2.  7/100,000  30% of all lymphomas  male predominance  heterogeneous group of tumors consisting of large, transformed B-cells with prominent nucleoli and basophilic cytoplasm, a diffuse growth pattern and a high (>40 percent) proliferation fraction  60% advanced at presentation  BM in 30%; EN 40%

4.  tumor cells in DLBCL generally express pan B-cell antigens (CD19, CD20, CD22, CD79a), as well as CD45, along with monoclonal surface membrane IgM; occasionally other heavy chain isotypes are present.  Ki 67: > 40%  70% BCL-6  25-80% BCL-2  T(14;18) 30%; cmyc translocation 5-15%

5.  T cell rich large B cell lymphoma  Primary diffuse large B-cell lymphoma of the mediastinum, also called primary mediastinal large B-cell lymphoma  Intravascular lymphoma  Lymphomatoid granulomatosis, an Epstein- Barr virus (EBV) positive large B-cell lymphoma

6.  7% of large B cell  Thymic B cell origin  Co-express weakly CD30  Female predominance 4 th decade  Presents with massive mediastinal disease, sometimes with SVC syndrome  Good prognosis  GEP similar to HD

7.  59 y.o lawyer referred for 20 lb weight loss over 3 months, night sweats and new axillary adenopathy. Previously healthy. Grew up on a farm. Non smoker. No family history. Married with 2 kids in university  On exam: looks unwell. Palpable 2-3 cm nodes in axillae, supraclavicular and inguinal regions  Labs: Hgb 120 g/L, LDH 400  CT scans and excisional biopsy ensue

8. Diffuse Large B cell Lymphoma (Aggressive)

10. CT scans of abdomen and pelvis: retroperitoneal nodes and mesenteric nodes  Bone marrow aspirate and biopsy: negative  Gallium scan: gallium avid disease above and below the diaphragm in sites of nodal enlargement  HIV negative  Stage IIIA

11.  How common is this cancer?  What does his sub-type mean?  What causes it? Are his kids at risk?  What is his prognosis?  What treatments are available?  Can we predict if he will relapse?  What if he does relapse?

12. Table 1 Estimated New Cases and Deaths for Cancer Sites by Sex, Canada - 2005

13.  What causes it? Are his kids at risk?  What is his prognosis?  What treatments are available?  Can we predict if he will relapse?  What if he does relapse?

14.  Familial/Genetic (RR=2-3)  Cancer susceptibility genes  Immunosuppression  acquired ▪ AIDS (100x), post transplant (30-50x)  congenital ▪ SCID, CVI, Wiskott Aldrich, AT  Viral:  HIV, HTLV-1(5%), EBV, HHV8, Hepatitis C  Bacterial:  H Pylori (6X)

15.  Occupational  Phenoxyacetic acid herbicides  Farmers: organophosphate insecticides  Fertilizers  solvents  Social  Increased diet of animal protein, fat and meat  Hair dyes

16.  What causes it? Are his kids at risk?  What is his prognosis?  What treatments are available?  Can we predict if he will relapse?  What if he does relapse?

18.  Patients of all ages  Age >=60  LDH > normal  Performance status 2-4  Ann Arbor stage III-IV  Extra-nodal involvement (>1 site) Age adjusted  Stage  LDH  Performance status

19. Armitage and Weisenburger, 1998

20. The International Non-Hodgkin's Lymphoma Prognostic Factors Project, N Engl J Med 1993;329:987-994 Outcome According to Risk Group Defined by the International Index and the Age-Adjusted International Index

21. Bad  Ki-67  P53  CD5+  LDH  B-2-microglobulin  C-reactive protein  BCL-2  C-myc  Survivin  Cyclin D2 Good  CD10  BCL-6  CD40

22. 5 yr OS CD10 negative positive 44% 74% Bcl-6 negative positive 30% 69% Cyclin D2 Negative positive 58% 11% MUM 1 negative postive 66% 36% TMA GCB Non-GCB 76% 34% Hans, C. P. et al. Blood 2004;103:275- 282

23. Rosenwald, A. et al. N Engl J Med 2002;346:1937-1947 Subgroups of Diffuse Large-B-Cell Lymphoma According to cDNA Gene-Expression Profiles

24. Copyright ©2004 American Society of Hematology. Copyright restrictions may apply. Hans, C. P. et al. Blood 2004;103:275-282 Figure 2. Results of immunoperoxidase staining They found that the GCB and non-GCB subtypes of DLBCL could be accurately predicted using a panel of only 3 immunostains

25. Copyright ©2004 American Society of Hematology. Copyright restrictions may apply. Hans, C. P. et al. Blood 2004;103:275-282 Figure 1. Decision tree for immunoperoxidase TMA classification of DLBCL

26.  CD20+  BCL2+  BCL6+  CD10+  Ki67+ 50%  CD5-  CD23-  Cyclin D1- John Has GCB- type DLBCL

27.  What is his prognosis?  What treatments are available?  Can we predict if he will relapse?  What if he does relapse?

28.  Q 3 week cycles  6-8 cycles  Cyclophosphamide 750 mg/m 2  Adriamycin: 50 mg/m 2 day 1  Vincristine 1.4 mg/m 2 IV day 1  Prednisone 100 mg po daily x 5 days

29. Fisher, R. I. et al. N Engl J Med 1993;328:1002-1006 Overall Survival in the Treatment Groups

30. Coiffier, B. J Clin Oncol; 23:6387-6393 2005 Fig 1. (A) Event-free survival, (B) progression-free survival, and (C) overall survival with a median follow-up of 5 years in CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and R-CHOP (rituximab-CHOP) -treated patients in the LNH-98.5 study 28% 50%

31. Coiffier, B. J Clin Oncol; 23:6387-6393 2005 Low Risk 0-1 High risk 2-3

32. Thieblemont, C. et al. J Clin Oncol; 25:1916-1923 2007 Fig 2. Five-year follow-up results of the Groupe d'Etude des Lymphomes de l'Adulte study in patients 60 to 80 years old comparing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with the rituximab plus CHOP (R-CHOP) regimen

33. Fu, K. et al. J Clin Oncol; 26:4587-4594 2008 Fig 3. Subclassification on the basis of the cell of origin was predictive of (A) overall and (B) event-free survival in patients with diffuse large B-cell lymphoma who were treated with rituximab plus standard chemotherapy

34. Fu, K. et al. J Clin Oncol; 26:4587-4594 2008 Fig 2. Addition of rituximab to standard chemotherapy improved the overall and event-free survival of patients in both the (A, B, respectively) germinal center B-cell-like and the (C, D, respectively) non- germinal center B-cell-like subgroups of diffuse large B-cell lymphoma

35. CD20 + DLBCL 18-60 years IPI 0,1 Stages II-IV, I with bulk 6 x CHOP-like + 30-40 Gy (Bulk, E) 6 x CHOP-like + Rituximab + 30-40 Gy (Bulk, E) Random. Trial Design

36. Chemo (n=411) R-Chemo (n=413) Complete remission (CR/CRu) 68%* 86%* Partial remission (PR) 12%7% No change (NC)4%1% Progressive disease (PD)11%**4%** ** p=0.0018 (Fisher’s exact test) * p<0.0005 (Fisher’s exact test) Remission Rates

37. R-CHEMO CHEMO p < 0.000005  crit = 0.00192 * 81% 58% Median time of observation: 24 months 0.0 5101525 30 354550 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0 M o n t h s Probability FTF 1.0 2040 *:  -crit for updated interim analysis Time to Treatment Failure

38. p=0.0026 Median time of observation: 24 months 0.0 510152530354550 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0 M o n t h s Probability Survival 1.0 R-CHEMO CHEMO 2040 95% 85% Overall Survival

39.  Improved overall survival of 10-14%  Improved progression-free survival of 20- 23%  Well tolerated, safe with no excess increased toxicity  Adds roughly $16,000 extra to cost of CHOP

40.  Should he have 6 or eight cycles of CHOP-R?

41. Six, not eight cycles of bi-weekly CHOP with rituximab (R-CHOP-14) is the preferred treatment for elderly patients with DLBCL: results of the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) RICOVER 60 M. Pfreundschuh, M. Kloess, R. Schmits, S. Zeynalova, E. Lengenfelder, A. Franke, H. Steinhauer, M. Reiser, M. Clemens, C. Nickenig, M. de Wit, A. Ho, H. Eimermacher, L. Truemper, M. Hoffmann, R. Mertelsmann, B. Metzner, H. Mergenthaler, R. Liersch, U. Duehrsen, L. Balleisen, F. Hartmann, V. Poeschel, N. Schmitz, M. Loeffler for the DSHNHL

42. Questions addressed Can CHOP-14 be improved by rituximab? Are 8 cycles better than 6? RICOVER 60: objectives

43. CD20 + DLBCL stages I–IV 61 – 80 years Random 2x2 Factorial design 6 x CHOP-14 + 36 Gy (Bulk, E) 8 x CHOP-14 + 36 Gy (Bulk, E) 6 x CHOP-14 + 36 Gy (Bulk, E) + 8 x rituximab 8 x CHOP-14 + 36 Gy (Bulk, E) + 8 x rituximab 8 doses of rituximab regardless of number of cycles of chemotherapy

44. CHOP-14 vs R-CHOP-14 Failure-free survival (%) 8 x (R)-CHOP-14 (n=415) 6 x (R)-CHOP-14 (n=413) p=0.000025  -crit* = 0.031 57% 70% 64% 62% p=0.23 Failure-free survival (%) 100 80 60 40 20 0 100 80 60 40 20 0 6/8 x R-CHOP-14 (n=414) 6/8 x CHOP-14 (n=414) 051015202530354045 Months 6 cycles vs 8 cycles RICOVER 60: time to treatment failure

45. 53% 58% p=0.125 p=0.724 70% 8 x R + 6 x CHOP-14 vs 8 x R-CHOP-14 100 80 60 40 20 0 051015202530354045 Months Failure-free (%) 8 x CHOP-14 (n=210) 6 x CHOP-14 (n=204) Failure-free (%) 100 80 60 40 20 0 8 x R-CHOP-14 (n=203) 8 x R + 6 x CHOP-14 (n=211) 051015202530354045 Months 6 x CHOP-14 vs 8 x CHOP-14 RICOVER 60: time to treatment failure

46. Median time of observation: 26 months Surviving (%) 100 80 60 40 20 0 051015202530354045 Months 6 x CHOP-14 (n=204) 8 x R + 6 x CHOP-14 (n=211) 8 x CHOP-14 (n=210) 8 x R-CHOP-14 (n=203) RICOVER 60: survival

47.  Should He Have Maintenance Therapy?

48. ECOG 4494 Phase III Trial: R-CHOP v CHOP +/- MR RANDOMIZEDRANDOMIZED Stratified by IPI (0-1 vs 2-4) Stratified by IPI (0-1 vs 2-4) CHOP 1 1 2 2 3 3 cycle 4 4 5 5 6 6 7 7 8 8 Rituximab RANDOMIZEDRANDOMIZED Stratified by IPI CR/PR; Induction Stratified by IPI CR/PR; Induction Maintenance Rituximab (MR) q 6 m x 2 yr Maintenance Rituximab (MR) q 6 m x 2 yr Observation (N=632) (N=415) 1 1 2 2 3 3 cycl e 4 4 5 5 6 6 7 7 8 8

49. Treatment 2 year FFS* 2 year OS R-CHOP + MR79% 87% R-CHOP + OBS77% 85% CHOP + MR74% 83% CHOP + OBS45% 72% * Significant FFS interaction (HR=2.10, p=0.05) This is the data on responding patients. This is the data on responding patients.

52.  How common is this cancer?  What does his sub-type mean?  What causes it? Are his kids at risk?  What is his prognosis?  What treatments are available?  Can we predict if he will relapse?  What if he does relapse?

53. Spaepen, K. et al. J Clin Oncol; 19:414-419 2001 Fig 4. Kaplan-Meier estimate of PFS in 26 patients with a positive [18F]FDG-PET after therapy compared with 67 patients with a negative [18F]FDG-PET after therapy N=26 N=67

54. Spaepen, K. et al. J Clin Oncol; 19:414-419 2001 Fig 2. Prognostic value of [18F]FDG-PET scan in a patient with presumed CR on CDM. Residual FDG-uptake cervical (left) and mesenteric (right). Patient relapsed after 838 days; a cervical biopsy was positive for NHL

55.  John returns to work  He is followed every 3 months for the first 2 years  At his 18 month visit, he complains of a new 2 cm neck node  An excisional biopsy confirms DLBCL identical to initial biopsy  On re-staging, he is found to be stage IIA, IPI LI

56. Options:  Salvage chemotherapy  Cisplatin or gemcitabine based  Salvage chemotherapy followed by ASCT  25% chance of 2 year disease free survival  Palliative radiation or low dose chemotherapy  Survival 6 months  Rituxan alone  Overall response 35%; time to progression 2 months  Radioimmunoconjugates

57. AutologousAllogeneic Availability90%25% Exploits dose- response yes Graft vs. lymphomanoyes Graft vs. Hostnoyes Graft contaminationlikelyno Treatment Related Mortality 2-5%20-30% Curative30%50%

58. Philip, T. et al. N Engl J Med 1995;333:1540-1545 Kaplan-Meier Curves for Event-free Survival of Patients in the Transplantation and Conventional-Treatment Groups

59. Philip, T. et al. N Engl J Med 1995;333:1540-1545 Kaplan-Meier Curves for Overall Survival of Patients in the Transplantation and Conventional-Treatment Groups

60. Fenske TS, et al. ASH 2007. Abstract 19. Patients with DLBCL in GBMTR database, 1996-2003 (N = 1006) Rituximab within 3 months of AuHCT (n = 188) AuHCT No Rituximab within 3 months of AuHCT (n = 818) CharacteristicRituximab (n = 188) No Rituximab (n = 818) P Value Median age, yrs (range)58 (20-76)52 (18-75)<.001 Karnofsky performance score < 90%, %3937.52 Largest mass size ≥ 5 cm before AuHCT, %2835.28 > 2 chemotherapy regimens given, %5640<.001 Year of AuHCT  Between 1996 and 1998  Between 1999 and 2001  Between 2002 and 2003 4 47 49 59 34 7 <.001  Retrospective analysis

61. Fenske TS, et al. ASH 2007. Abstract 19. Progression-Free Survival Percentage of Patients Rituximab (n = 188) No Rituximab (n = 818) Overall Survival 62 49 39 49 38 32 0 20 40 60 80 100 Year 1 P =.002 P =.01 P =.16 Year 3Year 5 68 57 48 60 45 40 P =.032 P =.003 P =.13 Year 1 Year 3Year 5 0 20 40 60 80 100

63. StudyNDesignPFS (p value)OS (p value) Miller NEJM 1998 401CHOP x 3 + IF RT CHOP x 8 77% 64% (.03) 82% 72% (.02) Bonnet JCO 2007 576 (age > 60) CHOP x 4 CHOP x 4 + IF RT 61% 64% (NS) 72% 68% (NS) Reyes NEJM 2005 648 (age < 61) CHOP x 3 + IF RT ACVBP + Seq consolidation 74% 82% (<.001) 81% 90% (.001)

64. Persky, D. O. et al. J Clin Oncol; 26:2258-2263 2008 Fig 1. (A) Progression-free and (B) overall survival of 60 eligible patients enrolled in a Southwest Oncology Group (SWOG) trial of three cycles of R-CHOP followed by involved-field radiation therapy

65. Persky, D. O. et al. J Clin Oncol; 26:2258-2263 2008 Fig 3. Overall survival of 60 eligible patients receiving R-CHOP(3) plus IFRT (from S0014) is compared with that of 68 eligible patients receiving CHOP(3) plus IFRT (from S8736), matched for limited disease, aggressive B-cell histologies, and presence of at least one stage-modified International Prognostic Index (IPI) risk factor Stage Modified IPI: age, stage 2, LDH and ECOG

66.  CHOP-R x 3 + IF RT  Patients with more than 1 RF on stage modified IPI might do as well with chemo alone x 6-8 cycles  This excludes bulky disease  No benefit to IF rads if 6-8 cycles chemo

67.  Radioimmunotherapy  Protein Kinase-C inhibitors  Velcade  Angiogenesis Inhibitors  Anti-BCL-2  Revlimid  Galiximab and epratuzumab  Newer humanized Rituxan  EPOCH-R

68.  LY-11: RCT of CHOP-r x 8 vs. CHOP-R x 6 then ASCT in newly diagnosed age < 65 with DLBCL with 2-3 aaIPI factors  Ly-12: RCT of R-DHAP vs. R-GDP in relapsed DLBCL or transformed NHL f/B ASCT then 2 nd randomization to R maintenance or observation  Sunitinib in relapsed DLBCL or primary mediastinal large cell NHL (pending)  Risk stratification by PET scans with modified therapy?

69.  NHL is the fifth most common cancer  Large cell lymphoma comprises 30% of all lymphomas  Untreated, survival in months  60% are curable today  Rituxan + anthracycline containing chemotherapy standard upfront  New techniques for prognosis and prediction of relapse  High dose chemotherapy and stem cell transplant is recommended for young relapsed patients  The roles of RIT and PET and new agents are emerging  The role of maintenance immunotherapy unknown at this time