1. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP Laurie H. Sehn, Brian Berry, Mukesh Chhanabhai, Catherine Fitzgerald, Karamjit Gill, Paul Hoskins, Richard Klasa, Kerry J. Savage, Tamara Shenkier, Judy Sutherland, Randy D. Gascoyne, and Joseph M. Connors Blood. 2007;109: 1857-1861 R2 Lee Jae Yeon

2. Background Diffuse large B-cell lymphoma (DLBCL) Diffuse large B-cell lymphoma (DLBCL) - m/c subtype of NHL ( 30% of new Dx, 80% of aggressive lymphomas) - m/c subtype of NHL ( 30% of new Dx, 80% of aggressive lymphomas) - suggested heterogeneous group of B-cell lymphomas - suggested heterogeneous group of B-cell lymphomas - 3 distinct molecular subtype - 3 distinct molecular subtype GCB subtype : similar to normal germinal center B cells GCB subtype : similar to normal germinal center B cells ABC subtype : mimicking activated pph-blood B cells ABC subtype : mimicking activated pph-blood B cells PMBCL subtype (primary mediastinal large B-cell lymphoma) PMBCL subtype (primary mediastinal large B-cell lymphoma) ; mediastinal lymphadenopathy, some molecular genetic ; mediastinal lymphadenopathy, some molecular genetic similarities to Hodgkin lymphoma similarities to Hodgkin lymphoma Unclassified Unclassified

3. Background ; R-CHOP  improved survival of DLBCL Groupe d’Etude de Lymphome d’Adultes (GELA) report (elderly) Groupe d’Etude de Lymphome d’Adultes (GELA) report (elderly) US Intergroup trial & RICOVER-60 trial (elderly) US Intergroup trial & RICOVER-60 trial (elderly) MINT trial (age < 60 years) MINT trial (age < 60 years) showed R-CHOP improved survival of DLBCL showed R-CHOP improved survival of DLBCL clinical tool previously used to predict outcome should be changed clinical tool previously used to predict outcome should be changed ; International Prognostic Index(IPI) ; International Prognostic Index(IPI)   revised International Prognostic Index (R-IPI)   revised International Prognostic Index (R-IPI) Rituximab (chimeric IgG1 monoclonal Ab to CD20) CHOP (cyclophosphamide, doxorubicin, vincristine, & prednisone)

4. Method Retrospective analysis Retrospective analysis unselected population of pt. with DLBCL treated unselected population of pt. with DLBCL treated in the province of British Columbia in the province of British Columbia Cases identified by Cases identified by : Lymphoid Cancer Database of the Center for Lymphoid : Lymphoid Cancer Database of the Center for Lymphoid Cancer of the BC Cancer Agency. Cancer of the BC Cancer Agency. (more than 10 000 pt, since 1981) (more than 10 000 pt, since 1981)

5. Method Patient included least 16 years of age least 16 years of age biopsy-proven biopsy-proven newly diagnosed, newly diagnosed, CD20(+) DLBCL CD20(+) DLBCL prior to January 15, 2005, prior to January 15, 2005, treated with R-CHOP treated with R-CHOP with curatve intent with curatve intent Patients excluded HIV positive HIV positive evidence of a secondary malignancy evidence of a secondary malignancy underlying indolent lymphoproliferative disorder, underlying indolent lymphoproliferative disorder, presence of major coincident illness precluded an attempt to cure the lymphoma presence of major coincident illness precluded an attempt to cure the lymphoma

6. Method BC Cancer Agency protocol for R-CHOP BC Cancer Agency protocol for R-CHOP : standard doses CTx + rituximab q 21 day : standard doses CTx + rituximab q 21 day 3 cycles of R-CHOP + involved field RTx 3 cycles of R-CHOP + involved field RTx Filgrastim (rG-CSF) when ANC 0.8*10 9 /L Filgrastim (rG-CSF) when ANC 0.8*10 9 /L Definition of advanced-stage disease Definition of advanced-stage disease - Ann Arbor stages III or IV, or stages I and II with B Sx - Ann Arbor stages III or IV, or stages I and II with B Sx - bulky dis. ( 10 cm) - bulky dis. ( 10 cm) - Dis. that could not be encompassed within a single involved field radiation port - Dis. that could not be encompassed within a single involved field radiation port  received 6 to 8 cycles of treatment  received 6 to 8 cycles of treatment

7. Result

8. Table 1. Patient characteristics

10. Figure 1. Overall outcome. Progression-free survival (A) and overall survival (B) in 365 patients with DLBCL treated with R-CHOP in British Columbia Progression-free survivaloverall survival Excellent outcome with R-CHOP ! Modest impact of secondary therapy !

11. Table 2. Outcome according to International Prognostic Index (IPI) factors in 365 patients treated with R-CHOP in British Columbia

12. Figure 2. Outcome according to the standard International Prognostic Index (IPI) Progression-free survival overall survival 2 low-risk and 2 high-risk groups exhibit closely overlapping curves !!

13. Figure 3. Outcome according to the number of International Prognostic Index (IPI) factors at Dx Progression-free survival

14. Figure 4. Outcome according to the revised International Prognostic Index (R-IPI) Progression-free survivaloverall survival

15. Discussion Addition of rituximab to CHOP Addition of rituximab to CHOP  marked improvement in outcome for patients with DLBCL  marked improvement in outcome for patients with DLBCL  altered risk assessment : IPI to R-IPI  altered risk assessment : IPI to R-IPI Redistribution of the IPI factors into the R-IPI Redistribution of the IPI factors into the R-IPI  provides a more clinically relevant prediction of outcome  provides a more clinically relevant prediction of outcome - “very good” ; therapeutic benefit - “very good” ; therapeutic benefit - ”good” ; progression warranted, - ”good” ; progression warranted, not to add excessive toxicity in view of the not to add excessive toxicity in view of the excellent outcome with R-CHOP excellent outcome with R-CHOP - “poor” ; consider investigational approaches - “poor” ; consider investigational approaches Bcl-6 protein expression is no longer a useful prognostic marker in DLBCL Bcl-6 protein expression is no longer a useful prognostic marker in DLBCL R-IPI should be validated prospectively in an independent population of patients R-IPI should be validated prospectively in an independent population of patients

16. Conclusion in the era of R-CHOP treatment, in the era of R-CHOP treatment, R-IPI is a clinically useful prognostic index that may help guide treatment planning and interpretation of clinical trials R-IPI is a clinically useful prognostic index that may help guide treatment planning and interpretation of clinical trials