Seyyed Reza Safaee MDSeyyed Reza Safaee MD

www.dr-safaee.blogspot.com

Hematopoietic Stem Cell Hematopoietic Stem Cell Transplantation (HSCT)Transplantation (HSCT)

Bone Marrow Transplantation (BMTBone Marrow Transplantation (BMT))

The collection and The collection and Transplantation of Hematopoietic Transplantation of Hematopoietic Stem Cells :Stem Cells :

The bone marrow The bone marrow

Peripheral blood Peripheral blood

Umbilical cord bloodUmbilical cord blood

TheThe purposes purposes of HSCT of HSCT

• 1- 1- Replace an abnormalReplace an abnormal but but nonmalignant lymphohematopietic nonmalignant lymphohematopietic system with one from a normal donorsystem with one from a normal donor

• 2-2-Treatmeant malignancyTreatmeant malignancy by allowing by allowing the administration of higher doses of the administration of higher doses of myelosuppersive therapy than would myelosuppersive therapy than would otherwise be possibleotherwise be possible

Features of Hematopoietic Stem Cell Features of Hematopoietic Stem Cell make Transplantation clinically feasible make Transplantation clinically feasible

including:including:

• Its remarkable regenerative capacity:Its remarkable regenerative capacity: Red cells ,granulocytes, B and T lymphocytes, platelets, Red cells ,granulocytes, B and T lymphocytes, platelets,

kupffer cells of the liver, pulmonary alveolar macrophages, kupffer cells of the liver, pulmonary alveolar macrophages, osteoclasts, langerhans cells of the skin, brain microglial osteoclasts, langerhans cells of the skin, brain microglial cells. cells.

• Its ability to home to the marrow Its ability to home to the marrow space following intravenous injection:space following intravenous injection:

At least in part, by the interaction of specific cell molecules, At least in part, by the interaction of specific cell molecules, termed selectins, on bone marrow endothelial cells with termed selectins, on bone marrow endothelial cells with their unique ligands, termed integrins, on early their unique ligands, termed integrins, on early

hematopoietic cellshematopoietic cells..• The ability of stem cell to be The ability of stem cell to be

cryopresevedcryopreseved

Categories of Hematopoietic Cell Categories of Hematopoietic Cell TransplantationTransplantation

• Syngenic donor (Identical Twins):Syngenic donor (Identical Twins):~1% ~1% (no GVHD ,no contaminated tumor cells)(no GVHD ,no contaminated tumor cells)

• Allogenic TransplantationAllogenic Transplantation (GVHD, graft (GVHD, graft rejection)rejection)

HLA-identical siblingsHLA-identical siblings : :1-(0.75)1-(0.75)nn

Related HLA-mismatched donorsRelated HLA-mismatched donors

HLA-match unrelated HLA-match unrelated donors:donors:1/100001/10000

• Autologous TransplantationAutologous Transplantation (no GVHD, no (no GVHD, no rejection , increased relapse)rejection , increased relapse)

The The SourceSource of Hematopoietic Stem of Hematopoietic Stem Cells for TransplantationCells for Transplantation

• Bone marrow aspiratedBone marrow aspirated from the from the posterior and anterior iliac crests posterior and anterior iliac crests (10-15mL/kg)(10-15mL/kg)

• Peripheral blood stem cellsPeripheral blood stem cells

• Umbilical cord bloodUmbilical cord blood

Transplantation ProcedureTransplantation Procedure

The Transplant The Transplant Preparative Regimens Preparative Regimens purposes:purposes:

• Eradicated the patient’s underling diseaseEradicated the patient’s underling disease

• Immunosuppress the patient adequately Immunosuppress the patient adequately to prevent rejection of transplanted to prevent rejection of transplanted marrowmarrow

• Intensive chemotherapy Intensive chemotherapy (Busulfan ,endoxan , melphalan, (Busulfan ,endoxan , melphalan, thiotepa,carmustine,etoposide)thiotepa,carmustine,etoposide)

• TBITBI

• Nonmyeloablative regimensNonmyeloablative regimens

ComplicationComplication following Hematopoietic Cell following Hematopoietic Cell

TransplantationTransplantation

Early direct chemoiradiotoxicities:Early direct chemoiradiotoxicities: nausia , vomiting , mild skin erythema nausia , vomiting , mild skin erythema

hemorrhagic cystitis ,acute hemorrhagic hemorrhagic cystitis ,acute hemorrhagic carditis (rare) , oral mucositis ,hair loss , carditis (rare) , oral mucositis ,hair loss , pancytopenia, venoocclusive disease of the pancytopenia, venoocclusive disease of the liver(~10%)liver(~10%)

(tender hepatomegaly ,ascits , jaundice, fluid (tender hepatomegaly ,ascits , jaundice, fluid retention)retention)

(Direct cytotoxic injury to hepatic-venular and (Direct cytotoxic injury to hepatic-venular and sinusoidal endothelium ,with subsequent sinusoidal endothelium ,with subsequent deposition of fibrin and the development of a local deposition of fibrin and the development of a local hypercoagulable state)hypercoagulable state)

PneumoniasPneumonias (diffuse interstitial Pneumonias)(diffuse interstitial Pneumonias)

ComplicationComplication following Hematopoietic Cell following Hematopoietic Cell TransplantationTransplantation

Late direct chemoiradiotoxicities:Late direct chemoiradiotoxicities:

• Decreased growth velocity in children Decreased growth velocity in children

• Delayed development of secondary sex Delayed development of secondary sex characteristics characteristics

• Azoospermia Ovarian failure Azoospermia Ovarian failure

• Thyroid dysfunction Thyroid dysfunction (usually well (usually well compensated)compensated)

• Cataracts(10-20%)Cataracts(10-20%)

• Aseptic necrosis of the femoral headAseptic necrosis of the femoral head (10%) (10%)

Graft-Versus-Host-DiseaseGraft-Versus-Host-Disease

GVHDGVHD is the result of allogeneic is the result of allogeneic T-T-cellscells that were either transferred with that were either transferred with the donor’s stem cell inoculums or the donor’s stem cell inoculums or develop from it, reacting with antigenic develop from it, reacting with antigenic targets on host cells.targets on host cells.

• Acute GVHDAcute GVHD developing within developing within the first the first 3 months3 months post transplantation post transplantation

• Chronic GVHDChronic GVHD developing or persisting developing or persisting beyond 3beyond 3 monthsmonths post transplantation post transplantation

Acute GVHDAcute GVHD

• SkinSkin Erythmatous maculopapular rash Erythmatous maculopapular rash

• Persistent Persistent anorexia anorexia oror diarrhea diarrhea or both or both

• Liver diseaseLiver disease, with increased serum , with increased serum levels of bilirubin,SGOT,SGPT,ALKP.levels of bilirubin,SGOT,SGPT,ALKP.

***In all these organs, ***In all these organs, endothelial damage endothelial damage and and lymphocytic infiltration lymphocytic infiltration are seen .are seen .

******The incidenceThe incidence of acute GVHD is higher in of acute GVHD is higher in recipients of stem cells from recipients of stem cells from mismatched mismatched ((30%)or 30%)or unrelated donorsunrelated donors(60%), in (60%), in older older patientspatients, and in , and in patients unable to receive full patients unable to receive full doses of drugs used to prevent the disease.doses of drugs used to prevent the disease.

Chronic GVHDChronic GVHD(20-50% allogeneic transplantation)(20-50% allogeneic transplantation)

An autoimmune disorder with :An autoimmune disorder with :• Malar rashMalar rash• Sicca syndrome Sicca syndrome • ArthritisArthritis• Obliterative Bronchiolitias Obliterative Bronchiolitias • Bile duct Bile duct

degeneration ,Cholestasisdegeneration ,Cholestasis

Graft Failure Graft Failure Marrow function either does not return or Marrow function either does not return or

after a brief period of engraftment is lost.after a brief period of engraftment is lost.

In autologous HSCT can be the result ofIn autologous HSCT can be the result of Inadequate numbers of stem cells being transplanted Inadequate numbers of stem cells being transplanted

Damage during ex vivo treatment or storage Damage during ex vivo treatment or storage

Exposure of the patient to myelotoxic agents Exposure of the patient to myelotoxic agents posttransplantposttransplant

Infections with CMV and human herpes virus type 6Infections with CMV and human herpes virus type 6

In allogeneic HSCT can also be due toIn allogeneic HSCT can also be due to Immunologic graft rejection of the graft by Immunologic graft rejection of the graft by

immunocopetent host cells.immunocopetent host cells.

IImmunologically based graft rejection is more common mmunologically based graft rejection is more common following use of less immunosuppressive preparative regiment, following use of less immunosuppressive preparative regiment, in recipients of T-cell-depleted stem cell products, and in in recipients of T-cell-depleted stem cell products, and in patients receiving grafts from mismatched donors.patients receiving grafts from mismatched donors.

Treatment of graft Treatment of graft failurefailure

• Removing all potentially myelotoxic drugs Removing all potentially myelotoxic drugs from the patient’s regimen from the patient’s regimen

• Treatment with myeloid growth factorTreatment with myeloid growth factor

• RetransplantationRetransplantation

Infection in HSCTInfection in HSCT

• Posttransplantation patients, particularly Posttransplantation patients, particularly recipient of allogeneic transplantation recipient of allogeneic transplantation complicated with complicated with infections:infections:Bacterial ,gram positive ,Fungi, Bacterial ,gram positive ,Fungi, particularly aspergillus, Viruses, CMV, particularly aspergillus, Viruses, CMV, Pneumcystis carinii pneumpniaPneumcystis carinii pneumpnia

• The risk of infection diminishes The risk of infection diminishes considerably beyond 3 months after considerably beyond 3 months after transplantation unless chronic GVHD transplantation unless chronic GVHD develops, requiring continuous develops, requiring continuous immunosupperssionimmunosupperssion

Management of the Management of the Infection in HSCTInfection in HSCT

•ProphylaxisProphylaxis

•TreatmentTreatment

Treatment of specific disease Treatment of specific disease using HSCTusing HSCT

Nonmalignant diseasesNonmalignant diseases Immunodeficiency disorders:Immunodeficiency disorders: ((Severe Combined Immunodeficiency , Wiskott-Aldrich Severe Combined Immunodeficiency , Wiskott-Aldrich

syndrome syndrome Chediak-Higashi syndrome)Chediak-Higashi syndrome)

Aplastic AnemiaAplastic Anemia (All form, PNH, Fanconi’s anemia …..)(All form, PNH, Fanconi’s anemia …..)

HemoglobinopathiesHemoglobinopathies (Thalassemias major, Sickle cell (Thalassemias major, Sickle cell Anemia)Anemia)

Congenital disorders of white blood cellsCongenital disorders of white blood cells (Kostmann’s syndrome, Chronic granulomatus disease, (Kostmann’s syndrome, Chronic granulomatus disease, Leukocyte adhesion deficiency, Congenital anemia such as Leukocyte adhesion deficiency, Congenital anemia such as Black-Fan-Diamond anemia ,Malignant Infantile osteopetrosis, Black-Fan-Diamond anemia ,Malignant Infantile osteopetrosis, Storage disease)Storage disease)

Severe acquired autoimmune disorder Severe acquired autoimmune disorder ( SLE,….)( SLE,….)

Treatment of specific disease Treatment of specific disease using HSCTusing HSCT

Malignant Disease Malignant Disease • Acute leukemiaAcute leukemia (AML,ALL)(AML,ALL)

• Chronic leukemiaChronic leukemia (CML, CLL)(CML, CLL)

• MDSMDS• Lymphoma Lymphoma (NHL, HL)(NHL, HL)

• MyelomaMyeloma• Solid tumorsSolid tumors (Breast cancer, testicular (Breast cancer, testicular

cancer, ovarian cancer, small cell lung cancer cancer, ovarian cancer, small cell lung cancer ,neuroblastoma, pediatric sarcoma ,renal cell ,neuroblastoma, pediatric sarcoma ,renal cell Ca)Ca)