Diffuse Large B-Cell Lymphoma: Current Standards of Care and Clinical Advances Christopher R. Flowers, MD, MS Director, Lymphoma Program Medical Director, Oncology Data Center Assistant Professor, Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Emory University Atlanta, Georgia Thank you for participating this program on “Optimal Management Strategies of Novel Agents in Lymphoma” presented by Clinical Care Options. I am Christopher R. Flowers, MD, MS, Director of the Lymphoma Program and Medical Director of the Oncology Data Center at the Emory University Department of Hematology and Oncology, Atlanta, Georgia. I will present on “Diffuse Large B-Cell Lymphoma: Current Standards of Care and Clinical Care Advances.” This program is supported by an educational grant from Image: 3D4Medical.com/Copyright©2010 Getty Images, Inc. All Rights Reserved.

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Diffuse Large B-Cell Lymphoma Overview and molecular biology Current treatment approaches Localized DLBCL Advanced-stage DLBCL Novel approaches and ongoing clinical trials DLBCL, diffuse large B-cell lymphoma.   This presentation will review the molecular biology and provide an overview of diffuse large B-cell lymphoma, followed by a discussion of current treatment approaches for localized and advanced-stage disease. It will conclude with a discussion on novel approaches and ongoing clinical trials for the care of this disease.

DLBCL: Prognostic Factors Adverse risk factors correlated with response to chemotherapy and survival Older than 60 yrs of age LDH > normal PS ≥ 2 Ann Arbor stage III/IV Extranodal involvement > 1 site* Risk Group Risk Factors, n CR, % 5-Yr OS, % Patients (all ages) Low 0-1 87 73 Low intermediate 2 67 51 High intermediate 3 55 43 High 4-5 44 26 Patients 60 yrs of age or younger 92 83 1 78 69 57 46 32 CR, complete response; DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; OS, overall survival; PS, performance score.   Diffuse large B-cell lymphoma has been identified as having a number of prognostic factors and, in fact, an international committee of investigators has put together an International Prognostic Index (IPI) that was initially published in the New England Journal of Medicine in 1993. This Index combined a number of adverse risk factors and multivariable regression models to identify prognostic information for diffuse large B-cell lymphoma outcomes with therapies that were available during that era. The factors emerging from the model as important prognostic indicators that could be combined into an index include: age older than 60 years, an LDH value > the upper limit of normal, an ECOG performance score ≥ 2, Ann Arbor stage III/IV disease, and > 1 extranodal site of involvement. When combined, these prognostic factors can stratify patients of all ages into 4 risk groups—low, low intermediate, high intermediate, and high risk—based on the number of risk factors, with each factor scoring 1 point. For patients who fall into the low-risk group, the expected complete remission rate was 87% with a 5-year overall survival of 73%. For those who fell into the high-risk group with an IPI score of ≥ 4, the complete remission rate was 44% and the 5-year overall survival was only 26%. The age-adjusted IPI score can be applied to patients aged 60 years or younger. The case patient falls into the group that would be stratified as high risk, with an IPI score of ≥ 4. This patient has a 45% to 55% chance of complete remission and a 30% to 45% chance of 5-year overall survival. Diffuse large B-cell prognostic factors initially devised by the IPI scoring system were developed in the era before rituximab was commonly used with chemotherapy. Later in this presentation, we will review data on patient outcomes after the use of rituximab was included routinely with chemotherapy. *Prognostic for patients older than 60 yrs of age only. International NHL Prognosis Factors Project. N Engl J Med. 1993;329:987-994. 4

Diffuse Large B-Cell Lymphoma Most common NHL: 31% Peak incidence in 6th decade Curable in 50% or more of cases Median survival: wks to mos if not treated Clinical outcomes and molecular features highly heterogeneous Large cells with loss of follicular architecture of node 30% to 40% present with rapidly enlarging, symptomatic mass with B symptoms May present as extranodal disease (stomach, CNS, testis, skin) CNS, central nervous system; NHL, non-Hodgkin’s lymphoma.   Diffuse large B-cell lymphoma is the most common form of non-Hodgkin’s lymphoma, comprising approximately 30% of non-Hodgkin’s lymphomas with a peak incidence in the sixth decade of life. More than 50% of individuals who are diagnosed with the disease can be cured with common forms of chemotherapy and chemoimmunotherapy. However, for individuals who do not receive treatment, approximately 92% will die within 1 year, with a median survival of weeks to months. The clinical and molecular features of this disease are highly heterogeneous. In general, this is a disease that comprises large cells with loss of the follicular nodal architecture, as shown on this slide. Michallet AS, et al. Blood Rev. 2009;23:11-23.

OS According to Revised IPI Risk Group IPI Factors, n Very good Good 1-2 Poor 3-5 IPI, revised International Prognostic Index; OS, overall survival.   The data just presented describe the use of the IPI in the era before rituximab was routinely used as part of chemotherapy. In a publication in Blood in 2007, Sehn and colleagues from British Columbia, Canada, reviewed their data after rituximab was routinely used with chemotherapy and restratified the IPI factors into 3 risk groups: very good, good, and poor, based on the number of IPI factors. These also help to stratify patients into groups with expected progression-free survival rates. Sehn LH, et al. Blood. 2007;109:1857-1861.

Diffuse Large B- Cell Lymphoma Gene Expression Defines Molecularly and Clinically Distinct Subgroups in DLBCL Diffuse Large B- Cell Lymphoma DLBCL, diffuse large B-cell lymphoma.   Beyond the use of the IPI, there have been other efforts to try to stratify patients with diffuse large B-cell lymphoma into distinct subgroups. Although the IPI helps us to identify prognosis for patients, the IPI factors are not modifiable with chemotherapy in ways that help to improve outcomes. The Lymphoma Molecular Profiling Project initially described stratification factors. This slide shows that patients with diffuse large B-cell lymphoma can be stratified into activated B-cell–like (ABC) diffuse large B-cell lymphomas, germinal center B-cell (GCB) lymphomas, and other groups of B-cell lymphomas based on gene expression profiles. Dave SS, et al. N Engl J Med 2006;354:2431-2442. Copyright © (2006) Massachusetts Medical Society. All rights reserved.

Diffuse Large B- Cell Lymphoma Gene Expression Defines Molecularly and Clinically Distinct Subgroups in DLBCL Diffuse Large B- Cell Lymphoma 1.0 DLBCL Subgroup 5-Yr OS, % PMBL 64 GCB DLBCL 59 ABC DLBCL 30 0.8 0.6 OS ABC, activated B cell; DLBCL, diffuse large B-cell lymphoma; GCB, germinal-center B cell; OS, overall survival; PMBL, primary mediastinal B-cell like.   These groups have important prognostic significance. Patients identified in the ABC subtype of diffuse large B-cell lymphoma have a 5-year overall survival of 30%, whereas patients in the GCB group and patients with primary mediastinal diffuse large B-cell lymphoma have much better 5-year overall survival rates. 0.4 0.2 2 4 6 8 10 Yrs Rosenwald A, et al. J Exp Med. 2003;198:851-862. Originally published in The Journal of Experimental Medicine.

DLBCL Subtype Retains Prognostic Value With R-CHOP Therapy CHOP-Rituximab OS CHOP-Rituximab PFS CHOP OS 1.0 1.0 1.0 0.8 0.8 0.8 0.6 0.6 0.6 Probability 0.4 0.4 0.4 0.2 0.2 0.2 P = 4 x 10-3 P = 1 x 10-4 P = 8 x 10-6 ABC, activated B cell; DLBCL, diffuse large B-cell lymphoma; GCB, germinal-center B cell; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin; vincristine, prednisone.   In addition, in the era where rituximab has been used with chemotherapy, diffuse large B-cell subtype retains its prognostic significance. This slide shows stratification into the GCB groups and ABC subgroup, both for patients treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy and those treated with CHOP plus rituximab in terms of overall survival (far left) and progression-free survival (middle) where GCB and ABC subtype stratify patients into distinct prognostic groups. 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 Yrs Yrs Yrs GCB DLBCL ABC DLBCL Lenz G, et al. N Engl J Med. 2008;359:2313-2323.

GCB vs Non-GCB Subtypes of DLBCL: Immunophenotypic Classification Lymphoma Subtype GCB CD 10+ CD 10- bcl-6 - Non-GCB CD 10- bcl-6 + MUM1+ Non-GCB DLBCL, diffuse large B-cell lymphoma; GCB, germinal-center B cell; MUM1, melanoma associated antigen (mutated) 1.   Gene expression profiling has been difficult to operationalize and extend to community practices. Therefore, efforts to use immunophenotyping have been made whereby immunohistochemical stains have been applied to paraffin-embedded tissue to identify the subgroups. This slide shows the Hans scoring system that is used to identify a lymphoma subtype as GCB or non-GCB based on immunohistochemical stains. GCB CD 10- bcl-6 + MUM1- Hans CP, et al. Blood. 2004;103:275-282. Hans et al. Blood. 2004.

GCB vs Non-GCB Subtypes of DLBCL: Clinical Features      Total     GCB   Non-GCB   P Value Total no.     152     64     88   Male, n (%)     82 (54)   29 (45) 53 (60)   .11   Median age, yrs   63     60     .56   Stage, n (%)    I/II 77 (51) 32 (51) 45 (51) .97 III/IV     74 (49)  31 (49) 43 (49) Karnofsky score, n (%)   Higher than 70   117 (77) 51 (80) 66 (76)   .51   70 or lower   34 (23) 13 (20) 21 (24) LDH, n (%)   Normal     65 (48) 32 (56) 33 (42) High     70 (52) 25 (44) 45 (58) IPI risk group, n (%)   Low 0-2   84 (66) 35 (65) 49 (66)   .80   High 3-5   44 (34) 19 (35) 25 (34) DLBCL, diffuse large B-cell lymphoma; GCB, germinal-center B cell; IPI, International Prognostic Index; LDH, lactate dehydrogenase.   From the Hans data stratifying patients into GCB vs non-GCB subtype groups and by IPI risk group, there were no clear differences within the high-risk group in terms of percentage of individuals who fell into the GCB vs non-GCB subtype. Our patient falls into the IPI high-risk group, and therefore, by clinical factors alone, we cannot clearly identify whether this patient would have a particular immunohistochemical stratified diffuse large B-cell lymphoma or a particular gene expression profile. Hans CP, et al. Blood. 2004;103:275-282. 11 Hans et al. Blood. 2004.

Current Treatment Approaches: Initial Therapy Turning to current treatment approaches for initial therapy for diffuse large B-cell lymphoma, the National Comprehensive Cancer Network has assembled a strategy reported in their guidelines.

DLBCL Treatment Localized stage I/II disease: Advanced-stage disease: Abbreviated course of chemotherapy with immunotherapy followed by radiation or a full course of chemotherapy Advanced-stage disease: Chemoimmunotherapy plus combination of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy for 6-8 cycles DLBCL, diffuse large B-cell lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   For patients with localized stage I/II disease, initial therapy usually constitutes an abbreviated course of chemotherapy with immunotherapy followed by radiation or a full course of chemotherapy. For patients with advanced-stage disease, chemoimmunotherapy with a combination of rituximab and CHOP chemotherapy for 6-8 cycles is currently routinely practiced. NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010. Available at: http://nccn.org/professionals/physician_gls/PDF/nhl.pdf.

SWOG 8736: CHOP ± Radiotherapy in NHL in Localized DLBCL Stratified by age (< vs ≥ 65 yrs), histology (DLBCL vs others), disease site (GI vs other), stage (I vs II), resection of all visible tumors (y vs n) CHOP q3w for 8 cycles (n = 201) Untreated patients with localized intermediate/high grade NHL (N = 401) CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; IFRT, involved-field radiation therapy; NHL, non-Hodgkin’s lymphoma; GI, gastrointestinal; OS, overall survival; PFS, progression-free survival.   For patients with localized disease, SWOG 8736, presented by Miller and colleagues and published in the New England Journal of Medicine in 1998, randomized patients to CHOP chemotherapy for a full course of 8 cycles vs an abbreviated course of CHOP chemotherapy for 6 cycles followed by involved-field radiation therapy. CHOP q3w for 3 cycles (n = 200) IFRT Endpoints: PFS, OS, toxicity Miller TP, et al. N Engl J Med. 1998;339:21-26. Coiffier et al. N Engl J Med. 2002;346:235 Feugier et al. J Clin Oncol. 2005;23:4117.

SWOG 8736: OS for DLBCL Patients Treated With CHOP ± Radiotherapy 100 80 60 OS (%) 40 Death, n 53 61 5-Yr Estimate, % 82 71 CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; OS, overall survival; RT, radiation therapy.   In this trial, there were no differences in terms of overall survival when comparing these 2 strategies for treating patients with localized diffuse large B-cell lymphoma. N 152 149 20 CHOP + RT CHOP 3 6 9 12 Yrs After Registration Miller T, et al. ASH 2001. Abstract 3024.

SWOG 0014: R-CHOP + IFRT in Localized DLBCL Patients (N = 60) with newly diagnosed, aggressive NHL DLBCL (n = 56) Burkitt-like (n = 3) High grade B (n = 1) Treatment Rituximab: Days -7, 1, 22, and 43 CHOP: Days 3, 24, 45 40-46 Gy IFRT given 3 wks following end of CHOP therapy CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; IFRT, involved-field radiation therapy; NHL, non-Hodgkin’s lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   More recently, the SWOG 0014 trial looked at the use of R-CHOP chemotherapy plus involved-field radiation to localized diffuse large B-cell lymphoma. In this trial, 60 patients were treated, with 56 having diffuse large B-cell lymphoma. Persky DO, et al. J Clin Oncol. 2008;26:2258-2263.

SWOG 0014: R-CHOP + IFRT in Localized DLBCL—Results Median follow-up: 5.3 yrs S0014 S0014 100 100 80 80 60 60 PFS (%) Surviving (%) 40 40 Relapse 2-Yr Estimate 4-Yr Estimate At Risk or Death (95% CI) (95% CI) S0014 60 14 93% (87%-100%) 88% (80%-96%) Relapse 2-Yr Estimate 4-Yr Estimate At Risk or Death (95% CI) (95% CI) S0014 60 11 95% (89%-100%) 92% (85%-99%) 20 20 CI, confidence interval; DLBCL, diffuse large B-cell lymphoma; IFRT, involved-field radiation therapy; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   The survival curves from the 0014 trial with a median follow-up of > 5 years and published in the Journal of Clinical Oncology in 2008 demonstrate an estimated 4-year progression-free survival of approximately 88% with R-CHOP plus involved-field radiation therapy and a 4-year overall survival of 92%. In retrospective comparison to data from the previous SWOG trial, this dosing strategy appears to be superior to an abbreviated course of CHOP chemotherapy plus involved-field radiation, and this has now emerged as the standard of care for localized diffuse large B-cell lymphoma in the United States. 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Time From Registration (Yrs) Time From Registration (Yrs) Persky DO, et al. J Clin Oncol. 2008;26:2258-2263. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

CHOP ± Rituximab in Advanced-Stage DLBCL: GELA LNH-98 CHOP ± Rituximab in Advanced-Stage DLBCL: GELA LNH-98.5 Phase III Study Stratified by center and risk factors (0-1 vs 2-3) Assessment R-CHOP q3w for 8 cycles (n = 202) Untreated elderly patients with stage II-IV DLBCL (N = 399) CHOP q3w for 8 cycles (n = 197) CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RR, response rate.   The first trial to present data on R-CHOP in advanced-stage diffuse large B-cell lymphoma was by the GELA group in the LNH 98.5 phase III clinical trial where patients were randomized to R-CHOP chemotherapy for 8 cycles vs 8 cycles of CHOP chemotherapy alone. These were patients with untreated advanced-stage disease who were older than 60 years of age. Primary endpoint: EFS Secondary endpoints: OS, RR Coiffier B, et al. N Engl J Med. 2002;346:235-242. Feugier P, et al. J Clin Oncol. 2005;23:4117-4126. Coiffier et al. N Engl J Med. 2002;346:235 Feugier et al. J Clin Oncol. 2005;23:4117.

CHOP ± Rituximab in DLBCL: 3-Yr Survival Results (GELA LNH-98.5 Study) EFS OS 1.0 1.0 CHOP plus rituximab 0.8 0.8 CHOP plus rituximab 0.6 0.6 Overall Probability of Survival Probability of EFS CHOP 0.4 0.4 CHOP 0.2 P < .001 0.2 P = .007 CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival.   In this trial, the event-free survival and overall survival for R-CHOP chemotherapy was superior to CHOP. 0.5 1.0 1.5 2.0 2.5 3.0 0.5 1.0 1.5 2.0 2.5 3.0 Yrs After Randomization Yrs After Randomization Pts at Risk, n CHOP plus 202 177 137 108 63 19 rituximab CHOP 197 144 101 72 42 17 Pts at Risk, n CHOP plus 202 187 167 118 64 21 rituximab CHOP 197 171 136 96 58 16 Coiffier B, et al. N Engl J Med. 2002;346:235-242. Copyright © (2002) Massachusetts Medical Society. All rights reserved.

CHOP ± Rituximab in DLBCL: 7-Yr Survival Results (GELA LNH-98.5 Study) OS (N = 399) Parameter, % Low Risk High Risk Age, < 70 vs ≥ 70 yrs 58.0 49.0 LDH, NI vs > NI 69.0 45.0* Stage, I/II vs III/IV 67.0 50.0 Bone marrow, yes vs no 60.0 34.5* Tumor size, < 10 vs ≥ 10 cm 36.5 β2-microglobulin, NI vs > NI 64.5 39.0* Serum albumin, ≥ 35 vs < 35 g/L 40.0 1 CHOP 0.8 R-CHOP 0.6 Survival Probability 0.4 0.2 CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   The benefit of chemoimmunotherapy over chemotherapy held with subsequent follow-up of the GELA LNH-98.5 study. These results were published and presented by the group from France. Shown here are the 7-year survival data from the GELA trial, demonstrating continued benefit of R-CHOP over CHOP chemotherapy. P = .0004 *P < .05 (multivariate analysis). 1 2 3 4 5 6 7 8 Yrs Coiffier B, et al. ASCO 2007. Abstract 8009.

CHOP-Like Regimen* + Rituximab 375 mg/m2 MInT: Phase III Study of CHOP-like Chemo ± Rituximab in Adv. DLBCL (Younger Pts) Cycle 6 CHOP-Like Regimen* + 30-40 Gy radiotherapy (n = 410) Patients with untreated CD20+ stage II-IV DLBCL (or bulky stage I), IPI 0-1, 18-60 yrs of age (N = 823) Stratified by age-adjusted IPI score (0 vs 1), bulky disease, treatment center, and regimen CHOEP-21, cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; MACOP-B, methotrexate, leucovorin, doxorubicin, vincristine, prednisone, bleomycin; PMitCEBO, prednisolone, mitoxantrone, cyclophosphamide, etoposide, bleomycin, vincristine; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   The MInT trial, an international study with younger patients with diffuse large B-cell lymphoma, randomized patients to a CHOP or CHOP-like regimen vs the same regimen defined by the site plus rituximab. CHOP-Like Regimen* + Rituximab 375 mg/m2 + 30-40 Gy radiotherapy (n = 413) *CHOP-21, CHOEP-21, MACOP-B, or PMitCEBO. Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391.

Impact of Rituximab: The MInT Trial Group For rituximab plus chemotherapy vs chemotherapy alone, the impact of rituximab that was demonstrated in the GELA trial also held true in the MInT trial with benefits in: EFS PFS OS EFS, event-free survival; OS, overall survival; PFS, progression-free survival.   The affect of rituximab that was demonstrated in the GELA trial also held true in the MInT trial with benefits in event-free survival, progression-free survival, and overall survival for rituximab plus chemotherapy vs chemotherapy alone. Pfreundschuh M, et al. Lancet Oncology. 2006; 7: 379-391.

CHOP-14 vs R-CHOP-14 RICOVER-60 Trial: Patients Aged 61-80 Yrs Randomized by 2 x 2 factorial design 6 x CHOP-14 (n = 307) 8 x CHOP-14 (n = 305) All patients were aged 61-80 yrs and had CD20+ DLBCL and stage I-IV disease (N = 1222) 6 x CHOP-14 + Rituximab 375 mg/m2 q2w x 8 (n = 306) CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   The benefit of R-CHOP has also been studied in the RICOVER-60 trial for patients older than 60 years of age. In this trial, CHOP-14 chemotherapy for 6 or 8 cycles—previously established by the German Lymphoma Study Group as their standard of care for patients older than 60 years—was compared with the same regimen for 6 or 8 cycles with the addition of rituximab. 8 x CHOP-14 + Rituximab 375 mg/m2 q2w x 8 (n = 304) Primary endpoint: EFS *Radiotherapy (36 Gy) was planned for patients with initial bulky disease or extranodal involvement. Pfreundschuh M, et al. Lancet Oncol. 2008;9:105-116. 23

CHOP-14 ± Rituximab in Elderly Patients With DLBCL (RICOVER-60 Trial): EFS EFS was significantly superior with R-CHOP-14 vs CHOP- 14 P < .0001 for both 6 cycles and 8 cycles 8 cycles of R-CHOP-14 not superior to 6 cycles 6 cycles R-CHOP-14 is preferred treatment for elderly patients CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   The results from the RICOVER-60 trial again demonstrated that rituximab plus chemotherapy provided improvements in event-free survival over chemotherapy alone, but there were no clear benefits to giving 8 cycles of R-CHOP chemotherapy over 6 cycles. Therefore, 6 cycles of R-CHOP-14 has become the preferred treatment strategy for elderly patients with diffuse large B-cell lymphoma. Pfreundschuh M, et al. Lancet Oncol. 2008;9:105-116. Pfreundschuh et al. Blood. 2005;106:9a. Abstract 13.

R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL (Phase III Study) CHOP-14 x 6 cycles + Rituximab x 8 cycles + Lenograstim on Days 4-12 (n = 540) Newly diagnosed CD20+ DLBCL patients (N = 1080) Stratified by IPI score, treatment center, and age CHOP-21 x 8 cycles + Rituximab x 8 cycles (n = 540) CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; FFS, failure-free survival; IPI, International Prognostic Index; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   More recently, there have been approaches to compare the R-CHOP-14 regimen to the R-CHOP-21 regimen in newly diagnosed patients with diffuse large B-cell lymphoma. Data presented by Cunningham and colleagues at the 2009 American Society of Clinical Oncology meeting compared R-CHOP chemotherapy for 6 cycles (as demonstrated in the RICOVER-60 trial) to the French trial of R-CHOP chemotherapy-21 given for 8 cycles. The primary endpoint of the study was overall survival. Primary endpoint: OS Secondary endpoint: FFS, toxicity, response rates Cunningham D, et al. ASCO 2009. Abstract 8506.

R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL: Responses Response (Based on End-of-Treatment Scan), % R-CHOP-21 (n = 405*) R-CHOP-14 (n = 426*) CR/CRu (P = .183) 63 58 CR/CRu/PR (P = .139) 88 91 CR 49 40 CRu 14 18 PR 24 32 SD 6 5 PD/relapse 4 CR, complete response; CRu, unconfirmed compete response; DLBCL, diffuse large B-cell lymphoma; PD, progressive disease; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; SD, stable disease.   Of the 1080 patients who were planned for enrollment, data have now been presented on 405 patients treated with R-CHOP chemotherapy given every 21 days for 8 cycles compared with 426 patients treated with R-CHOP chemotherapy given every 14 days. In the preliminary data, there appear to be no statistically significant differences in complete response rates or overall response rates between these 2 groups; however, this trial is still early in its follow-up. *249 patients not evaluable or data missing. Cunningham D, et al. ASCO 2009. Abstract 8506.

LNH03-6B GELA: R-CHOP-14 vs R-CHOP-21 in Elderly DLBCL Patients R-CHOP every 14 days for 8 cycles + IT MTX for 4 cycles (n = 103) Prophylactic Darbepoetin alfa Conventional treatment for chemotherapy- induced anemia DLBCL patients 60-80 yrs of age (N = 202) R-CHOP every 21 days for 8 cycles + IT MTX for 4 cycles (n = 99) Prophylactic Darbepoetin alfa Conventional treatment for chemotherapy- induced anemia CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; CRu, unconfirmed compete response; DFS, disease-free survival; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; IT MTX, intrathecal methotrexate; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   There was an additional trial presented by the GELA group at the 2009 American Society of Hematology meeting where investigators randomized patients to R-CHOP chemotherapy given every 14 days for 8 cycles vs R-CHOP chemotherapy given every 21 days for 8 cycles. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Hematology%202009/Tracks/Lymphomas/Capsules/406.aspx Primary endpoint: EFS Secondary endpoints: CR or CRu , ORR, PFS , DFS, OS, dose intensity, toxicity Delarue R, et al. ASH 2009. Abstract 406.

LNH03-6B GELA Trial: Results Outcome R-CHOP-21 (n = 99) R-CHOP-14 (n = 103) P Value End of treatment response rates CR/CRu 75 67 NS PR 9 14 ORR 84 81 2-yr EFS, % 61 48 .11 2-yr PFS, % 63 49 .12 2-yr DFS, % 70 57 .40 2-yr OS, % .37 Median EFS, mos Not reached 22 -- Median PFS, mos 23 CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; CRu, unconfirmed compete response; DFS, disease-free survival; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   In this trial, 99 patients were randomized to the R-CHOP-21 arm and 103 patients to the R-CHOP-14 group. There appeared to be no differences in complete response rates or overall response rates. With early follow-up, there also appear to be no statistically significant differences in event-free survival, progression-free survival, disease-free survival, or overall survival at 2 years. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Hematology%202009/Tracks/Lymphomas/Capsules/406.aspx Delarue R, et al. ASH 2009. Abstract 406.

LNH03-6B GELA Trial: Toxicities Hematologic toxicities greater for R-CHOP-14 Patients on R-CHOP-14 had higher rates of febrile neutropenia, hospitalization, and death due to toxicity 100 90 83 83 R-CHOP-14 80 73 R-CHOP-21 69 70 60 50 Patients (%) 50 40 36 30 26 22 21 22 15 R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   The toxicities of these regimens in the GELA trial demonstrate substantially more hematologic toxicities in the R-CHOP-14 arm compared with the R-CHOP-21 arm. However, growth factor support for R-CHOP-14 was not routinely given in this trial as it typically has been given in the United States for dose-dense chemotherapy regimens. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Hematology%202009/Tracks/Lymphomas/Capsules/406.aspx 20 11 10 Grade 3/4 Leukocytes Grade 3/4 Neutrophils Grade 3/4 Hemoglobin RBC Transfusion Grade 3/4 Platelets Platelet Transfusion Delarue R, et al. ASH 2009. Abstract 406.

Untreated patients with CD20+ DLBCL, 60 yrs of age or older, PS 0-3 Maint. Rituximab After R-CHOP or CHOP in Older DLBCL (E4494/C9793 Phase III Study) Maintenance Rituximab q6m x 2 yrs, starting 4 wks after last cycle (n = 207) R-CHOP x 6-8 cycles (n = 318) Untreated patients with CD20+ DLBCL, 60 yrs of age or older, PS 0-3 (N = 632) Responders (n = 415) Stratified by IPI score (0-1 vs 2-4) Stratified by IPI score, CR/PR, induction CHOP x 6-8 cycles (n = 314) Observation (n = 208) CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FFS, failure-free survival; IPI, International Prognostic Index; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   An additional trial, the ECOG 4494/CALGB 9793, an Intergroup trial published by Haberman and colleagues in the Journal of Clinical Oncology in 2006, examined the role of R-CHOP vs CHOP chemotherapy in older patients. Patients were randomized to R-CHOP chemotherapy for 6-8 cycles using a flexi-therapy approach vs CHOP chemotherapy for 6-8 cycles. Patients who responded to either chemoimmunotherapy or chemotherapy went on to a subsequent randomization to maintenance rituximab given every 6 months for 2 years starting 4 weeks after the last cycle of therapy or observation. Primary endpoint: FFS Morrison VA, et al. ASCO 2007. Abstract 8011. Habermann TM, et al. J Clin Oncol. 2006;24:3121-3127.

Maint. Rituximab After R-CHOP or CHOP in Older DLBCL: TTF 1.0 1.0 CHOP R-CHOP 0.8 Obs 0.8 MR 0.6 0.6 MR Probability Probability 0.4 0.4 Obs 0.2 0.2 P = .834 P = .0008 1 2 3 4 5 1 2 3 4 5 Yrs From Second Randomization Yrs From Second Randomization N = 352 evaluable CR/PR patients Morrison VA, et al. ASCO 2007. Abstract 8011. CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; DLBCL, diffuse large B-cell lymphoma; MR, maintenance rituximab; Obs, observation; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; TTF, time to treatment failure.   In this trial, patients who received R-CHOP chemotherapy as their up-front regimen also benefited compared with CHOP chemotherapy (data not shown on this slide). However, for patients who received R-CHOP chemotherapy, there was no additional benefit to receiving maintenance rituximab whereas patients who received CHOP chemotherapy as their initial up-front therapy did receive a benefit to maintenance rituximab in that setting.

Current Therapy: Relapsed DLBCL DLBCL, diffuse large B-cell lymphoma.   For relapsed diffuse large B-cell lymphoma, there are several clinical treatment options that are available, with the suggestions for therapy including many of those previously listed in the options for this particular case.

Guideline Recommendations for Treatment of Relapsed DLBCL Second-line therapy in candidates for high-dose therapy + ASCT DHAP ± rituximab ESHAP ± rituximab GDP ± rituximab GemOx ± rituximab ICE ± rituximab MINE ± rituximab Second-line therapy for patients who are not candidates for high-dose therapy Clinical trial Rituximab CEPP ± rituximab Lenalidomide EPOCH ± rituximab ASCT, autologous stem cell transplantation; CEPP, cyclophosphamide, etoposide, prednisone, procarbazine; DHAP, dexamethasone, cytarabine, cisplatin; DLBCL, diffuse large B-cell lymphoma; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; ESHAP, etoposide, methylprednisolone, cytarabine, cisplatin; GDP, gemcitabine, dexamethasone, cisplatin; GemOx, gemcitabine, oxaliplatin; ICE, ifosfamide, carboplatin, etoposide; MINE, mitoxantrone, ifosfamide, mesna, etoposide.   Second-line chemotherapy regimens in patients who are candidates for high-dose chemotherapy and stem cell transplantation would include dexamethasone, cytarabine, cisplatin (DHAP) chemotherapy plus rituximab; etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP) chemotherapy plus rituximab; gemcitabine, dexamethasone, cisplatin (GDP) chemotherapy plus rituximab; gemcitabine and oxaliplatin plus rituximab; ifosfamide, carboplatin, etoposide (ICE) chemotherapy plus rituximab; or mitoxantrone, ifosfamide, mesna, etoposide (MINE) chemotherapy plus rituximab. There are several other second-line regimens being considered for other individuals who may not be candidates for high-dose chemotherapy and stem cell transplantation. NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

PARMA Study: ABMT vs Conventional Chemotherapy in Relapsed NHL BEAC ± RT (n = 55) Bone marrow harvest ABMT Patients with chemosensitive NHL (int or high grade) in 1st or 2nd relapse following doxorubicin regimen and CR to initial induction regimen (N = 215) Sensitive (n = 109) D H A P D H A P DHAP ± RT (n = 54) ABMT, autologous bone marrow transplantation; BEAC, carmustine, etoposide, cytarabine, cyclophosphamide; DHAP, dexamethasone, cytarabine, cisplatin; NHL, non-Hodgkin’s lymphoma; RT, radiation therapy.   The approach for patients with relapsed diffuse large B-cell lymphoma comes from the PARMA study, a randomized controlled clinical trial that looked at patients with intermediate-grade or high-grade non-Hodgkin’s lymphoma who had relapsed following a doxorubicin-containing chemotherapy regimen and had evidence of chemo-sensitive disease. In total, 215 patients received DHAP chemotherapy; this was in the era before rituximab was routinely used. Patients who had evidence of chemo-sensitive disease following 2 cycles of DHAP were randomized to receive additional salvage chemotherapy alone or stem cell transplantation. Patients who received salvage chemotherapy alone had the option of receiving stem cell transplantation if they relapsed or did not respond to salvage chemotherapy. These data were initially published in the New England Journal of Medicine in 1995. Salvage Tx ABMT Resistant (n = 90) Philip T, et al. N Engl J Med. 1995;333:1540-1545.

PARMA Study: Bone Marrow Transplantation vs Salvage Chemotherapy 100 100 Conventional treatment 80 80 60 60 EFS (%) OS (%) 40 40 20 20 P = .001 P = .038 EFS, event-free survival; OS, overall survival.   Results of the PARMA trial demonstrate that stem cell transplantation for patients with relapsed, intermediate-grade and high-grade non-Hodgkin’s lymphomas provided more benefit over conventional chemotherapy in the salvage setting. Shown in the blue curve on this slide, there were benefits in event-free survival and overall survival for these patients. 15 30 45 60 75 90 15 30 45 60 75 90 Mos After Randomization Mos After Randomization Philip T, et al. N Engl J Med. 1995;333:1540-1545. Copyright © (1995) Massachusetts Medical Society. All rights reserved.

CORAL Trial: R-ICE vs R-DHAP in DLBCL RANDOMIZE R-ICE x 3 SD/PD  Off CD20-positive DLBCL, relapsed/ refractory ASCT BEAM RANDOMIZE R x 6 ASCT, autologous stem cell transplantation; BEAM, carmustine, etoposide, cytarabine, melphalan; CR, complete response; DLBCL, diffuse large B-cell lymphoma; Obs, observation; PD, progressive disease; PR, partial response; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin; R-ICE, rituximab, ifosfamide, carboplatin, etoposide; SD, stable disease.   Recently presented data from the CORAL trial sought to determine what the best salvage regimen is for patients with diffuse large B-cell lymphoma. In this trial, patients with diffuse large B-cell lymphoma with evidence of relapsed or refractory disease were randomized to 3 cycles of R-ICE chemotherapy given every 21 days or 3 cycles of R-DHAP chemotherapy with plans to proceed to autologous peripheral blood stem cell transplantation for patients with chemo-sensitive disease. These data were presented by Gisselbrecht and colleagues at the 2009 American Society of Clinical Oncology meeting. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202009/Tracks/Hematologic_Malignancies/Capsules/8509.aspx R-DHAP x 3 PR/CR Obs Gisselbrecht C, et al. ASCO 2009. Abstract 8509.

CORAL Study: Pts Included With Response After First-line Therapy R-ICE R-DHAP All n % CR 108 54 101 52 209 53 CRu 23 11 24 12 47 PR 40 20 37 19 77 SD 6 3 10 5 16 4 PD 44 Not evaluated 1 Rituximab 122 60 63 244 62 CR, complete response; CRu, unconfirmed complete response; PD, progressive disease; PR, partial response; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin; R-ICE, rituximab, ifosfamide, carboplatin, etoposide; SD, stable disease.   The initial presentation of patients who were randomized to R-ICE or R-DHAP chemotherapy showed balances in the randomization with approximately 65% of individuals in the trial having experienced complete response (or unconfirmed complete response) to initial chemotherapy. More than one half of the individuals in this trial had received rituximab as part of their induction chemotherapy. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202009/Tracks/Hematologic_Malignancies/Capsules/8509.aspx Gisselbrecht C, et al. ASCO 2009. Abstract 8509.

CORAL Study: OS and PFS 2-Year Outcome (Induction ITT), % R-ICE R-DHAP P Value OS 56 .4899 PFS 42 45 .4416 ITT, intent to treat; OS, overall survival; PFS, progression-free survival; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin; R-ICE, rituximab, ifosfamide, carboplatin, etoposide.   The comparisons of R-ICE to R-DHAP demonstrate no differences in overall survival or progression-free survival. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202009/Tracks/Hematologic_Malignancies/Capsules/8509.aspx Gisselbrecht C, et al. ASCO 2009. Abstract 8509.

CORAL Study: PFS 2-Year PFS According to Patient Subgroup (ITT) P Value Failure from diagnosis < .0001 ≥ 12 mos (n = 160) 64 < 12 mos (n = 228) 31 Previous rituximab No (n = 147) 62 Yes (n = 241) 30 ITT, intent to treat; PFS, progression-free survival.   However, a second analysis with these data looked at the timing of proceeding on to salvage therapy and patients who had a failure time from diagnosis of less than 12 months had an extremely poor prognosis, with only 30% of those individuals having progression-free survival at 48 months. In addition, patients who had received previous rituximab therapy and then received either R-ICE or R-DHAP chemotherapy, combining the 2 arms of this trial, the patients who received previous rituximab chemotherapy also had only a 30% progression-free survival rate at 4 years. Even worse, (not shown in table), were the patients who had an early relapse after initial therapy and had rituximab as part of their initial chemotherapy. For more information, please go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202009/Tracks/Hematologic_Malignancies/Capsules/8509.aspx Gisselbrecht C, et al. ASCO 2009. Abstract 8509.

Rituximab + BEAM vs Tositumomab and Iodine I 131 Tositumomab + BEAM Rituximab + BEAM* followed by ASCT Patients with advanced chemosensitive DLBCL (N = 224) Tositumomab and Iodine I 131 Tositumomab + BEAM† followed by ASCT *Rituximab 375 mg/m2 (Days -19 and -12); BCNU 300 mg/m2 (Day -6); VP-16 100 mg/m2 BID (Days -5 to -2); cytarabine 100 mg/m2 BID (Days -5 to -2); melphalan 140 mg/m2 (Day -1). †Tositumomab and iodine I 131 tositumomab dosimetric dose 5 mCi (Day -19); tositumomab and iodine I 131 tositumomab therapy dose 75 cGy TBD (Day -12); BCNU 300 mg/m2 (Day -6); VP-16 100 mg/m2 BID (Day -5 to -2); cytarabine 100 mg/m2 BID (Day -5 to -2); melphalan 140 mg/m2 (Day -1). BEAM, carmustine, etoposide, cytarabine, melphalan; DLBCL, diffuse large B-cell lymphoma; PFS, progression-free survival.   Moving on to the role of clinical trials and other options for treatment of patients who fall into the poor-risk categories, rituximab plus carmustine, etoposide, cytarabine, melphalan (BEAM) chemotherapy vs tositumomab and Iodine I 131 tositumomab plus BEAM chemotherapy has been evaluated in a randomized controlled trial, and data should be forthcoming in the years to come. Primary endpoint: PFS ClinicalTrials.gov. NCT00329030.

Investigational Therapies for DLBCL Bevacizumab: recombinant, humanized, monoclonal VEGF antibody Epratuzumab: humanized, monoclonal CD22 antibody Everolimus: mTOR inhibitor Lenalidomide: immunomodulator, antiangiogenic Radioimmunotherapy Tamatinib: inhibitor of Syk in B-cell signaling pathway Bortezomib: proteasome inhibitor Enzastaurin: PKCβ-selective inhibitor DLBCL, diffuse large B-cell lymphoma; mTOR, mammalian target of rapamycin; PKCβ-protein kinase C beta; Syk, spleen tyrosine kinase; VEGF, vascular endothelial growth factor.   There are several other investigational therapies for diffuse large B-cell lymphoma that have been studied in the up-front and relapsed settings, and some of these are shown on this slide. A few of these agents have emerged as a result of gene expression profiling data that was discussed earlier. Gene expression profiling

Epratuzumab Plus R-CHOP in First-line DLBCL (Phase II Study) N = 78 eligible patients 85% EFS at 12 mos (n = 34) compared with 67% to 79% EFS and PFS at 12 mos in R-CHOP trials 95% ORR 62% CR/CRu 33% PR ER-CHOP similar toxicity profile as R-CHOP Results provide rationale for development of randomized phase III trial to compare ER-CHOP with R-CHOP (ECOG) CR, complete response; CRu, unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; EFS, event-free survival; ER-CHOP; epratuzumab, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; PFS, progression-free survival; PR, partial response; ORR, overall response rate; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   There have been several approaches to address the subset of patients who fall into the poor-risk group by adding therapies to the R-CHOP chemotherapy regimen. In data presented by Micallef and colleagues at the 2008 American Society of Clinical Oncology meeting, there was an effort to add another antibody therapy, epratuzumab anti-CD22 antibody, to R-CHOP chemotherapy. In 78 eligible patients, event-free survival was 85% at 12 months with epratuzumab plus R-CHOP therapy compared with 67% to 79% event-free survival at 12 months with R-CHOP therapy as shown in some of the trials previously discussed. With this combination, there was a relatively high overall response rate, a high complete response and unconfirmed complete response rate of > 60%, and a similar toxicity profile to the R-CHOP chemotherapy regimen. This approach is moving forward into planned randomized trials comparing epratuzumab plus R-CHOP to R-CHOP chemotherapy within the Eastern Cooperative Oncology Group. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202008/Tracks/Hematology/Capsules/8500.aspx Micallef IN, et al. ASCO 2008. Abstract 8500. 42

ABC DLBCL Associated With High Expression of NF-kB TF Target Genes ABC, activated B cell; DLBCL, diffuse large B-cell lymphoma; GCB, germinal-center B cell; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells.   In addition, approaches using gene expression profiling have been developed to try to target patients with activated diffuse large B-cell lymphoma who would be expected to fare worse. One such signature that has been observed within activated diffuse large B-cell lymphoma has been high expression of the NF-κB pathway. Davis RE, et al, J Exp Med. 2001;194:1861-1874. Originally published in The Journal of Experimental Medicine.

R-CHOP + Bortezomib as Initial Therapy for DLBCL Evaluable patients: n = 35 Outcome Patients, n % (ITT) % (Evaluable) Response CR 17 42.5 48.6 CRu 11 27.5 31.4 PR 7 17.5 20.0 SD PD Inevaluable 5 Overall response 40 88 100 80% CR, complete response; CRu, unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; PD, progressive disease; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; SD, stable disease.   One trial examined the use of bortezomib plus R-CHOP chemotherapy as a way of addressing the NF-κB pathway for patients with activated diffuse large B-cell lymphoma and other aggressive lymphomas. Leonard and colleagues presented data on the combination of bortezomib and R-CHOP as initial therapy for patients with diffuse large B-cell lymphoma in a cohort of 35 individuals. The response rates in this trial were quite high, with complete response and unconfirmed complete response rates reaching 80% in this population. Leonard JP, et al. ASCO 2007. Abstract 8031.

R-CHOP + Bortezomib as Initial Therapy for DLBCL Non-GCB population appears to have similar outcome vs GCB when bortezomib was added to R-CHOP (N = 40) OS PFS 1.0 1.0 0.8 0.8 0.6 0.6 Probability Probability DLBCL, diffuse large B-cell lymphoma; GCB, germinal-center B cell; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   Within this study, for patients who were stratified into the non-GCB or GCB groups, the combination of bortezomib and R-CHOP demonstrated no differences in overall survival or in progression-free survival albeit with relatively short follow-up and relatively small numbers of patients. This was in contrast to the data shown earlier for GCB and non-GCB using R-CHOP chemotherapy where a survival difference was found between the 2 patient subgroups. 0.4 P = .48 0.4 P = .94 GCB Non-GCB GCB Non-GCB 0.2 0.2 10 20 30 10 20 30 Mos Since Enrollment Mos Since Enrollment Leonard JP, et al. ASCO 2007. Abstract 8031.

Randomized Phase II of VR-CHOP vs R-CHOP in non-GCB DLBCL Hans Algorithm Immunohistochemistry Lymphoma Subtype GCB R A N D O M I Z E CD 10+ Arm A (n = 150) Bortezomib on Days 1, 4 + R-CHOP-21 x 6 cycles CD 10- bcl-6 - Non-GCB CD 10- bcl-6 + MUM1+ Non-GCB Arm B (n = 150) R-CHOP 21 x 6 cycles GCB CD 10- bcl-6 + MUM1- DLBCL, diffuse large B-cell lymphoma; GCB, germinal-center B cell; IHC, immunohistochemistry; MUM1, melanoma associated antigen (mutated) 1; PFS, progression-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; VR-CHOP, bortezomib, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.   However, these data are quite provocative and set the stage for the use of this regimen in a randomized phase II clinical trial that will look at the combination of bortezomib and R-CHOP vs R-CHOP in non-GCB diffuse large B-cell lymphoma. In this trial, the Hans algorithm will be used as the strategy to define patients based on immunohistochemistry who have GCB or non-GCB diffuse large B-cell lymphoma. Patients will then be randomized to receive bortezomib given on Days 1 and 4 with R-CHOP chemotherapy given every 21 days for 6 cycles vs the same R-CHOP chemotherapy regimen. The primary endpoint for this study is progression-free survival at 1 year. Given the expected poor prognosis for the non-GCB subgroup and the poor outcomes shown earlier for R-CHOP chemotherapy, this approach and others to augment R-CHOP chemotherapy are warranted in this up-front setting for poor-risk patients. Patients: 300, non-GCB (by IHC) DLBCL Primary Endpoint: PFS at 1 yr; 80% power to detect an increase from 67% to 78% ClinicalTrials.gov. NCT00931918. 46

Enzastaurin: Efficacy in Relapsed/Refractory DLBCL PKCβ-selective serine/threonine kinase inhibitor Phase II study of once-daily oral enzastaurin in 55 pts with relapsed/refractory DLBCL administered as continuous 28-day cycles until PD or toxicity FFP for ≥ 2 cycles: 22% 15% remained FFP for ≥ 4 cycles 7% continue FFP 20-50 mos following study entry Only 1 grade 4 adverse event: hypomagnesemia Most frequent grade 3 adverse events: fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), thrombocytopenia (n = 1) No deaths or treatment discontinuation caused by toxicity DLBCL, diffuse large B-cell lymphoma; FFP, freedom from progression; PD, progressive disease; PKCβ, protein kinase C beta.   Other efforts that have come out of the use of gene expression profiling include the use of enzastaurin, a protein kinase C beta–selected serine threonine kinase inhibitor. This compound has been studied in a phase II clinical trial where once-daily enzastaurin was given to 55 patients with relapsed or refractory diffuse large B-cell lymphoma administered on a continuous basis until progressive disease. Freedom from progression after 2 cycles of therapy was approximately 22% of the individuals in the trial, with 15% of individuals remaining free from progression with more than 4 cycles of therapy. Robertson MJ, et al. J Clin Oncol. 2007;13:1741-1746.

Enzastaurin: Ongoing Phase II and III Studies in DLBCL Randomized trial of R-CHOP ± enzastaurin for first-line treatment of int/high-risk DLBCL (active, not recruiting)[1] R-GEMOX plus enzastaurin for relapsed DLBCL (active, not recruiting)[2] Phase III Trial investigating maintenance enzastaurin for the prevention of relapse in DLBCL (recruiting)[3] DLBCL, diffuse large B-cell lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-GEMOX, rituximab, gemcitabine, oxaliplatin.   Other phase II and phase III trials are ongoing with enzastaurin. This agent was well tolerated within the setting of relapsed/refractory diffuse large B-cell lymphoma. In the phase II setting, there is a randomized trial of R-CHOP with or without enzastaurin for patients in the high-risk and high-intermediate risk group and a trial looking at enzastaurin in the relapsed setting for diffuse large B-cell lymphoma. In the phase III setting, enzastaurin is being examined as maintenance therapy for prevention of relapse for patients with diffuse large B-cell lymphoma. 1. ClinicalTrials.gov. NCT00451178. 2. ClinicalTrials.gov. NCT00436280. 3. ClinicalTrials.gov. NCT00332202.

BCR Signaling in NHL: A Rational Therapeutic Target? BCR is maintained on most lymphoma cells Tonic signaling through BCR maintains lymphoma survival in vitro mlgM mlgM LYN BTK SYK Igα/β Igβ/α BLNK PLC- γ2 BTK, Bruton’s tyrosine kinase; DAG, diacylglycerol; IP3R, inositol triphosphate receptor; NHL, non-Hodgkin’s lymphoma; PKC, protein kinase C; PLC, phospholipase C; Syk, spleen tyrosine kinase.   Based on the results of data identifying BCR signaling as an important target for patients with lymphoma, a spleen tyrosine kinase inhibitor was developed—fostamatinib disodium. Syk amplifies BCR signal and initiates downstream events IP3R DAG Ca2+ PKC RAS Kraus M, et al. Cell. 2004;117:787-800.

Phase II: Fostamatinib Disodium 68 patients enrolled at 200 mg BID: relapsed and heavily treated refractory lymphoma Group 1: DLBCL (n = 23) ASCT: n = 12 ORR: 22% 1 CR and 4 PR (5/23); also 4 SD Group 2: FL (n = 21) RIT: n = 9 ASCT: n = 5 Group 3: “Other” (n = 24) ASCT, autologous stem cell transplantation; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; ORR, overall response rate; PR, partial response; SD, stable disease; RIT, radioimmunotherapy.   In a trial by Friedberg and colleagues and published in Blood in 2010, fostamatinib at a dose of 200 mg twice daily was administered and evaluated in 68 individuals. In a group of 23 patients with diffuse large B-cell lymphoma, 12 had received a previous stem cell transplantation. The overall response rate was 22% with 1 patient achieving complete response, 4 patients achieving partial response, and 4 additional patients having stable disease. Friedberg JW, et al. Blood. 2010;115:2578-2585.

Diffuse Large B-Cell Lymphoma: Nodal Response Before Treatment After Treatment Shown here is an example of a patient with diffuse large B-cell lymphoma enrolled in the fostamatinib trial. There was nodal involvement before treatment that resolved after treatment, demonstrating the activity of this agent in diffuse large B-cell lymphoma.

DLBCL Treatment: Summary Eminently curable with chemoimmunotherapy approaches, both for patients with limited‑stage disease and for those with advanced‑stage disease/localized stage I/II disease Modern era treatment Combination of rituximab and chemotherapy, typically using the R‑CHOP for an abbreviated course of therapy plus radiation for patients with limited‑stage disease or possibly R‑CHOP for 6-8 cycles for those patients without radiation For patients with advanced‑stage disease, R‑CHOP chemotherapy for 6-8 cycles total AA-IPI, age-adjusted International Prognostic Index; ASCT, autologous stem cell transplantation; CEPP, cyclophosphamide, etoposide, prednisone, procarbazine; CR, complete response; DLBCL, diffuse large B-cell lymphoma; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; PD, progressive disease; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RT, radiation therapy; Tx, treatment.   In summary, diffuse large B-cell lymphoma is an entity that is eminently curable with chemoimmunotherapy approaches, both for patients with limited-stage disease and for those with advance-stage disease. The approach to diffuse large B-cell lymphoma in the modern era commonly involves the combination of rituximab and chemotherapy, typically using the R-CHOP regimen for an abbreviated course of therapy plus radiation for patients with limited-stage disease or possibly R-CHOP for 6-8 cycles for those patients without radiation, and for patients with advanced-stage disease using R-CHOP chemotherapy for 6-8 cycles in total. There are several approaches to using this chemotherapy regimen with rituximab, with the German Lymphoma Study Group establishing R-CHOP-14 for 6 cycles as the standard of care in their setting. R-CHOP for 6-8 cycles using flexi-therapy has been established as the standard of care based on Haberman and colleagues’ data from the Eastern Cooperative Oncology Group in a US Intergroup trial. R-CHOP-21 for 8 cycles has been established as the standard based on the GELA data in older individuals with diffuse large B-cell lymphoma. However, in the modern era, we are now faced with individuals who relapse after R-CHOP chemotherapy. Preliminary data from the CORAL trial give us cause for concern that these patients, particularly those who relapse early after R-CHOP therapy, have a much worse prognosis than would be expected with transplantation given the PARMA data. We need to have new approaches for treating these patients. I have presented to you some of the data that are using approaches based on gene expression profiling and other novel agents that may be targets for diffuse large B-cell lymphoma. NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010. Available at: http://nccn.org/professionals/physician_gls/PDF/nhl.pdf.

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