Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement André Bosly, M.D., Ph.D....

Lymphomes diffus à grandes cellules B

Facteurs pronostiques et traitement

André Bosly, M.D., Ph.D.Université de Louvain

Mont-Godinne, Belgique

ESH Tunis, le 29 octobre 2010



Données épidémiologiques

Mortalité par cancer par an (nx 1000) en Europe

Age-standardized incidence rates (ASR) of NHL worldwide

0

2

4

6

8

10

12

14

16

EasternAsia

SouthernAfrica

WesternEurope

Australia NorthernAmerica

AS

R p

er10

0,00

0 w

orl

dw

ide

Males

Females

Müllier A et al, Ann Hematol 2005; 84 : 1-12

SEER 1975–2000 age-adjusted incidence rates of NHL by gender

Fischer SG et al, Oncogene 2004; 23:6524-6534

Frequency of subtypes of lymphomas

Non-Hodgkin's lymphomas. Coiffier, p. 7



Facteurs pronostiques cliniques : l’IPI

Smith A. Br J Haematol 2010; 148:739-753

International prognostic index

Survival according to IPI score6696 patients included in GELA randomized studies

Overall survival Progression-free survival

Revised IPI in the rituximab era

Risk groupNo of

IPI factors

Patients,%

4-year PFS, %

4-year OS, %

Standard IPI

Low 0–1 28 85 82

Low–intermed 2 27 80 81

High–intermed 3 21 57 49

High 4–5 24 51 49

Revised IPI

Very good 0 10 94 94

Good 1–2 45 80 79

Poor 3–5 45 53 55Sehn LH et al, Blood 2007; 109:1857–1861

Sehn et al, Blood 2007; 109 : 1857-61

RIPI

4-year PFS

4-year OS

Comparaison de 4 IPI

Advani RH et al, BHJ 2010; 151 : 143-151

Ziepert M., J Clin Oncol 2010; 28:2373-2380

Validity of IPI in the rituximab era (german group)



Facteurs biologiques :données de micro-array : au moins deux maladies

Gene expression arrays

Subclassification of diffuse large B-

celllymphoma

Alizadeh et al,Nature 2000

Clinical study according to phenotype of diffuse large cells lymphomas

(Alizadeh, 2000)

Subgroups of diffuse large B-cell lymphoma

defined by gene expression profiling

274 DLBCL Biopsy Samples

Diffuse Large B-cell Lymphoma :at least two diseases

Germinal centerB cell-like (GCB)

ActivatedB cell-like (ABC)

Cell of Origin

OncogenicMechanism

s

Clinical Outcom

e

Germinal centerB cell

? Post-Germinal Center B cell

- t(14;18) translocation of

BCL-2- Chr. 2p

amplification of c-rel locus

Constitutive activationof NF-kB

Favorable60% 5-yr survival

Poor35% 5-yr survival

GCB and ABC in R-CHOP treated patients

Lenz et al, NEJM 2008; 359 (22) : 2313-23

Hartmann & Rosenwald, EHA educational program 2009

Predictor score in R-CHOP treated patients

N Engl J MED. G. Lenz et al. 2008; 359 (22): 2313-23

Stromal 1


Stromal 2


Survival model in R-CHOP treated patients

N Engl J MED. G. Lenz et al. 2008; Suppl. to 359 (22): 2313-23

Survival model and IPI

N Engl J MED. G. Lenz et al. 2008; Suppl. to 359 (22): 2313-23



Facteurs biologiques :expression de gènes en

immunohistologie

Ott G et al, Blood 2010-03-276766

Ricover study : Hans algorithm

Ott G et al, Blood 2010-03-276766

RICOVER study : Hans algorithm

All patients :

EFS, R-CHOP patients (52 patients)

Ott et al, Blood 2010

Ott G et al, Blood 2010-03-276766

RICOVER study histology

Nyman H et al, Modern Pathology 2009; 22 : 1094-1101

Hansalgorithm

Murisalgorithm

Nymanalgorithm

Nyman H et al, Modern Pathology 2009; 22 : 1094-1101

Nyman

Muris

Hans

de Jong D et al, J Clin Pathol 2009; 62 : 128-138

CV1=2; CV2=1 CV1=26; CV2=4

CV1=20; CV2=11 CV1=15; CV2=16

Lunenburg consortium

CV1=31; CV2=21 CV1=23; CV2=20

CV1=21; CV2=11 CV1=27; CV2=21

de Jong D et al, J Clin Pathol 2009; 62 : 128-138

Lunenburg consortium



Réarrangements de MYC et survie

Smith SM et al, Blood Cells Mol Diseases 2010

Univariate Kaplan-Meier analysis of overall survival in the MYC rearrangement (MYC-R)versus nonrearranged patients. Patients with rearrangement of MYC have a significantly inferior outcome compared to those without (hazard ratio, 2.03; 95 % CI, 1.15 to 3.58). The probability of survival at 2 years was 0.35 in the MYC rearrangement group versus0.61 for all others, based on n=240 patients with MYC data and clinical follow-up.

Barrans S et al., J Clin Oncol 2010; 28:3360-3365

Réarrangement de c-myc et DLBCL

http://jco.ascopubs.org/content/28/20/3360/F2.large.jpg



Dose-intensité de chimiothérapie et survie

Bosly, Bron et al, Ann Hematol 2008

Effect of dose-intensity on survival



TEP et évaluation de la réponse précoce

TP 15112007

PET CT for staging

2-year outcome

Study n PET after . . . PET- PET+

Jerusalem 2000 28 Median : 3 cycles 62% (PFS) 0% (PFS)

Spaepen 2002 70 Median : 3 cycles 85% (PFS) 4% (PFS)

Kostakoglu 2002 30 1 cycle 85% (PFS) <15% (PFS)

Haioun 2005 90 2 cycles 82% (EFS) 43% (EFS)

Mickaeel 2005 121 Median : 2 cycles 87% (PFS) 34% (PFS)

Early treatment evaluation

Before treatment At 2 cycles At 4 cycles

FDG-PET2 (+)

Early treatment evaluation

Event-free survival and overall survival according

to response at 2 cycles on the basis of PET (n = 90)

PET– (n=54)

PET+ (n=36)

Pro

bab

ilit

y o

f E

FS

p<0.0001

Years after randomisation

Event-free survival

p=0.006

Median follow-up: 2 years

Overall survival

100

80

60

40

20

0

100

80

60

40

20

00 1 2 3 0 1 2 3

Years after randomisation

Pro

bab

ilit

y o

f O

S

Haioun C, et al, Blood 2005

Receiver operating characteristic (ROC) plotting for (A) advanced-stage Hodgkin's lymphoma and (B) diffuse large B-cell lymphoma. Individual study estimates of sensitivity and 1 − specificity are shown (open circles). Summary ROC curve is presented only for DLBCL. Closed square represents the summary estimates. Dashed boundary represents the 95% confidence region for the summary sensitivity and specificity.

Terasawa T et al, J Clin Oncol 2009; 27 : 1906-1914

Specificity and sensitivity of PET are not so good in DLBCL in comparison with HD

http://jco.ascopubs.org/content/27/11/1906/F2.large.jpg

Interim PET NHL (4 cycles)False positive PET scans – PPV 26%

Moskowitz et al, J Clin Oncol 28: 1896, 2010

False positive PET results

Visual assessment : normal

Interval : 10 – 14 days

G-CSF

SUV = 1.4

Gallamini, A. et al. J Clin Oncol; 25:3746-3752 2007

Interim PET in ABVD-treated HL patients

SUV = 3.5

Visual vs. quantitative analysis2 cycles, n=92

5.0

> 5.0

P = .002

Quantitative analysis(SUVmax at 2 cycles)

Visual analysis(Créteil, MRU)

Quantitative analysis(% reduction SUVmax)

Lin, Itti et al. J Nucl Med 2007;48:1626-32

Reduction of 14/17 false positives Cut-off may vary with histology, treatment, PET center

PET2 (-)

PET2 (+)

P =.009

Pro

bab

ility

of

EF

S

Months after inclusion Months after inclusion Months after inclusion

P < .0001

> 65.7%

65.7%

Visual analysis(Juweid, IHP)

Visual analysis(Créteil, MRU)

Quantitative analysis(% reduction SUVmax)

P < .0001 P < .0001P < .0001

PET4 (-)

PET4 (+)

> 72.9%

72.9%

PET4 (-)

PET4 (+)Pro

bab

ility

of

EF

S

Months after inclusion Months after inclusion Months after inclusion

Reduction of false positives if we wait for 4 cycles Juweid criteria acceptable, Créteil slightly better Visual analysis reliable, SUV more objective

Itti et al. J Nucl Med 2009;50:527-33

Visual vs. quantitative analysis4 cycles, n=80



Traitement des formes localisées

ACVBP compared with CHOP plus radiotherapy :

the LNH93-1 study

R

0 2 84

0 3 6 10

2210 12 14 16

weeks

weeks

ACVBP ACVBPACVBP

CHOP CHOP CHOP

Methotrexate3g/sqm

+ rescue

Ifosfamide1500 mg/sqm

Etoposide300 mg/sqm

Cytarabine100mg/sqm x4

Induction ConsolidationACVBP

Doxorubicin : 75 mg/sqm D1Cyclophosphamide : 1200 mg/sqm D1Vindesine : 2 mg/sqm D1, D5Bleomycin : 10 mg D1, D5Prednisone : 60 mg/sqm D1-5

CHOP

Doxorubicin : 50 mg/sqm D1Cyclophosphamide : 750 mg/sqm D1Vincristine : 1,4 mg/sqm D1Prednisone : 40 mg/sqm D1-5

involved field

radiotherapy, 40 Gy

(5 x 1,8 Gy / week)

18 20

ACVBP

CHOP plus radiotherapy

pro

ba

bil

ity

of

Ov

era

ll S

urv

iva

l

P = 0.001

No. at risk

ACVBP 318 307 296 286 271 236 206 163 126 80 34

CHOP plus 329 314 292 280 265 231 199 152 113 70 28radiotherapy

m f-up : 7.7 y

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11

years after randomization

The LNH93-1 study : overall survival

Reyes F. et al, 2005 - NEJM

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Years after Randomization

CHOP

CHOP plus radiotherapyP

roba

bilit

y

P = 0.5

No. at risk

CHOP 277 220 202 179 157 130 112 87 66 39

19 1

CHOP plus 299 249 226 193 170 143 112 90 64 48

30 9radiotherapy

93-4 study : Event Free Survival

n = 277

n = 299

med f-up= 7y

La radiothérapie n’a pas de place en première ligne

Bonnet C, Fillet G, JCO 2007

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Years after Randomization

Pro

bab

ilit

y

P = 0.5

No. at risk

CHOP 277 249 226 206 178 153 131 102 75 45

22 1

CHOP plus 299 265 243 211 187 155 123 98 68 50

30 9radiotherapy

93-4 study : Overall Survival

CHOP n=277

CHOP plus radiotherapy n=299

med f-up= 7y

La radiothérapie n’a pas de place en première ligne

Bonnet C, Fillet G, JCO 2007

Lymphoma-associated deaths:Chemo: 42R-Chemo : 13

0 5 10 15 20 25 30 35 40 45 50Months

Pro

bab

ilit

y

R-Chemo

Chemo

95%

86%

MInT : overall survival

Pfreundschuh M, et al. Blood 2004; 104:40a (Abstract 157)

P = 0.0002

Median observation time : 23 months

1.0

0.8

0.6

0.4

0.2

0

Coiffier

WHy a difference in Median observation time?22 months previous slide, here 23 months



Traitement des formes avancées chez le sujet agé

DLBCL Age 60–80 years No prior treatment PS 0–2 Stage II–IV

RANDOMIZATION

LNH 98.5 study : Design

CHOP q3wk x 8

Rituximab+

CHOPq3wk x 8

Coiffier B et al, N Engl J Med 2002;346:235

Rituximab: 375 mg/m2 on day 1Cyclophosphamide: 750 mg/m2 on day 1Doxorubicin: 50 mg/m2 on day 1Vincristine: 1.4 mg/m2 (up to 2 mg) on day 1Prednisolone: 40 mg/m2/d days 1–5

Rituximab: 375 mg/m2 on day 1Cyclophosphamide: 750 mg/m2 on day 1Doxorubicin: 50 mg/m2 on day 1Vincristine: 1.4 mg/m2 (up to 2 mg) on day 1Prednisolone: 40 mg/m2/d days 1–5

LNH-98.5 : Improved responserate and quality of response with R-

CHOP

63

6

ORR = 69 %(n = 197)

76

7

Pat

ien

ts (

%)

80

60

40

20

0

100

CHOPR-CHOP

Non-evaluable / otherDeath during treatmentProgressive diseasePartial responseComplete response / CRu

ORR = 83 %(n = 202)

Coiffier B et al, New Engl J Med 2002;346:235–242

9

6 6

22

R-CHOP vs CHOPp = 0.005

2 3

p = 0.005

Gela (french and belgian study)in aggressive lymphoma

OS – Median follow-up 7 y.

Coiffier, ASCO 2007

Overall survival according to age

60-69 years 75-80 years70-74 years

60-69 70-74 75-80

CHOP 40 41 21

R-CHOP 58 55 417-year OS (%)

Coiffier, B. et al. Blood 2010;116:2040-2045

Overall survival in patients treated with CHOP and R-CHOP(10 years FU)

N Chemo Response (%)Rituximab benefit

EFS or PFS OS

GELA1 399Elderly (60–80)

CHOP-21 x 876 vs 63

p = 0.0050.00002 0.0073

RICOVER-602 1222Elderly (61–80)

CHOP-14 x 6

CHOP-14 x 8

78 vs 68

76 vs 72< 0.001 0.003*

HOVON/NORDIC3 199 Elderly (65–80)

CHOP-14 x 8 ND < 0.01 0.05

Intergroup USA4†

(Habermann)632

Elderly (> 60)CHOP-21 77 vs 76 0.003 0.05

MInT5

824Young (18–60)

Low risk

CHOP-21or others

86 vs 68

p < 0.0001< 0.0001 0.0001

British Columbia6 292All ages

CHOP-like ND 0.002 < 0.0001

Czech Republic7 376Young

CHOP-like ND 0.0001 0.0007

1. Feugier P, et al. JCO 2005; 23:4117–4126; 2. Pfreundschuh M, et al. Blood 2006; Abstract 205;3. Sonneveld P, et al. J Blood 2006; 108:Abstract 210; 4. Habermann TM, et al. JCO 2006; 24:3121–3127;

5. Pfreundschuh M, et al. Lancet Oncol 2006; 7:379–391; 6. Sehn LH, et al. JCO 2005; 23:5027–5033;7. Trnĕný M, et al. Blood 2005; 106:Abstract 2444

* p-values for R-CHOP-14 x 6† Secondary analysis without maintenance

Improved EFS and OS with R-CHOP is consistent

in clinical trials and clinical practice

RICOVER-60 : Improved TTF with8 x rituximab + 6/8 x CHOP-14

R-CHOP-14 vs CHOP-14

Time (months)

Pro

bab

ilit

y

6 cycles vs 8 cycles

8 x (R)-CHOP-14(n = 415)

6 x (R)-CHOP-14(n = 413)

Time (months)

Pro

bab

ilit

y

05 10 15 200 30

0.2

0.4

0.6

0.8

1.0

450

5 10 15 20 35

0.2

0.4

0.6

0.8

1.0

45035 4025 25 30 40

p = 0.23

8 x rituximab+ 6/8 x CHOP-14(n = 414)

6/8 x CHOP-14(n = 414)

p = 0.000025 α-crit* = 0.031

Pfreundschuh M et al, Blood 2006;108:Abstract 205* R-CHOP-14 vs CHOP-14

LNH 03-6B : Study Design

Filgrastim or Pegfilgrastim according to physicians’decision

3 months

C5 FU1

R Response

R-CHOP14+ IT MTX

R-CHOP21

Response

C2 C7 C8

C1 C2 C3 C4 C5 C6 C7 C8 FU1FU0

FUn

R-CHOP21 + IT MTX

Response

C1

FUn

FU0

R-CHOP14

C3 C4 C6

3 months

3 months 3 months

Delarue et al Ash2009Delarue et al Ash2009

Distribution of patients

Patients randomizedbefore January 1st, 2006

N = 202

R-CHOP14N = 103

R-CHOP21N = 99

Complete treatment received : N = 73Premature withdrawal : N = 30

Complete treatment received : N = 74No treatment received : N = 1Premature withdrawal : N = 24

Dose-intensity

Is R-CHOP14 given every 14 days ?

R-CHOP14 R-CHOP21

Median interval between two cycles

15 days(9 – 70)

21 days(19 – 63)

Median dose-intensity

R-CHOP14 R-CHOP21

CPM 84 % 96%

DOX 83 % 95 %

18/103 patients in R-CHOP14 group

received R-CHOP ≥ 18

R-CHOP14 R-CHOP21

G-CSF use 90 % 68 %

R-CHOP14 = 125 % of R-CHOP21

Event-free survival

Median EFS : - 22 months (R-CHOP14) vs NR (R-CHOP21)2-year EFS :- 48% (R-CHOP14) vs 61% (R-CHOP21)

Overall survival

-2-year OS:- 67% (R-CHOP14) vs 70% (R-CHOP21)



Traitement des sujets jeunes de mauvais pronostic

The ACVBP regimen – a dose-intense chemotherapy regimen

LNH93-1: young, good prognosis

Reyes F et al. NEJM 2005

ACVBP

CHOPP = 0.03

0

20

40

60

80

100

0 2 4 6 8

Years

% survival

Tilly H et al. Blood 2003

LNH93-5: 60–70 y, poor prognosis

0

20

40

60

80

100

0 2 4 6 8

Years

% survival

1 3 5 7 9

P = 0.03

ACVBP

CHOP

Doxorubicin 75 mg/m² d1Cyclophosphamide 1200 mg/m² d1Vindesine 2 mg/m² d1, d5Bleomycin 10 mg d1, d5Prednison 60 mg/m² d1 to d5MTX intra-thecal 15 mg d2G-CSF 5 µg/kg d6 to d13

CH, Berlin EHA 2009

LNH 03-2B

• Lymphomes diffus grandes cellules B

• Patients <60 ans IPI=1

• R-ACVBP/R-CHOP

• Voir communication orale:

C.Recher ASH 2010

75%

60%

75%

60%

study N Median Min MaxFollow-up (months) LNH03-3 181 27 0 44Follow-up (months) LNH98-3 181 26 0 47

Matched control study : Progression free survival

PFS

R-ACVBP

ACVBP

CH, Berlin EHA 2009

Survival with ACVB in LNH Regimens

(in randomized studies)

3116 patients

R-ACVBP

R-CyclOBEAP in young patients with high-risk DLBCL

Niitsu N, Int J Hematol 2010; 92 : 231-237

77

EFS

with Rituximab

without Rituximab

6543210

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

p=0.013

Mega-CHOEP with and without Rituximab, Patients with DLBCL: EFS

Time (years)

n=64

n=29

Glass et al: Ann Oncol 2010, Epub doi:10.1093/annonc/mdq235

R

Rituximab (375mg/m²)

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

CH

OE

P-1

4

1 15 29 43 57 71 85 99

PBSC PBSCPBSC

mCHOEP IICYC 4500ADR 70VCR 2ETO 960PRD 500

43 64221 77 9814 36 56

mCHOEP IIICYC 4500ADR 70VCR 2ETO 960PRD 500

mCHOEP IVCYC 6000ADR 70VCR 2ETO 1480PRD 500

DSHNHL 2002-1 -- R-MegaCHOEPstudy design after amendment 1 for CD20-pos. B-NHL

mCHOEP ICYC 1500ADR 70VCR 2ETO 600PRD 500

CHOEP-14CYC 750ADR 50VCR 2ETO 300PRD 500

PRD and VCR doses are absolute, all others are per m²

days

DSHNHL 2002-1 -- MegaCHOEPProgression-free survival

Months

0 10 20 30 40 50 60 70

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

R-CHOEP-14

R-MegaCHOEP

p=0.119

DSHNHL 2002-1 -- MegaCHOEPOverall survival

0 10 20 30 40 50 60 70

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

p=0.142

R-CHOEP-14

R-MegaCHOEP

Months

Greb A et al, Cancer Treatment Reviews 2007; 33 : 338-346



Traitement des rechutes

Gisselbrecht C et al, J Clin Oncol 2010; ahead of print, July 26

OS (intent to treat)

Gisselbrecht C et al, J Clin Oncol 2010; ahead of print, July 26

PFS undergoing ASCT (ITT)

PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB

(INDUCTION ITT)

PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM

DIAGNOSIS (INDUCTION ITT)

N=160

N=22831%

64%N=147

N=24130%

62%

Aggressive B-NHL –CORAL Trial - PFS

Gisselbrecht et al JCO 2010, Epub

Failure from diagnosis > 12 months Failure from diagnosis =< 12 months

N= 106

N= 54

N= 41

N= 187

Aggressive B-NHL –CORAL Trial Response- EFS

Gisselbrecht et al JCO 2010, Epub

8787

Aggressive B-NHL Allogeneic and autologous SCT in aggressive B cell lymphoma

DSHNHLDSHNHL

Pro

bab

ility

of

EF

S

CORAL:HDT + autologous SCT

0 12 24 36 48

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72

Time after Transplant (Months)

DSHNHL R3 (B cell lymphoma):HDT + allogeneic SCT

Pro

bab

ility

of

EF

S

No prior rituximab: 54.6 (22,9-78,0)%, n=11

prior rituximab: 34,6 (19,9-49,7)%, n=45

Allogeneic SCT in relapsed DLBCLReduced intensity conditioning : Results

Thomson et al. JCO 2009; 27 (3): 426

OSNRM

RRPFS

sens

ref.



Nouveaux traitements

Briones J, Expert Rev Anticancer Ther 2009; 9 : 1305-1316

Phase III study testing a maintenance with lenalinomide

REMARC study

Role of new agents in lymphoma

Phase II combination studies in B-cell lymphoma

- Bortezomib with R-CHOP:V-R-CHOP (Mounier N et al. Cancer 2009)

- Dose finding combination of VEGF-Trap with R-CHOP-Phase I (Haioun C. et al,; accrual completed)

- Dose finding combination of Lenalinomide with R-CHOPPhase I (Tilly H. et al, ongoing)

CH, Berlin EHA 2009

Conclusions (1)

• Les lymphomes diffus à grandes cellules sont les LNH les plus fréquents

• L’IPI demeure le facteur pronostique clinique le plus important

• GCB et ABC représentent 2 sous-types de pronostic différent mais une méthode simple et reproductible pour les déterminer reste à définir

• L’évaluation de la réponse par TEP est prédictive de l’évolution à long terme

Conclusions (2)• Les formes localisées sont traitées par rituximab et

chimiothérapie sans irradiation• R-CHOP 21 est le standard de traitement des

formes avancées chez le sujet agé• Un traitement plus intense (R-ACVBP) est

nécessaire dans les formes avancées chez le sujet jeune

• Les traitements intensifs avec autogreffe sont indiqués en cas de rechute

• L’allogreffe avec conditionnement non myélo-ablatif est une option en cas de mauvais pronostic

Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement André Bosly, M.D., Ph.D....

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