traitement de première ligne du lymphome...

Traitement de première ligne du

lymphome folliculaire

F Morschhauser

DES, 17 novembre ,2017

Centre Hospitalier Universitaire de Lille, France

What do I say to a newly diagnosed FL patient ?

Until the end of the 20th century:

FL was considered as incurable

Until the end of the 90’s, FL natural history was thought not

to be influenced by any therapeutic strategy 1, 2, 3

1. Horning SJ. Semin Oncol 1993; 20 (Suppl. 5):75–88.2. Swenson WT et al., J Clin Oncol 2005; 23:5019-5026.

3. Lister TA, J Clin Oncol, 2005; 25:4830-31.

Pro

babili

ty (

%)

Years

1960–1976 (195)

1976–1987 (513)

1987–1992 (314)80

60

40

0

0 5 10 15 20 25

20

100

30

Pro

babili

ty (

%)

Months following diagnosis

1993–1999 (5,601)

1986–1999 (4,714)

1978–1985 (4,249)80

60

40

0

0 50 100 150 200 250

20

100

300

Log-rank

P=.006

Log-rank

P=.047

After 2000,

a new hope for FL patients

• Improved overall survival with anti-CD20 antibodies:

─ Multiple randomized trials and series1, plus 1 meta-analysis2

─ Epidemiological surveys: substantial OS improvement3

1. Fisher RI et al, J Clin Oncol 2005;23:8447–52

2. Schulz H et al., Cochrane Database of Systematic Reviews 2007; 4:CD003805.

3. Pulte D et al; Arch Intern Med. 2008;168:469-476.

Observation period

5-year

survival

Probability

(SD)

10-year

Survival

Probability

(SD)

1992-1994 70.7 (1.3) 52.2 (1.6)

2002-2004 84.9 (0.9) 71.5 (1.4)

CHOP + antibody

ProMACE

CHOP

0 2 4 6 8 10

p <0.0001

0

20

40

60

80

100

Overa

ll s

urv

iva

l %

Years

Survival of FL patients in the rituximab era

French 10 year OS: 79.8%

USA 10 year OS: 76.6%Lymphoma: 10 year

estimate: 10.4%

Cause of death

Sarkozy et al, ICML 2017, Abstr 016

OS

N = 1655

Follicular Lymphomaa very heterogeneous lymphoma

• Patients focussed on “I have Stage IV”

Dr Google

• Physician focussed on:– multiple FLIPI & FLIPI2 prognostic factors:

B2M, LDH, Stage, Hb, LODLIN, age, # nodal sites– Treatment criteria (GELF / BNLI) – patient age and comorbidities …– Emerging combined prognostic index ( m7 FLIPI, POD24 PI, PET MTV) which affect timing, choice and outcome of therapy.

When are we going to start

a cytotoxic treatment ?

GELA criteria BNLI criteria

✓ Rapid disease progression in

the preceding 3 months

✓ Life threatening organ

involvement

✓ Renal or liver infiltration

✓ Bone lesions

✓ Systemic symptoms or pruritus

✓ Hb<10 g/dL or WBC< 3.0×109/L

or Plat.<100×109/L ; related to

marrow involvement

✓ High tumor bulk defined by either:

- a tumor > 7 cm

- 3 nodes in 3 distinct areas

each > 3 cm

- symptomatic splenic enlargement

- organ compression

- ascites or pleural effusion

✓ Presence of systemic symptoms

✓ Serum LDH or β2-microglobulin

above normal values

GELF Criteria

GELF86 GELF 94 FL2000 PRIMA

B symptoms + + + +

PS > 1 + +

LDH > N + + +

β2-micro > N > 3 mg/L > 3 mg/L > N

Compression, effusion,

spleen + + + +

Cytopenia +

Tumor diameter > 7 cm + + + +

3+ lymph nodes > 3 cm + + +

Tumor

BurdenLow

High

P=0.003

0.0

0.2

0.4

0.6

0.8

1.0

Years0 4 8 12

GELF Criteria

Follicular Lymphoma TreatmentFirst line 2017

Stagingevaluation

LocalizedW&W

radiotherapy

Advancedindolent

W&W

Rituximab

Advanced

withsymptoms

R-chemo

G-chemo

no-chemo?

PFS of rigorously staged patients with stage I

follicular lymphoma by treatment modality

. Compared with patients treated with radiation therapy, patients treated with rituximab-

containing chemotherapy (R-chemotherapy) or systemic therapy and radiation therapy had

significantly better PFS. Friedberg et al J Clin Oncol. 2012 Sep 20; 30(27): 3368–3375

Modern Standard of Care of

Follicular lymphoma

Low tumor burden or

Advanced indolent or

No need for therapy

Rituximab monotherapy: M39006

Colombat P et al, Ann Oncol 2012; 23: 2380-2385

Control arm alongside W&W?

Compulsory

CT scan

Compulsory

CT scanCT scan

only if

clinical CR

Bone marrow for histology and MRD only if CT shows cCR

R

A

N

D

O

M

I

S

A

T

I

O

N

ARM A

Watch and Wait

ARM B

Rituximab Induction

ARM C

Rituximab Induction

& maintenance

Continued

follow up

Progressive disease

requiring therapy

stops protocol

treatment

Clinic visits

RWW Study(Ardeshna et al)

cc

RWW (NCRI)

W&W versus RTX in asymptomatic FL

Ardeshna KM, et al. Lancet Oncol. 2014;15:424-435.

100

75

50

25

00 1 2 3 4 5 6 7

HR: 0.21 (95% CI: 0.14-0.31;

log-rank P < .0001)

Pts at Risk, n

Watch and wait

Maintenance

rituximab

187

192

139

184

111

176

66

146

33

59

6

10

1

1

0

0

Time to Start of New Treatment

No

Ne

w T

rea

tmen

t (%

)

100

75

50

25

00 1 2 3 4 5 6 7

Pts at Risk, n

Watch and wait

Maintenance

rituximab

187

192

181

189

175

186

130

163

68

72

18

16

4

3

0

0

OS

Yrs From Randomization

100

75

50

25

00 1 2 3 4 5 6 7

187

192

121

183

92

165

54

138

28

56

6

9

1

1

0

0

PFS

PF

S (

%)

HR: 0.23 (95% CI: 0.16-0.32;

log-rank P < .0001)

HR: 0.62 (95% CI: 0.31-1.26;

log-rank P = .19)

100

75

50

25

00 1 2 3 4 5 6 7

187

192

177

187

168

182

121

158

64

69

15

15

4

3

0

0

Time to Histological Transformation

No

His

tolo

gic

al

Tra

ns

form

ati

on

(%

)HR: 0.73 (95% CI: 0.34-1.54;

log-rank P = .40)

OS

(%

)

Yrs From Randomization

16

E4402 (RESORT) Schema

Rituximabre-treatment atprogression*375 mg/m2 qw 4

R

A

N

D

O

M

I

Z

E

Rituximab375 mg/m2 qw

4

CR or PR

Rituximab

Maintenance*375 mg/m2

q 3 months

*Continue until treatment failure

No response to retreatment or PD within 6 months of R

Initiation of cytotoxic therapy or Inability to complete rx

RESORT trial

Primary Endpoint: Time to Treatment Failure

Treatment failure: no response to retreatment or PD within 6 months of R,

Initiation of an alternative therapy or Inability to complete planned therapy

Kahl BS, et al. J Clin Oncol. 2014;32:3096-3102.

RESORT Conclusions

• Both strategies appear to delay time to chemotherapy compared to historical controls

• How to interpret?

– Given the excellent outcomes with RR

▪ 86% chemotherapy free at 3 years

– Given the lack of QOL difference

– Given fewer AE failures

– Given fewer R doses required with RR

• Rituximab retreatment is our recommended strategy if opting for Rituximab monotherapy in LTB FL


Cytotoxic CD8+ T cellEffector CD4+ T cell

TCR

MHC class IMHC class II

Dendritic cell

Tumor peptide

Cross-presentation.

SC route improves exposure and may improve

anti-lymphoma imunity

Cartron G et al, Blood 2004; 104: 2634-2642

FcgRIIIa

FcgRIIa

CD11b

FLIRT Trial

Rituximab iv 375 mg/m2

Rituximab sc 1400 mg

J1 J8 J15 J21

J1 J8 J15 J21

M3 M5 M7 M9

Control arm

Experimental arm

E

E

E

E

E Evaluation

R

Endpoint: PFSHypothesis: Control arm: median 23.5 m vs median 45 month in experimental arm: Number of patients: 210First patient: Q1-Q2 2014

• Ancillary studies

– FCGRT and FcRn

– Rituximab PK and variability

– Immunity against FL Ag

– Prognostic value of t(14;18)

Ancillary studies

Low tumor burden FL

Conclusions

• W&W +++

• Rituximab: 4 to 8 or retreatment

• Radiotherapy? Still given in stage 1 in many countries

• Recommendation: No RT alone: Low dose+Rituximab?


Modern Standard of Care of

Follicular lymphoma

High tumor burden

Or Need for therapy

What are the relevant questions?

What is the best induction regimen?

What is the best treatment schedule following induction?

What is the best anti-CD20?

─ Does the choice of the anti-CD20 impact the choice of induction chemotherapy?

Is chemo-free an option?

FOLL05 Study

R-CVP vs R-CHOP vs R-FC

0.00

0.25

0.50

0.75

1.00

Prob

ab

ility

0 1 2 3 4 5 6 7 8 9

Years

R-CVP R-CHOP R-FM

ITT HR *(95CI) P

R-CHOP 0.73 (0.55-0.98) 0.033

R-FM 0.70 (0.52-0.93) 0.016

TTF

0.00

0.25

0.50

0.75

1.00

Prob

ab

ility

0 1 2 3 4 5 6 7 8 9

Years

R-CVP R-CHOP R-FM

OS

N = 500, median FU 7 years

Luminari et al, ICML 2017, abstr 15

FOLL05 Conclusions

❖ R-CHOP and R-FM are both superior to R-CVP in termsof TTF (Primary endpoint of the study)

❖ R-CHOP and R-FM have similar anti-lymphoma activity

❖ R-CHOP and R-CVP are less toxic than R-FM

❖ R-CHOP is associated with the best efficacy/toxicityratio

FL: StiL vs BRIGHT study (PFS)

Rummel MJ, et al. Lancet 2013.

0 12 24 36 48 60 72 84 96Time (months)

Hawkins et al. ICML 2017; abstract 131.

At Risk

1. 187 182 176 170 165 163 160 156 151 139 134 129 122 116 110 34 0

2. 186 175 172 168 165 162 159 149 135 126 118 107 101 97 92 11 0

0 2 4 6 8 10 12 18 24 30 36 42 48 54 60 66 72

iNHL†1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1 = BR

2 = R-CHOP/R-CVP

Surv

ival

Dis

trib

uti

on

Fu

nct

ion

▪ 5-yr rate % (95% CI): 70.3 (62.8, 76.5) vs 62.0 (54.1, 68.9)▪ HR = 0.70 (0.49-1.01; P = 0.0582)

BR

R-CHOP-CVP

Benda versus CHOP

Stil-NHL1 2003PRIMA:PFS -R-CHOP arm

Median for R-CHOP+ observation : 54,7 moMedian for R-CHOP+ observation : 40.9 mo

MJR

Bendamustine plus Rituximab versus CHOP plus Rituximab

as First-Line Treatment in Patients with

Indolent Lymphomas:

10-year updated results from the StiL NHL1-2003 study

on behalf of the StiL (Study Group indolent Lymphomas, Germany)

Mathias Rummel, Georg Maschmeyer, Arnold Ganser,

Andrea Heider, Ulrich v. Grünhagen, Christoph Losem,

Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich

Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald

Ballo, Martina Stauch, Wolfgang Blau, Alexander

Burchardt, Jürgen Barth, Frank Kauff, Axel Hinke,

and Wolfram Brugger on behalf of the StiL

MJR

Time to next treatment (117 months follow-up)

0

0,25

0,5

0,75

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Time (months)

Pro

bab

ility

Hazard ratio, 0.55 (95% CI 0.41 - 0.73)

p < 0.0001

months salvage

(median) (events)

B-R n. y. r. 77

CHOP-R 56.0 109

MJR

Overall survival according to entities

0

0,25

0,5

0,75

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Follicular

0

0,25

0,5

0,75

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Waldenstroem

0

0,25

0,5

0,75

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Small lymphocytic

0

0,25

0,5

0,75

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Marginal zone

B-R

CHOP-R

B-R

CHOP-R

B-R

CHOP-R

B-R

CHOP-R

MJR

Overall survival: LDH elevated ( > 240 U/l )

0

0,25

0,5

0,75

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Time (months)

Pro

bab

ility

Hazard ratio, 1.01 (95% CI 0.63 - 1.63)

p = 0.9576

median deaths

B-R 130 mo 37 (44%)

CHOP-R 127 mo 31 (46%)

MJR

OS: follicular, FLIPI high (3-5) (n=127)

0

0,25

0,5

0,75

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Time (months)

Pro

bab

ility

Hazard ratio, 1.04 (95% CI 0.61 - 1.79)

p = 0.8747

10 yrs deaths

B-R 56.3% 26 (41%)

CHOP-R 59.3% 27 (42%)

B-R vs CHOP-R - secondary malignancies (2nd-NPL)

B-R (n=215) CHOP-R (n=205)

Pat. with 2nd-NPL * 37 40

2nd-NPL 39 47

- Prostate 3 7

- Colon/gastric 6 6

- Bronchial 2 5

- Kidney / urothel 4 5

- Pancreatic - 1

- Breast 4 4

- Other carcinoma 18 16

- MDS 2 2

- AML - 1

* Patients may have reported

more than 1 new malignancy

Conclusion: B-R vs CHOP-R

➢ Prolonged TTNT for B-R

➢ No difference in Overall Survival

➢ Fewer salvage treatments needed after initial B-R

➢ No increased rate of 2nd NPL after B-R compared to CHOP-R

➢ Achieving a CR resulted in a longer overall survival

➢ Hint for a longer OS for B-R in the subgroup with initial low LDH

➢ OS rate at 10 years is 70% with 6 x B-R (without R-maintenance)

Symptomatic, high burden FL

Top 5 Regimens for FL From 2012 to 2014

*1396 pts with FL met the inclusion/exclusion criteria and started LOT1 regimens between 6/2012-

6/2014.

Market Connect: McKesson Specialty Health. 2014.

Bendamustine + rituximab

(n = 489, 35.0%)

Rituximab (n = 431, 30.9%)

R-CHOP (n = 266, 19.1%)

R-CVP (n = 153, 11.0%)

Other (n = 57, 4.1%)

Follicular Lymphoma LOT1 Top 5 Regimens

35%

31%

19%

11%

4%

Treatment options following R-Chemo

induction

6 – 8 x

R-ChemoMaintenance with

rituximab ?PRIMA study

Consolidate with

ASCT ?

Consolidate with

RIT ?FIT, SWOG study

FIT Study Schema

First-line therapy with

chlorambucil, CVP,CHOP,

CHOP-like, fludarabine

combination, or rituximab

combination

INDUCTION

90Y-ibritumomab

(n = 207)Rituximab 250 mg/m2 IV

on day −7 and day 0 +90Y-ibritumomab

14.8 MBq/kg

(0.4 mCi/kg) on day 0

CONSOLIDATION

NRPD

CR/CRu or PR

NOT ELIGIBLE

R

A

N

D

O

M

I

Z

A

T

I

O

N

No further

treatment

(n = 202)

CONTROL

Start of study

CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CVP = cyclophosphamide,

vincristine, prednisone; NR = no response; PD = progressive disease.

Morschhauser et al. J Clin Oncol. 2008;26:5156-5164.

6-12 weeks after

last dose of induction

Patients with previously

untreated follicular lymphoma

Overall PFS for Treatment Groups

90Y-ibritumomab

N FControl 202 15190Y-ibritumomab 207 119

At risk:

202

207

81

132

62

98

48

89

16

24

0

25

50

75

100

Years

0 2 4 6 8

Control

Cu

mu

lati

ve

pe

rce

nta

ge

Hazard ratio, 0.44

95% CI, 0.35-0.57

P < 0.001

90Y-Ibritumomab n = 207

Median PFS = 4.1 y

8-y PFS = 41%

Control n = 202

Median PFS = 1.1 y

8-y PFS = 22%

HR = 0.47

(95% CI: 0.36 – 0.61)

P < 0.001

0

25

50

75

100

0 2 4 6 8

Control n = 202

Median TTNT = 3.0 y

Years

90Y-Ibritumomab n = 207

Median TTNT = 8.1 y

N FControl 202 12890Y-ibritumomab 207 93

Cu

mu

lati

ve

pe

rce

nta

ge

At risk:

202

207

117

165

78

120

57

106

20

30

Control90Y-ibritumomab

Time to Next Treatment (TTNT)

Incidence of Secondary Malignancies

• Median time from study registration to incidence of secondary

AML/MDS was 4.6 y for Control vs 4.8 y for 90Y-Ibritumomab

• No additional late toxicities or congenital malformations were detected

Secondary Malignancies,

n (%)

Control

(n=202)

90Y-Ibritumomab

(n=207)

Total

(N=409)

Overall total (P = 0.086) 14 (7) 26 (13) 40 (10)

AML/MDS 1* (0.5) 7 (3) 8 (2)

Pancreas − 3 (1) 3 (1)

Prostate − 3 (1) 3 (1)

Other 13 (6) 13 (6) 26 (6)

*Patient received 90Y-Ibritumomab during follow-up, followed by secondary AML/MDS 2.9 years later.

SWOG study

Progression Free Survival

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10

Years from Registration

CHOP -RIT

CHOP-R

At Risk

265

267

Relapse

or Death

86

106

2-Year

Estimate

80%

76%

2-sided, multivariate p = .11

S0016

CHOP-RIT

CHOP-RMedian FU 4.9 yr

High tumor burden FL

PRIMA 6 years follow-upProgression free survival from randomization

Median follow-up since randomisation : 73 months

6 years = 42.7%

6 years = 59.2%

HR= 0.57

P<0001

PRIMA 6 years follow-upOverall survival

Median follow-up since randomisation : 73 months

6 years = 87.4%

6 years = 88.7%

HR= 1.027

P=.885

PDs/SDs

off study

Rituximab Maintenance

1 dose every 8 weeks

for 24 months

90Y-Ibritumomab

tiuxetan

1 dose

R* CR/PRR-CHOP

x 6

Untreated

FL

stages II–IV

Registration

ZAR study: Design

Induction Consolidation / Maintenance

ClinicalTrials.gov: NCT00662948

Follow-up

5 years

*Stratification by response (CR / PR)

Primary endpoint: Progression-free survival (PFS)

Rituximab

(N=62; failed 14)

90Y Ibritumomab Tiuxetan

(N=64; failed 25)

77%

63%

HR=0.517(95%CI: 0.269-0.996)

P=0.044

Time to next treatment (TTNT) by arm

P=NS


Rituximab

Overall survival (OS)

Causes of death: progression (6), GVHD (1)


Rituximab

Gallium: challenging rituximab in

indolent lymphomas

ASH 2016 – Marcus R, abstract 6

Bendamustine : 827, CHOP : 433, CVP : 141

52

INV-assessed PFS (FL; primary endpoint)

0.8

0.6

0.4

0.2

0

1.0

Pro

ba

bili

ty

R-chemo (N=601)

G-chemo (N=601)

+

Time (months)

12 18 24 30 36 42 48 5460

No. of patients at risk

R-chemo

G-chemo

505

536

463

502

378

405

266

278

160

168

68

75

10

13

562

570

601

601

0

0

R-chemo,

n=601

G-chemo,

n=601

Pts with event,

n (%)

144

(24.0)

101

(16.8)

3-yr PFS,

% (95% CI)

73.3

(68.8, 77.2)

80.0

(75.9, 83.6)

HR (95% CI),

p-value*

0.66 (0.51, 0.85),

p=0.0012

Median follow-up: 34.5 months

Censored

*Stratified analysis; stratification factors: chemotherapy regimen, FLIPI risk group, geographic region

53

Pts at risk, n

R-chemo

G-chemo

OS (FL)

R-chemo,

n=601

G-chemo,

n=601

Pts with event,

n (%)

46

(7.7)

35

(5.8)

3-yr OS,

% (95% CI)

92.1

(89.5, 94.1)

94.0

(91.6, 95.7)

HR (95% CI),

p-value*

0.75 (0.49, 1.17),

p=0.21

588

584

566

573

527

549

399

416

265

271

160

161

58

55

2549

563

12 18 24 30 36 42 48 546 60

0.8

0.6

0.4

0.2

0

1.0

Pro

ba

bili

ty

0

R-chemo (N=601)

G-chemo (N=601)

Censored+

601

601

Time (months)

*Stratified analysis; stratification factors: chemotherapy regimen, FLIPI risk group, geographic region

Median follow-up: 34.5 months

54

INV-assessed PFS by chemo regimen (FL)

Post-hoc analysis: study not powered to detect differences between chemotherapy

regimens in either treatment arm


G-B

G-CHOP

G-CVP

345

196

60

322

188

60

304

176

56

285

165

52

239

124

42

180

70

28

113

41

14

56

12

7

9

3

1

G-B (N=345)

G-CHOP (N=196)

G-CVP (N=60)

Time (months)

0.8

0.6

0.4

0.2

0

1.0

Pro

ba

bili

ty

12 18 24 30 36 42 48 5460


R-B

R-CHOP

R-CVP

341

203

57

319

194

49

283

181

41

260

164

39

217

128

33

164

77

25

108

42

10

49

14

5

G-chemo arm

9

1

R-B (N=341)

R-CHOP (N=203)

R-CVP (N=57)

Time (months)

0.8

0.6

0.4

0.2

0

1.0P

rob

ab

ility

12 18 24 30 36 42 48 5460

R-chemo arm HR*

(95% CI)

G-B vs R-B0.61

(0.43, 0.86)

G-CHOP vs R-CHOP0.77

(0.50,1.20)

G-CVP vs R-CVP0.63

(0.32, 1.21)

*Unstratified analysis

Gallium: MRD and PFS

25% relapse

ASH 2016 – Marcus R, abstract 6, and Pott C, abstract 613

PFS according to MRD at the end of induction

56

Safety summary (FL)

% (n)

R-chemo

(n=597)

G-chemo

(n=595)

Any AE 98.3% (587) 99.5% (592)

Grade ≥3 AEs (≥5% in either arm) 67.8% (405) 74.6% (444)

Neutropenia 37.9% (226) 43.9% (261)

Leucopenia 8.4% (50) 8.6% (51)

Febrile neutropenia 4.9% (29) 6.9% (41)

IRRs* 3.7% (22) 6.7% (40)

Thrombocytopenia 2.7% (16) 6.1% (36)

Grade ≥3 AEs of special interest by category (selected)

Infections† 15.6% (93) 20.0% (119)

IRRs‡ 6.7% (40) 12.4% (74)

Second neoplasms§ 2.7% (16) 4.7% (28)

SAEs 39.9% (238) 46.1% (274)

AEs causing treatment discontinuation 14.2% (85) 16.3% (97)

Grade 5 (fatal) AEs 3.4% (20) 4.0% (24)**

Median (range) change from baseline in IgG levels at end of induction, g/l¶ -1.46 (-16.4–9.1)†† -1.50 (-22.3–6.5) ‡‡

*As MedDRA preferred term; †All events in MedDRA System Organ Class ‘Infections and Infestations’; ‡Any AE occurring during or within 24h of infusion of G or R and considered

drug-related; §Standardized MedDRA query for malignant or unspecified tumors starting 6 mo after treatment start; ¶Ig levels were measured during screening, at EOI and end of

maintenance and during follow-up; **Includes patient who died after clinical cut-off date from AE starting before cut-off date; ††n=472; ‡‡n=462

57

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400

Induction Maintenance Follow-up

Grade 5 (fatal) AEs by treatment (FL)*

*Includes only pts who died before clinical cut-off date; †this patient (G-B group) was initially assigned three causes of death (Clostridium difficile colitis, prostate cancer, and myelodysplastic syndrome);

Clostridium difficile colitis was the most acute, so the patient has been assigned to the ‘Infections and infestations’ category and the number of fatal AEs in G-B pts in neoplasms SOC reduced from 5 to 3

1500

†

Number of days from Cycle 1, Day 1

Total Infections

G-B

N=33719 (5.6%) 9 (2.7%)

R-B

N=33815 (4.4%) 2 (0.6%)

G-CHOP

N=1913 (1.6%) 1 (0.5%)

R-CHOP

N=2014 (2.0%)

G-CVP

N=611 (1.6%)

R-CVP

N=561 (1.8%)

Infections and infestations General disorders and

administration site conditions

Cardiac disorders Gastrointestinal disorders

Neoplasms benign,

malignant, and unspecified

Nervous system disorders Respiratory, thoracic, and

mediastinal disorders

Metabolism and nutrition

disorders

Does everyone need maintenance?

Decision based on PET/MRD results?

Meta-analysis:toxicities of R-maintenance

Event Pts RR (95% CI)

Grade 3-4 AE 1598 1.60 (1.29-1.99)

AEs with D/C 1433 2.72 (1.30-5.68)

Infections 1656 1.67 (1.40-2.0)

Grade 3-4 Infections

1656 3.55 (1.88-6.69)

Vidal et al, JNCI 103:1799, 2011

Effect of MR after R-CHOP or BR

▪ STIL BR better than R-CHOP

no maintenance

▪ BRIGHT BR a little better than R-CHOP

half of patients with maintenance

▪ GALLIUM BR same as R-CHOP

all had maintenance

Hypothesis

▪ Maintenance improves prognosis after CVP and CHOP, but not after Bendamustine

▪ Reasons could be:

▪ R needs an intact immune system to be active

▪ R is too toxic after immunosupressive chemo

R-bendamustine and lymphopenia

1160 pts with indolent lymphoma

R-benda x 6 + R-maintenance

WBC 6’600/ul 3’800/ul

Lympho 1’500/ul 500/ul

CD4 555/ul 118/ul

IgM 0.76 g/l 0.42 g/l

124 infections (44 pneumonia, 3 pneumocystis)

17 toxic deaths (1.4 %)

Burchardt, et al., abstr. 32, ICML-12, 2013

GALLIUM: Selected grade 3–5 AEs by chemo

n (%) of pts reporting 1 event

R-benda,n=338

G-benda,n=338

R-CHOP,n=203

G-CHOP,n=193

R-CVP,n=56

G-CVP,n=61

Cardiac events 12 (3.6) 13 (3.8) 5 (2.5) 6 (3.1) 0 (0.0) 4 (6.6)

Neutropenia 107 (31.7) 107 (31.7) 115 (56.7) 142 (73.6) 14 (25.0) 29 (47.5)

Febrile neutropenia 13 (3.8) 18 (5.3) 14 (6.9) 22 (11.4) 2 (3.6) 2 (3.3)

Second malignancies† 12 (3.6) 21 (6.2) 7 (3.4) 7 (3.6) 2 (3.6) 1 (1.6)

Other solid tumours 9 (2.7) 11 (3.3) 7 (3.4) 4 (2.1) 2 (3.6) 0

Hematological tumours‡ 0 3 (0.9) 0 3 (1.6) 0 0

Non-melanoma skin cancer

3 (0.9) 7 (2.1) 0 0 0 1 (1.6)

Infections 66 (19.5) 89 (26.3) 25 (12.3) 23 (11.9) 7 (12.5) 8 (13.1)

Opportunistic infections§ 6 (1.8) 10 (3.0) 2 (1.0) 5 (2.6) 0 0

Hiddemann et al, ICML 2017, abstr 107

Grade 3–5 infections by chemo and by phase

n (%) of pts reporting 1 event

R-benda,n=338

G-benda,n=338

R-CHOP,n=203

G-CHOP,n=193

R-CVP,n=56

G-CVP,n=61

All study periods 66 (19.5) 89 (26.3) 25 (12.3) 23 (11.9) 7 (12.5) 8 (13.1)

Induction 26 (7.7) 27 (8.0) 13 (6.4) 14 (7.3) 4 (7.1) 3 (4.9)

Maintenance 39 (13.0) 51 (16.7) 11 (5.9) 7 (3.9) 1 (2.5) 5 (8.8)

Observation 12 (3.8) 28 (8.8) 6 (3.1) 3 (1.6) 3 (5.7) 1 (1.7)

N (%) of pts receiving G-CSF prophylaxis

48 (14.2) 54 (16.0) 108 (53.2) 112 (58.0) 13 (23.2) 10 (16.4)

*Safety population


CD4 T-cell counts over timeC

D3+

CD

4+ (

cells

/µl)

Mo

30

Mo

36

Mo

18

EOIC

4/C

5

C1

/C2

BL

Mo

30

Mo

36

Mo

18

EOIC

4/C

5

C1

/C2

BL

Mo

30

Mo

36

Mo

18

EOIC

4/C

5

C1

/C2

BL

Mo

30

Mo

36

Mo

18C

4/C

5

C1

/C2

BL


BENDAMUSTINE CHOP CVP

Postinduction PET status (cut-off ≥4) and

Outcome

PFS Score ≥4 OS Score ≥4

HR 3.9 (95% CI 2.5-5.9, p<.0001)

Median PFS:16.9 (10.8-31.4) vs.

74.0 mo (54.7-NR)

63%

23%

HR 6.7, 95% CI 2.4-18.5, p=0.0002

Median OS: 79 months vs. NR

87%

97%

FOLL12 TRIAL DESIGN Maintenance

INDUCTIONtherapy

Standardarm

Experimentalarm

R Maintenanceevery 2 months x 2yrs

CR,PR

<PR Salvage

Rituximabweekly x 4

PET-

PET+

Salvage

Neg

Pos

Observation

(90)Y Ibritumomab Tiuxetan +R Maintenance

every 2 months x 2yrs

<PR

MRD

Patients with no molecular markers

Towards a chemo-free first-line treatment in FL?

45% of chemo-naïveresponders still in first remission at 8 years

SAKK 35/98 – Long term outcomeR-maintenance after single agent rituximab

EFS in previously untreated patients responding to the induction treatment

Martinelli et al. JCO 2010; 28:4480-4

FL cells

TFH

Treg/TFR

Th

CD8

Tgd

NK

Stromal cells

Blood vessels

Anti-PD-1 mAb

CXCR4 antagonistsBtk/Syk inhibitors

Anti-VLA4 mAb

Anti-CTLA4 mAbAnti-PD-1 mAb

IMiDsAnti-CD137 mAb

IMiDsAnti-CD137 mAbAnti-PD-1 mAb

BrHPP/IL-2

ITKs

Anti-tumoral microenvironmentThe good guys

Pro-tumoral microenvironmentThe bad guys

TAM

IMIDsAnti-CD47 mAb

Btk/Syk inhibitors

The u

gly g

uys

Amé-Thomas Semin Cancer Biol 2014;24: 23

Pre-clinical rationale for lenalidomide in FL

Lenalidomide is able to repair FL T-cell immunologic synapse dysfunction with autologous tumor cells in

vitro (Ramsay et al., Blood 2009)

CD

3

-

sAg

CD

3

+sA

g

CD

3

-

sAg

CD3

+sA

g

706050403020100

P < .05

P < .01

Untreated (UT)

Lenalidomide (Len.)

R2 as Frontline Combination for Follicular

Lymphoma: Clinical Response

BY GELF CRITERIA N=45

GELF (+) N=22 (49%) GELF (-) N=23 (51%)

SD PR CR/CRu ORR SD PR CR/CRu ORR

0 1 (5%) 21(95%) 100% 1(5%) 4(17%) 18 (78%) 95%

BY BULK OF DISEASE N=45

BULKY N=13 (29%) NON-BULKY N=32 (71%)

SD PR CR/CRu ORR SD PR CR/CRu ORR

0 1(8%) 12(92%) 100% 1(3%) 4 (13%) 27 (84%) 97%

Fowler, N. et al. ICML 2011. Abst#137.

R2 as Frontline therapy in FL: PFS

PFS (months)

Perc

en

t su

rviv

al

0 12 24 360

20

40

60

80

100

N=4636 mo PFS: 81%

N=46

36 mo PFS: 81%

Fowler, N. et al. ASH 2012.

Eva Kimby - December 9, 201479NLG

SAKK-Nordic 35/10 Trial design

1:1

Randomization

1 3 5 7 9 11 13 15 22-24Wks.

Ritux i.v.375 mg/m2

Lenalidomide 15 mg daily

Firs

t res

tag

ing

Fo

llow

-up

Ritux i.v.375 mg/m2

10S

ec

on

d re

sta

gin

g

Therapy

off-protocolNo CR/PR/MR MR >25% decrease in SPD

2 wks pre-phase 2 wks post-phase

Stratification:• FL grade 1-2 vs 3A

• Bulky vs no bulk

• FLIPI score 1+2 vs >3

• Center


Assessment of primary endpoint [CR/CRu] at week 23

Addition of lenalidomide to rituximab results in a significantly higher

CR/CRu rate (IRR: 61% vs 36%) with increased but manageable

toxicityKimby et al. Blood 2014.124 (21):799, Zucca et al. Hematol Oncol 2015. 33 (s1):105

Now the analysis of secondary endpoints

at a median follow-up of 3.5 years ▪ Progression-free survival (PFS)

▪ Time to next anti-lymphoma treatment (TTNT)

▪ CR/CRu duration

▪ CR/CRu rate at 30 months (CR30)

▪ Overall survival (OS)

Results


Progression-free survival

Rituximab + Lenalidomide

Rituximab

HR (95% CI) = 0.58 (0.36-0.94)

Log-Rank test p-value = 0.03

Median

PFS

not reached

vs

2.3 years


Time to new therapy

Rituximab + Lenalidomide

Rituximab

HR (95% CI) = 0.56 (0.35-0.89)

Log-Rank test p-value = 0.01

Median

TTNT

not reached

vs

2.1 years

FLASH: Follicular Lymphoma Analysis of Surrogate

Hypotheses Group

Study Conclusions

83

Principal candidate CR30 met the surrogacy

qualification criteria for PFS overall and within trial types

Correlation of treatment effects on PFS and CR30

was more marked in patients with advanced disease

or high FLIPI score

CR30 may be considered an appropriate primary

endpoint in future first-line FL studies

Sargent et a, ICML 2015


A significantly improved CR30 in RL

– RL: 42% (95% CI 30-53%)

– R: 19% (95% CI 11-30%)

OS rates at 3 years similar between the arms

– RL: 93% (95% CI 85-97%)

– R: 92% (95% CI 82-96%)

CR30 and OS

(p=0.001)

The “RELEVANCE” Trial

R2 maintenance(lenalidomide 1 yr + rituximab 2 yrs)

Rituximab maintenance(2 yrs)

R

24 mos.

R2

R-Chemo

6 mos.

CR, CRu, PR

CR, CRu, PR

1st line

FL

N=1000

R-Chemo: Investigator choice of R-CHOP, R-CVP, or R-B

Eligibility: Patients who need treatment (GELF criteria)

Stratification: FLIPI (0-1 v 2 v 3-5), Age (>60 v ≤ 60), diameter of largest node (> 6 v ≤ 6 cm)

Endpoints: PFS, CR/CRu? At 30 months

R2 Regimen:

Rituximab weekly x 4, then day 1 of each cycle 2 to cycle 6, 8 weeks later responding patients continue every 8 weeks for 12 cycles

Lenalidomide 20 mg x 6 cycles

- CR-10 mg lenalidomide 10 mg for 12 cycles

- PR- 20 mg lenalidomide 3-6 months then, 10 mg ≤18 cycle

Conclusions

– R-Benda is equivalent to R-CHOP

– G-chemo + maintenance superior to R-chemo + maintenance in

untreated advanced FL

• Clinically meaningful improvement in PFS: 34% reduction in risk;

HR=0.66

• Non-fatal AEs were higher in the G arm

• Fatal AEs more common in patients on bendamustine in both arms

– PET and MRD? to decide upon maintenance duration

– R2 has made chemo-free therapy a near future reality but is it

appropriate for all first-line FL in need of treatment?

– Elaborate on better frontline molecular markers to select patients

– Surrogate endpoint (for median PFS) adapted to chemo-free

approaches needed

traitement de première ligne du lymphome...

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