1. Corinne Haioun Unité Hémopathies Lymphoides Hôpital Henri Mondor Créteil, France PET and Lymphoma

2. First and only rule: to cure the patient with first-line treatment Residual masses at the end of therapy are frequent (70% HL, 50% NHL) but only a minority of patients relapse (<20% HL, 25% NHL) Patients in apparent complete remission also relapse Early treatment of residual activedisease may improve survival Need for an accurate and sensitive tool to detect residual disease PET and Lymphoma : Background

3. Hodgkin Lymphoma is a curable disease, with more than 75% of the patients free of disease 10 years or more after standard treatment. However, nearly 15-20% of the patients treated with ABVD fail therapy either for progression or relapse. FDG-PET scan could be a surrogate test for chemosensitivity, due to its ability to predict treatment outcome with an overall accuracy of 90-95%. PET and Hodgkin Lymphoma : Background

4. HD prognostic score: clinical variables Hasenclever d. NEJM 1998; 339:1506

5. HD prognostic score: 7y-FFP and OS Hasenclever d. NEJM 1988; 339:1506 7% of the patients

6. According to IPSAccording to PET-2 (+vs.-) and IPS (0-2 vs 3-7) HL prognosis: from IPS to PET Intergruppo Italiano Linfomi

7. PET-0: 25.03.04 PET-2: 30.06.04 PET-6: 08.11.04 Gallamini: Hematologica 2006; 91, 475-81Gallamini: JCO 2007; 25, 3743-52 Hutchings: Blood 2006; 107, 52-59Kostakoglu: Cancer 2006; 107:2678-87

8. H10 Trial Randomisation FDG- PET 1 cycle ABVD IN-RT 30 Gy (+boost 6 Gy résiduals) whatever Favourable Group F Unfavourable Group U Randomisation ABVD 2 cycles FDG- PET FDG- PET FDG- PET ABVD 2 cycles BEACOPP 2 cycles esca IN-RT 30 Gy (+ boost 6 Gy) ABVD 4 cycles 2 cycles BEACOPP esca IN-RT 30 Gy (+ boost 6 Gy) ABVD 2 cycles IN-RT 30 Gy (+boost 6 Gy résiduels) négative positive negative positive The results whatever The results Second registration First registration Hodgkin Lymphoma Stage I/II

9. The situation in Diffuse Large B-Cell Lymphoma Weber W: J.Nucl. Med 2007: 48: 1580-82.

10. Current questions for DLBCL patients Role of PET to individualize treatment ? PET– (n = 54) PET+ (n = 36) Probability p < 0.0001 Years after randomisation Event-free survival p = 0.006 Overall survival 100 0123012301230123 Years after randomisation Pprobability 80 60 40 20 0 80 60 40 20 0 PET– (n = 54) PET+ (n = 36) Interim PET after 2 cycles may help stratify patients ? Haioun C, et al. Blood 2005

11. All the sites of FDG uptake are scored in PET-0 and PET-2. Each FDG uptake focus is quantified according to a score graded 1-3 (1 low, 2 moderate, 3 high) for extension and intensity PET-2 negative: Negative was defined as having no residual abnormal uptake or as having a unique residual site (with an extent score of 1) associated with an intensity score of 1, whereas all the other previously hypermetabolic sites were extinguished. PET-2 positive: Positive was defined as having at least one residual site (with an extent score of 1) associated with an intensity score of 2, or as having 2 or more residual sites with any extent and intensity scores. Haioun, Blood 2005; 106: 1376-1381 Early (after 2 cycles) PET treatment evaluation with visual analysis

12. Before treatmentAt 2 cyclesAt 4 cycles FDG-PET2 (+) Early treatment evaluation Haioun C, et al. Blood 2005; 106(4): 1376–81

13. FDG-PET2 (-) Before treatmentAt 2 cyclesAt 4 cycles Early treatment evaluation Haioun C, et al. Blood 2005; 106(4): 1376–81

14. 2-year outcome Study nPET after...PET-PET+ Jerusalem 2000 28median: 3 cycles 62% (PFS)0% (PFS) Spaepen 2002 70median: 3 cycles 85% (PFS)4% (PFS) Kostakoglu 2002 301 cycle85% (PFS)<15% (PFS) Haioun 2005 902 cycles82% (EFS)43% (EFS) Michaël 2005 121median: 2 cycles 87% (PFS)34% (PFS) Jerusalem et al. Haematologica, 85(6): 613-8 2000; Spaepen et al. Ann Oncol, 13(9): 1356- 63 2002; Kostakoglu et al. J Nucl Med, 43(8): 1018-27 2002; Haioun C et al. Blood 2005; 106(4): 1376–81; Mickaeel et al. 2005 Current questions for DLBCL patients Role of PET to individualize treatment ?

15. (High negative predictive value): NPV= TN TN +FN (Low positive predictive value): PPV= TP TP +FP FN FP FDG-PET in DLBCL

16. 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 < 0.0001 Years after randomisation Event-free survival p = 0.006 median f/u: 2 years Overall survival 100 0123012301230123 Years after randomisation probability of OS 80 60 40 20 0 80 60 40 20 0 Haioun C, et al. Blood 2005; 106(4): 1376–81 PET– (n = 54) PET+ (n = 36) PPV 50 % NPV 74 % Accuracy 68.5%

17. (Bq/g) Activité injectée Poids du corps C* totale = (Bq/g) Activité mesurée Volume du foyer C* tissulaire = C* tissulaire C* totale SUV = Si distribution homogène, SUV = 1  =1g/cm 3 SUV= Ci*(  ) dose/poids

18. Lin C.: J. Nucl. Med 2007; 48, 1626-1632 92 patients PET baseline and after 2 courses of CT IPI 0-1: 38; IPI 2-3: 54 Therapy: CHOP, R-CHOP, ACVPB/ACE, R- ACVBP

19. SUV-based Assessment versus Visual Analysis SUV and EFS : Optimal cut-off point of SUVmax reduction: 65.7% (ROC analysis) Lin C, Itti E. JNM 2007; 48:1626-32. PPV 81.3% NPV 75.0% Accuracy 76.1%

20. Months After Randomization > 65.7%  65.7% SUV max Reduction P <.0001 Probability of EFS (%) Visual Analysis PET (-) PET (+) P =.009 Visual Analysis versus SUV-based Assessment n=34 n=58 n=76 n=16 Linh C, Itti E. JNM 2007; 48:1626-32.

21. MSKCC 01-142-DLBCL: Risk Adapted Therapy Transplant-eligible, CS IIX, III or IV age-adjusted IPI 1, 2, or 3 Risk Factors Therapy interval-2 weeks with peg- filgrastim support PET 10-14 days post cycle 4 Treatment is adapted by biopsy, not PET No radiation therapy permitted except for testicular disease IT methotrexate for aaHR, paranasal sinus, testis, BM Moskowitz et al., Blood 108: Abstract 532, 2006

22. MSKCC 01-142-DLBCL: Risk Adapted Therapy Transplant-eligible, CS IIX, III or IV age-adjusted IPI 1, 2, or 3 Risk Factors

23. Outcome based upon Interim Restaging PET scan Interim PET does not predict EFS Moskowitz et al., Blood 108: Abstract 532, 2006

24. Optimize PET interpretation PET data sent over the internet via a dedicated server to 3 readers: review in 48 hours Medical Gateway Anonymization Double encryption Time : 10 mn 3 Readers Time : 10 mn Current questions for DLBCL patients Role of PET to individualize treatment ?

25. LNH07-3B DLBCL ; <60 years aa-IPI = 2-3 Role of PET to individualize treatment ?

26. Acknowledgements Lymphoma Unit –Karim Belhadj –Taoufik El Gnaoui –Isabelle Gaillard –Jehan Dupuis –Frederique Kuhnowski Radiology –Alain Luciani –Alain Rahmouni Biostatistics –François Hémery –Eric Lepage Nuclear Medicine –Emmanuel Itti –Eva Evangelista –Sophie Lin –Michel Meignan Hematopathology –Christiane Copie –Karen Leroy –Philippe Gaulard