Hematopoietic Stem Cell Therapy
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1 Hematopoietic Stem Cell Therapy Grace Totoe, MBChB, SBB CME August 2012 Accra-Ghana
2 Hematopoietic Stem Cells Cells capable of self renewal and differentiation into all blood cell lineages
3 Objectives Historical overview Sources Indications Complications
4
5 Historical Overview The search for stem cells began in the aftermath of the bombings in Hiroshima and Nagasaki in 1945 Survivors who died later developed myelodysplastic syndromes with recurrent infections, bleeding complications and severe anemia In 1949, Jacobson et al demonstrated that mice given doses of whole body X-irradiation developed the same radiation syndromes
6 Historical Overview At a minimal lethal dose, the mice died from hematopoietic failure approximately two weeks after radiation exposure In 1951, Lorenzo et al using inbred strains of mice, showed that whole-body-irradiated mice could be rescued from otherwise fatal hematopoietic failure by injection of suspensions of cells from blood-forming organs such as the bone marrow
7 Historical Overview In 1956, three laboratories demonstrated that the injected bone marrow cells directly regenerated the blood-forming system Hence the advent of hematopoietic (progenitor) stem cell (HPC) transplant
8 Sources of HPC Collection Peripheral blood by apheresis Bone marrow Umbilical cord blood Donor Primed/ mobilized with granulocyte colony stimulating factor (G-CSF) to increase number of HPC in the peripheral blood for about 3-4 days before collection on Day 5 Medications such as mozobil can be given to increase HPCs in the peripheral blood
9 NIHgov Hematopoietic and stromal cell differentiation
10 Important Terminology Autologous transplant- transplant using a person s own HPCs Allogeneic transplant-the infusion of HPCs from another individual into the patient Allogeneic cells may be from related or unrelated Syngeneic transplant- The infusion of HPCs from a twin into the other twin Xenogeneic transplant- using HPC from a non human source or from human cells that have had ex vivo contact with live non human animal cells
11 Important Terminology CD 34+ cells- cell surface glycoprotein that functions as an adhesion molecule Used to identify hematopoietic stem cells Engraftment- sign of cell recovery after transplant An absolute neutrophil count >500mm 3 in 3 consecutive days, or platelet count 20-50K
12 Important Terminology GVHD-Post transplant complication characterized by skin, liver and GI complications Occurs when the donor cells are recognized by the recipient cells as foreign and immunologically rejects the donor cells mediated by T-lymphocytes
13 What occurs prior to stem cell collection The routine workup of the donor includes a history, CBC, BMP, Red blood type and screening for RBC allo antibodies, chest x-ray, and electrocardiogram (EKG) Infectious disease screening for hepatitis B and C, HIV, Human T-cell lymphoma virus, syphilis, and other viral diseases such as cytomegalovirus, herpes, and West Nile
14 When and how are stem cells stored? Stored in cellular therapy labs under regulated and monitored temperatures according to standards set up by governing agencies- FDA, FACT, AABB, etc If the collected stem cells are to be frozen or stored for a longer period, they are cryopreserved with dimethyl sulphoxide (DMSO)
15 When are the stem cells given to the patient? Stem cells are infused after the patient has undergone the necessary treatment- chemotherapy, radiation or both- conditioning This is to reduce the tumor burden and suppress the recipient s immune system, in order to allow engraftment of stem cells Conditioning can be myeloblative, nonmyeloablative or reduced intensity-classification is based on the duration of cytopenia and the requirement for stem cell support Bacigalupo et al, Defining the intensity of conditioning regimens: Working definitions Biol Blood Marrow Transplant 2009 December; 15(12): l
16 How are stem cells infused Stem cells are infused similar to a regular blood transfusion They may be infused on the same day of collection or stored in a cellular therapy lab and infused later
17 Current Uses and Outcomes of Hematopoietic Stem Cell Transplantation 2011 Summary Slides Worldwide SUM-WW11_1ppt
18 Center for International Blood and Marrow Transplant Research-CIBMTR Collaborates with the global scientific community to advance hematopoietic cell transplantation and cellular therapy research worldwide Has a combined research program with the National Marrow Donor Program (NMDP) and the Medical College of Wisconsin, US
19 Location of Centers participating in the CIBMTR 2011 SUM-WW11_2ppt
20 Number of Transplants Indications for Hematopoietic Stem Cell Transplants in the United States, ,500 5,000 4,500 Allogeneic (Total N=7,012) Autologous (Total N=9,778) 4,000 3,500 3,000 2,500 2,000 1,500 1, Multiple Myeloma NHL AML HD ALL MDS/MPD Aplastic Anemia CML Other Leuk Non- Malig Disease Other Cancer SUM-WW11_8ppt
21 Other Indications for HPCs Stem Cell Transplant Congenital immune deficiencies Severe combined immunodeficiency disease Wiskott-Aldrich syndromes Marrow failure syndromes Severe aplastic anemia Fanconi s anemia Diamond- Blackfan anemia ( Congenital hypoplastic anemia) Solid tumors Breast cancer Ovarian cancer Renal cell carcinoma Testicular cancer Childhood solid tumors Wilms tumor Inborn disorders of metabolism Neuroblastoma Mucopolysaccharidoses eg Hunter or Hurler syndrome Leukodystrophies eg adrenoleukodystrophy Glycoprotein disorders eg fucosidosis, mannosidosis Lysosomal disorders eg Gaucher, Pompe, Neimann-Pick disease Osteropetrosis Osteogenesis imperfecta Hemoglobinopathies Thalasemia Sickle cell disease AABB Technical Manual 17 th Edition
22 Transplants Transplant Activity in the US ,000 12,000 Autologous Related Donor Unrelated Donor 10,000 8,000 6,000 4,000 2,000 0 '80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03'04' '05 '06 '07 '08 '09 '10 SUM11_41ppt
23 Transplants, % 100 Autologous Stem Cell Sources by Recipient Age Bone Marrow (BM) Peripheral Blood (PB) BM + PB Age 20 yrs Age > 20 yrs SUM-WW11_4ppt
24 Transplants, % Allogeneic Stem Cell Sources by Recipient Age Bone Marrow (BM) Peripheral Blood (PB) Cord Blood (CB) Age 20 yrs Age > 20 yrs SUM-WW11_3ppt
25 One-Year Survival, % One-year survival after myeloablative conditioning for acute leukemias in any remission phase, CML or MDS, age <50 years, by year of transplant and graft source, HLA-matched sibling Unrelated Donor '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09 SUM11_40ppt
26 Mortality, % day Mortality after Autologous Transplants, Early Disease Intermediate/Advance Disease Sensitive Resistant Unknown Other Acute Leukemia Non-Hodgkin Lymphoma Hodgkin Disease Multiple Myeloma SUM-WW11_14ppt
27 Mortality, % day Mortality after Unrelated Donor Transplants, Early Disease Intermediate Disease Advanced Disease Chronic Phase Accelerated Phase Blast Phase Other AML ALL CML MDS/MPS Aplastic Anemia Immune Deficiency SUM-WW11_16ppt
28 Causes of Death after Transplants performed in HLA-identical Sibling Primary Disease (47%) New Malignancy (1%) GVHD (14%) Primary Disease (33%) Unrelated Donor New Malignancy (1%) GVHD (15%) Infection (12%) Organ Failure (4%) Other (21%) Primary Disease (73%) Autologous New Malignancy (1%) Other (29%) Organ Failure (6%) Infection (16%) Infection (8%) Organ Failure (2%) Other (16%) SUM-WW11_17ppt
29 In summary After more than 50 years of research and clinical use, hematopoietic stem cells have become the best-studied stem cells with several indications There is still active research ongoing to expand its use
30 REFERENCES 1 Cellular Therapy AABB 16 th Edition 2 AABB Techical Manual 17 th edition 3 WWWNIHGOV 4 WWWCIBMTRORG 5 Jacobsen LO, Marks EK, Gaston EO, Zirkle RE Effect of spleen protection on mortality following X-irradiation J Lab Clin Med Vol 34; 1949: Lorenz E, Uphoff ED, Reid TR, Shelton E Modification of acute irradiation injury in mice and guinea pigs by bone marrow injection Radiology Vol 58; 1951: Ford CE, Hamerton JL, Barnes DWH, Loutit JF Cytological identification of radiation-chimaeras Nature Vol 177; 1956: Nowell PC, Cole LJ, Habermyer JG, Roan PL Growth and continued function of rat marrow cells in x-irradiated mice Cancer Res Vol 16; 1956: Weissman IL Translating stem and progenitor cell biology to the clinic: barriers and opportunities Science Vol 287; 2000: Manz MG, Akashi K, Weissman IL Biology of Hematopoietic Stem and Progenitor Cells In: Appelbaum FR, ed Thomas' Hematopoietic Cell Transplantation Third ed Malden, MA: Blackwell Publishing; Bacigalupo et al, Defining the intensity of conditioning regimens: Working definitions Biol Blood Marrow Transplant 2009 December; 15(12): l
31 Acknowledgements Thanks to faculty of Post Graduate Medical Training Program Thanks to the Africa Partners Medical Thanks to all for attending the conference
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