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DLBCL

DLBCL. Matthew Cheung Sunnybrook Health Sciences Centre November 2011. Outline. Review of DLBCL A focus on key trials/advances Highlights of disease/treatment mechanisms Advanced stage Limited stage Relapsed. Key Points. Current classification system - WHO. Composite lymphomas (13%).

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DLBCL

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  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

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

  4. Ann Arbor Staging Lymphomation.com

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

  6. 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.

  7. Basic Science - Mechanism Mechanisms of Antibody-Mediated Cell Killing NK cell Target cell Target cell Target cell Apoptosis viainduction of intracellularsignaling pathways Antibody-dependentcellular cytotoxicity (ADCC) Complement-dependentcytotoxicity (CDC)

  8. Coiffier, NEJM 2002

  9. 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)

  10. 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

  11. IPI

  12. Outcome According to Revised IPI (R-IPI) Sehn et al, ASH 2006

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

  14. DLBCL (ABC type)

  15. GCB subtype correlated with better survival NEJM, 2002

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

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

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

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

  20. AMC RCT of CHOP-R vs. CHOP (+ HAART) Kaplan et al. (AMC Study), Blood 2005

  21. Rituximab and Infection 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 Kaplan et al. (AMC Study), ASH 2003

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

  23. 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

  24. R-CHOP14 R-CHOP21 R-CHOP14 R-CHOP21 Median interval between two cycles 15 days(9 – 70)‏ 21 days(19 – 63)‏ Cyclo 84 % 96% Dox 83 % 95 % R-CHOP14 R-CHOP21 G-CSF use 90 % 68 % Dose-intensity Is R-CHOP14 given every 14 days ? Median dose-intensity R-CHOP14 = 125 % of R-CHOP21 18/103 patients in R-CHOP14 groupreceived R-CHOP ≥ 18 days

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

  26. LNH03-6B GELA Trial: Results Delarue R, et al. ASH 2009. Abstract 406.

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

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

  29. 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

  30. 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

  31. Stiff PJ Abstract 8001 ASCO 2011

  32. 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)

  33. 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

  34. 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.

  35. 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)

  36. Response Assessment of Aggressive NHL Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005

  37. Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005

  38. Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005

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

  40. 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 in GTD if >1.5 cm pretreatment if variable FDG-avid lymphoma or PET negative prior to treatment • Bone marrow negative • CRu - now obsolete

  41. 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)

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

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

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

  45. Fisher, Miller et al Am Soc Hematol Educ Program 2004: 221-236 Updated analysis of SWOG8736 accounting for IPI risk factors 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%

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