Stem Cell Transplantation for Severe Aplastic Anemia
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1 Number of Transplants 10/24/2011 Stem Cell Transplantation for Severe Aplastic Anemia Claudio Anasetti, MD Professor of Oncology and Medicine Chair, Blood and Marrow Transplant Dpt Moffitt Cancer Center Indications for allogeneic hematopoietic stem cell transplantation in North America ,000 2,500 Related Donor (n=3,282) Unrelated Donor (n=3,389) 2,000 1,500 1, AML ALL MDS/MPS NHL Aplastic Anemia CML Multiple Myeloma HD Other Leuk Other Cancer Non- Malig Disease Slide 11 SUM10_13.ppt 1
2 Why Stem Cell Transplantation? Replaces dysfunctional marrow Myelodysplastic Syndromes Aplastic anemia Intense chemotherapy Where standard therapy is insufficient Relapse risk is high Lymphoma Leukemias Myeloma Immune therapy against the cancer What is the Bone Marrow? Central portion of bone Contains basic blood elements In adults, marrow is replaced by fat in long bones In hips, sternum, ribs and skull are rich of marrow 2
3 The production of blood Stem Cells Progenitors Erythrocytes Thrombocytes T-Cell B-Cell Myeloid Progenitor Granulocytes, Monocytes Types of Transplants Allogeneic (from another person) Tissue Type Matched Related Unrelated Tissue Type Mismatched Unrelated Cord Syngenic identical twin Autologous (from yourself) 3
4 Timing of Transplant Consultation for Severe Aplastic Anemia (SAA) At diagnosis Sibling Transplant outcome: Second line therapy worse than first line therapy British Journal of Haematology 135: ,
5 Timely Referral Affects Survival Early referral is the single most important step that can affect survival Lee, et al. Blood 2007 Transplantation Process Minimize sensitization Tissue typing Donor Search Evaluation Conditioning therapy Transplantation Engraftment Recovery 5
6 Donor Search We look for a genetic match Not your blood type! Human Leukocyte Antigens Typing blood or buccal swab Chance of match 1 in 4 if sibling 1 in 1,000 if unrelated Father a b HLA inheritance A B DR Possible Offspring a c a d 25% 25% Mother c d b c 25% b d 25% 6
7 Probability of finding an HLA-A, B, C, DRB1 matched donor Total 8/8 7/8 none Caucasians 89% 62% 27% 11% Hispanics 77% 34% 43% 23% African- Americans 64% 15% 48% 37% p=<
8 Total time to transplant % at risk Median days [95% CI] Search to first donor 85% 20 [11-59] First donor to backup donor 34% 8 [3-85] Donor to transplant 48% 81 [45-199] Growth in Unrelated Transplants Unrelated transplant is growing in nearly all diseases for which transplant is indicated NMDP Transplant Recipients by Diagnosis 1,200 1, AML ALL Non-Malignant MDS NHL CML National Marrow Donor Program
9 Pre-transplant Evaluation Medical Assessment Disease status, assess for Fanconi, Dyskeratosis, PNH, MDS Organ function Infectious status by transplant physician psychologist social worker dentist Education of the recipient and family Transplantation Procedure Conditioning Therapy Stem Cells Anti-rejection Drugs day 0 9
10 % of patients 10/24/2011 Conditioning Therapy Suppressive drugs to prevent rejection SAA none additional MDS chemotherapy Side effects: Low blood counts Hair loss Mouth sores Vomiting Diarrhea Death: 0-2% Effect of Co-Morbidity Score One Year Transplant Mortality By Conditioning Less Intense More intense 36% 19% 14% 67% 28% Months after HCT Months after HCT Sorror M, et al Blood 106:
11 Older Patients Eligible Transplants for patients over age 50 now account for 35% of all NMDP-facilitated transplants National Marrow Donor Program 2008 Sources of Stem Cells Bone Marrow Peripheral Blood Umbilical Cord Blood 11
12 Bone Marrow Harvest 1-2 hour surgery Anesthesia required No growth factors Blood Stem Cell Collection - Apheresis - Outpatient procedure 4-6 hours Growth factors given No sedation Peripheral veins used 12
13 Umbilical Cord Blood Obtained from placenta remnants Typed and banked Less GVHD Stem Cell Dosage may be an issue Stem Cell Transplant 13
14 Immune suppressive Drugs Anti-rejection Tacrolimus Cyclosporine Sirolimus Methotrexate Mycophenolate Anti-Thymocyte Globulin Prednisone Issues in Transplants Rejection Graft Versus Host Disease Infection Organ damage Late effects 14
15 Issues in Transplants Rejection <1-10% Graft Versus Host Disease Organ damage - chemotherapy Infection Late Effects Major impact of Fludarabine and low dose irradiation Issues in Transplants Rejection <1% Graft Versus Host Disease ~50% Organ damage - chemotherapy Infection Late Effects Modest impact of tacrolimus and ATG, promising sirolimus 15
16 Skin rash Clinical manifestations Acute Nausea, vomiting Diarrhea Abdominal cramps Intestinal bleeding Hepatitis: AST, ALT elevation Cholestasis: GGT, AP, Bili elevation Thomas E, et al. Bone-marrow transplantation. N Engl J Med ;292: and Stage 1 GVHD of Skin 16
17 Acute GVHD mortality Overall % Non-Relapse Grade Mortality 0 15% 5% I 5% 5% II 60% 15% III 15% 60% IV 5% 95% Skin Dark or light spots Hardening Mouth Clinical manifestations Chronic White plaques Thickening Restriction of mouth opening Genitalia Vaginal stenosis Gastro-Intestina Esophageal stricture Lung Chronic Asthma Joints Stiffness or contractures 17
18 Complications Infections From immunodeficiency From glucocorticoid use Burn syndrome GI bleeding Liver failure Respiratory Failure Late effects Sterility Secondary cancers Coronary artery disease 18
19 Probability of Survival, % 10/24/2011 Probability of survival after allogeneic transplant for severe aplastic anemia, by age and donor type, P < HLA-matched sibling, 20 y (N=1,388) HLA-matched sibling, >20 y (N=1,408) Unrelated, 20 y (N=562) Unrelated, >20 y (N=532) Years Slide 41 SUM10_48.ppt Survival for Severe Aplastic Anemia has improved over time Sibling BMT Unrelated BMT IST Locasciulli A et al. Haematologica 2007;92:11-18 Passweg, J. R. et al. Hematology 2010;2010:
20 Transplant Conditioning Cyclophosphamide Total Body Irradiation Anti-thymocyte-globulin Fludarabine Sib transplant conditioning: ATGAM is marginally beneficial Champlin et al. Blood 2007, 109:
21 Sib transplant conditioning: Fludarabine is beneficial in SAA Maury S et al. Haematologica 2009;94: Unrelated transplant conditioning: Fludarabine is beneficial in FA Wagner J E et al. Blood 2007;109:
22 Sib conditioning: Cy + Fludarabine Survival of SAA patients by age Maury S et al. Haematologica 2009;94: Unrelated transplant conditioning: Low dose irradiation is beneficial 200 cgy Total Body Irradiation is well tolerated: outpatient, does not cause loss of hair, mouth sores, diarrhea. Bacigalupo A et al. Haematologica 2010;95:
23 Unrelated transplant outcome: improved survival after 2004 Bacigalupo A et al. Haematologica 2010;95: Worse outcome with delayed unrelated transplant Bacigalupo A et al. Haematologica 2010;95:
24 GVHD prophylaxis: Improved outcome with Tacrolimus Yagasaki et al, BBMT 2009, 15: Stem cell source: Better outcome with Bone Marrow compared to Blood Stem Cells Schrezenmeier H et al. Blood 2007;110:
25 Promising survival in 12 patients with SAA after unrelated cord blood transplantation Yamamoto H et al. Blood 2011;117: Conditioning before Unrelated Cord Blood Transplantation for Severe Aplastic Anemia Yoshimi et al, BBMT 2008, 14:
26 Summary (1) Transplant outcome has improved with less toxic but more immune suppressive conditioning with less rejection, and with better GVHD prevention. Summary (2) Tissue matched sibling transplants should be considered for first line therapy in patients with SAA at diagnosis up to age 40 or 50 depending on comorbidities 26
27 Summary (3) Transplants should be considered for second line therapy after immune suppression failure in patients over 50 years of age, or patients without a tissue matched sibling Summary (4) Research continues in the area of GVHD prevention, immune reconstitution, and prevention of late effects. 27
28 Questions? 28
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