Rob Wynn RMCH & University of Manchester, UK. HCT in Children

Transcription

1 Rob Wynn RMCH & University of Manchester, UK HCT in Children

2 Summary Indications for HCT in children Donor selection for Paediatric HCT Using cords Achieving engraftment in HCT Conditioning Immune action of graft Toxicities of HCT and how to reduce Organ Toxicities Infection GVHD Governance in BMT

3 Indications Malignant diseases (not the dominant indication in paediatric HCT) Intensity of conditioning Graft versus Tumour Haematological diseases Disorders of blood cells number (mature cells, stem cells) Disorders of blood cell function Lymphocytes, red cells, neutrophils Non malignant and non haematological disease

4 a-l-iduronidase Deficiency = Hurler Syndrome (MPSIH) Defect in the gene that encodes for a-liduronidase chromosome 4 locus 4p16.3 Inability to catabolize dermatan and heparan sulphate - glycosoaminoglycans (GAGs)

5 Lysosomal Storage of GAGs

6

7

8 Successful SCT influences long term survival of HS patient (n=196)

9 Summary Indications for HCT in children Donor selection for Paediatric HCT Using cords Achieving engraftment in HCT Conditioning Immune action of graft Toxicities of HCT and how to reduce Organ Toxicities Infection GVHD Governance in BMT

10 Donor Selection Donor source you want we sometimes want the cord rather than adult donor Tissue Type CMV serostatus (pos donor for pos recipient, neg donor for neg recipient) Blood group (where marrow donor) Young male donor

11 Where a cord blood donor? Metabolic disease Better engraftment chimerism Better survival Relapsed and refractory myeloid malignancy RIC conditioning No serotherapy Rapid immune reconstitution of UCB derived T cells (CD4 cells) Engraftment syndrome Where best donor (in other diseases)

12 EFS by type of donor and HLA 1,0,9 HLA identical sibling or HLA matched unrelated CB 81±8% n=59,8,7,6,5 HLA matched unrelated donor 10/10 or CB 5/6 or CB 4/6 high CD34 cell dose 67±7% n=124,4,3 HLA matched low resolution or mismatched (antigen or allelic level) Incl TCD or CB 4/6 low CD34 cell dose 42±6% n=75,2,1 P=0.001,

13 Changing use of stem cell sources BM CORD PBSC

14 Summary Indications for HCT in children Donor selection for Paediatric HCT Using cords Achieving engraftment in HCT Conditioning Immune action of graft Toxicities of HCT and how to reduce Organ Toxicities Infection GVHD Governance in BMT

15 The 3 phases of successful stem cell transplant Stem cell return Supportive care whilst recover from conditioning therapy and whilst new Immune system becomes established Conditioning Therapy a) Gets rid of host bone marrow - space b) Gets rid of host immune system does not reject

16 Achieving engraftment Conditioning therapy empties the stem cell niche of host Haemopoietic Stem cells Immune action of graft Graft versus Leukaemia, Graft versus Host Disease, Graft versus Infection

17 Conditioning Drugs Myeloablative drugs Busulfan Treosulfan Thiotepa Immune suppression Fludarabine Cyclophosphamide T-depleting antibodies ATG and Alemtuzumab

18 Regimens Full intensity Fludarabine / Busulfan Busulfan / Cyclophosphamide Etoposide / TBI Fludarabine / Treosulfan / Thiotepa Reduced intensity Fludarabine / Melphalan Fludarabine / Cyclophosphamide (aplastic)

19 1985 Busulfan route and Dosing Conditioning T cell Depletion Oral Busulfan 20mg/Kg :No Pk testing (n=30) Busulfan + Cyclophosphamide (n=58) Various Oral Busulfan Pk tested (n=7) IV Busulfan PK tested (n=28) Busulfan + Fludarabine (n=11) In vivo T cell depletion (Alemtuzumab) n=20

20 Overall results of 79 patients

21 Influence of pharmokinetic guided dosing of Busulfan Since 2005: -N=42 -MUD=26 -MUD cord=20

22 HSCT in Hurler disease: Cell Source Comparison EFS according to Year of HSCT 1,0,9,8,7,6 > ± 5% n= ±8% n= ±6% n=69,5 < ±6% n=64,4,3,2,1 P = ,

23 Summary Indications for HCT in children Donor selection for Paediatric HCT Using cords Achieving engraftment in HCT Conditioning Immune action of graft Toxicities of HCT and how to reduce Organ Toxicities Infection GVHD Governance in BMT

24 Toxicities of HCT: What do children die from in HCT? Organ toxicity Liver failure - VOD Infection Bacteria, Fungus, Virus Graft versus Host Disease Affecting skin, gut and liver Graded I IV depending on number and extent of organ involvement

25 Toxicities of HCT: Preventing death Organ Toxicity Reducing intensity of conditioning where children have co-morbidities Individualised conditioning Busulfan highly variable pharmacokinetics High levels toxicity Low levels graft failure pk guided busulfan in children

26 Toxicities of HCT: Preventing death Infection Prophylaxis Isolation / Filtered air Screening for virus infection Protocols for infection management

27 Toxicities of HCT: Preventing death GVHD Match T cell depleting antibodies (T cell deplete recipient to prevent rejection that T-deplete donor to prevent GVHD) Post-SCT ciclosporin

28 Hazard Ratio Acute Graft vs. Host Disease Grades P=0.005 P= P= P< ATG 0.04 Alemtuzumab ATG Alemtuzumab 1 month > 1 month

29 Incidence, % Acute Graft vs. Host Disease T-cell replete, 58% ATG, 39% Alemtuzumab, 19% Days Vh11_1.ppt

30 Hazard Ratio Chronic Graft vs. Host Disease P< ATG P< Alemtuzumab ATG vs alemtuzumab: 2.59 ( ), p=0.0003

31 Summary Indications for HCT in children Donor selection for Paediatric HCT Using cords Achieving engraftment in HCT Conditioning Immune action of graft Toxicities of HCT and how to reduce Organ Toxicities Infection GVHD Governance in BMT

32 Governance in Paediatric BMT National Consensus Indications National Consensus Conditioning Agreed donor algorithms National Annual Mortality Meetings National Monthly Video-MDT to discuss difficult cases

33 The Future Cord in Metabolic Disease Cord in Refractory Haematological Malignancy Cord in Solid Tumour Gene Therapy Protocols CAR in Haematological Malignancy In metabolic diseases

34 BMT team and Transplantation Lab in Manchester Ed Wraith, Willink Unit, Manchester Simon Jones, Willink Unit Brian Bigger, University of Manchester International collaborators Patients and Families