Clinical Considerations and Strategies for Managing Patients With DLBCL Richard I. Fisher, MD Samuel E. Durand Professor of Medicine Director, James P. Wilmot Cancer Center Director, University of Rochester Medical Faculty Group Senior Associate Dean for Clinical Affairs Vice President, University of Rochester Medical Center Rochester, New York This program is supported by an educational grant from

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clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Diffuse Large B-Cell Lymphoma  Most common NHL, peak incidence 6th decade  Large cells with loss of follicular architecture of node  May present as extranodal disease (stomach, CNS, testis, skin)  Curable in 50% or more of the cases  Median survival, wks to months if not treated Fisher RI, et al. Hematology Am Soc Hematology Educ Program. 2004: Photo available at: Photo available at:

Comparison of a Standard Regimen (CHOP) With 3 Intensive Chemotherapy Regimens for Advanced Non-Hodgkin’s Lymphoma Results of the National High Priority Lymphoma Study Fisher RI, Gaynor ER, Dahlberg S, et al. N Engl J Med. 1993;328:

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma OS by Arm, S Yrs From Registration ProMACE-CytaBOM m-BACOD CHOP MACOP-B At Risk Events, n 10-Yr Estimate, % Patients (%) Fisher RI, et al. N Engl J Med. 1993;328:

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma International Index for NHL Staging  Adverse risk factors –Older than 60 yrs of age –Stage III or IV –> 2 extranodal sites  Risk category –Low –Low intermediate –High intermediate –High –Performance score > 2 –LDH > normal  No. of risk factors –0, 1 –2 –3 –4, 5 N Engl J Med. 1993;329:

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma International Index (Patients of All Ages) N Engl J Med. 1993;329: Copyright © [1993] Massachusetts Medical Society. All rights reserved. *Score 0 or 1 for each factor: 0 = absent; 1= present. Factors: older than 60 yrs of age, LDH > normal, performance score > 1, stage III/IV, extranodal involvement > 1 site. Risk Group*Risk Factors, n Distribution of Cases, % CR Rate, % Survival Rate, % 2 Yrs5 Yrs Low0, Low Intermediate High Intermediate High4,

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Lymphoma Biopsies Genes Diffuse Large B- Cell Lymphoma Three Different Categories of Aggressive Lymphoma Activated B-cell–like diffuse large B-cell lymphoma Germinal center B-cell– like diffuse large B-cell lymphoma Primary mediastinal B-cell lymphoma

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma OS (Yrs) Probability Diffuse Large B- Cell Lymphoma PMBL64% GCB59% DLBCL 5-Yr Survival Survival Rates in Different Genetic Groups ABC30% DLBCL

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Diffuse Large B- Cell Lymphoma c-rel Amplification BCL-2 Translocation Gain Chromosome 3q Gain/amp Chromosome 9p24 Constitutive NF-  B Activation Dissecting a Cancer Into Molecularly and Clinically Distinct Subgroups GCB DLBCL ABC DLBCL PMBL 16%025% 45%018% 024%5% 06%43% -++

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma GELA Phase III Trial: Elderly DLBCL: CHOP ± Rituximab Protocol RANDOMIZERANDOMIZE Patients Stratified by risk factors (0-1 vs 2-3) Days Repeat cycle (8 cycles total) RituximabPrednisone Cyclophosphamide Doxorubicin Vincristine Coiffier B, et al. N Engl J Med. 2002;346:

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma 12/2004 7/2000: Interim analysis (ASH 2000) 5/2001: Update of interim analysis (EHA 2001) 9/2001: Analysis at end of study (NEJM 2002) 12/2002: 3-yr follow-up analysis 12/2004: 5-yr analysis (Feugier JCO. 2005;23: ) 9/2001 5/2001 7/ /2002 Yrs LNH-98.5: Event-Free Survival

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CD20 + DLBCL yrs IPI 0,1 Stages II-IV, I with bulk 6 x CHOP-like Gy (Bulk, E) 6 x CHOP-like + Rituximab Gy (Bulk, E) Randomize Pfreundschuh M, et al. Lancet Oncol. 2006;7: MInT Trial: Study Design  MabThera International Trial

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Pfreundschuh M, et al. Lancet Oncol. 2006;7: MInT Trial: Time to Treatment Failure  The addition of rituximab to chemotherapy, primarily R-CHOP, produced significantly better survival compared with chemotherapy alone (79.9% vs 60.8%)  Median observation time: 22 mos

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma MInT Trial: Overall Survival Pfreundschuh M, et al. Lancet Oncol. 2006;7:  An OS advantage was observed in the group receiving rituximab vs chemotherapy alone (95% vs 86%, respectively; P =.002)

CHOP-Rituximab Is Standard Initial Therapy for All Patients With Advanced-Stage, Diffuse Large B-Cell Lymphoma

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Lenz G, et al. N Engl J Med. 2008;359: Copyright © [2008] Massachusetts Medical Society. All rights reserved. The Distinction Between the GCB and ABC Subtypes of DLBCL CHOP-Rituximab OS Probability Yrs P = 4 x CHOP-Rituximab PFS CHOP OS Yrs P = 1 x Yrs 6 P = 8 x GCB DLBCLABC DLBCL

What Is the Role for Dose Intensification for Patients With DLBCL?

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Chemotherapy in Older Patients With DLBCL (German Study) Pfreundschuh M, et al. Blood. 2004;104: RANDOMIZERANDOMIZE CHOP-14 q2w x 6 (n = 172) CHOP-21 q3w x 6 (n = 178) ASSESSASSESS Older, treatment-naive patients with DLBCL (N = 689) CHOEP-14 q2w x 6 (n = 169) CHOEP-21 q3w x 6 (n = 170)

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CHOP Chemotherapy in Older Patients With DLBCL (German Study): OS This research was originally published in Blood. Pfreundschuh M, et al. Blood. 2004;104: © The American Society of Hematology. Alive (%) Mos CHOP-21 (n = 178) 40.6% CHOP-14 (n = 172) 53.3% 5-Yr OS

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CHOP-14 ± Rituximab in Elderly Patients With DLBCL (RICOVER-60 Trial) Pfreundschuh M, et al. Blood. 2005;106:9a. Abstract 13. Primary endpoint: FFTF Radiotherapy was planned for patients with initial bulky disease or extranodal involvement. FFTF is defined as additional therapy, failure to achieve CR, progressive disease, relapse, or death. CHOP-14 x 6 (n = 204) RANDOMIZERANDOMIZE Patients with CD20+ DLBCL, aged yrs, stages I-IV (N = 1330) CHOP-14 x 8 + Rituximab q2w x 8 (n = 203) CHOP-14 x 6 + Rituximab q2w x 8 (n = 211) CHOP-14 x 8 (n = 210)

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CHOP-14 vs R-CHOP-14 CHOP-14 ± Rituximab in Elderly Patients With DLBCL (RICOVER-60 Trial): TTF by Regimen Pfreundschuh M, et al. Blood. 2005;106:9a. Abstract 13. P = % 70% FFS (%) 6/8 × CHOP-14 + R × 8 (n = 414) 6/8 × CHOP-14 (n = 414) Mos

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma R R-CHOP Wks Wks812 Prophylactic darbepoetin alfa Supportive care R-CHOP-14 Primary endpoint: EFS Expected improvement: 10% at 3 yrs with R-CHOP-14 (55% to 65%) 600 patients required (over 4 yrs) LNH 03-6B: Study Design ClinicalTrials.gov. NCT yrs of age, aaIPI = 1,2,3

R-CHOP-14 Compared to R-CHOP-21 in Elderly Patients With Diffuse Large B-Cell Lymphoma: Results of the Interim Analysis of the LNH03-6B GELA Study Delarue R, Tilly H, MD, Salles G, et al. ASH Abstract 406.

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma R-CHOP-14 Compared With R-CHOP-21 in Elderly Patients With DLBCL: Interim Results  202 patients randomized; R-CHOP-14: 103; R-CHOP-21: 98  Median follow-up: 24 mos  90% of R-CHOP-14 patients received G-CSF; only 66% of R- CHOP-21 patients received G-CSF  Response rate (CR + CRu): 67% in R-CHOP-14 vs 75% in R-CHOP-21 arm (P = NS)  2-yr EFS: 48% in R-CHOP-14 arm vs 61% in R-CHOP-21 (P = NS)  2-yr PFS (49% vs 63%), 2-yr DFS (57% vs 70%) and 2-yr OS (67% vs 70%) trended similarly (P = NS for all).  Conclusions: interim analysis favors R-CHOP-21

A Phase III Trial Comparing R-CHOP-14 and R-CHOP-21 for the Treatment of Newly Diagnosed DLBCL Results from a UK NCRI Lymphoma Group Study Cunningham D, Smith P, Mouncey P, et al. ASCO Abstract 8506.

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Overall Response Rates Based on End of Treatment Scan (N = 831) R-CHOP-21, % (n = 405) R-CHO-14, % (n = 426) CR4940 CRu1418 PR2432 SD65 PD/relapse64 CR/CRu (P =.183)6358 CR/CRu/PR (P =.139) patients not evaluable or data missing Cunningham D, et al. ASCO Abstract 8506.

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Should Older DLBCL Patients Receive Dose-Escalated CHOP (CHOP-14)? Answer: not at this time

Phase II Study of Dose-Adjusted EPOCH-R in Untreated CD20+ Diffuse Large B-Cell Lymphoma: CALGB Wilson WH, Porcu P, Hurd D, et al. ASCO Abstract 6530.

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Wilson WH, et al. J Clin Oncol. 2005;23(16s). Abstract CALGB Phase II Study: Responses Study Population Patients, nCR/CRu, n (%) PR, n (%)Total, n (%) All patients7149 (69)22 (31)71 (100) Relapsed117 (14)4 (18)11 (15)

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Wilson WH, et al. J Clin Oncol. 2005;23(16s). Abstract CALGB Phase II Study: PFS  With a very short median follow-up, PFS at 1.5 yrs was 83%  According to the IPI, the low-, low-intermediate–, and high- intermediate–risk groups did well in terms of PFS; the high-risk group did not do well  To date in the poorest risk group, where progress is most needed, there is no evidence that the use of dose- adjusted EPOCH-R has a significant benefit

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Randomization Arm A: R-CHOP Arm B: DA-EPOCH-R C1 C2 C3 C4 C5 C6 C1 C2 C3 C4 C5 C6 StageStage/PET/CT Treatment completed Time Line (Wks) PET/CTBiopsy ClinicalTria\s.gov NCT Treatment Flow Chart of CALGB 50303

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Is There a Role for Maintenance Rituximab Therapy in DLBCL? Answer: not at this time

Maintenance Rituximab vs Observation After R-CHOP or CHOP in Older DLBCL Patients An Intergroup E4494/C9793 Update Morrison VA, Weller EA, Habermann TM, et al. ASCO Abstract 8011.

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Probability Yrs From Second Randomization R-CHOP P = MR Obs P =.0008 MR Obs CHOP Yrs From Second Randomization Morrison VA, et al. J Clin Oncol. 2007;25(18s).Abstract Arm Analysis: TTF—Evaluable CR/PR Patients N = 352 Probability

What Is the Role of Autologous Stem Cell Transplantation for Patients With Advanced-Stage DLBCL?

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma The PARMA Study: Objectives and Design  Evaluation of efficacy of ABMT vs conventional chemotherapy in relapsed NHL Hagenbeek,et al. Blood. 1995;86(suppl 1);Abstract 458a. DHAPDHAP DHAPDHAP N = 216 1st or 2nd relapse Bone marrow harvest Sensitive (n = 109) Resistant (n = 90) n = 55 n = 54 BEAC ± RT DHAP ± RT ABMT Salvage Tx ABMT

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma PARMA Randomized Trial: OS Philip T, et al. N Engl J Med. 1995;333: Copyright © [1995] Massachusetts Medical Society. All rights reserved. Mos From Randomization 100 Survival (%) ABMT 53% DHAP 32% ITT analysis P =

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Auto Transplantation in Poor-Risk DLBCL: Results of Randomized Trials Haioun C, et al. J Clin Oncol. 1997;15: Martelli M, et al. J Clin Oncol. 2003;21: Kaiser U, et al. J Clin Oncol. 2002;20: First AuthorInitial Induction Therapy Treatment Arm Favored TransplantConventionalNo Difference Retrospective Subset Analyses HaiounFull courseDFS,OS SantiniFull courseDFS, PFS Prospective Trials ReyesAbbreviatedEFS,OS MartelliAbbreviatedEFS,OS KaiserAbbreviatedEFS,OS

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CHOP/CHOP- R x 5 PR or CR < PR Off protocol therapy CHOP/CHOP- R x 1 + Transplant CHOP/CHOP- R x 3 Closed: 12/15/07 with 276 randomized patients ClinicalTrials.gov. NCT RANDOMIZEDRANDOMIZED REGISTERREGISTER SWOG, ECOG, CALGB, NCIC-S9704 Study: Early vs Delayed High-Dose Therapy

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Expression of Angiogenesis Factors in Non-Hodgkin’s Lymphoma Low Grade (SWOG 8809) High Grade (SWOG 8516) 2/9 9/11 11/20 0/9 9/11 9/20 0/9 5/11 5/20 VEGFFlt-1KDR

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma SWOG-0515 Phase II Trial: R-CHOP Plus Bevacizumab in Advanced-Stage DLBCL  Objective: to determine the CR rate and 2-yr FFS  Eligibility: older than 18 yrs of age; DLBCL; stage bulky II, III, IV  Projected accrual: N = 80  Therapy: R-CHOP plus bevacizumab x 8  Closed 9/15/08 with 71 patients accrued Available at: Accessed 9/1/08.

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Targets Identified by Transcriptional Profiling of DLBCLs  PKC beta signaling pathway  Phosphodiesterase 4B/cAMP signaling pathways

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Enzastaurin in Relapsed/Refractory DLBCL Duration: ≥ 1 cycle≥ 2 cycles ≥ 4 cycles ≥ 12 cycles patients progression free at 15+, 16+, 21+, and 37+ mos Robertson MJ, et al. Blood. 2005;106:275a.

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Courtesy of L. Staudt Lymphoma Biopsy Samples NF-  B Is Overexpressed in ABC DLBCL and Is a Potential Target Activated B cell-like DLBCL Germinal Center B cell-like DLBCL NF-kB Target Gene P Value

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma T  B kinase  inhibitor Validation of the NF-  B Pathway as a Therapeutic Target in DLBCL

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Dunleavy K, et al Blood. 2009;113: Median survival: 10.8 mos Median survival: 3.4 mos Dose-Adjusted R-EPOCH Plus Bortezomib ABC DLBCL GCB DLBCL P =.0026 OS Following Bortezomib/EPOCH (Yrs) Probability SubtypeTotal, N CR, n (%)PR, n (%)No Response, n (%) P Value ABC DLBCL125 (41.7) 2 (17.0).0004 GCB DLBCL151 (6.5) 13 (87.0)

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma BCR Signaling in NHL: A Rational Therapeutic Target?  BCR is maintained on most lymphoma cells  Tonic signaling through BCR maintains lymphoma survival in vitro Syk (spleen tyrosine kinase) amplifies BCR signal and initiates downstream events mlgM Igα/β Igβ/α IP3R DAG Ca 2+ PKC RAS LYN Syk BTK PLC- γ2 BLNK mlgM Kraus M, et al. Cell. 2004;117:

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Syk Is a Rational Therapeutic Target in NHL  Tamatinib fosdium (fostamatinib disodium, R788/R406) –Potent and specific inhibitor of Syk –In vitro activity against NHL –DLBCL –MCL –Human experience –Safety demonstrated in healthy human subjects –Activity demonstrated in phase II trials –Rheumatoid arthritis –ITP

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma R788 in DLBCL: Efficacy—ORR: 21% (5/21 Patients) Friedberg J, et al. Ann Oncol. 2008;19(suppl 4).Abstract 102 and oral presentation at ICML X. PatientCategoryDuration (Mos) 94-02PR PR PR PR PR SD4.8+

What Is Standard Initial Therapy for Patients With Early-Stage DLBCL?

Chemotherapy Alone Compared With Chemotherapy Plus Radiotherapy for Localized Intermediate- and High- Grade Non-Hodgkin’s Lymphoma Miller TP, Dahlberg S, Cassady R, et al. N Engl J Med. 1998;339:21-26.

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma S8736: OS for DLBCL Yrs After Registration OS (%) Yr Estimate, % Death, n N CHOP + RT CHOP Miller TP, et al. N Engl J Med. 1998;339:21-26.

Effect of Adding Rituximab to Three Cycles of CHOP, Plus Involved-Field Radiotherapy for Limited-Stage Aggressive Diffuse B-Cell Lymphoma Southwest Oncology Group Study 0014 Persky DO, Unger J, Spier CM, et al. J Clin Oncol. 2008;26:

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Persky D, et al. J Clin Oncol. 2008;26: Effect of Adding Rituximab to 3 Cycles of CHOP + Involved-Field Radiotherapy for Limited-Stage Aggressive DLBCL: Results  In a comparison of studies, poor-risk patients experienced a PFS benefit with the addition of rituximab to CHOP  Similarly, OS was also improved with the addition of rituximab to CHOP  Despite the lack of prospective randomized data, R-CHOP has become the standard of care for these patients

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma New Agents With Activity in DLBCL  Proteosome inhibitors –Bortezomib –Carfilzomib  IMiDs –Lenalidomide –Pomalidomide  Antibodies –RO —a humanized engineered anti CD20 monoclonal antibody –Blinatumomab—anti-CD19 monoclonal antibody –Inotuzumab ozogamicin—anti-CD2 monoclonal antibody attached to calicheamicin –Milatuzumab—anti-CD74 monoclonal antibody –Galiximab—anti-CD80 monoclonal antibody –Dacetuzumab—anti-CD40 monoclonal antibody

clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma New Agents With Activity in DLBCL  Histone deacetylase inhibitors –Vorinostat –LBH589 –MS-275 –Romidespin  Inhibitor of apoptosis proteins –YM155—survivin protein inhibitor  Small molecule inhibitors –BI2536—targets Polo-like kinase-1 –PS1145—kappaB kinase inhibitor –PX478—inhibits HIF1a transcription factor that regulates cellular response to hypoxia –TW-37—small-molecule inhibitor of Bcl-2  Heat shock protein inhibitors –IPI-504

For more information on this important clinical topic, go online: 2 CE-certified didactic educational modules 4 CME-certified Interactive Virtual Presentations clinicaloptions.com/Lymphoma09