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 Pre-B cell BFU-E CFU-Mk CFU-E CFU-Mast CFU-GM CFU-Eos CFU-M CFU-G CFU-Ost (?) T Lymphocyte B Lymphocyte Erythrocyte Megakaryocyte / Platelets Basophil / Mast cell Eosinophil Neutrophil Monocyte / Macrophage Osteoclast Lymphoid Stem Cell Myeloid Pluripotent Stem Cell Self-renewal

Hematopoietic stem cells Treatment Principles Bone marrow Mobilized blood Umbilical cord blood Hematopoietic stem cells Conditioning Therapy -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 Immune suppression Destroy BM cells and the Host’s Immune System Prevention of Graft Failure and GVHD Myeloablation Immunosuppression Principles

Engraftment Pace of recovery after marrow infusion White Cell Recovery 8 White Cell Recovery 6 WBC Counts (x10e9) 4 2 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 Haploidentical 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® Worldwide there are 24 millions registered donors

Growth of Cord Blood Units on the Be The Match Registry® Worldwide there are over 600,000 UCB units available

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.

> 1.4 X 1023 unique combinations HLA Genes HLA genes are extremely diverse. HLA genes tend to run within racial groups. > 1.4 X 1023 unique combinations HLA-A 697 HLA-B 1010 HLA-C 382 HLA-DR 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 75% 19% 34% 30-40% 30-50% X 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) Peripheral Blood (PBSC) 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 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 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

Pathophysiology and Treatment of Fanconi Anemia M.L. MacMillan M.D. Risks and Benefits of HSCT High Risk : Benefit Ratio Restoration of Normal Blood Making Capacity Risk of Early and Late Toxicities RRT (e.g. mucositis, VOD) Acute GVHD Chronic GVHD Endocrinopathies Sterility Second malignancies No transfusion need Avoidance of steroids and subsequent side effects Improved iron status

Early Complications Expected Potential 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 Risk depends on time post transplant and other transplant related factors. While the early neutropenia puts patients at very high risk early, the lymphopenia persists even after engraftment and patients are immune suppressed for a year or more post transplant.

Infection Prophylaxis Antiviral Antifungal Antibacterial Isolation, HEPA filtered air systems/laminar airflow rooms, masks, hand washing, oral hygiene However, most of the infections seen post transplant come from the patients own body and are difficult to prevent – skin, mouth/GI tract, viral reactivation etc.

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. Occurs because of differences between the cells of your body and the donated cells. The new immune system from the donor sees the patients cells as different and they attack them.

Pathophysiology and Treatment of Fanconi Anemia M.L. MacMillan M.D. GVHD Pathophysiology and Treatment of Fanconi Anemia M.L. MacMillan M.D. Acute GVHD Usually within first 3 months after HSCT Fever, rash, nausea, diarrhea, liver issues Chronic GVHD Usually 3-6 months after HSCT 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. Acute 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 Unrelated 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. All are relatively small studies with ~30-60 patients each. DBAR data show: OS – MSD 77% (<9 yrs 90%, >9 yrs 70%), Alt donor 32% (<2000 23%, >2000 86%) IBMTR data show: OS – MSD 76%, Alt donor 39% Japanese DBA registry study: OS – BMT (related and URD) 100%, UCBT (related and URD) 40% Italian Registry study: OS – MSD 80%, Alt donor 70% (no signif difference), significantly better in those <10 years and after the year 2000

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. Better outcomes after 2000 likely secondary to improved HLA typing techniques and improved supportive care regimens. Better outcomes in children likely because less iron burden and organ toxicity coming into transplant.

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. Given dramatic improvement in alternative donor transplant outcomes, this approach no longer needs to be reserved for those with secondary aplastic anemia, leukemia or other major problems.

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.

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