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

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

Mortalité par cancer par an (nx 1000) en Europe

Age-standardized incidence rates (ASR) of NHL worldwide 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 Lymphomes diffus à grandes cellules B Facteurs pronostiques et traitement Facteurs pronostiques cliniques : l’IPI

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

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

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

RIPI 4-year PFS 4-year OS Sehn et al, Blood 2007; 109 : 1857-61

Comparaison de 4 IPI Advani RH et al, BHJ 2010; 151 : 143-151

Validity of IPI in the rituximab era (german group) Ziepert M., J Clin Oncol 2010; 28:2373-2380

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

Gene expression arrays Subclassification of diffuse large B-cell lymphoma 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 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

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

Stromal 2 N Engl J MED. G. Lenz et al. 2008; 359 (22): 2313-23

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

Ricover study : Hans algorithm Ott G et al, Blood 2010-03-276766

RICOVER study : Hans algorithm All patients : Ott G et al, Blood 2010-03-276766

EFS, R-CHOP patients (52 patients)

Ott et al, Blood 2010

RICOVER study histology Ott G et al, Blood 2010-03-276766

RICOVER study histology Ott G et al, Blood 2010-03-276766

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

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

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 : 128-138

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 : 128-138

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

Smith SM et al, Blood Cells Mol Diseases 2010

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; 28:3360-3365

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

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

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

PET CT for staging TP 15112007

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)

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

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 0 1 2 3 0 1 2 3 Years after randomisation Years after randomisation Haioun C, et al, Blood 2005

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 : 1906-1914

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

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; 25:3746-3752 2007

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;48:1626-32

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

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

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

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 318 307 296 286 271 236 206 163 126 80 34 CHOP plus 329 314 292 280 265 231 199 152 113 70 28 radiotherapy Reyes F. et al, 2005 - NEJM

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 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 9 radiotherapy Bonnet C, Fillet G, JCO 2007

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 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 9 radiotherapy Bonnet C, Fillet G, JCO 2007

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 = 0.0002 0 5 10 15 20 25 30 35 40 45 50 Months Median observation time : 23 months Pfreundschuh M, et al. Blood 2004; 104:40a (Abstract 157)

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

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

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

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 70-74 years 75-80 years 60-69 70-74 75-80 CHOP 40 41 21 R-CHOP 58 55 7-year OS (%)

Overall survival in patients treated with CHOP and R-CHOP(10 years FU) Coiffier, B. et al. Blood 2010;116:2040-2045

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 0.00002 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 < 0.0001 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

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 = 0.000025 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

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

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

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

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

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

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

The ACVBP regimen – a dose-intense chemotherapy regimen LNH93-1: young, good prognosis LNH93-5: 60–70 y, poor prognosis 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 % 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

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

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

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

R-CyclOBEAP in young patients with high-risk DLBCL Niitsu N, Int J Hematol 2010; 92 : 231-237

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:10.1093/annonc/mdq235 77 77

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

Progression-free survival DSHNHL 2002-1 -- 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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