Stem cell transplantation
Contents
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History
Types
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Stem cell procurementIndications
Procedure
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Complications
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History of HSCT?
Human patients
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? 1959?1963 : firstMouse
Dog
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al ogeneic HSCT in
humans
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First successful bone marrowtransplant
1956
Dr E Donnal Thomas in
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New York
Patient- leukaemia
Donor-identical twin
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The Nobel Prize, 1990
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E. Donnall Thomas
first succsessful HSCT in treatment of acute leukemias
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Thomas ED, Lochte HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patientsreceiving radiation and chemotherapy. N. Engl. J. Med. 1957; 257: 491.
1958
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Dr Georges Math?
Defined the
`graft versus host'
disease
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1968
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Major landmark year for BMT in
immunodeficiency disorders
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Children with X-linked lymphopenic immunedeficiency
Wiskott-Aldrich syndrome
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Aplastic anemiaStem cells
undifferentiated cells which are able
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?to divide for indefinite period
?
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to self renew
?
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to generate a functional progeny of highly specialised cells--- Content provided by FirstRanker.com ---
HSCTAllogeneic HSCT
Syngeneic-identical twin
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from sibling/related donorfrom unrelated donor
Autologous HSCT
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Sources of stem cellsBone
Peripheral
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Umbilical
marrow
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bloodcord blood
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Bone marrow
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Peripheral blood
Umbilical Cord
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Indications for HSCT
Neoplastic disorders
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Hematological malignanciesLymphomas
Leukemias
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Multiple myeloma
Solid tumors
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Non-neoplastic disordersAplastic anemia
Autoimmune diseases
Immunodeficiency
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Inborn errors of metabolismIndications -Autologous HSCT
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Multiple myelomaNon-Hodgkin lymphoma
Hodgkin disease, Acute myeloid
leukemia
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Neuroblastoma, Germ cel
tumors
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Autoimmune disorders (systemiclupus erythematosus [SLE],
systemic sclerosis), Amyloidosis
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Indications - Allogeneic HSCTAcute myeloid
Hodgkin disease
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metabolism
leukemia
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Aplastic anemiaEpidermolysis bul osa
Acute lymphoblastic Pure red-cel aplasia
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Severe congenital
leukemia
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Paroxysmal nocturnalneutropenia
Chronic myeloid
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hemoglobinuria
Shwachman-
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leukemiaFanconi anemia
Diamond syndrome
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Chronic lymphocytic Thalassemia major
Diamond-Blackfan
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leukemiaSickle cel anemia
anemia
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Myeloproliferative
Severe combined
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Leukocyte adhesiondisorders
immunodeficiency
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deficiency
Myelodysplastic
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Wiskott-AldrichHSCT-related
syndromes
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syndrome
morbidity and
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Multiple myelomaHemophagocytic
mortality
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Non-Hodgkin
lymphohistiocytosis
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lymphomaInborn errors of
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Major steps
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Selection of donor
Based on tissue typing -HLA antigens
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Harvest of stem cells from donorBone marrow harvest or pheresis of peripheral blood
Preparative regimen
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Chemo-radiation for ablation and immune suppression
Stem cell infusion
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Post-transplant supportive careAutologous 100 days
Allogeneic 180 days or longer
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Stem cell donors
Identical twins
Matched related or unrelated donors
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Mismatched related donorsHaploidentical donors
Umbilical cord blood donors
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Donor selectionHistory and physical examination
Investigations
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Serum creatinine, electrolyte, and liver functionstudies.
Serologic studies
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cytomegalovirus (CMV), herpes virus, HIV RNA, anti-HIV
antibodies, hepatitis B and C viruses, syphilis (VDRL)
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ABO blood typingHuman leukocyte antigen (HLA) typing
Chest radiography
Electrocardiography (ECG)
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Mobilization of stem cellsMobilization of peripheral
blood stem cells (PBSC) in
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healthy volunteers withgranulocyte colony-
stimulating factor (G-CSF)
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Stem cell procurement
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Amount of stem cel s collected is based onrecipients body weight
Minimal number
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2 x 108/kg nucleated cel s
2 x 106/kg CD 34 + cel s
Procedure
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Recipient undergoes myeloablative
conditioning
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high-dose radiotherapy and immunosuppressiveagents
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Recipient preparation
Cyclophosphamide 60 mg/kg/day
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During two days and Toal body irradiationBusulfan 4mg/kg/day for four days and
Cyclophosphamide without irradiation
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Etoposide ,Cytarabine as a maximizer antitumor
properties,myeloblation,immunosuppression
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Procedure? Donor stem cel s are
infused
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? Migrate to the bone
marrow to repopulate the
immune system
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? "Home" to micro-
environment niches in
marrow and spleen
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Hematopoietic stem cell infusion
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Special Blood Requirement
? Irradiated
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? CMV Negative? Leukocyte-Reduced
? Saline-washed or volume reduced
ABO compatibility
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Is not a MUST!!
major or minor ABO incompatibility?
patient's /donor's antibody titers
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Post HSCT
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Infection prophylaxis is essential
Care in HEPA-filtered, positive-air-pressure
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accomodation, with strict hand hygieneAntibacterial and antifungal prophylaxis
Bone marrow transplantation unit
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Outcome is influenced by:
Stage of disease
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Patient - related factors: age, comorbidity
Donor - related factors: Histocompatibility (HLA)
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Peri-transplant factors:ConditioningPost-transplant factors:GVHD
Complications
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Early
Infection, aGVHD, bleeding, toxicity, graft failure
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LatechGVHD, infection, relapse, gonadal failure, secondary
malignancy, toxicity
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Cord Blood
Less prone to rejection than
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either bone marrow or
peripheral blood stem cells.
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Limitations of Allogeneic HSCTScarcity of suitable donors
Graft versus Host Disease
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Infections
HLA Typing
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Human Leukocyte Antigen
HLA are proteins found on short arm of chromosome 6
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3-antigens important in HSCT- one set of 3 from eachparent
HLA-A
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HLA-BHLA-DR
Brings to a total of six antigens to match
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A full match is "6/6" or "perfect" match
HLA or Tissue Typing
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Rate of GVHDDonor
Incidence
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6/6
40%
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5/650%
4/6
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80%
3/6
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Graft-versus-host diseaseDonor immune cel s attack recipient tissues,
often skin, gut and liver.
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It can be very debilitating or even fatal.
Acute GVHD
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Within the first 100 days afterthe procedure
It starts as an erythematous,
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macular skin rash, blistering,
abdominal pain, profound
diarrhea, and
hyperbilirubinemia.
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Acute GVHD: Skin
Acute GVHD
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Stage I disease is confined to the skin and is
mild
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Stage II-IV have systemic involvementStage III and IV acute GVHD carry a grave
prognosis
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Acute GVHD
Risk factors for acute GVHD
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HLA-mismatched grafts
MUD grafts (Matched unrelated donor)
grafts from a parous female donor
advanced patient age
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Acute GVHD
Prophylaxis
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imunosuppressive agentsTreatment
high-dose steroids and antithymocyte globulin
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(ATG)
Chronic GVHD
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? Risk factors
peripheral blood stem cel transplants
mismatched or unrelated donors
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second transplantdonor leukocyte infusions (DLIs)
acute GVHD
Chronic GVHD
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? approximately 40-80% of long-term survivors
? 2-12 months after HSCT
? almost any organ in the body
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? Treatment- ImmunosuppressionGraft-versus-leukaemia (GvL)- is essential to
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prevent relapse when treating malignantdisease.
Graft failure -failure to establish hematologic
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engraftmentGraft failure is associated with increased risk of
infection and peritransplant mortality.
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Cost of BMT
Variable due to several factors:
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Complications: hospital days, blood productsStem cel source: PBSC<Marrow (faster
engraftment)
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Preparative regimen: TBI expensiveUnrelated>>Al ogeneic>Autologous
Outcome
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Nonmalignant disease- more favorable
70-90% if the donor is a matched sibling
36-65% if the donor is unrelated.
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Transplants for acute leukemias (eg- ALL,
AML) in remission
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55-68% if the donor is related26-50% if the donor is unrelated.
Donor registries- datri
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Developing Applications II
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Damaged Heart muscleInjection of stem cel s into area of dead heart
muscle regenerates viable muscle
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Promotes formation of new blood vessels in
injured heart muscle
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Gene therapy
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Deficiency in a patient's own hematopoieticstem cel is rectified by gene correction or
addition and is reinfused
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similar to autologous HSCTHIV infection
Beta-thalassemia
Sickle cel disease
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iPS- induced pluripotent stem cells
Dedifferentiation of cells into induced pluripotent stem cells
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Correction of gene mutation in vitroSubsequently stimulation to differentiate into hematopoietic stem cells
Transplantation
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Conclusions
Stem cel s can be derived from adult, cord blood
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and embryonic stem cel s
Bone marrow transplantation (BMT) is rapidly
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expanding as a therapeutic modality with theadvancements in techniques, indications, and
supportive therapy
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