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11/6/2009 Disclosure Information I have no financial relationships to disclose relevant to the content of this presentation. A Comprehensive Cancer Center Designated by the National Cancer Institute Characteristics of Hematopoietic Stem Cells Current Concepts in All Allogeneic i Stem St Cell C ll Transplantation A Comprehensive Cancer Center Designated by the National Cancer Institute Sources of Stem Cells • Frequency: 2-10 stem cells per 105 marrow cells • Pluripotent: Give rise to all mature hematopoietic cell types • Self-renewing: Can undergo cell division without differentiation • Long-term reconstituting activity: Between 1 and 10 pluripotent stem cells can repopulate the entire hematopoiesis of a mouse. • Bone marrow • Bloodstream • Cord blood • Quiescent or only slowly cycling A Comprehensive Cancer Center Designated by the National Cancer Institute A Comprehensive Cancer Center Designated by the National Cancer Institute 1 11/6/2009 First marrow transplantation from an identical twin donor for refractory acute lymphocytic leukemia by Dr. Thomas (Seattle), in 1958. Photo shows patient 4 weeks after transplant (right) and her donor. History of Blood and Marrow Transplantation 1968 Good: First successful marrow transplant from an HLA-identical sibling 1973 Speck: First marrow transplant from an unrelated donor 1977 Seattle Group: Results of HLA-identical sibling transplants in 100 patients with end-stage leukemia: 13 long-term disease-free survivors 1988 Gluckman: First successful cord blood transplant from an HLAidentical sibling 1990 Thomas: Awarded Nobel Prize in Medicine for endeavors in experimental and clinical bone marrow transplantation A Comprehensive Cancer Center Designated by the National Cancer Institute Dr. E. Donall Thomas receives Nobel Prize for Medicine from King Carl Gustav of Sweden. A Comprehensive Cancer Center Designated by the National Cancer Institute A Comprehensive Cancer Center Designated by the National Cancer Institute Types of Stem Cell Transplants Autologous: The patient’s own stem cells are used. Allogeneic: Stem cells are obtained from an appropriate related or unrelated donor. A Comprehensive Cancer Center Designated by the National Cancer Institute 2 11/6/2009 Stem Cell Transplantation Procedure Collection of Peripheral Blood Stem Cells by Leukapheresis 1) Harvest of stem cells from patient or appropriate related or unrelated donor: a) from pelvic bone in general anesthesia (marrow stem cells) b) from f arm veins i by b leukapheresis l k h i (peripheral ( i h l blood stem cells) c) from placenta after delivery (cord blood stem cells) A Comprehensive Cancer Center Designated by the National Cancer Institute Stem Cell Transplantation Procedure (continued) A Comprehensive Cancer Center Designated by the National Cancer Institute Intravenous Infusion of Blood Stem Cells 2) Treatment of patient with high dose chemotherapy with or without high dose irradiation of whole body to: a) destroy all tumor cells in the body of the patient b) suppress the immune system of the patient to prevent rejection of the allogeneic stem cell transplant 3) Infuse stem cells into a central vein of the patient like a blood transfusion. A Comprehensive Cancer Center Designated by the National Cancer Institute A Comprehensive Cancer Center Designated by the National Cancer Institute 3 11/6/2009 Indications and Numbers of Allogeneic Hematopoietic Stem Cell Transplants Worldwide in 2006 Strategy of Myeloablative Allogeneic Stem Cell Transplant 1) 6,500 Conditioning with high doses of systemic chemotherapeutic agents with or without additional TBI. Unrelated donor (Total N=8,350) Related donor (Total N=10,260) 6,000 2) High dose therapy is designed to eradicate the underlying disease and suppress the recipient’s immune system to prevent graft rejection. 3) Stem cell transplant to “rescue” the patient from the toxic effects of the high-dose conditioning regimen on the bone marrow. 4) Postgrafting immunosuppressive treatment is given to prevent GVHD and to establish long-term graft / host tolerance. 5) Toxicities of high-dose conditioning to GI tract, lung, heart and liver have restricted the use of conventional, myeloablative allogeneic SCT to younger, medically fit patients. Number of Tran nsplants 5,500 5,000 4,500 4,000 3,500 3,000 2,500 2,000 1,500 1,000 500 0 A Comprehensive Cancer Center Designated by the National Cancer Institute AML ALL MDS/MPD NHL CML Multiple Myeloma HD Aplastic Anemia Other Leuk Other Cancer NonMalig Disease A Comprehensive Cancer Center Designated by the National Cancer Institute One-Year Survival after a Myeloablative Conditioning Regimen for Acute Leukemias in any Remission, CML or MDS, Age 50 Years, 1988-2007, by Year of Transplant and Graft Source One-Year Surviva al, percent 100 80 HLA-matched sibling URD Reduced Intensity Allogeneic Reduced-Intensity Stem Cell Transplantation 60 40 20 0 1988- 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 1990 A Comprehensive Cancer Center Designated by the National Cancer Institute Slide 13 A Comprehensive Cancer Center Designated by the National Cancer Institute SUM09_14.ppt 4 11/6/2009 Age at Myeloablative SCT versus Age at Diagnosis Graft-versus-Tumor Effect after Allogeneic Marrow Transplant Median Age (years) Allogeneic SCT Recipients (FHCRC) Disease Related Donor At Diagnosis Unrelated Donor CML 40 36 67 AML 28 33 68 NHL 33 35 65 MM 45 45 70 CLL 51 46 71 HD 29 28 34 MDS 40 41 68 Overall 40 (n=1428) 35 (n=1277) -- A Comprehensive Cancer Center Designated by the National Cancer Institute A Comprehensive Cancer Center Designated by the National Cancer Institute Strategy of Reduced-Intensity Stem Cell Transplant Principle of Reduced-Intensity Transplant Tumor Cell Kill by Donor T-cells Instead of Cytotoxic Chemo-Radiotherapy A Comprehensive Cancer Center Designated by the National Cancer Institute 1) Non-myeloablative conditioning with purine analogues and alkylating agents or low-dose TBI to suppress the immune system of the recipient to allow engraftment. 2) Post-transplant Post transplant immunosuppression with tacrolimus or cyclosporine combined with mycophenolate mofetil and/or anti-T-cell globulin to prevent GVHD and graft rejection. 3) Post-transplant immune manipulation by modifying immunosuppressive treatment or by infusion of donor lymphocytes to increase donor chimerism and/or to improve disease control. A Comprehensive Cancer Center Designated by the National Cancer Institute 5 5 11/6/2009 Effect of Post-transplant Immunosuppression on Engraftment of DLA-Identical Marrow Grafts after Different Doses of TBI (Seattle) Reduced-Intensity Hematopoietic Cell Transplant Post-Transplant # of Dogs w/Stable Engraftment/ TBI Dose (cGy) Immunosuppression # of Dogs Transplanted 920 None 20/21 450 None 16/39 450 7/7 450 CSP Prednisone 200 CSP 0/4 200 MTX + CSP 2/5 200 100 MMF + CSP MMF + CSP 11/12 0/6 100 MMF + CSP + CTLA4Ig* 4/6 0/5 * Peptide that binds to B7 and blocks T-cell-activating CD28: B7 pathway A Comprehensive Cancer Center Designated by the National Cancer Institute A Comprehensive Cancer Center Designated by the National Cancer Institute Candidates for Reduced-Intensity Stem Cell Transplants Non-Myeloablative Regimens Center Regimen Donor Postgrafting Immunosuppression Seattle Flu + TBI (2 Gy) MRD, URD CSP + MMF Houston Flu + Mel MRD, URD FK-506 + MTX Jerusalem Flu + Bu + ATG MRD, URD CSP London Flu + Mel + Campath MRD, URD CSP + MTX A Comprehensive Cancer Center Designated by the National Cancer Institute 7 Patients who are ineligible for myeloablative stem cell transplants because of: 1) Age >55 years (related SCT) or > 50 years (unrelated SCT) 2) Medical contraindications like renal, cardiac or pulmonary insufficiencies. 9 A Comprehensive Cancer Center Designated by the National Cancer Institute 11 6 11/6/2009 The Potential Benefits of Allotransplantation Using a Non-Myeloablative Regimen Low toxicity and mortality Low anticipated late effects Treatment of elderly patients is feasible Suitable for treatment of patients with comorbid conditions Can be carried out on an out-patient basis Fast recovery with fewer complications and less infection A Comprehensive Cancer Center Designated by the National Cancer Institute Retrospective comparison of (a) transplant-related mortality and (b) relapse in patients over 50 years of age with AML receiving either a myeloablative (MA; n=407) or a reduced-intensity (RIC; n=315) transplant from an HLA-identical sibling (EBMT) TRM A Comprehensive Cancer Center Designated by the National Cancer Institute Retrospective comparison of (c) leukemia-free survival and (d) overall survival in patients over 50 years of age with AML receiving either a myeloablative (MA) or a reduced-intensity (RIC) transplant from an HLAidentical sibling (EBMT) LFS 32% 44% P < 0.001 18% Relapse 41% 24% NS 40% OS P < 0.0001 46% 44% Aoudjhane M et al. Leukemia 2005; 19: 2304-2312 A Comprehensive Cancer Center Designated by the National Cancer Institute NS Aoudjhane M et al. Leukemia 2005, 19: 2304-2312 A Comprehensive Cancer Center Designated by the National Cancer Institute 7 11/6/2009 Probability of Survival After HLA-Identical Sibling Transplants for AML, Age 50 Years, 1998–2006 Probability of Survival After HLA-Identical Sibling Allotransplants for Follicular Lymphoma, 1998–2006 By Disease Status and Conditioning Regimen Intensity By Disease Status and Conditioning Regimen 100 90 90 80 80 70 70 60 60 Early, myeloablative Early, myeloablative (N=660)(N=660) 50 50 40 40 30 30 Early, reduced-intensity conditioning (N=544) Intermediate, myeloablative (N=206) 20 20 Intermediate, reduced-intensity conditioning (N=77) 10 10 P.3745. 0 3 Years 2 4 5 100 90 Chemosensitive, myeloablative (N=316) 70 60 60 50 50 Chemoresistant, reduced–intensity conditioning (N=46) 40 30 40 30 Chemoresistant, myeloablative (N=69) 20 20 10 10 P.0127. 0 0 0 1 2 A Comprehensive Cancer Center Designated by the National Cancer Institute 3 Years 4 5 6 A Comprehensive Cancer Center Designated by the National Cancer Institute Autologous Transplantation Followed by Reduced-Intensity Allogeneic Transplantation in Myeloma Probability of Survival After Transplants for Mantle Cell Lymphoma, 1998–2006 By Donor Type and Conditioning Regimen Probability of Su urvival, % 80 70 6 100 90 Chemosensitive, reduced–intensity conditioning (N=325) 80 0 1 0 100 Probability of Su urvival, % Probability of Su urvival, % 100 100 90 90 HLA-identical sibling, reduced-intensity conditioning (N=179) 80 80 HLA-identical sibling, myeloablative (N=258) 70 70 Autotransplant p ((N=1,769)) , )) 60 60 50 Study Maloney 50 40 Diagnosis Relapsed, refractory or untreated myeloma Procedure N OS, % DFS, % Auto / Matched Sib 54 78 55 Double auto Auto / Matched Sib 46 58 45 75 20 50 40 Bruno Unrelated, myeloablative (N=63) 30 30 Unrelated, reduced-intensity conditioning (N=133) 20 Newly diagnosed myeloma 20 10 10 Antin JA. Hematology 2007; 47-54 P.0001. 0 0 0 1 2 3 Years 4 5 6 A Comprehensive Cancer Center Designated by the National Cancer Institute A Comprehensive Cancer Center Designated by the National Cancer Institute 8 11/6/2009 Conclusions 1. Reduced-intensity transplants are most successful in less aggressive diseases such as low-grade lymphomas and chronic lymphocytic leukemia because a graft-versus-tumor reaction takes several weeks to develop after transplant. 2 M 2. More aggressive i diseases di like lik AML, AML MDS or aggressive i lymphomas have best results with RIC transplants if diseases are in complete remission at the time of transplant. Neither the publisher nor the authors assume any liability for any injury and/or damage to persons or property arising from this website and its contents. 3. One strategy to obtain both dose intensity and a graftversus-malignancy effect is to follow a high-dose autologous transplant with a RIC allogeneic transplant. This has been shown, for instance, in multiple myeloma to improve both event-free and overall survival. A Comprehensive Cancer Center Designated by the National Cancer Institute A Comprehensive Cancer Center Designated by the National Cancer Institute 9