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The University of Kansas Hospital Blood & Marrow Transplant Program. Joseph McGuirk, D.O. Clinical Program Director. Rationale for High-Dose Therapy. 100%. Cures. Dose. Lethal Bone Marrow Toxicity. Lethal Toxicity to Other Organs. Allogeneic vs Autologous Stem Cell Support.

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The University of Kansas Hospital Blood & Marrow Transplant Program


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    1. The University of Kansas HospitalBlood & Marrow Transplant Program Joseph McGuirk, D.O. Clinical Program Director

    2. Rationale for High-Dose Therapy 100% Cures Dose Lethal Bone Marrow Toxicity Lethal Toxicity to Other Organs

    3. Allogeneic vs Autologous Stem Cell Support Allogeneic Autologous Age limits 40 - 55 (conventional) 60 - 75 up to 70 (mini-transplant) Pros Tumor free stem cells No GVHD Untreated stem cells No rejection Graft vs Tumor Cons GVHD Tumor contamination Graft rejection Treatment damage Age & match restricted Relapse of disease

    4. Recovery of Neutrophils Following Transplant Days to Reach 500 Neutrophils/uL 120 100 80 60 40 20 0 Auto blood % Patients Auto marrow Allo marrow 0 10 20 30 40 Days Post Transplantation

    5. Autologous Stem Cell Sources1995 - 1998 % of Transplants IBMTR/ABMTR 2000

    6. Umbilical Cord Blood Hypothesis 1) Superior proliferative capacity will compensate for low cell dose 2) Naïve immune system è reduced GVHD è extension of donor pool 3) Unlimited supply, rapid availability Courtesy of Dan Weisdorf, M.D.

    7. Allogeneic Course of BMT • Conditioning therapy • Transplantation • Immediate post-BMT period • Engraftment • Graft versus host disease • Disease-free survival • Long term effects

    8. Conditioning Therapy • Myelo-ablative therapy • Irradiation: TBI, TLI • High dose chemotherapy: Cytoxan, VP-16, Busulfan, BCNU • Immuno-ablative therapy • Irradiation • Chemotherapy - Cytoxan, Fludarabine • Immunosuppressant: steroids, ATG

    9. Allogeneic Course of BMT • Conditioning therapy • Transplantation • Immediate post-BMT period • Engraftment • Graft versus host disease • Disease-free survival • Long term effects

    10. Allogeneic Course of BMT • Conditioning therapy • Transplantation • Immediate post-BMT period • Engraftment • Graft versus host disease • Disease-free survival • Long term effects

    11. Immediate post-BMT Period • High risk of infection • Neutrophil/T-cell/B-cell/NK-cell/dendritic and macrophage dysfunction or absence • Mucositis • High risk of bleed • Low platelet count • Chemo-radio therapy side effects • Diarrhea and vomiting • Liver problems - VOD • Damage to other organs

    12. Phase I, Pre-engraftment, < 30 days Phase II, Post-engraftment, 30 - 100 days Phase III, Late phase, > 100 days Neutropenia, mucositis and aGvHD Neutropenia, mucositis and aGvHD and cGvHD Impaired cellular and humoral immunity and cGvHD Host immune system defect (continuous risk) Device risk Central line Respiratory and enteric viruses Allogeneic patients Herpes simplex virus Cytomegalovirus Varicella-zoster virus Facultative Gram-neg. bacilli Epstein-Barr virus lymphoproliferative ds Staphlococcus epidermidis GI tract Streptococci species Encapsulated bacteria (eg., pneumococcus) All Candida species Aspergillus species Aspergillus species KEY: High incidence Pneumocystis carinii Low incidence Toxoplasma gondii Episodic Strongyloides stercoralis 0 30 100 360 Days after transplant

    13. Single-Organism Bacteremia In EORTC-IATCG Trials I III V IX 1973-78 1980-83 1986-88 1992-94 Gram-negative Bacteremia (%) 103 (71) 85 (59) 76 (37) 53 (33) E. Coli 46 38 45 22 P. aeruginosa 18 23 14 10 Gram-positive Bacteremia (%) 42 (29) 58 (41) 135 (63) 108 (67) S. aureus 28 14 20 10 Coag-neg staph 5 24 49 53 S. pneumoniae 5 4 4 0 Other streptococci 0 14 46 40 Other gram-positive 4 2 16 5

    14. CMV in BMT Patients • CMV interstitial pneumonitis • Mononucleosis syndrome • Hepatitis • Enteritis • Retinitis • Encephalitis

    15. Aspergillosis and Other Molds After HCT: Clinical Syndromes and Mortality Syndromes# Patients% Mortality Aspergillus only: Pneumonia 21 62 Brain 1 100 Oral invasive 2 0 Multiple organ 17 100 Other syndrome 2 50 Total 43 74 Other molds: Mucomycosis 1 100 Rhizopus 2 50 Fusarium 2 100 Petrielidiem 1 100 Total 6 83 Total 49 84

    16. Causes of Death Following Conventional Allogeneic Transplant GvHD Disease IPn Infection Other GvHD and IPn

    17. Number of Different Respiratory Viruses per Month During a Typical Season (1991-1992) at Fred Hutchinson Cancer Research Center # of cases 1991 1992

    18. Allogeneic Course of BMT • Conditioning therapy • Transplantation • Immediate post-BMT period • Engraftment • Graft versus host disease • Disease-free survival • Long term effects

    19. Engraftment CBC with manual differential on an allogeneic PBSCT patient day + 11: CBCManual differential WBC 0.7 K/uL RBC 2.57 M/uL HGB 8.2 g/dL HCT 23.8 % MCV 92.7 fL MCH 31.9 Pg MCHC 34.5 g/dL RDW 15.0 % PLT 28 K/uL SEG 7 % BAND 4 % LYMP 27 % MONO 45 % VAR LYM 17 % Absolute Neutrophil Count 77

    20. Allogeneic Course of BMT • Conditioning therapy • Transplantation • Immediate post-BMT period • Engraftment • Graft versus host disease • Disease-free survival • Long term effects

    21. Causes of Death Following Conventional Allogeneic Transplant GvHD Disease IPn Infection Other GvHD and IPn

    22. Risk Factors for GvHD • HLA mis-match or unrelated donor • Non-T cell depleted marrow • Older age • Female donors (?)

    23. Graft versus Host Disease • Skin rash • Gastrointestinal - diarrhea, vomiting • Liver - high bilirubin

    24. Approach to GvHD • Prevention • Prevention • Prevention • Prevention

    25. Prophylaxis for GvHD • Pre-transplant • T-cell depletion of the graft / ATG • Post transplant (most commonly used) • Cyclosporine • Tacrolimus • Steroids • Methotrexate • Anti-thymocyte globulin • Monoclonal antibodies • Mycophenolate mofetil (Cellcept)

    26. Allogeneic Course of BMT • Conditioning therapy • Transplantation • Immediate post-BMT period • Engraftment • Graft versus host disease • Disease-free survival • Long term effects

    27. 100 80 60 40 20 0 Probability of Survival after HLA-identical Sibling Donor Transplants for AML with Myeloablative Conditioning, 1998-2004- by Disease Status - Early (N=3,174) Probability, % Intermediate (N=785) Advanced (N=1,278) P < 0.001 1 3 0 2 4 5 6 Years CIBMTR data 2005

    28. 100 80 60 40 20 0 Probability of Survival after HLA-identical Sibling Transplants for ALL, Age >20 Years, 1998-2004- by Disease Status - Probability, % Early (N=879) Intermediate (N=323) Advanced (N=360) P < 0.001 1 3 0 2 4 5 6 Years CIBMTR data 2005

    29. 100 80 60 40 20 0 Probability of Survival after HLA-identical Sibling Transplants for CML - by Disease Status and Transplant Year - CP, 2000-04 (N=2,344) CP, 1996-99 (N=3,391) Probability, % AP, 2000-04 (N=278) AP, 1996-99 (N=598) P < 0.001 1 3 0 2 4 5 6 Years CIBMTR data 2005

    30. 100 80 60 40 20 0 Probability of Survival after HLA-identical Sibling Transplants for Follicular Lymphoma, 1998-2004- by Disease Status and Conditioning Regimen - Chemo-sensitive, RIC (N=195) Chemo-sensitive, Myeloablative (N=267) Probability, % Chemo-resistant, RIC (N=37) Chemo-resistant, Myeloablative (N=60) P = 0.0258 1 3 0 2 4 5 6 Years RIC = Reduced Intensity Conditioning CIBMTR data 2005

    31. 100 80 60 40 20 0 Probability of Survival after Transplants for Severe Aplastic Anemia, 1998-2004- by Donor Type and Age - HLA-id sib, £20y (N=915) HLA-id sib, >20y (N=822) Unrelated, £20y (N=388) Probability, % Unrelated, >20y (N=212) P < 0.001 1 3 0 2 4 5 6 Years CIBMTR data 2005

    32. Allogeneic Course of BMT • Conditioning therapy • Transplantation • Immediate post-BMT period • Engraftment • Graft versus host disease • Disease-free survival • Long term effects