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Hematopoietic Stem Cell Transplant Angela Smith, MD Assistant Professor University of Minnesota Outline • • • • • • Basic Principles Donor Sources Stem Cell Sources Conditioning Therapy Risks and Benefits HSCT in DBA Basic Principles of HSCT • Delivery of chemotherapy +/- radiation therapy to create space in the bone marrow and immunosuppress the recipient. • Replacement of the abnormally functioning bone marrow derived cells with healthy hematopoietic cells. Hematopoietic Stem Cells Pre-T cell T Lymphocyte Pre-B cell Pluripotent Stem Cell Lymphoid Stem Cell Myeloid Stem Cell BFU-E B Lymphocyte CFU-E Erythrocyte CFU-Mk Megakaryocyte / Platelets CFU-Mast Basophil / Mast cell CFU-Eos Self-renewal CFU-GM Eosinophil CFU-G CFU-M CFU-Ost (?) Neutrophil Monocyte / Macrophage Osteoclast Treatment Principles Bone marrow Hematopoietic stem cells Conditioning Therapy Mobilized blood Umbilical cord blood -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 Immune suppression Myeloablation Destroy BM cells and the Host’s Immune System Principles Immunosuppression Prevention of Graft Failure and GVHD Engraftment 8 6 4 2 WBC Counts (x10e9) White Cell Recovery 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Days Pace of recovery after marrow infusion What do we use HSCT for? • Cancer – leukemia, lymphoma, solid tumors. • Bone marrow failure/Blood disorders – Diamond Blackfan Anemia, severe aplastic anemia, Dyskeratosis Congenita, Fanconi anemia, PNH, SDS, Thalassemia, Sickle cell disease. • Immune deficiency – Severe combined immune deficiency, Wiskott-Aldrich syndrome, HLH. • Metabolic disorders – Hurler syndrome, leukodystrophies. Types of HSCT • Autologous • Allogeneic – Related/Unrelated – Match/Mismatch – Source of stem cells Related Donors • Sibling – Factors to consider include HLA match, age, disease status (if genetic), health, ease of getting stem cells etc. • Haploidentical – “Half matched” transplant – generally a parent or sibling. – Special considerations for prevention of graft vs. host disease (GVHD). Likelihood of a Having a Related Donor • Sibling – Assuming shared mother and father, each child has a 20-25% chance of being HLA matched. • Haploidentical – Parents ~100% chance, full siblings 50% chance Unrelated Donors • Adult volunteer donors • Umbilical cord blood Growth of Adult Donors on the Be The Match Registry® Growth of Cord Blood Units on the Be The Match Registry® HLA Matching • The transplantation antigens (HLA) are located on chromosome 6. • They are important in immune recognition of tissue compatibility. • Risk of graft failure, GVHD and mortality increase in parallel with the number of HLA disparities. HLA Genes • HLA genes are extremely diverse. • HLA genes tend to run within racial groups. HLA-A 697 HLA-B 1010 HLA-C 382 > 1.4 X 1023 unique combinations HLADR 603 HLA Matching Requirements for Unrelated Adult Donors • At least 8 HLA genes are reviewed (A, B, C, DRB1), but some centers review 10 (including DQ). • Must match at a minimum of 7/8 or 9/10 HLA genes. Likelihood of Finding a Matching Unrelated Adult Donor X X X X X 75% 30-50% 34% 30-40% 19% SOURCE: National Marrow Donor Program / Be The Match 2013 fiscal year reports. HLA Matching Requirements for UCB donors • Because cord blood cells are less mature than adult donor cells they have less strict matching criteria. • Must match at least 4 of 6 HLA genes – Look at HLA-A, -B and –DRB1. Likelihood of Finding a Matching UCB Unit • Depends more on size/age of patient rather than ethnic group. – However, double cord transplant and expanded cord blood units are becoming increasingly available making age/size less of an issue. • Very few have 6/6 HLA matches available regardless of age/size. • 4/6 or 5/6 HLA matched units are available for 95+% of those <20 years of age and >80% of those >20 years. Stem Cell Sources • Bone Marrow (BM) – Traditional source of stem cells. – Obtained from the iliac crests in the OR. • Peripheral Blood (PBSC) – Growth factor used to increase number of stem cells in the blood. – Collected by apheresis. Stem Cell Sources (cont’d) • Umbilical Cord Blood (UCB) – Blood from umbilical cord and placenta are rich in stem cells. – Harvested from umbilical cord/placenta after delivery. Advantages of Stem Cell Sources • BM – Most experience with this source – Faster engraftment than cord blood – Able to re-approach donor if needed • PBSC – Quick time to engraftment – Able to re-approach donor if needed • UCB – No risk to the donor – Rapid availability – Large and ethnically diverse inventories – Can be cryopreserved and stored – Limited GVH activity (acute +/- chronic) – Lower infectious risk (EBV, CMV) – HLA mismatch more acceptable Limitations of Stem Cell Sources • BM – Risk of anesthesia/discomfort for the donor – Lack of HLA-matched donors – Long wait time – Risk of GVHD is 30-60% • PBSC – High risk of GVHD – Lack of HLA-matched donors – Long wait time • UCB – Limited by size of the units (i.e. cell dose is fixed in each unit) – Longer time to engraftment – Unable to use the donor again in the case of disease progression/relapse – Less experience – Theoretical risk of transmission of genetic diseases How Do We Choose a Donor and Stem Cell Source for DBA Patients?? • Individualized – Sibling > Unrelated donor – Adult donor > UCB – BM > PBSC – Haploidentical? Conditioning Therapy • Overall Goals: – Ablate the bone marrow and create space for donor cells. – Suppress the recipients immune system to prevent rejection. • Historically includes both Total Body Irradiation (TBI) and Chemotherapy. Conditioning Therapy • Chemotherapy only regimens – to prevent complications associated with TBI in certain populations. – Very young children – History of radiation – Nonmalignant diseases • Regimen used depend on the underlying disease being treated, desired conditioning intensity and the stem cell source used. Conditioning Intensity Conditioning Intensity Conditioning Intensity • MA regimens limited by toxicity. – Infections, organ toxicity, etc. • RIC and NMA regimens allow HSCT to be an option for patients with nonmalignant diseases and those who would otherwise be ineligible due to underlying medical problems. – Decreased toxicity – Increased risk of graft rejection, especially in those with nonmalignant disorders. How Do We Choose The Conditioning Regimen/Intensity for DBA Patients? • Individualized – Donor – Health status • Age, iron status, comorbid conditions – Patient/family preference Risks and Benefits of HSCT High Risk : Benefit Ratio Restoration of Normal Blood Making Capacity Risk of Early and Late Toxicities • No transfusion need • • • • • • • Avoidance of steroids and subsequent side effects • Improved iron status RRT (e.g. mucositis, VOD) Acute GVHD Chronic GVHD Endocrinopathies Sterility Second malignancies Early Complications • Expected – Nausea, vomiting, loss of appetite, diarrhea, fatigue, hair loss, mucositis (mouth sores). • Potential – – – – Infection Organ toxicity Graft vs. Host disease (GVHD) Graft Failure Infection Risk Infection Prophylaxis • • • • Antiviral Antifungal Antibacterial Isolation, HEPA filtered air systems/laminar airflow rooms, masks, hand washing, oral hygiene Organ Toxicity • Kidney damage (generally from medications) • Lung damage (infection, fluid, bleeding) • Liver damage (VOD/SOS) • High blood pressure Organ Toxicity Prevention/Treatment • Optimizing function before HSCT • Targeted medication dosing (e.g. busulfan, CSA) • Chelation pre-HSCT, ursodiol for VOD prevention. – Early defibrotide if SSx’s of VOD • Antihypertensives Graft-Versus-Host Disease (GVHD) • Cause = activated donor T cells directed against the patient. • Range in severity from mild to severe. GVHD Acute GVHD Chronic GVHD • • Usually 3-6 months after HSCT • Usually within first 3 months after HSCT Fever, rash, nausea, diarrhea, liver issues • Insidious onset • Dry eyes, dry mouth, loss of appetite, weight loss, rash, poor lung function, liver abnormalities, weakness, contractures, decreasing blood counts Risk of GVHD • Depends on HLA disparity, donor source, age, etc. – PBSC > BM > UCB – Unrelated > Related – Adults > Children • Acute – 20-30% in children • Chronic – 10-20% in children GVHD Prophylaxis • All patients get prophylaxis. • Generally multimodal immune suppression. – Cyclosporine, tacrolimus, MMF, steroids, methotrexate. • T cell depletion. – Haploidentical transplants Graft Failure/Rejection • Contributing factors – HLA disparity, allosensitization from transfusions, too few stem cells, low conditioning intensity, etc. • Prevention – HLA matching, intensify conditioning therapy, etc. • Treatment – Nothing, stem cell boost, 2nd transplant. Late Complications • Number and severity depend on age, lifestyle factors, conditioning intensity, type/severity of early complications. – – – – – – – Endocrine (thyroid, growth) Fertility Cardiac/Lung issues Bone health Metabolic syndrome Secondary cancers Infections Late Complications Follow-up • All patients should be followed life long for the development of complications. – Close monitoring and routine screening. • Most large centers have Long Term Follow-up clinics run by oncologists and transplant physicians. HSCT for DBA • First HSCT for DBA was reported in 1976, confirming DBA was a “transplantable” disease. • HSCT is the only definitive treatment for the hematologic manifestations of DBA. HSCT Outcomes in DBA • Matched sibling donor – Excellent outcomes (75-100%), best if younger. • Unrelated donor – Early reports discouraging (30-40%). – Significantly improved in recent era (70-90%). • Haploidentical donor – Very little data. Conditioning Choice for HSCT in DBA • Most experience with myeloablative conditioning. – Better outcomes without the use of radiation. • Reduced intensity conditioning has been used with success, but less experience. – Indicated in adults with high iron burden or anyone with serious underlying medical conditions. HSCT Outcomes in DBA • Overall significantly better since the year 2000 and in patients younger than 10 years of age. • Iron burden prior to HSCT could have negative effect on outcomes. – Best outcomes observed when aggressive chelation is administered prior to HSCT to achieve good iron balance. Indications for HSCT in DBA • Highly individualized. • Must take into account clinical status, response to therapies, quality of life, donor options, patient/family preferences. When to Consider HSCT in DBA • Patients with unaffected matched sibling donors. – Ideally early in childhood (<10 years of age). • Transfusion dependent patients that are refractory to steroids and other therapies regardless of donor options. • Secondary aplastic anemia, MDS/leukemia, steroid intolerance, transfusion intolerance, development of red cell antibodies or chelator intolerance. HSCT for DBA • Transplant consults for all transfusion dependent patients for HLA typing, education, discussion of the risks/benefits. • Strongly recommend cord blood storage from subsequent pregnancies. – Sibling must be proven to be unaffected before use. Questions??