Pediatric Blood/Marrow Transplant Overview...Pediatric Blood/Marrow Transplant Overview In Vitro...
Transcript of Pediatric Blood/Marrow Transplant Overview...Pediatric Blood/Marrow Transplant Overview In Vitro...
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Pediatric Blood/Marrow Transplant Overview
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Pediatric Blood/Marrow Transplant Overview
Aims What are potential Hematopoietic Stem Cell Sources? What are indications for HSCT in Pediatrics? What are outcomes for HSCT in Pediatric
Patients/diseases?
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Pediatric Blood/Marrow Transplant Overview
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Pediatric Blood/Marrow Transplant Overview
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Pediatric Blood/Marrow Transplant Overview
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Pediatric Blood/Marrow Transplant Overview
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Pediatric Blood/Marrow Transplant Overview
CD34+
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Pediatric Blood/Marrow Transplant Overview
HSC/HPC Sources Marrow Peripheral Blood Mobilization: G-CSF +/- chemoRx, CXCR4<—>SDF-1 inhib (Plerixafor) (SDF = stromal cell derived factor) Umbilical Cord Blood Total Nucleated Cells (TNC): ~107-8/kg Mononuclear Cells (MNC): ~107-8/kg CD 34+ Cells: ~105-6/kg
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Pediatric Blood/Marrow Transplant Overview
In Vitro T-cell depletion Sheep RBC Rosettes Mab + Complement Immunotoxin linked to Anti-T-cell mAb CD 34 Selection Isolex Column Miltenyi device Alpha-Beta T-cell depletion Post HSCT In Vivo T-cell depletion Post HSCT Cyclophosphamide
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Pediatric Blood/Marrow Transplant Overview
In Vitro T-cell depletion Sheep RBC Rosettes Mab + Complement Immunotoxin linked to Anti-Tcell mAb CD 34 Selection Isolex Column Miltenyi device
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Pediatric Blood/Marrow Transplant Overview
Post HSCT Cyclophosphamide in mice Reduces lethality of GVHD to 0
Owens et Santos Transplantation 1971, 11, 4 p378
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Pediatric Blood/Marrow Transplant Overview
T-cell Tolerance-- a goal of Allogeneic Transplantation
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Pediatric Blood/Marrow Transplant Overview
Marrow Failure Aplastic Anemia, Fanconi, DKC
Neutrophil Deficits CGD, Kostmann’s
Immune Deficiencies or Dysregulation
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Pediatric Blood/Marrow Transplant Overview
Marrow Failure Aplastic Anemia, Fanconi, DKC
Neutrophil Deficits CGD, Kostmann’s
Immune Deficiencies or Dysregulation
Metabolic Defects Hurler’s, Leukodystrophies
Hemoglobinopathies-- Thalassemia,
Sickle Cell Disease
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Pediatric Blood/Marrow Transplant Overview
Non-malignant Diagnoses: Marrow Failure Severe Aplastic Anemia, Fanconi, DKC, DBA Schwachman-Diamond, Congenital Osteopetrosis Immune Deficiencies/Dysregulation SCID, HLH, WAS, CHS, IPEX, NEMO Neutrophil Deficits CGD, Kostmann’s Metabolic Defects Hurler’s (Mucopolysacharidoses), Leukodystrophies Hemoglobinopathies Thalassemia, Sickle Cell Disease
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Pediatric Blood/Marrow Transplant Overview
Malignant Diagnoses: Hi-Risk/Resistant Malignancies Allogeneic: ALL-recurrence, cytogenetics/molecular characteristics AML-cytogenetics, recurrence, phenotype/molecular JMML- NHL-recurrent/refractory disease HL-recurrent/refractory disease Autologous:
Neuroblastoma-high risk characteristics CNS Malignancies-Medulloblastoma, ATRT
NHL-recurrent/refractory disease HL-recurrent/refractory disease Germ Cell Tumors
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Pediatric Blood/Marrow Transplant Overview
Hi-Risk/Resistant Malignancies Allogeneic: ALL-MRD > 0.01% CRLF2 rearranged (Ph like) AML-cytogenetics: 5-, 5q- or 7-, t w 11q23, t(10,11), t(6,9) MRD > 0.1%, phenotype –e.g. RAM molecular: Flt 3/ITD+ Autologous:
Neuroblastoma-high risk characteristics St 4—metastases to bone, bone marrow > 18 mo, N-myc amplified, unfavorable pathology 12 -18 mo N-myc amp, unfav path, DNA Index = 1 St 3: N-myc amp, unfav path or DNA Index = 1
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Pediatric Blood/Marrow Transplant Overview
Marsh, et al, Blood, 2010 116 p 5824
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Pediatric Blood/Marrow Transplant Overview
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Pediatric Blood/Marrow Transplant Overview
Sibling Donor Transplant for Thalassemia Marrow vs Umbilical Cord Blood
Locatelli Blood 2013, 122, 6 p1072
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Pediatric Blood/Marrow Transplant Overview
Genetic Modification of Autologous HSC Persistence of transfected genes- ADA deficiency Thalassemia
Thompson et al NEJM 2018, 378, 16 p1479
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Pediatric Blood/Marrow Transplant Overview
Genetic Modification of Autologous HSC Dosage of transfected genes- Adrenoleukodystrophy
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Pediatric Blood/Marrow Transplant Overview
Summary HSCT in Pediatrics effective for broad range of disease states
affecting blood, risk of infection, CNS multiple sources for “HSC” including
selection for HSC, depletion of T-cells & genetic manipulation of HSC