Is there Long-Term Benefit from Maintenance Rituximab?

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