Stem Cell Transplantation

H. Atilla Özkan, MD.

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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Definition

Infusion of hematopoietic stem cells from oneself or another person

Usually follows high dose chemotherapyand/or irradiation

CD34+

CD38-

CD38+

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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.)

Stem Cell Sources

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Hematopoietic Nich

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PBSC Collection

BoneMarrow Harvest

BoneMarrow Harvest

Peripheral blood stem cell mobilization

1. G-CSF

2. G-CSF + Plerixafor (Mozobil)

3. Chemotherapy + G-CSF

4. Chemotherapy + G-CSF + Plerixafor

Mobilization of Stem Cells

Goal collection:

> 2 x 106 cells/kg (auto-SCT)

> 5 x 106 cells/kg (allo-SCT)

Factors Influencing SuccessfulMobilization

Pelvic or abdominal irradiation Marrow hypocellularity Prior stem cell toxic agents Prior no of chemo. regimens Age Type of underlying disease

Autologous BMT

Reinfusion of patient’s own cells Regimens do not include

immunosuppression Older patients Worry about reinfusion of cancer cells Chemotherapy associated toxicity

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

Allogeneic BMT

HLA Matched sibling HLA matched unrelated donor (MUD) HLA mismatched related donor HLA mismatched unrelated donor

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

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

Syngeneic BMT

Reinfusion of identical twin’s cells Need to insure twins are identical

Deciding on type of SCT

Type and stage of disease Availability of stem cells Age Performance status Clinical condition of patient

Preparative RegimenPurpose

Kill tumor cells Provide space in marrow Suppress immune system

Components of Ideal Regimen

Myeloablative Immunosuppressive Non-overlapping toxicities

Myeloablative Regimens Cyclophosphamide/TBI Busulfan/Cyclophosphamide Carmustine/Etoposide/Cytarabine/

Cyclophosphamide Carmustine/Etoposide/Cytarabine/Melphalan Melphalan

Nonmyeloablative Regimens

Fludarabine/Melphalan Fludarabine/cyclophosphamide Fludarabine/busulfan

Regimen Related Toxicities Nausea/vomiting Diarrhea Mucositis Myelosuppression Electrolyte

abnormalities Pulmonary Hemorrhagic

cystitis Sterility

Cardiomyopathy Hepatotoxicity Nephrotoxcitiy Peripheral

neuropathies Ototoxicity Secondary

malignancies Infections

Hepatic Veno-occlusive

Day +14 - 28 Hyperbilirubinemia Weight gain Ascites Hepatomegaly

Infectious Complications

Bacterial Fungal CMV VZV PCP

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

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

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

Risk Factors

MHC disparity (Histocompatibility) Age Sex mismatch CMV serology Intensity of preparative regimen Prior donor transfusions Disease stage

aGVHD Prevention

Cyclosporine Tacrolimus Methylprednisolone Methotrexate Cyclophosphamide ATG

aGVHD Treatment

Methylprednisolone Antithymocyte globulin Supportive care Monoclonal antibodies PUVA Thalidomide

Chronic GVHD

Incidence 15-60% Increased risk if AGVHD Skin Mucosal changes Esophageal strictures Liver disease Thrombocytopenia

cGVHD Treatment

Prednisone Cyclosporine Supportive care Other

PUVA Photopheresis Thalidomide Mycophenolate mofetil

Late BMT Complications

Endocrine dysfunction Pulmonary fibrosis Sterility Cataract formation Infections

Otolog Hematopoetik Kök Hücre nakli endikasyonları

Malign hastalıklar: AML, HL, NHL, KLL Myeloma, Germ hücreli tümör, nöroblastoma, medullablastoma

Malign hastalıklar dışı: Otoimmün hastalıklar, Amiloidozis

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

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

PBSC

Engraftment Transfusion support Shorter hospital stay # stem cells # T cells Acute GVHD Chronic GVHD

Reinfusion of Cells