1. Hematopoietic Stem Cell Transplant
Angela Smith, MD
Assistant Professor
University of Minnesota

2. Outline Basic Principles Donor Sources Stem Cell Sources
Conditioning Therapy
Risks and Benefits
HSCT in DBA

3. 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.

4. 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

5. Hematopoietic stem cells
Treatment Principles
Bone marrow
Mobilized blood
Umbilical cord blood
Hematopoietic stem cells
Conditioning Therapy
Immune suppression
Destroy BM cells and the Host’s Immune System
Prevention of Graft Failure and GVHD
Myeloablation
Immunosuppression
Principles

6. Engraftment Pace of recovery after marrow infusion White Cell Recovery8
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

7. 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.

8. Types of HSCT Autologous Allogeneic Related/Unrelated Match/Mismatch
Source of stem cells

9. 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).

10. 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

11. Unrelated Donors
Adult volunteer donors
Umbilical cord blood

12. Growth of Adult Donors on the Be The Match Registry®
Worldwide there are 24 millions registered donors

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

14. 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.

15. > 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

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. Advantages of Stem Cell SourcesBM
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

23. Limitations of Stem Cell SourcesBM
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

24. How Do We Choose a Donor and Stem Cell Source for DBA Patients??
Individualized
Sibling > Unrelated donor
Adult donor > UCB
BM > PBSC
Haploidentical?

25. 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.

26. 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.

27. Conditioning Intensity

28. Conditioning Intensity

29. 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.

30. How Do We Choose The Conditioning Regimen/Intensity for DBA Patients?
Individualized
Donor
Health status
Age, iron status, comorbid conditions
Patient/family preference

31. 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

32. 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

33. 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.

34. 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.

35. Organ Toxicity Kidney damage (generally from medications)
Lung damage (infection, fluid, bleeding)
Liver damage (VOD/SOS)
High blood pressure

36. 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

37. 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.

38. 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

39. 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

40. GVHD Prophylaxis All patients get prophylaxis.
Generally multimodal immune suppression.
Cyclosporine, tacrolimus, MMF, steroids, methotrexate.
T cell depletion.
Haploidentical transplants

41. 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.

42. 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

43. 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.

44. 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.

45. 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% (< %, > %)
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

46. 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.

47. 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.

48. Indications for HSCT in DBA
Highly individualized.
Must take into account clinical status, response to therapies, quality of life, donor options, patient/family preferences.

49. 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.

50. 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.

51. Questions??