Treatment of follicular lymphoma

(1)

MJR MJR

Treatment of follicular lymphoma

Mathias J. Rummel Mathias J. Rummel Med. Klinik IV/ V

Med. Klinik IV/ V -- HämatologieHämatologie Klinikum der Justus

(2)

Therapy of Follicular

Lymphoma

wait and see policywait and see policy

alkylatingalkylating agentsagents

anthracyclineanthracycline-based chemotherapy-based chemotherapy

purinepurine analogsanalogs

bendamustinebendamustine

unconjugatedunconjugated monoclonal antibodiesmonoclonal antibodies

radiolabelledradiolabelled monoclonal antibodiesmonoclonal antibodies

autologousautologous stem cell transplantationstem cell transplantation

allogeneicallogeneic stem cell transplantationstem cell transplantation

nonnon-myeloablative -myeloablative allogeneicallogeneic SCTSCT

(DNA vaccination, antisense, etc)(DNA vaccination, antisense, etc)

1 2 3 4 5 6 7 8 years 100% 50% NHL Classification Project: NHL Classification Project:

OS for 306 patients with follicular NHL:

Adapted from Armitage et al, JCO 1998; 16:2780

(3)

Watch & wait or early treatment?

Ardeshna KM et al. Watch & wait versus immediate systemic treatm

Ardeshna KM et al. Watch & wait versus immediate systemic treatment. Lancet 262: 516, 2003ent. Lancet 262: 516, 2003

Watchful waiting versus Chlorambucil 10 mg daily contin.

prospective randomized, n = 309, recruitement phase 1981

prospective randomized, n = 309, recruitement phase 1981--19901990

Survival

Survival watch & waitwatch & wait immediate treatmentimmediate treatment 5 years 5 years 58 %58 % 57 %57 % 10 years 10 years 34 %34 % 35 %35 % 15 years 15 years 22 %22 % 21 %21 % Median

(4)

Watch & wait or early treatment ?

Overall survival

Disease

-

associated survival

Ardeshna KM et al. Lancet 262: 516, 2003

(5)

MJR MJR

Watch & wait or early treatment ?

(6)

MJR MJR

Watch & wait: time to first treatment

Median time to first treatment: 2,6 years

Actuarial chance of not needing

chemotherapy at 10 yrs was 19%

and 40% in patients older than 70 years

Watch & wait or early treatment ?

(7)

MJR MJR

Indications for treatment in indolent lymphomas:

Stages I, II, limited stage III (up to 5 involved lymph node regions: curative intention?Stages I, II, limited stage III (up to 5 involved lymph node regions: curative intention?

Disease associated symptoms (B-Disease associated symptoms (B-symptoms) symptoms)

Hematopoetic insufficiency: anemia, granulocytopenia, thrombocytopeniaHematopoetic insufficiency: anemia, granulocytopenia, thrombocytopenia

Rapid tumor progression: doubling of manifestations within 1 yearRapid tumor progression: doubling of manifestations within 1 year

Bulky disease (> 6 cm diameter) Bulky disease (> 6 cm diameter)

Autoimmune phenomens, such as AIHA or ITPAutoimmune phenomens, such as AIHA or ITP

Hypogammaglobulinemia with recurrent infectionsHypogammaglobulinemia with recurrent infections

(8)

Indolent

Non

-

Hodgkin

-

Lymphomas

100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 00 0 1987 1987--1996 (n=668)1996 (n=668) 1976 1976--1987 (n=513)1987 (n=513) 1960 1960--1976 (n=195)1976 (n=195) Horning et al.

Horning et al.Semin OncolSemin Oncol. 20 (5,. 20 (5,supplsuppl5): 75-5): 75-88, 199688, 1996

00 0 555 101010 151515 202020 252525 303030 Years Years

Overall Survival

(9)

More Intensive Treatment

Does Not Alter Survival in Follicular

Peterson BA, et al. J Clin Oncol 2003;21:5–15

1.0 0.8 0.6 0.4 0.2 0 Proportion disease-free 1.0 0.8 0.6 0.4 0.2 0 Proportion surviving Cyclophosphamide CHOP + bleomycin Cyclophosphamide CHOP + bleomycin DFS OS 0 2 4 6 8 10 12 14 16 18 Years from entry

0 2 4 6 8 10 12 14 16 18 Years from entry

(10)

MJR MJR

FND

vs Alternating Triple Therapy

(ATT) bei

(ATT)

bei

indolenten NHL

FND

FND (n=73)(n=73)(max(max88x)x) ATTATT((n=69) (max 12 x, 4 jeweils)n=69) (max 12 x, 4 jeweils)

Fludarabin

Fludarabin CHODCHOD--BB (Cyclophosphamid, Doxorubicin, Vincristin, Dexameth.,(Cyclophosphamid, Doxorubicin, Vincristin, Dexameth., Bleomycin)Bleomycin)

Mitoxantron

Mitoxantron ESHAPESHAP (Etoposid,(Etoposid, AraAra--C,C,CisplatinCisplatin, , Prednison)Prednison)

Dexamethasone

Dexamethasone NOPPNOPP (Mitoxantron,(Mitoxantron, Vincristin,Vincristin,Procarbazin,Procarbazin, Prednison)Prednison)

FND ATT

FND ATT FNDFND ATT ATT pp ORR

ORR (%)(%) 9797 9797 Neutropenie (%)Neutropenie (%) 8181 94 0.003 94 0.003 Deaths

Deaths 1313 12 12 ThrombocytopenieThrombocytopenie 1212 78 0.000178 0.0001 Überleben

Überleben i d e n t i c a l i d e n t i c a l Infektionen (%)Infektionen (%) 1212 27 0.022 27 0.022

Tsimberidou

(11)

Secondary Malignancies after ASCT in Follicular Lymphoma

Trial

Trial ReferenceReference ChemotherapyChemotherapy ASCTASCT

GLSG

GLSG Lenz et alLenz et al CHOP/IFN (n=236)CHOP/IFN (n=236) CHOP/TBI/Cyclo (n=195) CHOP/TBI/Cyclo (n=195) 2nd malign

2nd malign 0,0 %0,0 % n=5n=5(2 AL, 3 MDS), median follow up 44 months(2 AL, 3 MDS), median follow up 44 months occurred between 9 and 51 months

occurred between 9 and 51 months

estimated risk of

estimated risk of 3,8% at 5 years3,8% at 5 years

(only report of hematological malignancies)

GOELAMS

GOELAMS DeconinckDeconinck CHVP (n=80)CHVP (n=80) VCAP/TBI/Cyclo (n=86)VCAP/TBI/Cyclo (n=86)

2nd malign

2nd malign 0,0 %0,0 % n=10n=10, 7 were fatal, 3 in CR (3 AL, 3 MDS, 2 BC), 7 were fatal, 3 in CR (3 AL, 3 MDS, 2 BC) occurred between 12 and 45 months

occurred between 12 and 45 months

actuarial risk of

actuarial risk of 18.6% at 5 years18.6% at 5 years

Dana Faber

Dana Faber Brown et alBrown et al all standard chemo plusall standard chemo plusTBI/Cyclo (n=605), median follow up 9.5 yearsTBI/Cyclo (n=605), median follow up 9.5 years

42 solid tumors, 6 non

42 solid tumors, 6 non--MDS hem. Malignancies, 39 nonMDS hem. Malignancies, 39 non--melanoma skin cancers, 68 MDS/AMLmelanoma skin cancers, 68 MDS/AML 10

10--year incidence of secondary malignancies is 21% with 10% nonyear incidence of secondary malignancies is 21% with 10% non--MDS malignancies.MDS malignancies. Incidence of MDS/AML levels off at 14% at 5 years, incidence of

(12)

Follicular lymphoma

CHVP + IFN

209 CHOP + auHSCT

192

(13)

Sebban. Blood, 2006;108:2540

CHVP + IFN

209

(14)

Clinical

Clinical trialstrials comparingcomparing transplantationtransplantation (SCT) versus (SCT) versus conventionalconventional therapytherapy (CT)(CT)

Reference

Reference yearyear propro-- randrand.. multimulti ageage n / n / yrsyrs timetime versusversus PFSPFS Difference in Overall SurvivalDifference in Overall Survival spect

spect.. centercenter

Ladetto

Ladetto 20082008 yesyes yesyes yesyes 5151 136 (5)136 (5) 1st line1st line CHOP+RCHOP+R SCT > CTSCT > CT nono 80% at 4 80% at 4 yrsyrsforforbothboth Lenz

Lenz 20052005 yesyes yesyes yesyes 5959 375 (4)375 (4) 1st line1st line chemochemo SCT > CTSCT > CT n.r.n.r. shortshortobsobs. 2 . 2 yrsyrs Sebban

Sebban 20062006 yesyes yesyes yesyes 4949 401 (7)401 (7) 1st line1st line chemochemo 33 vs 40 mo33 vs 40 mo nono 76 vs 71% at 7 76 vs 71% at 7 yrsyrs Deconninck

Deconninck 20052005 yesyes yesyes yesyes 5151 172 (7)172 (7) 1st line1st line chemochemo SCT > CT**SCT > CT** nono 78 vs 84% at 5 78 vs 84% at 5 yrsyrs

Schouten

Schouten 20032003 yesyes yesyes yesyes 4747 89 (4)89 (4) 2nd line2nd line chemochemo SCT > CTSCT > CT nono SCT > CT, p = 0.079SCT > CT, p = 0.079

Freedman

Freedman 19991999 nono nono nono 4343 153 (10)153 (10) 3 prior3 priortxtx 42% at 8 yrs42% at 8 yrs** 66% at 8 66% at 8 yrsyrs Rohatiner

Rohatiner 20072007 nono nono no, 2no, 2 4343 121 (7)121 (7) 3 priot3 priottxtx 48% at 10 yrs48% at 10 yrs 54% at 10 54% at 10 yrsyrs Ingram

Ingram 20082008 nono nono no, 2no, 2 5656 82 (13)82 (13) 2 prior2 priortxtx 56% at 3 yrs56% at 3 yrs** 67% at 3 67% at 3 yrsyrs

*

(15)

MJR MJR

ASCT in follicular lymphomas

ASCT is an appropriate treatment choice for younger patients

with chemosensitive recurrent follicular lymphoma

ASCT remains investigational in the initial treatment of

follicular lymphoma

¾

No demonstrated overall survival benefit

¾

Possible improvement in overall survival by adding

Rituximab in treatment strategies

¾

Increase of 2nd malignancies

ASH, 2005

(16)

Does combined

immuno-chemotherapy with rituxan improve

overall survival in patients with

indolent non-hodgkin’s

lymphoma compared to

chemotherapy alone?

A Meta-Analysis

Holger Schulz, Nicole Skoetz, Julia F. Bohlius, Sven Trelle, Alexander Greb, Thilo Kober

and Andreas Engert

Cochrane Review

Cochrane Haematological Malignancies Group (CHMG) Internal Medicine I, University of Cologne. www.CHMG.de

(17)

Overall

survival

: Meta

-

Analysis Total Group

Study HR [95%-CI) Weight [%] HR [95%-CI)

Total events: 100/760 143/718

Test for heterogeneity: (P = 0.60), I² = 0%

Total (95% CI) 100.00 0.62 (0.49 - 0.77) Favors R + Chemo 0.2 0.5 1 2 Favors Chemo Baez 2005 6.90 0.96 0.42 Forstpointner 2005 15.10 Marcus 2005 16.10 0.70 Hiddemann 2005 28.86 0.60 Herold 2005 28.92 0.60 0.96 Lenz 2005 4.11

(18)

R

A

N

D

O

M

I

Z

E

D

CHOP every 21 days maximum 6 cycles Rituximab + CHOP every 21 days maximum 6 cycles

Intergroup phase III trial:

study design

R

A

N

D

O

M

I

Z

E

D

Observation Rituximab maintenance* *375mg/m

*375mg/m22 every 3 months every 3 months for

for 2 years or until relapse2 years or until relapse

CR PR

Van

(19)

(years) 0 1 2 3 4 5 0 10 20 30 40 50 60 70 80 90 100

O N Number of patients at risk : Treatment

110 167 90 42 17 5

66 167 126 86 47 12

O bservation M abthera

Progression free survival

from 2nd random ization

O verall Logrank test: p<0.0001

Rituximab maintenance median: 51.6months

Observation median: 15 months

Intergroup phase III trial

Progression free survival from 2nd randomization

(20)

MJR MJR

Abstr. ASH 2005 (Maint 1 x R, q 3 mo, up to 2 yrs Induction n=465, Maint n=334, med. foll. up 33 months

observation

maintenance

Rituximab

PFS* (months)

15.0

51.6

51.6 p < 0.0001

p < 0.0001

after CHOP

11.6

42

42 after CHOP

after CHOP

-

R

23.1

52

52 p = 0.004

p = 0.004

after CR

14.5

51.6

51.6 after PR

after PR

15.6

45.4

45.4 OS (3 years)

OS (3 years)

77.1%

85.1%

p = 0.011 **

* after 2nd randomization ** HR = 0.52 * after 2nd randomization ** HR = 0.52

EORTC 20981

(21)

MJR MJR

observation

maintenance

Rituximab

PFS* (months)

15.0

51.6

51.6 p < 0.0001

p < 0.0001

after CHOP

11.6

42

42 after CHOP

after CHOP

-

R

23.1

52

52 p = 0.004

p = 0.004

after CR

14.5

51.6

51.6 after PR

after PR

15.6

45.4

45.4 OS (3 years)

OS (3 years)

77.1%

85.1%

p = 0.011 **

EORTC 20981

(22)

MJR MJR

observation

maintenance

Rituximab

PFS* (montths)

15.0

51.6

51.6 p < 0.0001

p < 0.0001

after CHOP

11.6

42

42 after CHOP

after CHOP

-

R

23.1

52

52 p = 0.004

p = 0.004

after CR

14.5

51.6

51.6 after PR

after PR

15.6

45.4

45.4 OS (3 years)

OS (3 years)

77.1%

85.1%

p = 0.011 **

EORTC 20981

(23)

(years) 0 1 2 3 4 5 6 0 10 20 30 40 50 60 70 80 90 100

O N Number of patients at risk : Treatment

39 167 148 99 50 14 2

23 167 155 112 69 19 4

O bservation M abthera

O verall survival

from 2nd random ization

O verall Logrank test: p=0.011

Intergroup phase III trial

Overall survival from 2nd randomization

R-maintenance 3 yrs 85.1 %

observation 3 yrs 77.1 %

(24)

Randomized studies Rituximab maintenance

Study Group

Study Group TreatmentTreatment EntitiesEntities InductionInduction

SAKK

SAKK 1st line1st line FollicularFollicular RituximabRituximab Relapsed

Relapsed Mantle cellMantle cell ECOG

ECOG 1st line1st line FollicularFollicular CVPCVP Small lymphocytic

Small lymphocytic

Hainsworth

Hainsworth RelapsedRelapsed FollicularFollicular RituximabRituximab Refractory

Refractory Small lymphocyticSmall lymphocytic GLSG

GLSG RelapsedRelapsed FollicularFollicular RR--FCM vs FCMFCM vs FCM Refractory

Refractory Manle cellManle cell EORTC

EORTC RelapsedRelapsed FollicularFollicular RR--CHOP vs CHOPCHOP vs CHOP Refractory

(25)

Overall PFS for Treatment Groups

90 90_Y_Y_-_-_ibritumomab_ibritumomab Control 202 207 173 115 132 80 96 53 34 17 9 6 0 25 50 75 100 months 0 12 24 36 48 60 Cumulat ive Per centage 90

90_Y_Y_-_-_{ibritumomab arm}_{ibritumomab arm}

Median PFS: 53.8 months Median PFS: 53.8 months N = 207 N = 207 control arm control arm Median PFS: 13.8 months Median PFS: 13.8 months N = 202 N = 202 Log-rank P = .0001 HR 0.45 (95% CI: 0.35-0.59) The 4

The 4--year overall PFS is year overall PFS is 52% in the

(26)

Effect of Treatment Arm on PFS by First-line Treatment

and Response to First-line Treatment

Control 90_{Y-Ibritumomab} _{Hazard Ratio}

PFS No. of Patients No. Failed Median PFS, mo No. of

Patients No. Failed

Median PFS,

mo (95% CI)*

First

First--line treatment*line treatment*

CHOP 57 43 12.4 65 33 36.5 2.39 (1.52-3.78) CVP/COP 53 40 7.9 53 30 29.6 2.25 (1.40-3.63) CHOP-like 31 19 29.1 30 11 > 67 2.11 (1.00-4.44) Fludarabine 11 6 28.7 11 6 41.4 1.11 (0.36-3.46) Chlorambucil 19 15 11.9 20 10 37.2 2.76 (1.23-6.21) Rituximab combination 31 13 > 44 28 9 > 45 1.39 (0.60-3.26)

*Note: FIT was not powered to detect significant differences in outcomes according to individual types of induction therapy.

(27)

Overall Survival

All patients

19 deaths

Control

8 deaths

90

_{Y-ibritumomab}

11 deaths

• At current follow-up no significant difference in overall survival was observed between treatment arms (P = .593)

• No significant difference in incidence of secondary malignancies

– 6 secondary malignancies in 90_{Y-ibritumomab arm vs 5 in control arm}

(28)

Secondary Malignancies That Have

Emerged During Extended Follow-up

Control Arm

• Mammary carcinoma

• Basocellular epithelioma

• Endometrial carcinoma

• Papillary carcinoma of thyroid

• Basocellular carcinoma of the skin

90_{Y-Ibritumomab}_Arm

• AML after MDS*

• AML**

• Lung cancer (now in remission)

• Pancreas carcinoma

• Basal cell carcinoma skin

• Basocellular carcinoma of the skin

* Patient achieved a CR after 6 cycles of FC from Sept 2003 until Feb 2004.

He received 90_{Y-ibritumomab in 04/2004. Pat progressed in 09/2004, and received radiotherapy in 12/2004}

AML was recorded in Aug 2007

**Patient received 8 cycles of CHOP as the induction regimen

(29)

Subsequent Management After PD

Treatment After PD Control (n = 137) 90_{Y-Ibritumomab} (n = 103) Chemotherapy

(incl. involved-field radiotherapy), n (%) 9 (7) 6 (6)

Radiotherapy, n (%) 0 6 (6)

Total patients receiving 90_{Y-ibritumomab, n (%)} _{11 (8)} _{1 (1)}

Rituximab monotherapy, n (%) 22 (16) 15 (15)

Rituximab-containing chemotherapy combination, n

(%) 47 (34) 26 (25)

Allogeneic transplantation,* n (%) 2 (1) 1

Autologous transplantation,* n (%) 27 (20) 10 (9)

Total patients receiving rituximab, n (%) 93 (68) 50 (49)

No treatment given 30 (22) 39 (38)

(30)

Patients in Control and

90

_{Y-Ibritumomab Arms Achieved}

Comparable Responses to

Second-Line Therapy

Responders Response to Second-Line Therapy After

Progressive Disease, % Control (n = 108) 90_{Y-Ibritumomab} (n = 63) CR 42% 49% CRu 14% 8% PR 18% 24% No response 27% 19%

(31)

MJR MJR

¾

¾ There is still a role for watch & wait in asymptomatic patientsThere is still a role for watch & wait in asymptomatic patients

¾

¾ Combined ImmunoCombined Immuno--ChemotherapyChemotherapy is the standard of is the standard of carecare

¾

¾ RR--chemotherapychemotherapy plus plus RR--maintenancemaintenance appears as appears as the optimal strategy

the optimal strategy for patients for patients with relapsed diseasewith relapsed disease

¾

¾ Which chemotherapy in combination with Rituximab?Which chemotherapy in combination with Rituximab?

Æ

Æ ChlorambucilChlorambucil--based (MCP), Fbased (MCP), F--based (FCM), CHOPbased (FCM), CHOP--like, CVPlike, CVP

Æ

Æ Role of bendamustine in this setting is under investigationRole of bendamustine in this setting is under investigation

¾

¾ RR--maintenance after 1stmaintenance after 1st--line Rline R--containing regimens? containing regimens?

Æ

Æ PRIMA study addresses this question, first results at ASH 2010PRIMA study addresses this question, first results at ASH 2010

Æ

Æ StiL NHL 7StiL NHL 7--2008 study proves duration of maintenance2008 study proves duration of maintenance

Æ

Æ SAKK study proves duration of maintenance after R SAKK study proves duration of maintenance after R

Standard of care in pts with indolent lymphomas

(32)

Bendamustine plus Rituximab versus CHOP plus Rituximab in the Fi

Bendamustine plus Rituximab versus CHOP plus Rituximab in the Firstrst--Line Line Treatment of Patients with Indolent and Mantle Cell Lymphoma

Treatment of Patients with Indolent and Mantle Cell Lymphoma –– First Results of a Randomized Phase III Study of the

First Results of a Randomized Phase III Study of the

StiL (Study Group indolent Lymphomas, Germany)

Mathias J. Rummel, U. von Grünhagen, N. Niederle, F. Rothmann, H

Mathias J. Rummel, U. von Grünhagen, N. Niederle, F. Rothmann, H. Ballo, E. . Ballo, E. Weidmann, M. Welslau, G. Heil, H. Dürk, M. Stauch, C. Losem, A.

Weidmann, M. Welslau, G. Heil, H. Dürk, M. Stauch, C. Losem, A. Matzdorff, Matzdorff, C. Balser, K. Schalk, D. Kofahl

C. Balser, K. Schalk, D. Kofahl-Krause, U. Kaiser, W. Knauf, A. Banat, D. -Krause, U. Kaiser, W. Knauf, A. Banat, D. Hoelzer, W. Brugger on the behalf of the StiL

Hoelzer, W. Brugger on the behalf of the StiL

Giessen, Cottbus, Leverkusen, Potsdam, Offenbach, Frankfurt, Asc

Giessen, Cottbus, Leverkusen, Potsdam, Offenbach, Frankfurt, Aschaffenburg, haffenburg, Lüdenscheid, Hamm, Kronach, Neuss, Saarbrücken, Marburg, Limburg

Lüdenscheid, Hamm, Kronach, Neuss, Saarbrücken, Marburg, Limburg, , Hannover, Hildesheim, Villingen

Hannover, Hildesheim, Villingen--Schwenningen.Schwenningen. Germany

(33)

MJR MJR

CHOP plus Rituximab (CHOP CHOP plus Rituximab (CHOP--R)R) Randomization

Randomization

Bendamustine

Bendamustine plus Rituximab (Bplus Rituximab (B-R)-R)

B = Bendamustine 90 mg/qm day 1+2 29+30 57+58 85+86 113+114 141+142 R = Rituximab 375 mg/qm day 0 29 57 85 113 141 0 1 29 57 85 113 141 R B B-R B-R B-R Tag B-R B-R 0 1 22 43 64 85 106 R

CHOP CHOP-R CHOP-R CHOP-R

Tag

CHOP-R CHOP-R

CHOP day 1 22 43 64 85 106 Rituximab 375 mg/qm day 0 22 43 64 85 106

(34)

MJR MJR 30

30thth _Nov_Nov₂₀₀₈₂₀₀₈ B-_B-R CHOPR CHOP--R R 462

462evaluableevaluableptspts.. (n=235)(n=235) (n=227)(n=227)

Age (median)

Age (median) 64 64 yrsyrs 64 64 yrsyrs Age > 70

Age > 70 yrsyrs.. 23 %23 % 2424%% Age > 60

Age > 60 yrsyrs.. 6363%% 6363%% Stage Stage IVIV 7979%% 7676%% B B--Symptoms Symptoms 4040%% 2828%% IPI > 2 IPI > 2 (n=162)(n=162) 37 %37 % 3838%% FLIPI FLIPI 00--1 1 1010%% 2020%% FLIPI FLIPI 2 2 4545%% 3333% % FLIPI FLIPI >>33 4646%% 4747%% LDH > 240 U/l LDH > 240 U/l 3838%% 3232%% Bone

Bone marrowmarrow 6969%% 6767%%

Bulky disease

Bulky disease 2828%% 2626%%

Patients

(35)

MJR MJR

462

462 patientspatients evaluable, interim (not final analysis)evaluable, interim (not final analysis)

B B--RR CHOPCHOP--RR (n=235) (n=235) (n=227)(n=227) Alopecia Alopecia 0 %0 % 9191 %% Leucocytopenia Leucocytopenia 3/43/4 1414 %% 3838 %% G G--CSF used CSF used 5 %5 % 21 %21 % Inf.

Inf. complicationscomplications 3131 %% 41 %41 % PNP (any grade)

PNP (any grade) 4 %4 % 9 %9 %

Toxicity

(36)

MJR MJR

454

454 patientspatients evaluableevaluable forfor response,response, median median observationobservation periodperiod 2727 monthsmonths

B B--RR CHOPCHOP--RR (n=232) (n=232) (n=224)(n=224) ORR ORR 94 %94 % 93 %93 % CR CR 41 %41 % 32 %32 % SD SD 3 %3 % 4 %4 % Prim.

Prim. refrrefr.. 3 %3 % 3 %3 %

PD /

PD / relapserelapse n = 63n = 63 n = 89n = 89 Deaths

Deaths n = 26n = 26 n = 27n = 27

Results

(37)

Bendamustine

-

R

vs CHOP

-

R

Conclusion

¾

¾ In In thisthis analysisanalysis consistingconsisting of 462 of 462 randomizedrandomized patientspatients Bendamustine plus Rituximab

Bendamustine plus Rituximab isis notnot inferior to inferior to CHOPCHOP--RR in

in regardregard to to efficacyefficacy and and isis againagain associated associated withwith lessless toxicitytoxicity

¾

¾ TheThe final final resultsresults withwith a a longerlonger observationobservation up to 36 up to 36 monthsmonths and and with

with fullfull analysisanalysis of all of all randomizedrandomized patientspatients (n=549) will (n=549) will furtherfurther define

define thethe rolerole of Bendamustine plus Rituximab in of Bendamustine plus Rituximab in thethe treatment treatment algorithm

(38)

Bendamustine

-

Rituximab

+ 2

years

Rituximab

q 2

months

Bendamustine

-

Rituximab

+ 4

years

Rituximab

q 2

months

Follicular Lymphoma

Randomized

Phase III

Study of the StiL

R

(39)

B-R + Watch & Wait vs B-R + 2 years Rituximab

Bendamustine

-

Rituximab

+ Watch & Wait

Bendamustine

-

Rituximab

+

2

2 years

years

Rituximab

q 2

months

Immunocytoma Immunocytoma Marginalzone Marginalzone Mantle cell Mantle cell (

(forfor mantlemantlecell not cell not eligibleeligibleforfor APBSCT)APBSCT)

Randomized

Phase

II

Studies of the StiL

R

(40)

¾

¾ Which chemotherapy in combination with Rituximab?Which chemotherapy in combination with Rituximab?

-- ChlorambucilChlorambucil--based (MCP), Fbased (MCP), F--based (FCM), CHOPbased (FCM), CHOP--like, CVPlike, CVP

-- Role of bendamustine in this setting is under investigationRole of bendamustine in this setting is under investigation

¾

¾ The analysis with 462 randomized patients shows that BThe analysis with 462 randomized patients shows that B--R is not inferior R is not inferior to CHOP

to CHOP--R in regard to efficacy while being associated with less toxicitR in regard to efficacy while being associated with less toxicityy

¾

¾ The final results (longer observation) will further define the r_{The final results (longer observation) will further define the r}ole of Bole of B--R in R in the treatment algorithm of patients with indolent and mantle cel

the treatment algorithm of patients with indolent and mantle cell lymphomal lymphoma

¾

¾ Does BDoes B--R have the potential to change standard approaches in NHL?R have the potential to change standard approaches in NHL?

¾

¾ RR--maintenance after 1stmaintenance after 1st--line Rline R--containing regimens? containing regimens?

Æ

Æ PRIMA study addresses this question, first results at ASH 2010PRIMA study addresses this question, first results at ASH 2010

Æ

Æ NHL 7NHL 7--2008 StiL study: duration of maintenance after B2008 StiL study: duration of maintenance after B--R R

Æ

Æ SAKK study: duration of maintenance after RSAKK study: duration of maintenance after R--monotherapy monotherapy