Mont-Godinne, Belgique

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1 Mont-Godinne, Belgique
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

2 Données épidémiologiques
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Données épidémiologiques

3 Mortalité par cancer par an (nx 1000) en Europe

4 Age-standardized incidence rates (ASR) of NHL worldwide
Müllier A et al, Ann Hematol 2005; 84 : 1-12

5 SEER 1975–2000 age-adjusted incidence rates of NHL by gender
Fischer SG et al, Oncogene 2004; 23:

6 Frequency of subtypes of lymphomas
Non-Hodgkin's lymphomas. Coiffier, p. 7

7 Facteurs pronostiques cliniques : l’IPI
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Facteurs pronostiques cliniques : l’IPI

8 International prognostic index
Smith A. Br J Haematol 2010; 148:

9 Survival according to IPI score
6696 patients included in GELA randomized studies Overall survival Progression-free survival

10 Revised IPI in the rituximab era
Risk group No 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 Revised IPI Very good 10 94 Good 1–2 45 79 Poor 3–5 53 55 Sehn LH et al, Blood 2007; 109:1857–1861

11 RIPI 4-year PFS 4-year OS Sehn et al, Blood 2007; 109 :

12 Comparaison de 4 IPI Advani RH et al, BHJ 2010; 151 :

13 Validity of IPI in the rituximab era (german group)
Ziepert M., J Clin Oncol 2010; 28:

14 Facteurs biologiques : données de micro-array : au moins deux maladies
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Facteurs biologiques : données de micro-array : au moins deux maladies

15 Gene expression arrays Subclassification of diffuse large B-cell
lymphoma Alizadeh et al, Nature 2000

16 Clinical study according to phenotype of diffuse large cells lymphomas
(Alizadeh, 2000)

17 Subgroups of diffuse large B-cell lymphoma
defined by gene expression profiling 274 DLBCL Biopsy Samples

18 Diffuse Large B-cell Lymphoma : at least two diseases
Germinal center B cell-like (GCB) Activated B cell-like (ABC) Germinal center B cell ? Post-Germinal Center B cell Cell of Origin - t(14;18) translocation of BCL-2 - Chr. 2p amplification of c-rel locus Oncogenic Mechanisms Constitutive activation of NF-kB Clinical Outcome Favorable 60% 5-yr survival Poor 35% 5-yr survival

19 GCB and ABC in R-CHOP treated patients
Lenz et al, NEJM 2008; 359 (22) :

20 Hartmann & Rosenwald, EHA educational program 2009

21 Predictor score in R-CHOP treated patients
N Engl J MED. G. Lenz et al. 2008; 359 (22):

22 Stromal 1 N Engl J MED. G. Lenz et al. 2008; 359 (22):

23 Stromal 2 N Engl J MED. G. Lenz et al. 2008; 359 (22):

24 Survival model in R-CHOP treated patients
N Engl J MED. G. Lenz et al. 2008; Suppl. to 359 (22):

25 Survival model and IPI N Engl J MED. G. Lenz et al. 2008; Suppl. to 359 (22):

26 Facteurs biologiques : expression de gènes en immunohistologie
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Facteurs biologiques : expression de gènes en immunohistologie

27 Ricover study : Hans algorithm
Ott G et al, Blood

28 RICOVER study : Hans algorithm
All patients : Ott G et al, Blood

29 EFS, R-CHOP patients (52 patients)

30 Ott et al, Blood 2010

31 RICOVER study histology
Ott G et al, Blood

32 RICOVER study histology
Ott G et al, Blood

33 Hans algorithm Muris algorithm Nyman algorithm
Nyman H et al, Modern Pathology 2009; 22 :

34 Nyman Muris Hans Nyman H et al, Modern Pathology 2009; 22 :

35 Lunenburg consortium 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 de Jong D et al, J Clin Pathol 2009; 62 :

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

37 Réarrangements de MYC et survie
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Réarrangements de MYC et survie

38 Smith SM et al, Blood Cells Mol Diseases 2010

39 Réarrangement de c-myc et DLBCL
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 versus 0.61 for all others, based on n=240 patients with MYC data and clinical follow-up. Barrans S et al., J Clin Oncol 2010; 28:

40 Dose-intensité de chimiothérapie et survie
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Dose-intensité de chimiothérapie et survie

41 Effect of dose-intensity on survival
Bosly, Bron et al, Ann Hematol 2008

42 TEP et évaluation de la réponse précoce
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement TEP et évaluation de la réponse précoce

43 PET CT for staging TP

44 Early treatment evaluation
2-year outcome Study n PET after . . . PET- PET+ Jerusalem 2000 28 Median : 3 cycles 62% (PFS) 0% (PFS) Spaepen 2002 70 85% (PFS) 4% (PFS) Kostakoglu 2002 30 1 cycle <15% (PFS) Haioun 2005 90 2 cycles 82% (EFS) 43% (EFS) Mickaeel 2005 121 Median : 2 cycles 87% (PFS) 34% (PFS)

45 Early treatment evaluation
Before treatment At 2 cycles At 4 cycles FDG-PET2 (+)

46 Years after randomisation Years after randomisation
Event-free survival and overall survival according to response at 2 cycles on the basis of PET (n = 90) Event-free survival Overall survival 100 80 60 40 20 100 80 60 40 20 PET– (n=54) Probability of EFS Probability of OS Median follow-up: 2 years PET+ (n=36) p<0.0001 p=0.006 Years after randomisation Years after randomisation Haioun C, et al, Blood 2005

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

48 Interim PET NHL (4 cycles)
False positive PET scans – PPV 26% SUV = 1.4 False positive PET results Visual assessment : normal Interval : 10 – 14 days G-CSF Moskowitz et al, J Clin Oncol 28: 1896, 2010

49 Interim PET in ABVD-treated HL patients
SUV = 3.5 This prognostic value has been confirmed in HL after 2 cycles of ABVD. This has suggested that interim PET could be used to tailor therapy and to define a risk based strategy. Gallamini, A. et al. J Clin Oncol; 25:

50 Visual vs. quantitative analysis
2 cycles, n=92 Visual analysis (Créteil, MRU) Quantitative analysis (SUVmax at 2 cycles) Quantitative analysis (% reduction SUVmax) > 65.7% PET2 (-)  5.0 Probability of EFS P < .0001 PET2 (+) P = .002 P =.009 > 5.0  65.7% Months after inclusion Months after inclusion Months after inclusion  Reduction of 14/17 false positives  Cut-off may vary with histology, treatment, PET center Lin, Itti et al. J Nucl Med 2007;48:

51 Visual vs. quantitative analysis
4 cycles, n=80 Visual analysis (Créteil, MRU) Visual analysis (Juweid, IHP) Quantitative analysis (% reduction SUVmax) PET4 (-) PET4 (-) > 72.9% Probability of EFS P < .0001 P < .0001 P < .0001 PET4 (+)  72.9% PET4 (+) 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

52 Traitement des formes localisées
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Traitement des formes localisées

53 ACVBP compared with CHOP plus radiotherapy : the LNH93-1 study
Doxorubicin : 75 mg/sqm D1 Cyclophosphamide : 1200 mg/sqm D1 Vindesine : 2 mg/sqm D1, D5 Bleomycin : 10 mg D1, D5 Prednisone : 60 mg/sqm D1-5 Induction Consolidation Ifosfamide 1500 mg/sqm Etoposide 300 mg/sqm Methotrexate 3g/sqm + rescue Cytarabine 100mg/sqm x4 ACVBP ACVBP ACVBP 2 4 8 10 12 14 16 18 20 22 weeks R 3 6 10 CHOP CHOP CHOP involved field radiotherapy, 40 Gy (5 x 1,8 Gy / week) weeks CHOP Doxorubicin : 50 mg/sqm D1 Cyclophosphamide : 750 mg/sqm D1 Vincristine : 1,4 mg/sqm D1 Prednisone : 40 mg/sqm D1-5

54 CHOP plus radiotherapy
The LNH93-1 study : overall survival 100 ACVBP 90 80 70 CHOP plus radiotherapy 60 probability of Overall Survival 50 40 30 P = 0.001 m f-up : 7.7 y 20 10 1 2 3 4 5 6 7 8 9 10 11 years after randomization No. at risk ACVBP CHOP plus radiotherapy Reyes F. et al, NEJM

55 93-4 study : Event Free Survival
La radiothérapie n’a pas de place en première ligne 93-4 study : Event Free Survival CHOP n = 277 Probability CHOP plus radiotherapy n = 299 P = 0.5 med f-up= 7y No. at risk CHOP CHOP plus radiotherapy Bonnet C, Fillet G, JCO 2007

56 CHOP plus radiotherapy
La radiothérapie n’a pas de place en première ligne 93-4 study : Overall Survival CHOP n=277 Probability CHOP plus radiotherapy n=299 P = 0.5 med f-up= 7y No. at risk CHOP CHOP plus radiotherapy Bonnet C, Fillet G, JCO 2007

57 MInT : overall survival
1.0 0.8 0.6 0.4 0.2 95% R-Chemo 86% Chemo Probability Lymphoma-associated deaths: Chemo: 42 R-Chemo : 13 P = Months Median observation time : 23 months Pfreundschuh M, et al. Blood 2004; 104:40a (Abstract 157)

58 Traitement des formes avancées chez le sujet agé
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Traitement des formes avancées chez le sujet agé

59 LNH 98.5 study : Design Rituximab + CHOP q3wk x 8 DLBCL
Z T ON Rituximab + CHOP q3wk x 8 DLBCL Age 60–80 years No prior treatment PS 0–2 Stage II–IV CHOP q3wk x 8 Rituximab: 375 mg/m2 on day 1 Cyclophosphamide: 750 mg/m2 on day 1 Doxorubicin: 50 mg/m2 on day 1 Vincristine: 1.4 mg/m2 (up to 2 mg) on day 1 Prednisolone: 40 mg/m2/d days 1–5 Coiffier B et al, N Engl J Med 2002;346:235 59

60 LNH-98.5 : Improved response rate and quality of response with R-CHOP
ORR = 83 % (n = 202) ORR = 69 % (n = 197) 100 2 3 6 6 9 22 Non-evaluable / other Death during treatment Progressive disease Partial response Complete response / CRu 80 7 76 6 60 63 Patients (%) p = 0.005 R-CHOP vs CHOP p = 0.005 40 20 R-CHOP CHOP Coiffier B et al, New Engl J Med 2002;346:235–242

61 Gela (french and belgian study) in aggressive lymphoma OS – Median follow-up 7 y.
Coiffier, ASCO 2007

62 Overall survival according to age
60-69 years 70-74 years 75-80 years 60-69 70-74 75-80 CHOP 40 41 21 R-CHOP 58 55 7-year OS (%)

63 Overall survival in patients treated with CHOP and R-CHOP(10 years FU)
Coiffier, B. et al. Blood 2010;116:

64 Improved EFS and OS with R-CHOP is consistent in clinical trials and clinical practice
Chemo Response (%) Rituximab benefit EFS or PFS OS GELA1 399 Elderly (60–80) CHOP-21 x 8 76 vs 63 p = 0.005 0.0073 RICOVER-602 1222 Elderly (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) ND < 0.01 0.05 Intergroup USA4† (Habermann) 632 Elderly (> 60) CHOP-21 77 vs 76 0.003 MInT5 824 Young (18–60) Low risk CHOP-21 or others 86 vs 68 p < < 0.0001 British Columbia6 292 All ages CHOP-like 0.002 Czech Republic7 376 Young 0.0007 * p-values for R-CHOP-14 x 6 † Secondary analysis without maintenance 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

65 RICOVER-60 : Improved TTF with 8 x rituximab + 6/8 x CHOP-14
6 cycles vs 8 cycles R-CHOP-14 vs CHOP-14 1.0 1.0 8 x rituximab + 6/8 x CHOP-14 (n = 414) 0.8 0.8 8 x (R)-CHOP-14 (n = 415) 0.6 0.6 Probability Probability 0.4 0.4 6 x (R)-CHOP-14 (n = 413) 6/8 x CHOP-14 (n = 414) 0.2 0.2 p = 0.23 p = α-crit* = 0.031 5 10 15 20 25 30 35 40 45 5 10 15 20 25 30 35 40 45 Time (months) Time (months) * R-CHOP-14 vs CHOP-14 Pfreundschuh M et al, Blood 2006;108:Abstract 205

66 LNH 03-6B : Study Design C5 FU1 R Response R-CHOP14 + IT MTX R-CHOP21
3 months C5 FU1 R Response R-CHOP14 + IT MTX R-CHOP21 C2 C7 C8 C1 C3 C4 C6 FU0 FUn + IT MTX R-CHOP14 Filgrastim or Pegfilgrastim according to physicians’decision Delarue et al Ash2009 66

67 Distribution of patients
Patients randomized before January 1st, 2006 N = 202 R-CHOP14 N = 103 R-CHOP21 N = 99 Complete treatment received : N = 73 Premature withdrawal : N = 30 Complete treatment received : N = 74 No treatment received : N = 1 Premature withdrawal : N = 24

68 Is R-CHOP14 given every 14 days ? Median dose-intensity
Median interval between two cycles 15 days (9 – 70)‏ 21 days (19 – 63)‏ R-CHOP14 R-CHOP21 CPM 84 % 96% DOX 83 % 95 % R-CHOP14 = 125 % of R-CHOP21 18/103 patients in R-CHOP14 group received R-CHOP ≥ 18 R-CHOP14 R-CHOP21 G-CSF use 90 % 68 % 68

69 Event-free survival Median EFS :
22 months (R-CHOP14) vs NR (R-CHOP21)‏ 2-year EFS : 48% (R-CHOP14) vs 61% (R-CHOP21)‏ 69 69

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

71 Traitement des sujets jeunes de mauvais pronostic
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Traitement des sujets jeunes de mauvais pronostic

72 The ACVBP regimen – a dose-intense chemotherapy regimen
LNH93-1: young, good prognosis LNH93-5: 60–70 y, poor prognosis Doxorubicin mg/m² d1 Cyclophosphamide mg/m² d1 Vindesine mg/m² d1, d5 Bleomycin mg d1, d5 Prednison mg/m² d1 to d5 MTX intra-thecal mg d2 G-CSF µg/kg d6 to d13 % survival % survival 100 ACVBP 100 80 80 CHOP 60 60 ACVBP 40 40 20 20 CHOP P = 0.03 P = 0.03 1 2 3 4 5 6 7 8 9 2 4 6 8 Years Years Reyes F et al. NEJM 2005 Tilly H et al. Blood 2003 CH, Berlin EHA 2009

73 LNH 03-2B Lymphomes diffus grandes cellules B
Patients <60 ans IPI=1 R-ACVBP/R-CHOP Voir communication orale: C.Recher ASH 2010

74 Matched control study : Progression free survival
R-ACVBP ACVBP PFS study N Median Min Max Follow-up (months) LNH03-3 181 27 44 LNH98-3 26 47 CH, Berlin EHA 2009

75 Survival with ACVB in LNH Regimens
(in randomized studies) R-ACVBP 3116 patients 75

76 R-CyclOBEAP in young patients with high-risk DLBCL
Niitsu N, Int J Hematol 2010; 92 :

77 Mega-CHOEP with and without Rituximab, Patients with DLBCL: EFS
1.0 .9 .8 with Rituximab n=64 .7 .6 p=0.013 .5 without Rituximab .4 n=29 .3 .2 .1 0.0 1 2 3 4 5 6 Time (years) Glass et al: Ann Oncol 2010, Epub doi: /annonc/mdq235 77 77

78 R Rituximab (375mg/m²) DSHNHL 2002-1 -- R-MegaCHOEP
study design after amendment 1 for CD20-pos. B-NHL PBSC PBSC PBSC mCHOEP I CYC 1500 ADR 70 VCR 2 ETO 600 PRD 500 mCHOEP II CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mCHOEP III CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mCHOEP IV CYC 6000 ADR 70 VCR 2 ETO 1480 PRD 500 1 14 22 36 43 56 64 77 98 R days 1 15 29 43 57 71 85 99 CHOEP-14 CYC 750 ADR 50 VCR 2 ETO 300 PRD 500 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 Rituximab (375mg/m²) PRD and VCR doses are absolute, all others are per m²

79 Progression-free survival
DSHNHL MegaCHOEP Progression-free survival 1 0.9 p=0.119 0.8 0.7 0.6 0.5 0.4 R-CHOEP-14 0.3 R-MegaCHOEP 0.2 0.1 10 20 30 40 50 60 70 Months

80 DSHNHL 2002-1 -- MegaCHOEP Overall survival Months 10 20 30 40 50 60
10 20 30 40 50 60 70 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

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

82 Traitement des rechutes
Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Traitement des rechutes

83 OS (intent to treat) Gisselbrecht C et al, J Clin Oncol 2010; ahead of print, July 26

84 PFS undergoing ASCT (ITT)
Gisselbrecht C et al, J Clin Oncol 2010; ahead of print, July 26

85 Aggressive B-NHL – CORAL Trial - PFS
PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT) PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) N=147 N=241 30% 62% N=160 N=228 31% 64% Gisselbrecht et al JCO 2010, Epub

86 Aggressive B-NHL – CORAL Trial Response- EFS
Failure from diagnosis > 12 months Failure from diagnosis =< 12 months N= 106 N= 41 N= 54 N= 187 Gisselbrecht et al JCO 2010, Epub

87 Allogeneic and autologous SCT in aggressive B cell lymphoma
Aggressive B-NHL Allogeneic and autologous SCT in aggressive B cell lymphoma DSHNHL DSHNHL R3 (B cell lymphoma): HDT + allogeneic SCT CORAL: HDT + autologous SCT 1.0 0.9 0.8 0.7 No prior rituximab: 54.6 (22,9-78,0)%, n=11 0.6 Probability of EFS Probability of EFS 0.5 0.4 0.3 prior rituximab: 34,6 (19,9-49,7)%, n=45 0.2 0.1 0.0 12 24 36 48 60 72 12 24 36 48 Time after Transplant (Months) 87 87 87 87

88 Allogeneic SCT in relapsed DLBCL
Reduced intensity conditioning : Results NRM OS PFS RR sens ref. Thomson et al. JCO 2009; 27 (3): 426 88

89 Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement
Nouveaux traitements

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

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

92 Phase III study testing a maintenance with lenalinomide
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-CHOP Phase I (Tilly H. et al, ongoing) Phase III study testing a maintenance with lenalinomide REMARC study CH, Berlin EHA 2009

93 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

94 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