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Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement André Bosly, M.D., Ph.D. Université de Louvain Mont-Godinne, Belgique ESH Tunis,

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1 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 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 Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Facteurs pronostiques cliniques : lIPI

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

9 Survival according to IPI score 6696 patients included in GELA randomized studies Overall survivalProgression-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– Low–intermed High–intermed High 4– Revised IPI Very good Good 1– Poor 3– Sehn LH et al, Blood 2007; 109:1857–1861

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

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

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

14 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) Cell of Origin Oncogenic Mechanisms Clinical Outcome Germinal center B cell ? Post-Germinal Center B cell - t(14;18) translocation of BCL-2 - Chr. 2p amplification of c-rel locus Constitutive activation of NF-kB 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 Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Facteurs biologiques : expression de gènes en immunohistologie

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

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

29 EFS, R-CHOP patients (52 patients)

30 Ott et al, Blood 2010

31 Ott G et al, Blood RICOVER study histology

32 Ott G et al, Blood RICOVER study histology

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

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

35 de Jong D et al, J Clin Pathol 2009; 62 : CV1=2; CV2=1CV1=26; CV2=4 CV1=20; CV2=11CV1=15; CV2=16 Lunenburg consortium

36 CV1=31; CV2=21CV1=23; CV2=20 CV1=21; CV2=11CV1=27; CV2=21 de Jong D et al, J Clin Pathol 2009; 62 : Lunenburg consortium

37 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 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: Réarrangement de c-myc et DLBCL

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

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

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

43 TP PET CT for staging

44 2-year outcome Study nPET after...PET-PET+ Jerusalem Median : 3 cycles62% (PFS)0% (PFS) Spaepen Median : 3 cycles85% (PFS)4% (PFS) Kostakoglu cycle85% (PFS)<15% (PFS) Haioun cycles82% (EFS)43% (EFS) Mickaeel Median : 2 cycles87% (PFS)34% (PFS) Early treatment evaluation

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

46 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) Probability of EFS p< Years after randomisation Event-free survival p=0.006 Median follow-up: 2 years Overall survival Years after randomisation Probability of OS Haioun C, et al, Blood 2005

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

48 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

49 Gallamini, A. et al. J Clin Oncol; 25: Interim PET in ABVD-treated HL patients SUV = 3.5

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

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

52 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 R weeks ACVBP CHOP Methotrexate 3g/sqm + rescue Ifosfamide 1500 mg/sqm Etoposide 300 mg/sqm Cytarabine 100mg/sqm x4 InductionConsolidation ACVBP 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 CHOP Doxorubicin : 50 mg/sqm D1 Cyclophosphamide : 750 mg/sqm D1 Vincristine : 1,4 mg/sqm D1 Prednisone : 40 mg/sqm D1-5 involved field radiotherapy, 40 Gy (5 x 1,8 Gy / week) 1820

54 ACVBP CHOP plus radiotherapy probability of Overall Survival P = No. at risk ACVBP CHOP plus radiotherapy m f-up : 7.7 y years after randomization The LNH93-1 study : overall survival Reyes F. et al, NEJM

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

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

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

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

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

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

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

62 Overall survival according to age years75-80 years70-74 years CHOP R-CHOP year OS (%)

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

64 NChemoResponse (%) Rituximab benefit EFS or PFSOS GELA Elderly (60–80) CHOP-21 x 8 76 vs 63 p = RICOVER Elderly (61–80) CHOP-14 x 6 CHOP-14 x 8 78 vs vs 72 < * HOVON/NORDIC Elderly (65–80) CHOP-14 x 8ND< Intergroup USA 4 (Habermann) 632 Elderly (> 60) CHOP-2177 vs MInT Young (18–60) Low risk CHOP-21 or others 86 vs 68 p < < British Columbia All ages CHOP-likeND0.002< Czech Republic Young CHOP-likeND 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

65 RICOVER-60 : Improved TTF with 8 x rituximab + 6/8 x CHOP-14 R-CHOP-14 vs CHOP-14 Time (months) Probability 6 cycles vs 8 cycles 8 x (R)-CHOP-14 (n = 415) 6 x (R)-CHOP-14 (n = 413) Time (months) Probability p = x rituximab + 6/8 x CHOP-14 (n = 414) 6/8 x CHOP-14 (n = 414) p = α-crit* = Pfreundschuh M et al, Blood 2006;108:Abstract 205 * R-CHOP-14 vs CHOP-14

66 LNH 03-6B : Study Design Filgrastim or Pegfilgrastim according to physiciansdecision 3 months C5 FU1 R Response R-CHOP14 + IT MTX R-CHOP21 Response C2 C7 C8 C1 C2 C3 C4 C5 C6C7 C8 FU1 FU0 FUn R-CHOP21 + IT MTX Response C1 FUn FU0 R-CHOP14 C3 C4 C6 3 months Delarue et al Ash2009

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 Dose-intensity Is R-CHOP14 given every 14 days ? R-CHOP14R-CHOP21 Median interval between two cycles 15 days (9 – 70) 21 days (19 – 63) Median dose-intensity R-CHOP14R-CHOP21 CPM84 %96% DOX83 %95 % 18/103 patients in R-CHOP14 group received R-CHOP 18 R-CHOP14R-CHOP21 G-CSF use90 %68 % R-CHOP14 = 125 % of R-CHOP21

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

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

71 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 Reyes F et al. NEJM 2005 ACVBP CHOP P = Years % survival Tilly H et al. Blood 2003 LNH93-5: 60–70 y, poor prognosis Years % survival P = 0.03 ACVBP CHOP Doxorubicin 75 mg/m² d1 Cyclophosphamide 1200 mg/m² d1 Vindesine 2 mg/m² d1, d5 Bleomycin 10 mg d1, d5 Prednison 60 mg/m² d1 to d5 MTX intra-thecal 15 mg d2 G-CSF 5 µg/kg d6 to d13 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 studyNMedianMinMax Follow-up (months)LNH Follow-up (months)LNH Matched control study : Progression free survival PFS R-ACVBP ACVBP CH, Berlin EHA 2009

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

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

77 77 EFS with Rituximab without Rituximab 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: /annonc/mdq235

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

79 DSHNHL MegaCHOEP Progression-free survival Months R-CHOEP-14 R-MegaCHOEP p=0.119

80 DSHNHL MegaCHOEP Overall survival

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

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

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

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

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

86 Failure from diagnosis > 12 monthsFailure 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

87 87 Aggressive B-NHL Allogeneic and autologous SCT in aggressive B cell lymphoma Probability of EFS CORAL: HDT + autologous SCT Time after Transplant (Months) DSHNHL R3 (B cell lymphoma): HDT + allogeneic SCT Probability of EFS No prior rituximab: 54.6 (22,9-78,0)%, n=11 prior rituximab: 34,6 (19,9-49,7)%, n=45

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

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

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

91

92 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-CHOP Phase I (Tilly H. et al, ongoing) CH, Berlin EHA 2009

93 Conclusions (1) Les lymphomes diffus à grandes cellules sont les LNH les plus fréquents LIPI 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 Lévaluation de la réponse par TEP est prédictive de lévolution 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 Lallogreffe avec conditionnement non myélo- ablatif est une option en cas de mauvais pronostic


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