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Francisco Hernandez-Ilizaliturri MD Farhana Malik MBBS Myron Czuczman MD

Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) with Non-Germinal center B-cell Phenotype is associated with a Higher response to Lenalidomide (L) or in Combination with Rituximab(R). Francisco Hernandez-Ilizaliturri MD Farhana Malik MBBS Myron Czuczman MD.

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Francisco Hernandez-Ilizaliturri MD Farhana Malik MBBS Myron Czuczman MD

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  1. Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) with Non-Germinal center B-cell Phenotype is associated with a Higher response to Lenalidomide (L) or in Combination with Rituximab(R) Francisco Hernandez-Ilizaliturri MDFarhana Malik MBBSMyron Czuczman MD Departments of Medical Oncology, Immunology and Pharmacology Roswell Park Cancer Institute

  2. Classification of Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) According to the Hans Criteria Defines Two Groups of Patients with Different Clinical Outcomes Following Systemic Rituximab-Multi Agent Anthracycline-Based Therapy

  3. Evolution in the management of aggressive B-cell lymphomas • Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma diagnosed in the Western Hemisphere • Patients with DLBCL exhibit a heterogeneous clinical behavior and prognosis • Several biomarkers that predict the clinical outcome of DLBCL patients had been identified and validated (i.e. Bcl-2 expression, IPI score or gene profiling studies) • The addition of rituximab to systemic chemotherapy has improved the clinical outcome of DLBCL patients, challenging previously established biomarkers of response

  4. Distinct types of DLBCL identified by gene expression profiling Rosenwald et Al, NEJM 2002; 346:1937-47 Studies included patients with DLBCL treated with CHOP or CHOP-like chemotherapy prior to rituximab Alizadeth A, et al. Nature 2000; 403:503 - 511

  5. GCB GCB + - MUM1 CD10 + + - Non-GCB Bcl-6 - Non-GCB Algorithm for Subtype classification of DLBCL The concordance rate of the Han’s Algorithm to gene profiling studies is 80% Hans et al, Blood 2004, 103: 275-282

  6. Differences in outcomes among patients with DLBCL treated with R+CHOP subdivided by IHC

  7. To study clinical differences between GCB- and non-GCB DLBCL treated at RPCI • Retrospective study of 191 patients DLBCL treated at our Institution between 2000 and 2007 with the following characteristics • Previously untreated DLBCL • Patients that received front line therapy with rituximab in combination with CHOP or DA-EPOCH • Tumor specimen available for immunohistochemistry (IHC) studies • CD20, CD10, BCL2, BCL6 and MUM1 • Patients were excluded from the analysis if any of the following: • Incomplete clinical data • Transformed lymphoma and primary CNS DLBCL • HIV related DLBCL • Demographic, clinical and pharmacological (i.e. cumulative doses of rituximab, chemotherapy and growth factor support) were included in the analysis

  8. Patients were classified as GCB- or non-GCB DLBCL using the Hans algorithm (Hans et al, Blood 2004, 103: 275-282) • Differences in end-point studies were evaluated between GCB- and non-GCB patients • Repsonse rate • Cumulative chemoimmunotherapy doses received • Overall survival (OS) • Progression free survival (PFS)

  9. DLBCL with a non-GCB phenotype by IHC had an inferior PFS following R-CHOP-21 than GCB-DLBCL Log Rank P = 0.017 GCB DLBCL Non-GCB DLBCL The median survival for non-GCB DLBCL was 45.1 months, whereas the median survival for patients with GCB-DLBCL has not be reach.

  10. P = 0.037 GCB DLBCL Non-GCB DLBCL DLBCL with a non-GCB phenotype by IHC had an inferior overall survival following R-CHOP-21 than GCB-DLBCL The median survival for non-GCB DLBCL was 75.4 months, whereas the median survival for patients with GCB-DLBCL has not be reach.

  11. In summary • Our data suggest that the Hans algorithm can predict clinical outcomes of patients with DLBCL undergoing frontline chemo-immunotherapy • Patients with Non-GCB DLBCL while having a comparable initial overall response rate (CR and PR) to R+CHOP had a shorter PFS and OS than GCB-DLBCL • Non-GCB DLBCL represent a subgroup of DLBCL for which innovative therapeutic strategies targeting key regulatory pathways in the induction and/or maintenance setting are need in an attempt to improve their PFS and OS

  12. CALGB 50303 Phase III Randomized Study of R-CHOP vs. Dose-Adjusted EPOCH-R with Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas R+CHOP x 6 De Novo CD20+ DLBCL stage II,III or IV Tumor Biopsy for GEP studies Randomization R-DA-EPOCH x 6

  13. Lenalidomide in diffuse large B-cell lymphoma (DLBCL): correlating response with tumor characteristcs

  14. N N N H H H 2 2 2 Thalidomide analogues: immune-mediated inflammatory disease (IMiDs) in B-cell lymphomas Thalidomide/IMiDs target MM cells in the bone marrow (BM) microenviroment O O H C. Thalidomide/IMiD N MM cells O N IL-6 TNFa IL-1b  O B. Thalidomide/IMiD Thalidomide BM stromalcells O O A. Thalidomide/IMiD ICAM-1 H N N O BM vessels VEGF bFGF  IL-2 IFN CC-5013 (Revimid) PBMC O O H E. Thalidomide/IMiD D. Thalidomide/IMiD CD8+ T cellsNK cells N N O MM = multiple myeloma; VEGF = vascular endothelial growth factorPBMC = peripheral-blood mononuclear cells; NK = natural killerTNF = tumour necrosis factor O N N N H H H 2 2 2 Davies FE, et al. Blood, 2001;98:210–6Hayashi T, et al. Blood 2002;100:314b (Abstract 4800) CC-4047 (Actimid)

  15. NF-kB target genes are highly expressed in activated B cell-like diffuse large B-cell lymphoma Courtesy of L. Staudt

  16. IMiDs in vitro decrease NFB activity and arrest DNA synthesis in NHL cells CC5013 Raji cells 40,000 30,000 20,000 10,000 0 400,000 300,000 200,000 100,000 0 CPU 48 hoursRaji cells 0 2.5 5 10 20 40 µg/mL Relative light units CC4047 400,000 300,000 200,000 100,000 0 CPU 48 hours Raji cells 0 2.5 5 10 20 40 µg/mL Positivecontrol CC4047 CC5013 Placebo Negativecontrol Hernandez-Ilizaliturri FJ, et al. Clin Can Res 2005;11:5984–92

  17. Stromal-1 signature encodes extracellular matrix components and macrophage/myeloid restricted proteins (favourable)

  18. The stromal-2 signature encodes regulators and components of angiogenesis (unfavourable)

  19. Tumor micro vessel density decreases after treatment with lenalidomide Placebo CD31 staining Lenalidomide CD31 staining Raji xenografts Actimid CD31 staining Bars show meansError bars show mean ± 1.0 SE 125 100 75 50 25 0 *† † * MVD (vessels/llpf) Placebo Lenalidomide Actimid *p=0.009†p=0.005 Reddy N, et. al. Br J Haematol 2007, 140:36-45

  20. Lenalidomide induces CRs and PRs in patients with relapsed and treatment-refractory CLL • Plasma levels of TNF-, soluble TNF receptor 1 (TNF-R1), interferon (IFN)-, VEGF, bFGF, interleukin (IL)-1β, -2, -6, -8, -10, -12, IL-1 receptor antagonist (IL-1RA), and soluble IL-2 receptor (IL-2R) were measured at different time intervals pre and post-treatment • A significant reduction in plasma VEGF level was observed on day 28 in four patients that achieved a response (mean reduction of 55.6pg/mL [± 15.3], p=0.036) and on day 90 in four patients with SD or clinical improvement (mean reduction of 50.9pg/mL [± 3.3], p=0.003). Ferrajoli A, et al. Blood 2006;108:94a (Abstract 305)

  21. Cytokine secretion by DC after in-vitro exposure to lenalidomide * 20 15 10 5 0 INF-*p=0.014 †p=0.004 † pg/mL * 4,000 3,000 2,000 1,000 0 MCP-1*p<0.001 †p=0.001 † *† pg/mL DMSO Lenalidomide Actimid 700 600 500 400 300 200 100 0 TNF-a*p=0.013 †p=0.024 *† † * DMSO Lenalidomide Actimid pg/mL *† DMSO Lenalidomide Actimid Reddy N, et. al. Br J Haematol 2007, 140:36-45

  22. Differences in the number and pattern of NK cells infiltrating the tumour bed oflymphoma-bearing SCID mice treated with IMiDs Placebo-treated infiltration of NK-cells(CD49b+) in the periphery of the tumour Raji xenografts Bars show meansError bars show mean ± 1.0 SE 60 40 20 0 * † *† Lenalidomide-treated infiltration ofNK-cells (CD49b+) within the tumour Tumour infiltrated with NK-cells (%) Placebo Lenalidomide Actimid *p=0.012†p=0.015 Reddy N, et. al. Br J Haematol 2007, 140:36-45

  23. IMiD enhancement of rituximab-dependent ADCC ex vivo is mediated via co-stimulation of NK-cells by DCs Co-stimulation with DCs Without co-stimulation with DCs 30 20 10 0 30 20 10 0 Raji Raji DMSO Lenalidomide Pomalidomide Bars show means DMSO Lenalidomide Pomalidomide Bars show means p<0.007 Error bars show mean± 1.0 SE Error bars show mean± 1.0 SE Specific lysis (%) Specific lysis (%) Rituximab Isotype Splenocytes Rituximab Isotype PBMC Reddy N, et. al. Br J Haematol 2007, 140:36-45

  24. Pomalidomide in combination with rituximab improves survival in lymphoma-bearing severe combined immunodeficiency (SCID) mice 1.2 1.0 0.8 0.6 0.4 0.2 0 Pomalidomide* + rituximab Cumulative survival Pomalidomide Rituximab* Placebo 0 20 40 60 80 100 120 Time to development of limb paralysis (days) *p=0.0012 CI = confidence interval Hernandez-Ilizaliturri FJ, et al. Clin Can Res 2005;11:5984–92

  25. Lenalidomide in combination with rituximab improves survival in lymphoma-bearing SCID mice 1.2 1.0 0.8 0.6 0.4 0.2 0 Lenalidomide* + rituximab Cumulative survival Lenalidomide Rituximab* Placebo 0 20 40 60 80 100 120 Time to development of limb paralysis (days) Hernandez-Ilizaliturri FJ, et al. Clin Can Res 2005;11:5984–92 *p=0.167

  26. Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma: NHL-002 Patients self-administered oral lenalidomide (25 mg once daily) on days 1 to 21 of every 28-day cycle. Patients continued therapy for 52 weeks as tolerated or until disease progression. O O O H N N O Wiernik P, et al. Journal of Clinical Oncology, 26; 2008: 4952-4957 N H 2

  27. Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma The estimated median duration of response was 6.2 months (range, 0 to 12.8 months), and median PFS was 4.0 months (range, 0 to 14.5 months). Wiernik P, et al. Journal of Clinical Oncology, 26; 2008: 4952-4957

  28. Confirmation of the Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Relapsed or Refractory Diffuse Large-B-Cell Lymphoma: Results of An International Study (NHL-003) • NHL-003 evaluated the efficacy of single-agent lenalidomide in patients with relapsed/refractory aggressive NHL that hadreceived at least one prior treatment and had measurable disease (Median 3, range 1-6) • Lenalidomide was administered at 25mg/day p.o. on days 1–21 of a 4-week cycle until disease progression or unacceptable toxicity • Results in patients with DLBCL (N=73) demonstrated: • The overall response rate to lenalidomide was 29% (21/73) • While some complete response were observed (4%, 3/73), most of the patients achieved a partial remission (25%, 18/73). • Eleven patients (15%) had stable disease • The most common grade3 or 4 adverse events were neutropenia (32%), thrombocytopenia(15%), asthenia (8%) and anemia (7%). Czuczman M, et al. Blood (ASH Annual Meeting Abstracts) 2008 112: 268a

  29. GCB GCB + - MUM1 CD10 + + - Non-GCB Bcl-6 - Non-GCB Algorithm for Subtype Differentiation Iqbal J et al. Leukemia 2007, 1–12 Hans et al, Blood 2004, 103: 275-282

  30. Can we predict clinical response to Lenalidomide in DLBCL patients? • Retrospective study of patients with DLBCL treated with lenalidomide at Roswell Park Cancer Institute (RPCI) • Patients were divided into two cohorts using the criteria proposed by Hans et al and Igbal et al : • Germinal center B-cell-like (GCB) • Non-GCB • Tumor biopsies are routinely stained for MUM1, CD10, Bcl-6 and Ki67 by the Pathology Department at RPCI • Responses to lenalidomide were assessed by standard and/or revised Cheson criteria • Differences in response rate, duration of response to lenalidomide and overall survival were analyzed using the software program SPSS 14

  31. Can we predict clinical response to Lenalidomide in DLBCL patients? • Sample size 19, 11F/8M • Histological Diagnosis: • DLBCL = 13 • FL and DLBCL (Composite) = 5 • Transformed NHL = 1 • IHC classification of the patients: • Non-GCB = 9 • GBC = 9 • Unknown = 1 (Bcl-6 positive, T-cell rich DLBCL) • Median Age 64 (43 to 89) • Median number of prior therapies = 4 (2 – 13) • Median cycles of lenalidomide = 3 (1 – 20)

  32. * *P = 0.011 * Differences in response rate between Non-GCB and GCB-like DLBCL to lenalidomide Median number of prior treatment: Non-GCB = 4.88 (+/- 1.03) vs. GCB = 4.33 (+/- 0.64), Chi square P = 0.46 No differences in IPI score, histology, stage or other demographic characteristics were seen at time of lenalidomide Rx between the two groups

  33. Progression free survival following Lenalidomide therapy in DLBCL according to histological subtype

  34. Progression free survival following Lenalidomide therapy in pure DLBCL

  35. DLBCL with a non-GCB phenotype by IHC had a better overall survival following lenalidomide

  36. Response rate in DLBCL with a non-GCB phenotype by IHC treated with rituximab and lenalidomide • Patients with refractory/relapsed NHL treated at University of Bologna with rituximab in combination with lenalidomide (mean number of cycles =4) • Tissue array submitted to RPCI for MUM-1, Bcl-6, and CD10 IHC • Histological Diagnosis (revised and re-classified at RPCI): • DLBCL = 10 • FL3a/b = 3 • Transformed NHL = 1 • IHC classification of the patients by the Hans algorithm was feasible in 10pts: • Non-GCB = 8 • GBC = 0 • Other (FL) = 2 • ORR for all cases submitted = 50% (7/14) • ORR for Non-GCB = 50% (4/8)

  37. In summary • Lenalidomide monotherapy or in combination with rituximab are active salvage therapies in relapsed/refractory DLBCL • Our data strongly suggest that two previously identified groups of patients with DLBCL (GCB vs. non-GCB) appear to have dramatically different degrees of responsiveness to lenalidomide with or without rituximab in the relapsed/refractory setting • Tumor specimens from patients treated at two additional institutions (i.e. Mayo Clinic and the John Theurer Cancer Center at Hackensack University Medical Center) are currently being evaluated and classified in order to further validate our findings

  38. CD10 Bcl-6 MUM1 Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma Immuno-histochemistry (IHC) Gene expression profiling (GEP) Relapsed/Refractory DLBCL (N=49) Biopsy Proceed to Part B if clinically indicated Part A Bortezomib (N=23) ABC DLBCL (N=5) GCB DLBCL (N=10) ABC DLBCL (N=12) GCB DLBCL (N=12) Treat until disease progression or maximum allowable cycles DLBCL subtype classification by GEP or IHC Part B Bortezomib + DA-EPOCH (N=44) ABC DLBCL (N=12) GCB DLBCL (N=15) Treat until disease progression or maximum allowable cycles Dunleavy et al. Blood. 2009; 113:6069-76

  39. Overall study schema for proposed Phase III registrational trial of lenalidomide in r/r DLBCL Lenalidomide N=25 Lenalidomide N=74 Non-GCB Non-GCB Control N=25 Control N=74 Relapse Refractory DLBCL Stratify by IHC subtyping Lenalidomide N=25 Lenalidomide N=74 GCB GCB Control N=25 Control N=74 Stage 1 N = 100 Stage 2 N = 148 or 296 Go/No-go Analysis

  40. Lymphoma Translational Research Group Lenalidomide project Medical Oncology/immunology Myron S. Czuczman M.D. Francisco J. Hernandez-Ilizaliturri M.D. Asher Chanan-Khan M.D. Zale Berstein M.D. Jeyanthi Ramanarayanan M.D. Philip McCarthy M.D. Kelvin Lee M.D., Ph.D. Navine Bangia Ph.D. Elizabeth Repasky Ph.D. Departments of Hematology, Anatomic Pathology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN Thomas Witzig MD William Macon MD Department of Hematology and Pathology, Bologna University School of Medicine, Bologna, Italy, Pier Luigi Zinzani MD Stefano A. Pileri MD The John Theurer Cancer Center at Hackensack University Medical Center, Hackensack NJ. Andrew Goy MD Pathology/molecular diagnostics Maurice Barcos M.D. George Deeb M.D. Paul Wallace Ph.D. Peter Sterostick Ph.D. Ann Marie Block Ph.D. IMIDs pre-clinical project Malik Farhana MBBS Nishitha Reddy M.D. Beata Holkova M.D.

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