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Transplantation in Low Grade Lymphomas

Transplantation in Low Grade Lymphomas. John G. Gribben, MD, DSc, FMedSci Professor of Experimental Cancer Medicine Barts and The London School of Medicine University of London United Kingdom.

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Transplantation in Low Grade Lymphomas

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  1. Transplantation in Low Grade Lymphomas John G. Gribben, MD, DSc, FMedSci Professor of Experimental Cancer Medicine Barts and The London School of Medicine University of London United Kingdom

  2. Benefit of Autologous BMT Over Salvage Chemotherapy in Chemotherapy-Sensitive Relapsed Non-Hodgkin Lymphoma* Role of high-dose therapy over standard-dose salvage therapy has been established in randomized clinical trials in DLBCL Event-Free Survival 100 80 60 ABMT Percentage 40 20 P=0.001 Conventional Therapy 1 2 3 4 5 7 6 Years Philip T et al. N Engl J Med. 1995;333:1540-1545.

  3. Salvage Therapy for Low-Grade Lymphomas Factors determining salvage therapy Age Performance status Previous therapy administered Response and duration of response to last therapy Goal of therapy

  4. Salvage Treatment Options for Low-Grade Lymphomas Watchful waiting Chemotherapy Alkylating agent Purine analog Combination chemotherapy Monoclonal antibodies alone Rituximab Alemtuzumab Monoclonal antibodies + chemotherapy Stem cell transplantation

  5. Role of High-Dose Therapy inLow-Grade Lymphomas Several phase II studies have demonstrated good outcome after high-dose therapy and autologous stem cell rescue Small randomized trial suggests benefit of high-dose therapy over conventional chemotherapy for follicular lymphoma (CUP trial)1 1. Schouten HC et al. J Clin Oncol. 2003;21:3918-3927.

  6. Autologous Transplant in First Remission Phase II trial suggested outcome after auto-SCT in 1st remission not better than after relapse and similar incidence of MDS (Freedman, Gribben et al, Blood, 1996;88:2780-6) Three recent phase III studies have not suggested clear benefit for auto-SCT. All showed a better DFS, but no impact on OS GLGLSG GELA GOELAMS

  7. “CUP” Trial for Follicular Lymphoma Events Total Chemotherapy 20 24 Unpurged 9 22 Purged 11 24 Patients at: Chemotherapy 24 9 6 6 4 2 1 1 22 16 11 11 11 9 8 2 Unpurged 24 16 12 12 12 8 6 3 Purged Progression-Free Survival 1.0 0.8 0.6 Probability 0.4 0.2 0 0 12 24 36 48 60 72 84 Months Schouten HC et al. J Clin Oncol. 2003;21:3918-3927.

  8. Autologous SCT Using Cyclophosphamide and Total Body Irradiation in Relapsed Follicular Lymphoma Overall Survival 1.00 0.75 Probability 0.50 (n=121) 0.25 0.00 0 4 8 12 16 20 Years Barts and DFCI -Rohatiner et al JCO 2008

  9. Autologous SCT Using Cyclophosphamide and Total Body Irradiation in Relapsed Follicular Lymphoma 1.00 0.75 0.50 0.25 0.00 0 2 4 6 8 10 12 14 16 18 20 Overall Survival 2nd Remission Probability P<0.005 >3rd Remission Years

  10. MDS After Autologous BMT for Low-Grade Lymphoma Time to MDS After Autologous BMT* 1.0 0.8 0.6 Probability 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 Years After BMT *41/552 patients developed MDS. Friedberg JW et al. J Clin Oncol. 1999;17:3128-3135.

  11. Allogeneic BMT for Low-Grade Lymphoma Disease-Free Survival After BMT 100 High Treatment-Related Mortality Low Probability of Relapse 80 60 Percentage 40 20 0 0 2 1 3 4 5 6 Years After BMT van Besien K et al. Blood. 1998;92:1832-1836.

  12. Autologous Versus Allogeneic SCT for FL No randomized trials Retrospective analyses: K van Besien et al. Blood. 2003;102:3521-3529. LF Verdonck et al. Leuk Lymphoma. 1999;34:129-136. C Hosing et al. Ann Oncol. 2003;14:737-744.

  13. Stem cell transplant for CLL Most patients with CLL have indolent course and are never candidates for aggressive therapy approaches. It is possible to identify poor risk patients with short survival No randomized clinical trial data demonstrating advantage of SCT in CLL Phase II studies of autologous SCT Feasible No demonstration of plateau on PFS Myeloablative SCT Not applicable to many patients with CLL Very high TRM RIC SCT has suitable for more patients with CLL and has produced impressive results

  14. Poor prognosis of advanced, relapsed CLL There is therefore an outstanding need for more effective,feasible therapies in relapsed/refractory CLL

  15. PFS after auto-SCT in CLL: Retrospective studies only Esteve, 2001 1.0 1.0 0.8 0.6 Allo 42% Probability 0.8 0.4 0.2 P = 0.04 Auto 24% n = 124 0.6 0.0 0 5 10 15 Years Probability 1.0 0.4 EBMT, 2005 Autologous 0.8 0.2 0.6 Probability TCD Allogeneic 0.4 0.0 0.2 n = 1323 0 5 10 15 Years 0.0 0 20 40 60 140 80 100 120 Months Gribben, 2005 n = 137 Esteve 2001. EBMT 2005. 106:4389–4396 Gribben JG, et al. Blood 2005;.

  16. Graft-Versus-Lymphoma Effect in SLL Clinical Relapse DLI BMT 1E+07 1E+06 1E+05 1E+04 1E+03 1E+02 1E+01 Limit of Detection 0 2 4 6 Years Post SCT 2 4 6 8 Years Post DLI Gribben JG et al. Blood. 2005;106:4389-96.

  17. Rationale for Immunotherapy Approach Rationale for reduced-intensity conditioning transplantations T-cell depletion increases risk of relapse Response to donor-lymphocyte infusions This approach relies on the immune effector cells of the donor to eradicate disease Additional use of monoclonal antibodies may help control disease until GVL effect emerges

  18. Overall Survival After Reduced-Intensity Allogeneic SCT Using Alemtuzumab-Containing Conditioning Regimens 12 100 90 Low Grade (n=41) 80 70 60 MCL (n=10) Probability of Overall Survival (%) 50 High Grade (n=37) 40 30 20 10 P<0.001 0 0 24 36 48 50 Time After Transplantation (mo) Morris E et al. Blood. 2004;104:3865-3871.

  19. Phase II Studies of RIC Transplants in CLL

  20. Phase II Studies of RIC Transplants in CLL

  21. CLL: MRD after RIC allogeneic SCT – VH unmutated cases 100 10–1 10–2 10–3 10–4 10–5 dx befSCT 100 200 360 720 > 720 Ritgen M, et al. Blood 2004; 104:2600–2602.

  22. Allogeneic transplantation for CLL CLL transplant EBMT consensus Allogeneic SCT is a reasonable treatment option for younger patients with non-response or early relapse (<12 months)after purine analogue-based therapy relapse <24 months after purine analogue combinations or auto-SCT (plus high-risk genetics) p53 mutation with treatment indication Dreger P, et al. Leukemia 2007;21:12–17

  23. SCT for CLL with 17p deletion 44 pts from EBMT database Matched sibling 24, Unrelated donor 20 RIC transplant in 89% 53% in CR at transplant Improved outcome with no T cell depletion No late relapses 3-yr OS 52% 3-yr PFS 44% Schetelig et al J Clin Oncol 2008 Epub

  24. Targets of GVL Effect NHL Peptide MHC Adhesion and costimulatory molecules

  25. Targets of GVL Effect NHL Peptide MHC Minor histocompatibility Ags GVL = GVHD Adhesion and costimulatory molecules

  26. Targets of GVL Effect NHL Peptide MHC Minor histocompatibility Ags GVL = GVHD Tumour associated Ags GVL = GVHD Adhesion and costimulatory molecules

  27. 0.0 2.5 1.2 Tumor Burden and Assessment of Peptide Specific Immune Responses After SCT 1E+07 1E+06 1E+05 1E+04 0.0 IgH /GAPDH copy number 1E+03 1E+02 1E+01 1E+00 48 0 3 6 9 12 months post SCT

  28. Id Peptide Specific CD8 Cells are Detectable After SCT 1 0.9 0.8 0.7 0.6 0.5 Tetramer Specific CD8 Cells 0.4 0.3 0.2 0.1 0 0 3 6 9 12 15 18 21 24 Months post SCT

  29. Donor Peptide Specific T Cells Kill Tumor Cells 80 FACS sort 60 Ex vivo expansion 40 20

  30. CD4 and CD8 T cells from CLL patients have altered gene expression pathways Healthy CLL CLL Healthy CD8 CD4 We hypothesized that CLL T cells may inappropriately respond to APCs due to an inability to regulate actin remodeling. Gorgun, G. et al. J. Clin. Invest. 2005;115:1797-1805

  31. CD8 CD4 CD4 FOSB CALM2 JUN CD69 CALM2 PTPRC CALM1 JUN FOSB ATM FYB FYB ACTN1 ATM Healthy AML Healthy AML Altered Gene Expression Profile of T Cells in AML Le Dieu et al submitted

  32. T cells from CLL patients have impaired synapse formation Ramsay et al JCI 2008

  33. Autologous CD4 and CD8 T cells from FL and DLBCL have impaired synapse formation

  34. Direct Contact with Tumor Cells Induce Defects in healthy allogeneic T cells Subsequent conjugation experiment:

  35. Following short-term contact with CLL cells, previously healthy T cells show suppressed recruitment of cytoskeletal signaling molecules Global T cell defect in cytoskeletal and immune synapse organization

  36. Treatment of FL cells with lenalidomide enhances synapse formation

  37. Immunological synapse assay: • Molecular nature of the FL-induced T cell defect: • Global defect in cytoskeletal protein • and immune synapse organisation including: • LFA-1, Lck, RAB27a and FILAMINA Following co-culture with FL cells, previously healthy T cells show suppressed recruitment of cytoskeletal signaling molecules

  38. E-TCL1 mice closely model molecular changes observed in patients with CLL CLL patient TCL1 CLL mouse CLL patient TCL1 CLL mouse • ~ 50 commonly dysregulated genes in both CD4/8 T cells from mice and patients • Differentially expressed genes in cell proliferation and activation, and actin cytoskeleton pathways in CD4 T cells (mice and patients) • Altered cytotoxicity (perforin) and actin cytoskeletal formation pathway genes in CD8 T cells Gorgun, Ramsay et al PNAS 2009

  39. Future Directions Repair T cell defects lenalidomide studies CD3/CD28 beads Assess impact of novel therapies on immune cell function Allogeneic responses RIC transplants CB transplants Immune reconstitution after RIC transplants Examine NK cells

  40. Stem cell transplant for FL and CLLConclusions • These diseases have a heterogenous clinical course • Treatment options depend on • First line therapy used • Duration of response • Age and performance status of the patient • Goal of therapy • Many patients not candidates for aggressive therapy approaches • Limited phase III, but considerable phase II data supporting use of high dose therapy and autologous SCT • Role of autologous SCT in FL unproven and no role for autologous SCT in CLL

  41. Stem cell transplant for FL and CLLConclusions • FL and CLL are excellent GVL targets • The slow rate of tumor growth may allows time for GVL to be effective • Allogeneic SCT remains the only potentially curative approach in these diseases • RIC regimens a major advance in these disease • Ongoing and planned clinical trials are addressing whether this will result in improved outcome • Understanding the nature of the GVL effect will be crucial to improve outcome • How to induce autologous immune responses will require repair of induced immune defects

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