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Stem cell transplantation: indications, preparation, follow up, results

Stem cell transplantation: indications, preparation, follow up, results. Dr Kriván Gergely Szent László Kórház. E. Donnall Thomas (1920-2012). Transplant activity worldwide 1980-2009. 35,000. Autologous Allogeneic. 30,000. 25,000. 20,000. Transplants. 15,000. 10,000. 5,000. 0.

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Stem cell transplantation: indications, preparation, follow up, results

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  1. Stem cell transplantation: indications, preparation, follow up, results Dr Kriván Gergely Szent László Kórház

  2. E. Donnall Thomas (1920-2012)

  3. Transplant activity worldwide 1980-2009 35,000 Autologous Allogeneic 30,000 25,000 20,000 Transplants 15,000 10,000 5,000 0 '84 '80 '81 '82 '83 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09

  4. Rationale for stem cell transplant donor allogeneic Patient cured drug engraftment irradiation freezing autologous

  5. No. of transplants 01.01.1992.-06.03.2014. (n=481)

  6. Distribution of transplants according todisease categories01.01.1992.- 06.03.2014. N=481

  7. Sex ratioMedian age at time of transplant: 8,4 years

  8. About autologous transplantations

  9. Results- NBL n=54

  10. NBL - OS according to disease status Follow up (years)

  11. About allogeneic transplantations

  12. HLA antigens on cell surface - codominant expression

  13. Donor type • HLA identical family donor • HLA identical unrelated donor • HLA non identical (eg. haploidentical family member) • HLA non identical unrelated donor

  14. Submissions for HSCT in Hungary in children

  15. Unrelated donors for hungarian patients, according to the donor nationality (1990-2009) N: 242

  16. Allogeneic transplants according to donor origin n = 171 n =84

  17. Survival of allogeneic transplants according to sibling or unrelated donors01. 01. 1992. – 30.11.2011. n=198unrelated n=92, sibling n=106 n= p= n= n=96 p= n=96 Sibling 61,3% Overall:56,6% Testvér 61,3% n=66 MUD 51,1% Idegen % p=0,082 p=0,082 n=66 p=0,21

  18. Survival according to donor type 01. 01. 1992. -31. 12. 2002. 01. 01. 2003. - 30. 11. 2011. P=0,003 p=0,002

  19. Stem cell source • Bone marrow • Peripheral blood • Cord blood

  20. Peripheral stem cell Txp advantages and disadvantages Advanteges: • Rapid engraftment  shorter aplasia • Less toxicity • Earlier discharge from hospital • Less costs • More cells could be harvested with repeated apheresis  graft manipulation (CD34+ selection, T cell removal) • More convenient for donors; ambulatory harvesting; only possibility in case of high donor/recipient bw ratio Disadvantages: • Higher chronic graft versus host ratio

  21. Advantages and disadvantages of CBUs Advantages: • Easy and safe collection; quick delivery • Contains more premature progenitor cells, superior proliferative capacity • Less alloreactive lymphocytes (↓ aGvH and cGvH)) • Less probability to transfer infections (eg. CMV) • Less toxicity • No need for full HLA match (results with 1 antigen difference and full HLA matching are identical), greater probability for suitable donor Disadvantages : • Limited stem cell content • Delayed engraftment and immunreconstitution, more infections • DLI (donor lymphocyta infusion) not available • Possible transmission of genetic diseases

  22. Distribution of Txp. according to stem cell source n=400

  23. Changes in graft sources n=289 n=111

  24. Survival of cord blood transplants(02. 10. 2001. -30. 11. 2011.) n=26 OS:69,2% n=14 Diagnosis: X-adrenoleukodystrophy 2/26, ALL 3/26; AML 3/26; CML 2/26; Lesch-Nyhan sy. 1/26 MDS 2/26 NHL 1/26; SAA 1/26 , SCID 3/26 Wiscott-Aldrich sy. 1/26 WHIM sy. 1/26. Blackfan-Diamond sy. 1/26, Thalassaemia-beta 1/26, Congenital dyserythropoietic anaemia 1/26, Hurler-syndrome 1/26, Juvenile myelomonocytic leukaemia 1/26, Juvenile rheumatoid arthritis 1/26,

  25. Stages of transplantation • Conditioning • Immediate posttransplant period aplasia (0-30. days) • Early posttransplant period (30-100. days) • Late posttransplant period (100-365. days)

  26. Conditioning regimen • Mega chemo-radiotherapy • Goal: • Eradication of malignant clones • Immunosuppression (rejection ) • „Space” for the donor hematopoesis in the bone marrow stroma

  27. 1. phase: before engraftment 2. phase: after engraftment 3. phase: late chronic Graft versus host disease: acute Neutropenia, Barrier damage (mucositis, central catheter) Decreased humoral and cellular immunity; NK cells appear first, but restricted T cell repertoire Decreased humoral and cellular immunity; B- and CD4 T cell count increases with a widening repertoire Bacteria Gram negative bacteria Rare Gram positive bacteria Encapsulated bacteria Gastrointestinal streptococci Viruses Herpes simplex CMV Varicella zoster Respiratory and enteral viruses Common Other viruses: pl. HHV EBV PTLD Fungi Aspergillus species Aspergillus species Candida species Pneumocystis Day 0. Day 15 - 45. Day 100. Beyond day 365.

  28. Infection-control Protective environment Isolation technics: Single room sterile box HEPA-filter High pressure air flow: 0,5 bar laminar air flow Surveillance

  29. Immunologic recovery after Txp Transplantation 140 120 Normal range 100 80 60 Neutrophils, monocytes, NK 40 B and CD8 T cells CD4 T cells 20 Plasma- and dendritic cells Time elapsed since Txp 0 Weeks Months Years

  30. Immunological reconstitution • NK (CD16+, CD 56+) cells: < 1 month • At beginning: ↑CD8+, ↓CD4/CD8 • B cell mitogen responsiveness: 2-3 months • Antigen specific B cell responsiveness : > 3 months • Normal IgM production: 4-6 months • Normal IgG production: 9 months • T cell depleted graft: > 12 months • Normal B cell (CD19+) count: 12 months • IgA, IgG2 and IgG4: > 1 y → sinopulmonary infections, encapsulated bacteria • Principal marker: CD4+ (helper) T cell count

  31. Prerequisites of acute graft versus host disease (GvHD) • Graft must contain immunocompetent cells • Donor – host alloantigens are different • Host cells are severely immunodeficient

  32. Acute graft versus host disease Underlying disease Conditioning Concomittant infection Epithel- and endothel damage Citokin release (TNF, IL-1, IFN, GM-CSF, IL-6) MHC II, Adhesion molecule expression: Donor T cell activation Target cell apoptosis

  33. Acute GvHd and survival (SAA) N=27 pts. No aGvHD: 93% Acute GvHD: 37% p=0,015

  34. Acute liver GvH

  35. Chronic GvHD • In early phase: changes resemble to lichen planus  poikiloderma • Localized form: epidermal atrophy, focal fibrosis, morphea-like changes, without significant inflammation • Generalized form: inflammed changes  extended fibrosis, scleroderma

  36. Changes in survival within decades I. decade: 01.01.1992.- 31.12.2002. (n=104) OS:45,2% II. decade: 01.01.2003.-28.02.2012. (n=253) OS:66,8% OS: 66,8% 65,5% p=0,025 46,7% OS: 45,2%

  37. Survival according to disease groups01.01.1992.- 28.02.2012. n=354

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