stem cell transplantation h. atilla Özkan, md.. the nobel prize, 1990 e. donnall thomas first...
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Stem Cell Transplantation
H. Atilla Özkan, MD.
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The Nobel Prize, 1990
E. Donnall Thomas
first succsessful HSCT in treatment of acute leukemias
Thomas ED, Lochte HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med.
1957; 257: 491.
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21.04.23 3
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Definition
Infusion of hematopoietic stem cells from oneself or another person
Usually follows high dose chemotherapyand/or irradiation
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CD34+
CD38-
CD38+
6
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Hematopoietic Stem Cell TransplantationHematopoietic Stem Cell Transplantation
1. 1. Hematologic Malignancies Hematologic Malignancies
Acute and Chronic Myeloid LeukemiaAcute and Chronic Myeloid Leukemia
Acute and Chronic lymphocytic leukemia Acute and Chronic lymphocytic leukemia Myeloddysplastic SyndromeMyeloddysplastic SyndromeLymphomas – Hadgkins and Non HodgkinsLymphomas – Hadgkins and Non HodgkinsMultiple MyelomasMultiple Myelomas
2. 2. Non Malignant DisordersNon Malignant Disorders Severe Aplastic Anemias (SAA)Severe Aplastic Anemias (SAA)Hurler’s SyndromeHurler’s SyndromeWiskott – Aldrich Syndrome Wiskott – Aldrich Syndrome Diamond – Blackfan AnemiaDiamond – Blackfan AnemiaOsteopetrosisOsteopetrosis
3. 3. Inherited Blood DisordersInherited Blood DisordersBeta Thalassaemia MajorBeta Thalassaemia Major
4. 4. Severe combined immunodeficiency (SCID)Severe combined immunodeficiency (SCID)
5. 5. Pathologic States including autoimmune diseasesPathologic States including autoimmune diseases
6. 6. Solid Tumors (Breast cancer, Teratomas, ovarian tumors etc.)Solid Tumors (Breast cancer, Teratomas, ovarian tumors etc.)
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Stem Cell Sources
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Hematopoietic Nich
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PBSC Collection
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BoneMarrow Harvest
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BoneMarrow Harvest
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Peripheral blood stem cell mobilization
1. G-CSF
2. G-CSF + Plerixafor (Mozobil)
3. Chemotherapy + G-CSF
4. Chemotherapy + G-CSF + Plerixafor
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Mobilization of Stem Cells
Goal collection:
> 2 x 106 cells/kg (auto-SCT)
> 5 x 106 cells/kg (allo-SCT)
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Factors Influencing SuccessfulMobilization
Pelvic or abdominal irradiation Marrow hypocellularity Prior stem cell toxic agents Prior no of chemo. regimens Age Type of underlying disease
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Autologous BMT
Reinfusion of patient’s own cells Regimens do not include
immunosuppression Older patients Worry about reinfusion of cancer cells Chemotherapy associated toxicity
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Allogeneic BMT
Reinfusion of someone else’s (donor) cells into patient (recipient)
Regimens usually aggressive and contain immunosuppression
Younger patients Finding a HLA-matched donor is difficult GVHD and infectious complications Chemotherapy toxicity
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Allogeneic BMT
HLA Matched sibling HLA matched unrelated donor (MUD) HLA mismatched related donor HLA mismatched unrelated donor
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Compatible Donor Search -Compatible Donor Search -Matching HLAMatching HLA
Family- ¼ chanceFamily- ¼ chance
Unrelated – Unrelated –
1/500 - 0/10 million chance of 1/500 - 0/10 million chance of matchmatch
70% patients70% patientsdo not have family do not have family donordonor
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Chromosome 6 Chromosome 6
Gene map of the HLA regionGene map of the HLA region
Class Class IIII
Class Class IIIIII
Class IClass I
1.8 Mb1.8 Mb
40 % of which have assumed immune 40 % of which have assumed immune functions functions
tel. Long arm cen. short arm tel. Long arm cen. short arm tel. tel.
6p 21.36p 21.3HLA regionHLA region
Bf Bf DP DP
DM DM
DQ DQ
DR DR
C4 C4 C2Hsp70TNF C2Hsp70TNF
B C E A G B C E A G F F
128 functional 128 functional genes genes
Most polymorphic Most polymorphic
Ag presentation, crucial in organ and HSCTAg presentation, crucial in organ and HSCT
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Syngeneic BMT
Reinfusion of identical twin’s cells Need to insure twins are identical
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Deciding on type of SCT
Type and stage of disease Availability of stem cells Age Performance status Clinical condition of patient
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Preparative RegimenPurpose
Kill tumor cells Provide space in marrow Suppress immune system
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Components of Ideal Regimen
Myeloablative Immunosuppressive Non-overlapping toxicities
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Myeloablative Regimens Cyclophosphamide/TBI Busulfan/Cyclophosphamide Carmustine/Etoposide/Cytarabine/
Cyclophosphamide Carmustine/Etoposide/Cytarabine/Melphalan Melphalan
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Nonmyeloablative Regimens
Fludarabine/Melphalan Fludarabine/cyclophosphamide Fludarabine/busulfan
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Regimen Related Toxicities Nausea/vomiting Diarrhea Mucositis Myelosuppression Electrolyte
abnormalities Pulmonary Hemorrhagic
cystitis Sterility
Cardiomyopathy Hepatotoxicity Nephrotoxcitiy Peripheral
neuropathies Ototoxicity Secondary
malignancies Infections
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Hepatic Veno-occlusive
Day +14 - 28 Hyperbilirubinemia Weight gain Ascites Hepatomegaly
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Infectious Complications
Bacterial Fungal CMV VZV PCP
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Graft Versus Host Disease (GVHD)
Reaction of donor T-cells against host tissues PBSCT or BMT Blood transfusions
Billingham criteria Graft must contain immunocompetent cells Recipient must express antigens not present in
donor Recipient incapable of mounting immune
response against graft
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Pathophysiology
Afferent phase Recipient tissues active donor T lymphocytes Antigen presentation T cell activation Proliferation and differentiation of T cells
Efferent phase Attack of donor cells on host target tissues Activated T cells secrete cytokines Secondary effector cells damage tissues
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Acute GVHD
Occurs in 25-70% of all BMT patients Graded based on combination of
severity of presentation Survival based on grade (0-90%) Death usually due to infections,
hemorrhage or organ failure
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Risk Factors
MHC disparity (Histocompatibility) Age Sex mismatch CMV serology Intensity of preparative regimen Prior donor transfusions Disease stage
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aGVHD Prevention
Cyclosporine Tacrolimus Methylprednisolone Methotrexate Cyclophosphamide ATG
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aGVHD Treatment
Methylprednisolone Antithymocyte globulin Supportive care Monoclonal antibodies PUVA Thalidomide
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Chronic GVHD
Incidence 15-60% Increased risk if AGVHD Skin Mucosal changes Esophageal strictures Liver disease Thrombocytopenia
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cGVHD Treatment
Prednisone Cyclosporine Supportive care Other
PUVA Photopheresis Thalidomide Mycophenolate mofetil
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Late BMT Complications
Endocrine dysfunction Pulmonary fibrosis Sterility Cataract formation Infections
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Otolog Hematopoetik Kök Hücre nakli endikasyonları
Malign hastalıklar: AML, HL, NHL, KLL Myeloma, Germ hücreli tümör, nöroblastoma, medullablastoma
Malign hastalıklar dışı: Otoimmün hastalıklar, Amiloidozis
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Allojeneik Hematopoetik Kök Hücre nakli endikasyonları
Malign hastalıklar: AML,ALL, MDS HL, NHL, KML, KLL Myeloma,
Malign hastalıklar dışı: Otoimmün hastalıklar, orak hücreli anemi, aplastik anemi,
fankoni anemi, thal majör, wiskot aldrich, PNH, osteopetrozis, ciddi kombine immün yetmezlik
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HKHN neyi sağlar?
Kemik iliği yetmezliği durumlarında normal hematopoezin
oluşmasını sağlar
Hastalıklı kemik ilğinin yerini sağlıklı kemik iliği alır
Kemik ilği ablasyonu sonrası tekrar hematopoezi sağlar
Konjenital immün yetmezlikleri düzeltir
Graft versus tümör etkisi sağlar
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Bone Marrow
Engraftment Transfusion support Longer hospital stay # stem cells # T cells Acute GVHD Chronic GVHD
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PBSC
Engraftment Transfusion support Shorter hospital stay # stem cells # T cells Acute GVHD Chronic GVHD
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Reinfusion of Cells