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Hematopoietic Stem Cell Transplantation

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  1. Hematopoietic Stem Cell Transplantation Lynn Savoie September 30, 2006

  2. Hematopoietic stem cell transplantation is potentially life-saving therapy in patients with SAA or MDS • Generally done when benefits thought to outweigh risks • Only allogeneic stem cell transplantation considered for these diseases therefore need a donor • Recipient and donor factors considered when assessing risk

  3. General Concept • Blood cell production and immune system very closely linked and ultimately derived from bone marrow • Goal of high dose chemotherapy is to kill “defective” marrow – MDS or malfunctioning immune system – SAA • Replace with healthy marrow/immune system • Unfortunately not straightforward – mostly due to the new immune system

  4. Risks • Infections • Potentially life or organ threatening • Due to neutropenia then immunosupression • Graft versus host disease • New immune system attacking recipient organs • Acute and chronic • Can affect many different organs • Potentially life or organ threatening • Potentially life altering • Graft failure • Rare but potentially fatal • Increased risk in aplastic anemia

  5. Types of transplants 3 main factors

  6. Type of donor • Related • Unrelated • Source of stem cell • Bone marrow • Peripheral blood • Cord blood • Conditioning Regimens • Myeloablative • Non-myeloablative • TBI containing

  7. Type of donor Related vs. Unrelated

  8. HLA Matching

  9. HLA antigens • Proteins that help the immune system identify self vs. non-self • Genetically inherited together on chromosome 6 • Most important determinant of compatibility between donor and recipient • Each sibling pair has a 25% chance of inheriting the same HLA antigens • Approximately 30% of patients will have an HLA matched sibling

  10. MOTHER FATHER

  11. Statistically unlikely for an extended family member to have 2 similar HLA groupings to patient just by chance • Able to find a unrelated donor in 70% of cases that is fully matched but not likely “identical” • Search can take time • More difficult in some ethnic groups due to genetic diversity • Generally increased and more severe graft versus host disease than with related donor

  12. Other important factors in donor selection • Age • Younger generally better • Sex • Males generally better • Number of pregnancies • Few the better • Blood group • Same is better • CMV status • Negative donor is best if patient is negative • Health • Some health conditions preclude donation from a recipient perspective and some from a donor perspective

  13. Source of Stem Cell Bone marrow vs. peripheral blood vs. cord blood

  14. Still unclear whether bone marrow or peripheral blood stem cells better for recipients – studies ongoing • Currently using bone marrow in SAA and peripheral blood in MDS • Faster count recovery with peripheral blood stem cells but increase chronic graft versus host disease that may or may not translate into decreased relapse • Peripheral blood collection generally felt to be easier for donor but long term effects of G-CSF not known

  15. Cord Blood Stem Cells • Rapidly available • Can accept a lesser match • Less graft versus host disease • Immune cells naive • Cell doses often a concern in adults • Because based on weight • Longer time to count recovery • can increase risk of infection due to prolonged neutropenia • Combinations or expansion being investigated

  16. Conditioning Regimens Myeloablative vs. Non-myeloablative vs. TBI containing

  17. Myeloablative • Generally used for SAA or MDS • Calgary regimens somewhat less myeloablative than other regimens…..but not technically non-myeloablative • Non-myeloablative • Unclear if really safer – generally more graft vs. host disease, particularly chronic due to mixture of cells present • Unclear if really a role in these disorders since don’t need much graft vs. leukemia effect-under investigation • TBI containing • Used in acute leukemia and at times in MDS if transforming – felt to decrease relapse

  18. IBMTR, MDS, Sib HSCT

  19. IBMTR, MDS, Sib HSCT

  20. EBMT, SAA

  21. IBMTR, SAA, Sib HSCT

  22. Calgary – FLUBUP +/- TBI • From 05/99 to 05/05 • Matched related donor (MRD) • 201 pts, survival 60% • Mismatched related donor (MMRD) • 22 pts, survival 58% • Matched unrelated donor (MUD) • 81 pts, survival 57% • Mismatched unrelated donor (MMUD) • 40 pts, survival 38%

  23. Calgary • MDS • MRD – 15 pts • Survival 79% • Alt – 10 pts • Survival 38% • SAA • MRD -20 pts • survival 90%, 100% in last 13 yrs • Alt – 10 pts • survival 38%

  24. Indications

  25. Myelodysplasia • Patients < 65 yrs of age • Before transfusion dependence and/or clinically significant neutropenia • Before transformation to acute leukemia • Severe aplastic anemia • If pt < 40 y.o. with sib match • If >60 y.o. pt > 40 y.o. with sib match trial after failure of immunosupression • No sib match – Failure of immunosupression X 2, consider after 1 if pt is young

  26. Donor Search • Type sibling at presentation if HSCT at all a consideration now or later • Can identify an unrelated donor when HSCT strongly under consideration • Costs • Can only “hold” a donor for 3 months

  27. UBMDR • Established in 1989 • Administered by Canadian Blood Services • 215 000 potential volunteer donors • If no Canadian donor can search the world

  28. NMDP • United States • 6 million donors • 50 000 cord blood units

  29. Bone Marrow Donors Worldwide • As of August 22, 2006 – 10 733 542 donors and cord blood units • 58 stem cell donor registries from 43 countries • 38 cord blood banks from 21 countries • 571 users from 420 organizations