1. DLBCL Matthew Cheung Sunnybrook Health Sciences Centre November 2011

2. Outline Review of DLBCL –A focus on key trials/advances –Highlights of disease/treatment mechanisms Advanced stage Limited stage Relapsed

4. Key Points Current classification system - WHO Follicular (22%) Diffuse large B cell (31%) Small lymphocytic (6%) Mantle cell (6%) Peripheral T cell (6%) Marginal zone B cell, MALT (5%) Other subtypes with a frequency < 2% (9%) Marginal zone B cell, nodal (1%) Lymphoplasmacytic (1%) Composite lymphomas (13%)

5. Ann Arbor Staging Lymphomation.com

6. Comparison of CHOP with Three Intensive Chemotherapy Regimens for Advanced NHL Fisher, NEJM 1993 Overall Survival

7. CD20: An Ideal B-cell Target 297 amino acid membrane-associated phosphoprotein (33–37 kD) –Not shed –No known membrane/secreted molecular analogues (target interference) –Calcium channel function (?) B-cell lineage antigen, not on: –Stem cells, early pre-B cells, or plasma cells Anti-CD20 binding: –Does not down-modulate expression of CD20 –Does not cause internalization of CD20 Johnson P, Glennie M. Semin Oncol. 2003;30:3-8. Golay J et al. Blood. 2000;95:3900–3908.

9. Mechanisms of Antibody-Mediated Cell Killing Antibody-dependent cellular cytotoxicity (ADCC) Apoptosis via induction of intracellular signaling pathways Complement-dependent cytotoxicity (CDC) Target cell NK cell Basic Science - Mechanism

10. Coiffier, NEJM 2002

11. Clinical trials –Infusional side effects (~10% grade III/IV) 2009 - product monograph –Hepatitis B reactivation (1 in 10,000) –Bowel perforation (1 in 20,000) –PML (cases)

12. International Prognostic Index One point each for: Age >60 years Performance status 2+ LDH >ULN Stage III or IV More than one extranodal site Low risk: 0-1 factor, Int: 2-3, high: 4-5

13. IPI

14. Risk Group # Factors % Patients 4-year PFS (%) 4-year OS (%) Very Good 01094 Good1,2458079 Poor3,4,5455355 Sehn et al, ASH 2006 Outcome According to Revised IPI (R-IPI)

15. Progression-Free Survival According to Revised IPI (R-IPI) Percent Survival Very Good Good Poor P<0.0001

16. DLBCL (ABC type)

17. GCB subtype correlated with better survival NEJM, 2002

18. IHC can be used to differentiate GC vs. non-GC

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

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

21. Rituximab + CHOP is recommended in all the following except? Transformed NHL (FL --> DLBCL) Primary Mediastinal B-cell Lymphoma DLBCL HIV-related DLBCL Pediatric DLBCL

22. Kaplan et al. (AMC Study), Blood 2005 AMC RCT of CHOP-R vs. CHOP (+ HAART) AMC RCT of CHOP-R vs. CHOP (+ HAART) CHOP + RCHOPp-value Regimen CHOP+R + rituximab q month x3 CHOP n9647 CR57%49%NS Death due to lymphoma 10%19.5%NS

23. Rituximab and Infection Kaplan et al. (AMC Study), ASH 2003 CHOP + RCHOPp-value Infectious deaths 14%2%0.027 n=14 patients dying of infection -7 culture-positive sepsis -4 culture-negative sepsis -2 pneumonia -1 fungal 60% deaths in patients with CD4 <50 40% deaths during the maintenance phase of R

24. Alternatives to R-CHOP-21 R-CHOP-14 (GELA study) R-EPOCH –Dose-adjusted/continuous infusion –Phase III pending

25. LNH03-6B GELA Trial IPI ≥1, age 60-80 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

26. 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 Cyclo84 %96% Dox83 %95 % 18/103 patients in R-CHOP14 group received R-CHOP ≥ 18 days R-CHOP14R-CHOP21 G-CSF use90 %68 % R-CHOP14 = 125 % of R-CHOP21

27. Hematologic toxicities greater for R-CHOP14 Patients on R-CHOP14 had higher rates of febrile neutropenia, hospitalization, and death due to toxicity LNH03-6B GELA Trial: Toxicities Delarue R, et al. ASH 2009. Abstract 406. R-CHOP14 R-CHOP21 11 15 22 21 36 50 22 26 69 83 73 83 Patients (%) 100 90 80 70 60 50 40 30 20 10 0 Grade 3/4 Leukocytes Grade 3/4 Neutrophiles Grade 3/4 Hemoglobin RBC Transfusion Grade 3/4 Platelets Platelet Transfusion

28. LNH03-6B GELA Trial: Results Delarue R, et al. ASH 2009. Abstract 406. OutcomeR-CHOP21 (n = 99) R-CHOP14 (n = 103) P Value 2-yr EFS, %6148.11 Median EFS, mosNot reached22-- 2-yr PFS, %6349.12 Median PFS, mosNot reached23-- 2-yr OS, %7067.37  CR + CRu7567NS  ORR8481NS

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

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

31. Role of upfront high-dose therapy and ASCT? Prior to rituximab era: –Phase II studies suggested 60-80% of high-risk aggressive lymphomas could achieve long-term PFS. –Eleven phase III studies have now addressed this question – mixed results –Meta-analyses – heterogeneity and conflicting results preclude definite answer re: benefit of HDT/ASCT Low-risk patients do not benefit compared to conventional therapy Benefit in the era of rituximab unknown –ASBMT – upfront transplant indicated for high-intermediate and high-risk IPI groups –NCCN – appropriate for trials

32. Randomized phase III U.S./Canadian intergroup trial (SWOGS9704) comparing CHOP-R for eight cycles to CHOP-R for six cycles followed by autotransplant for patients with high-intermediate (H-Int) or high IPI grade diffuse aggressive non-Hodgkin lymphoma (NHL) Study design: Stiff PJ Abstract 8001 ASCO 2011

33. Outcome % ASCT armConventional arm Hazard ratioP-value 2-year PFS69561.72.005 2-year OS74711.24.16 Stiff PJ Abstract 8001 ASCO 2011

35. Other Alternatives: Cardiac toxicity –Substitution of etoposide (R-CEOP) –ASH 2009 –50mg/m2 day 1 and 100mg/m2 po days 2-3 –Pts with LV dysfunction or intolerance of doxorubicin –BCCA Retrospective/Population review (n=81)

36. Elderly R-mini-CHOP (ASH 2010) doxorubucin 25mg/m2 N=151 patients ORR 74% (CR 40% and CRu 23%) 2-year PFS 47.4% 2-year OS 59% FN 7% Pre-treatment (vincristine/prednisone) Liposomal doxorubicin DA-(E)POCH

37. Revised Response Criteria for Malignant Lymphomas from the Members of the International Harmonization Project of the Competence Network Malignant Lymphoma Cheson BD, Pfistner B, Juweid ME, Spect L, Rosen ST, Gascoyne R, Stroobants S, Diehl V.

38. Rationale IWG response criteria (1999) extranodal sites not included dependent on older technologies/methods –CXR/CT/MRI unable to distinguish tumour vs. necrosis –SPECT-gallium outdated unclear (?CRu)

39. Response Assessment of Aggressive NHL Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005 IWC + PET IWCCRCRuPRSDPDTotal CR170000 CRu502007 PR10090019 SD201609 PD100012 Total350126154

40. Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005 IWC + PET IWCCRCRuPRSDPDTotal CR170000 CRu502007 PR10090019 SD201609 PD100012 Total350126154

41. Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005 IWC + PET IWC CRCRuPRSDPDTotal CR170000 CRu502007 PR10090019 SD201609 PD100012 Total350126154

42. Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005 Progression-free survival by the International Workshop Criteria (IWC) and IWC plus positron emission tomography (PET) based on the Kaplan- Meier method

43. IHP Recommendations FDG PET or PET/CT should be integrated into new IWG criteria Pre-treatment - recommended, not required Response assessment –required for DLBCL/HL CR - new definition No clinical evidence of disease or symptoms Residual mass/node of any size allowable if PET negative if typical FDG-avid lymphoma or PET positive prior to treatment Regression to 1.5 cm pretreatment if variable FDG-avid lymphoma or PET negative prior to treatment Bone marrow negative CRu - now obsolete

44. Conclusion - Advanced DLBCL R-CHOP x 6 cycles is the standard of care –In elderly population: expect to cure ~60% expect long-term survival ~70% –6 cycles equivalent to 8 cycles (and less neurotoxicity) –R-CHOP-21 likely as good as R-CHOP-14 (and better tolerated) –Role of upfront ASCT – still unclear –Rituximab not recommended for HIV+ DLBCL –No role for maintenance rituximab in DLBCL Prognosis –Improved in the rituximab era –Also determined by gene expression profile Response criteria –PET is now included at the end of therapy to confirm CR vs. PR (and eliminate CRu designation)

46. Eligible Patients Stage I – II aggressive NHL CHOP x 3 + IF-RT 40 - 55 Gy CHOP x 8  SWOG prospective RCT of 401 patients  Patients with bulky ( > 10 cm ) stage II were not included

48. Miller et al Update: Ann Hematol 2001; 80 Results: With a median FU of 8 years: PFS and OS overlap at 7 and 9 years respectively Published only as an abstract

49. Updated SWOG study –suggests that XRT cannot replace inadequate/abbreviated chemotherapy Is there a group of patients that do well with abbreviated chemotherapy + RT?

50. Fisher, Miller et al Am Soc Hematol Educ Program 2004: 221-236 Patients with unfavourable risk factors do poorly with only 3 cycles of CHOP In contrast, in patients with no stage adjusted risk factors, 3 CHOP + RT yielded a 5Y OS of 94% Updated analysis of SWOG 8736 accounting for IPI risk factors

51. IS THERE ANY ROLE FOR RT? Horning JCO 2004 8 CHOP 8 CHOP + RT 6Y DFS 56% 73%p = 0.05 6Y TTP67%80%p = 0.06 6Y OS71% 82%p = 0.24 For patients in CR after CHOP, low-dose RT prolonged DFS and improved local control, but yielded no survival benefit

52. Exam Answer: CHOP-R x 3 cycles and IFRT –However….if >1 IPI risk factor - evolving evidence suggests high risk of late (?distant) relapses - would recommend 6 cycles –IFRT appears to improve long-term local control

53. Failure of Primary Therapy Patients who relapse after a good response have poor prognosis Patients who progress on therapy do even worse Only curative potential is aggressive chemotherapy followed by stem cell transplantation –<65 years –Functionally well

54. Parma Study

55. RANDOMISEDRANDOMISED ARM 1: R maintenance ARM 2: Observation C1C2C3 C1C2C3 S0S3S6 S0S3S6 Evaluation ARM B: R-DHAP ARM A: R-ICE S9 BEAM + autograft Evaluation +M1+M3+M5+M9+M7+M11+M12 +M3+M7+M12 RANDOMISEDRANDOMISED CORAL trial: R-ICE vs R-DHAP

56. Coral Study: Patient Characteristics Chemotherapy:CHOP-like85% ACVB-like13% rituximab62% ─ Local radiation23% Age-adjusted IPI0,1 50% (PS, stage, LDH) 2,3 50% Prior CR/CRu 65% progression on Rx 11%

57. CORAL: main results Response ICEDHAP CR36%40% Overall 63% 64% C Gisselbrecht, et al, J Clin Oncol 2010

58. Secondary analysis: importance of prior rituximab, time to progression Progression < 12 mosProgression > 12 mos C Gisselbrecht, et al, J Clin Oncol 2010

59. At a median follow-up of 45 months, mobilization-adjusted ORR comparable after induction therapy –51.5% for R-ICE vs 56.5% for R-DHAP –Fewer adverse events observed with R-ICE EFS and OS rates comparable between R-ICE (29% and 48%, respectively) and R- DHAP (33% and 51%) Nearly all patients achieved PR or better after induction therapy Outcome 4- years %R-maintenanceNo further treatmentP-value EFS5553.7435 PFS5557.8314 OS6467.7547 Gisselbrecht C. Abstract 8004 ASCO 2011

60. Limitations to second line therapy All relapses Eligible for intensive salvage Response to second line therapy Able to proceed to ASCT Long-term survivors 100 50 25 20 10