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AAMAC - HSCT

AAMAC - HSCT. Lynn Savoie October 19, 2019. Process of Hematopoietic Stem Cell Transplantation. “conditioning”- high doses of chemotherapy  total body radiation to kill all the bone marrow Stem cells are then infused to salvage marrow function

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AAMAC - HSCT

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  1. AAMAC - HSCT Lynn Savoie October 19, 2019

  2. Process of Hematopoietic Stem Cell Transplantation • “conditioning”- high doses of chemotherapy  total body radiation to kill all the bone marrow • Stem cells are then infused to salvage marrow function • If autotransplant the patient’s own peripheral blood stem cells are collected ahead of time

  3. Hematopoiesis

  4. Hematopoietic Stem Cells are Self-Renewing Quiescent hematopoietic stem cell Dividing stem cell Hematopoietic cells

  5. Types of stem cell transplants • Autologous – patient’s own cells infused • Growth factors (ie. G-CSF) and/or chemo followed by apheresis of peripheral blood to collect stem cells • Allogeneic – donor cells (8/8 HLA matched, mismatched or haploidentical) • Bone marrow source • Peripheral blood (mobilized with G-CSF) • Umbilical cord • Syngeneic – identical twin

  6. AUTOLOGOUS Less treatment-related mortality and morbidity (1-2%) No graft vs host disease Relapse major cause of death ALLOGENEIC Higher treatment-related mortality (15-30%) GVHD Toxicity major cause of death, lower relapse rate Graft vs. leukemia (tumour) effect No contamination of graft with tumour cells Comparison between Allotransplant and Autotransplant

  7. Requirements for Autologous SCT • Chemosensitive disease • chemo and sometimes total body irradiation is given to eliminate cancer cells • Adequate stem cell numbers in the graft to regenerate marrow • No contamination of the stem cells with tumor

  8. Allogeneic Stem Cell Transplantation • Chemotherapy +/- total body irradiation (TBI) • Kill all the bone marrow • Suppress immune system to prevent rejection of donor cells • Donor stem cells are not contaminated with tumor • Graft vs leukemia effect • Donor immune system can fight residual malignant cells it sees as non-self/abnormal • Reduced intensity conditioning regimens take advantage of this principle

  9. How are stem cells collected?

  10. What advantages could there be to different stem cell sources for allotransplantation?

  11. Features of Stem Cells from Different Sources

  12. Umbilical Cord Blood Donor • Advantages: • stem cells already stored • no risk to donor • ability to use mismatched cells (increasing HLA disparity associated with worse outcomes) • Disadvantages: • lower cell dose for adults • longer time to engraftment • higher treatment-related mortality and lower survival compared to matched donor marrow • Overall: Unrelated cord blood transplantation is an option if matched marrow or peripheral blood unavailable • As experience with haploidentical transplantation increases, there is also another good option for patients without matched donors

  13. Donor Selection • 30% of patients have a matched sibling donor • 70% of patients have a fully matched donor on the unrelated donor registry • >25 million people on unrelated donor registry • Patients of minority/mixed ethnic groups less likely to have donor (linkage dysequilibrium) • Generally accept 1 antigen mismatch if no 10/10 full match but increased treatment-related mortality • 95% of patients have a 4/6 matched cord, most patients have haploidentical donors (half-matched ie sibling, parent, child)

  14. When to do a transplant • Disease-related factors • MDS Risk of progession to AML • Risk of dying from MDS • SAA • Lack of response to immun0suppresive therapy • Patient-related factors • Age • Healthy overall (comorbidity score to gauge risk of transplant) • Patient wishes and supports

  15. Complications of allogeneic BMT

  16. Post Transplant Complications

  17. Bacterial Infections post BMT • Loss of barrier function; mouth and gut inflammation, IV catheters • Low white cells 1st 3-4 weeks • Antibody production is decreased • require repeat exposure to antigens and revaccination • Longer time for immune function to fully return (>1year)

  18. Infections post BMT • Viral – largely herpesviruses (HSV, CMV, VZV), also EBV, BK • T cell mediated immunity profoundly depressed even up to 1 year post allotransplant or longer • Fungal and Parasitic – • Prolonged immunosuppression allows opportunistic organisms

  19. Regimen-related toxicities • Direct effects of chemotherapy and radiation on body organ • Liver eg. Sinusoidal obstruction syndrome • Thrombosis in sinusoids of liver with liver failure • GI tract eg. Mucositis with oral ulcers, diarrhea

  20. Graft vs Host Disease

  21. Acute graft vs host disease • Occurs in 1st 100 days after allogeneic transplantation • Donor immune system activated by antigens on host cells • “rejects” tissues in recipient • cause of morbidity and mortality for allogeneic transplants

  22. Risk Factors for GVHD • HLA mismatch • Unrelated donor • Age (older recipient or donor) • Female donor to male recipient • Multiparous donor • Peripheral blood stem cell source • Lack of prophylactic immune suppression

  23. ORGAN AFFECTED Skin Gut Liver MANIFESTATION Rash Diarrhea Jaundice Abnormal liver function tests Acute graft-versus-host disease (GVHD)

  24. Chronic graft vs host disease(>100 days post BMT) • Lungs – shortness of breath, cough, chest infiltrates, infections • Skin – pigmentation changes, thickening of skin and soft tissue with contractures • Eyes – dryness, pain, tearing, corneal abrasions • Mouth – dryness, pain

  25. Prevention and treatment of graft vs host disease • Prevention: • Immune suppressant drugs eg. methotrexate, cyclosporine are routinely given • T cell depletion of graft by antibodies against T cells like ATG (anti-thymocyte globulin) • Treatment: • Steroids (topical or oral) • Additional immunosuppressant drugs and monoclonal antibodies

  26. Late complications of allogeneic transplantation • Treatment-related toxicities: • Cataracts • Second malignancy • Endocrine (thyroid, ovarian, bones) • Metabolic syndrome (DM, cholesterol, HTN, CAD) • Chronic GVHD • Treatment of GVHD

  27. Appropriate Patient Selection for Transplant is Important • Younger age (selected patients up to 70y) • Disease status (ie. in remission, not heavily pretreated) • Donor availability for allogeneic transplant • Adequate organ function

  28. Saber, Hematology 2016

  29. Saber, Hematology 2016

  30. Transplant-eligible patients with symptomatic cytopenias or evidence of disease progression who have Intermediate R-IPSS scores can be considered for allogeneic HCT; with consideration of patient values and discussion around risks of transplant compared to the underlying disease. • Patients with high (>4.5 to 6 points) or very high (>6 points) IPSS-R score should be offered stem cell transplantation if they are transplant-eligible. • Disease reduction with induction chemotherapy or hypomethylating agents such as azacytidine should be considered for patients with higher risk disease or elevated blast counts at presentation. In untreated patients, a bone marrow biopsy 6 weeks prior to transplant is recommended to allow for treatment planning and risk stratification. • Efforts should be taken to minimize iron overload pretransplant to minimize the adverse effects of iron overload on treatment-related mortality. • In very high risk patients ie complex karyotype and p53 mutations by NGS, alternatives to transplant should be considered.

  31. Bacigalupo, Blood 2017

  32. Bacigalupo, Blood 2017

  33. Bacigalupo, Blood 2017

  34. Patients less than 40 years old with a matched sibling donor should proceed directly to stem cell transplantation provided no contraindication to transplant exists. • Patients greater than 40 years old and patients less than 40 years old without a matched sibling onor should receive immunosuppressive therapy with cyclosporine and equine antithymocyte globulin. They should proceed to stem cell transplantation from a matched sibling, matched unrelated donor, or a haploidentical donor if there is no clinically significant response after 6 months or if relapse. • A search for a MUD or ahaploidentical donor should be initiated on patients without a matched sibling who show no response to immunosuppressive therapy after 3 months to allow a transplant to take place at 6 months.

  35. Summary • Allogeneic transplant is the only potential cure of myelodysplasia and an important option for SAA • It has toxicities including treatment-related mortality • Recovery takes a long time (most intensive over the first year, most patients settle into a “new normal”) • Supportive care is extremely important • Important to offer transplant to patients with higher risk disease who are otherwise healthy enough to undergo treatment • Maximize long term survival

  36. Questions

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