12 mosP = 0.024
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48 Months
Ghielmini M, et al. Blood. 2004; 103(12):4416-23
SAKK 35/98R-maintenance after single agent rituximab
Long-term EFS by arm according to response to the induction treatment
Martinelli JCO 2010
35% of respondersstill in remissionat 8 years
Martinelli et al. JCO 2010
SAKK 35/98: long-term follow-up
Martinelli G, et al. J Clin Oncol. 2010;28:4480-4
Event-free survival in randomized follicular lymphoma patients
Event-free survival in chemo-naive patients with CR/PR at 12 weeks
Pro
babi
lity
Years since start of treatment
0.0
0.4
0.6
0.8
1.0
0.2
2 4 6 8 101 3 5 7 9
ProlongedStandard
p = 0.0007
/ / / // / ////// / /// /
/ //
Pro
babi
lity
Years since start of treatment
0.0
0.4
0.6
0.8
1.0
0.2
2 4 6 8 101 3 5 7 9
ProlongedStandard
p = 0.045
/ / /
/ ///
/ /
27% still in remission at 8 years
45% of chemo-naïve responders in remission at 8
years
SAKK 35/98: Overall Survival
Martinelli G, et al. J Clin Oncol. 2010;28:4480-4
• The optimal way to give single-agent rituximab is at a prolonged schedule
• When treated this way, the chance of being still in remission at 8 years is ~25%
• For chemotherapy naïve patients responding to induction, the chance is ~45% at 8 years
• Schedule is the only and most potent prognostic factor for response duration
• Prolonged rituximab treatment appears safe and improves EFS
SAKK 35/98 Long-Term Results
Nordic Lymphoma Group ML16865 trial
R + IFN vs. R (313 randomized patients)
E. Kimby et al. 11-ICML, Lugano 2011
375 mg/m²weekly x 4
375 mg/m²weekly x 4 +/- IFN
Rituximab 375 mg/m² q2 monthsuntil progression (max. 5 years) Long maintenance
Rituximab maintenance for how long?SAKK 35/03 study design
Taverna CJ, et al. J Clin Oncol. 2009;27:[abstract 8534]
Rituximab375 mg/m²qwk x 4
restageweek 12
SD + PDoff study
PR + CR
Short maintenanceRituximab 375 mg/m² q2 months x 4
SAKK 35/03 trial
Randomization
Rituximab maintenance for how long?
SAKK 35/03 trial: short vs. prolonged maintenance
Final results (“per arm” analysis) to be first presented at ASH 2013
Taverna CJ, et al. ASH 2013 (submitted)
Median OS: 8.1 years (95% CI 7.8-NA)7-year OS: 85% (95% CI 77-90)
Median PFS: 5.5 years (95% CI 3.6-7.7)7-year PFS: 44.5% (95% CI 35-53)Median follow-up time: 6.4 years (95% CI 6.1-6.5) Median follow-up time: 6.4 years (95% CI 6.1-6.5)
• Role of maintenance rituximab is still unclear in DLBCL (and MCL), while is better defined in FL where it improves PFS either front-line or at relapse.
• OS improvement is less evident.• It is generally accepted that FL patients in need of therapy should
receive rituximab with and after R-CVP or R-CHOP relapse• However, is this true for all patients ? and is this true for any
chemotherapy? • Moreover, is chemotherapy always needed?• The long term results of SAKK 35/98 together with few available
data from other studies indicate immunotherapy alone can have a role in FL
• This should be specifically addressed in controlled trials
Conclusions
• Christian J. Taverna, Giovanni Martinelli, Felicitas Hitz, Walter Mingrone, Thomas Pabst, Andreas Lohri, Christine Biaggi Rudolf, Stéphanie Rondeau, Corinne Rusterholz, Simona Berardi and Michele Ghielmini, for the Swiss Group for Clinical Cancer Research SAKK
• Eva Kimby and all the Nordic Lymphoma Group Investigators
Acknowledgements