1. The Role of Bone Marrow Transplant in Oncology
Diane Hill-Polerecky RN, BSN, MS Leukemia Transplant Case Manager & Transplant Clinical Projects Coordinator Nebraska Medicine

2. Objectives
Define and identify indication for Hematopoietic Stem Cell Transplant
Identify donor sources
Identify sources of Hematopoietic Cells
Describe the transplant process and timeline
Identify short-term and long-term complications and follow up of the Transplant patient

3. Transplant may be referred to as:
BMT – Bone Marrow Transplant
PBSCT – Peripheral Blood Stem Cell Transplant
UCBT – Umbilical Cord Blood Transplant
** HSCT/HCT – Hematopoietic (Stem) Cell Transplant
BMT PBSCT Umbilical – differentiates the way we get the cell. HSCT/HCT general encompassing –see this most in the literature. Don’t confuse HCT with hematocrit 

4. Hematopoietic Cell Transplantation
Definition:
High doses of chemotherapy and/or radiation are given to eradicate malignancies followed by an infusion of hematopoietic cells to reestablish marrow function.
In addition HSCT from allo donor has additional anti tumor effect

5. Hematopoietic Stem Cell Cascade
Hematopoiesis the formation of blood cellular components. All cellular blood components are derived from hematopoietic stem cells. In a healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation

6. A small number of transplanted stem cells can replicate to repopulate a patient’s entire hematopoietic system
A small number of transplanted cells can replicate to repopulate a patient’s entire hematopoietic system

7. Further defined by donor source
Autologous
Patient’s own hematopoietic stem cells
Allogeneic
Cells collected from a donor
Related or unrelated
Syngeneic
Cells collected from an identical twin
Talk some more about why we do each of these in a bit

8. Just a little history
1959 Dr. E Donnall Thomas 1st attempt at treating leukemia with hi dose chemo and syngeneic marrow transplant
Mid 1960s before they figured out HLA matching
Late 1960s first successful (matched sibling) allogeneic for leukemia
1973 first unrelated allogeneic transplant
Mid 1970s success with autologous for lymphoma, became widespread 1980s
1988 first successful UCB
*Late 1960 Univ of Minnesota ** Auto/Lymphoma success due to peripheral collection ** UCB treated child with Fanconi anemia – lots learned since then, multiple banks established - viable option for adults and children

9. Autologous Transplants
Patient’s own cells are collected prior to receiving myeloablative (hi dose) chemotherapy
Goal is to rescue the bone marrow after it has been destroyed by this lethal therapy
Chemotherapy is the treatment, stem cells are the rescue.
May be part of initial treatment plan or reserved for relapse or persistent disease states

10. Diseases treated with Autologous Transplant
Multiple Myeloma
Hodgkins Disease
Non Hodgkins Lymphoma
Acute Promyelocytic Leukemia
Germ Cell tumors
Neuroblastoma
Brain tumors
Sarcomas
Recurrent Wilms Tumors
Clinical Trials: other solid tumors, Crohns, Juvenile Rheum Arthritis, autoimmune disorders

11. Advantages of Autologous Transplant
Ready access to the stem cells
Decreased incidence and severity of side effects
Earlier engraftment
No risk of Graft VS Host Disease

12. Disadvantages of Autologous Transplant
Risk of potential tumor contamination in the infused cell product
Lack of Graft vs Tumor effect may contribute to relapse

13. Allogeneic Transplants
Treatment of choice for patients with diseased bone marrow or patients with genetic and immunologic disorders
Myeloablative chemotherapy and/or radiation are given to eradicate malignancy AND to prepare recipient for donor cells
Donor cells repopulate the marrow and provide GRAFT vs TUMOR effect
Chemotherapy is the preparative regimen, stem cells are the treatment

14. Malignant Diseases treated with Allogeneic Transplant
AML and ALL with intermediate and hi risk prognostic factors
Myelodysplastic Syndromes
Chronic Myeloid Leukemia (blast phase)
Myeloproliferative Disorders
Non Hodgkin Lymphomas
Multiple Myeloma / Hodgkins - rare
Relapse after Autologous Transplant

15. Non Malignant Diseases treated with Allogeneic Transplant
Severe Aplastic Anemia
Fanconi Anemia
Thalassemia
Sickle Cell Disease
Diamond-Blackfan Anemia
Congenital Neutropenia
Severe Combined Immunodeficiency (SCID)
Hurler Syndrome
Hunter Disease
Fanconi is a rare genetic disease. Among those affected the majority develop cancer, most often acute myelogenous leukemia, and 90% develop bone marrow failure.
SCID rare genetic disorder, absent immune system “boy in the plastic bubble”
Hurler and Hunter are genetic disorders build of lysomal enzymes in the organs

16. Advantages of Allogeneic Transplant
Replacement of diseased or damaged bone marrow/stem cells with healthy cells
Graft vs Tumor effect – powerful immune reaction wherein the newly transplanted immune cells react against any residual disease

17. Disadvantages of Allogeneic Transplant
Longer periods of immunosuppression
Complex often long term medication regimens
Graft vs Host Disease (GVHD) both acute and chronic

18. Syngeneic Transplant Stem cells are collected from identical twin
Considered allogeneic as a donor is involved. Acts more like autologous rescue.
Lack of Graft vs Tumor effect
Rare Graft vs Host Disease
Recovery is more like an Autologous Transplant

19. Sources of Hematopoietic Cells
Bone Marrow
Peripheral Stem Cell
Umbilical Cord Blood

20. Bone Marrow Harvest Multiple needle aspirations of marrow from iliac crests
Advantages
Disadvantages
Completed in several hours
No mobilization required
Decreased risk of GVHD
Preferred in nonmalignant disorders
May still require multiple trips to donor center
Need for general or epidural anesthesia
Risk of bleeding, increased pain, infection, bone, soft tissue or nerve damage
Slower Engraftment
BM less GVHD due to less T cells in product. Used more in allo donors – see it with young women who have not had children. Used in auto donors who may have allergy to growth factors
Preferred in those diseases where no graft vs tumor effect is required.
Collect autologous blood

21. Bone Marrow Harvest

22. Peripheral Blood Stem Cell Collection
Autologous and Allogeneic Donors
Stem Cells are mobilized out of the bone marrow into the peripheral blood in larger quantities with the use of growth factors and sometimes chemotherapy (auto donors)
Stem cells then collected via apheresis process and remaining blood components returned to the donor
Revolutionized the ability to do transplants – less risk to auto patients that may already be beaten up by chemo
Made donation less risky, more appealing to unrelated donors

23. Peripheral Blood Stem Cell Collection
Advantages
Disadvantages
Outpatient, no anesthesia
Generally well tolerated
Cells obtained are more mature and engraft earlier – improved outcomes for recipient
Can be utilized in patients that have received pelvis irradiation
Side effects of growth factor (bone pain, flu like sx)
Low blood counts with chemomobilization
Requires apheresis catheter or large bore IVs
Hypocalcemia
Hypovolemia

24. Peripheral Stem Cell Collection
Do we need to ask permission to use this photo? Does NMDP have a stock photo we can use?
Walk through what a PBSC collection is like.

26. Umbilical Cord Blood Transplant
Rich source of stem cells collected at time of childbirth. No risk to mother/child
UCB cells have not matured immunologically, naïve, allows for greater degree of mismatch
Can be frozen and stored
Limited and finite number of cells. Can not go back to donor if additional cells are needed
Slow engraftment, decreased graft vs tumor, increased graft failure
UCB – cell dose is more important determinant of outcome and survival than cell source

27. Transplant Timeline Evaluation Recovery Consultation Chemotherapy ?
Ascertain Donor Harvest Cells
** Consultation – the earlier the better especially with potential Allo patients as donor identification can take awhile. Role of our Transplant Case Manager – consistent throughout process
** Additional chemotherapy as transplant works best with disease under control
**Evaluation – allo prefer to be done at our facility for future comparison
Preparative Therapy
Transplant Day 0

28. Eligibility Considerations for Transplant
The malignancy is sensitive to therapy
The disease is in an early stage
Low tumor burden
Marrow toxicity is the only dose-limiting effect of the treatment - Comorbidities
Age
Psychosocial well-being
Compliance
Caregiver availability

29. Care Partner Responsibilities
Assist with daily living activities
Participate in educational sessions
Collect data (VS, I/O, Wt)
Assist patient with self-medication
Ensure compliance with treatment and care schedule
Care for central venous catheter
Assist with oral care
Encourage use of incentive spirometer
Transportation
Observe for therapy-related side effects and symptoms
Contact the transplant team to report new symptoms or emergencies

30. Transplant Timeline Evaluation Recovery Consultation Chemotherapy ?
Ascertain Donor Harvest Cells
** Consultation – the earlier the better especially with potential Allo patients as donor identification can take awhile. Role of our Transplant Case Manager – consistent throughout process
** Additional chemotherapy as transplant works best with disease under control
**Evaluation – allo prefer to be done at our facility for future comparison
Preparative Therapy
Transplant Day 0

31. Allogeneic Donors and HLA Matching
Human Leukocyte Antigens (HLA) are proteins found on the surface of most cells in the body
The immune system uses HLA to verify that a given cell is part of the body and not foreign
There are many different HLA proteins (HLA-A, -B, -C, -DRB1, -DQ, -DP) and there are many varieties of each one

32. Why is HLA Matching Important?
If donor cells are not the same HLA type as the recipient the Tcells will recognize the recipient as being different and attack – and vice versa
If the recipient cells win, you get graft rejection
If the donor cells win, you get graft-versus-host disease (GVHD)

34. HLA Inheritance Mother Father A A B B C C DR DR Child 1 Child 29 10 3 4 B B 11 12 C C 5 6 13 14 DR 7 8 DR 15 16
Child 1
Child 2
Child 3
Child 4 A
Inherit a haplotype from each parent.
Usually inherit the entire haplotype from each parent, not parts of it (e.g. 1, 3, 5, 7 together). 1 9 A 1 10 A 2 9 A 2 10 B 3 11 B 3 12 B 4 11 B 4 12 C 5 13 C 5 14 C 6 13 C 6 14 DR 7 15 DR 7 16 DR 8 15 DR 8 16

35. What If No Family Members Match?
>17,000,000 people around the world have signed up to be volunteer donors for unrelated patients in need
NMDP’s Be The Match Registry
World’s largest pool of donors
Domestic and International donors and cord blood units
The transplant center is responsible for initiating a donor search

36. What if no NMDP match?
9/10 Unrelated Donor – some mismatches are better than others
Haploidentical Related Matches
Data supporting similar outcomes to unrelated10/10 match
Further testing for antibodies
More flexibility with scheduling – move to Transplant faster
Post Transplant Cytoxan to reduce GVHD

37. Transplant Timeline Evaluation Recovery Consultation Chemotherapy ?
Ascertain Donor Harvest Cells
** Consultation – the earlier the better especially with potential Allo patients as donor identification can take awhile
** Additional chemotherapy as transplant works best with disease under control
**Evaluation – allo prefer to be done at our facility for future comparison
Preparative Therapy
Transplant Day 0

38. Preparative Regimens: Myeloblative Full Intensity
Higher doses of chemo/radiation with goal of killing ALL the patient’s diseased cells and stem cells
Generally more side effects – healthy cells are killed as well
Auto conditioning vs Allo conditioning
Allo patients begin receiving immunosupressive meds to prevent GVHD and graft rejection
Autologous conditioning - blood counts could recover several weeks after regimen without PBSC rescue, but counts would not recover with allogeneic conditioning regimen without PBSCinfusion

39. Preparative Regimens: Nonmyeloablative - Reduced Intensity
Allogeneic Transplants only
Lower doses of chemo/radiation
Main goal to suppress recipient immune system to allow donor cells to engraft
Primary benefit Graft vs Tumor Effect
Patients less likely to tolerate side effects of high dose
Age, Comorbidities, Lower Performance Status, Prior Therapies
Blood Counts depressed for shorter time
Most effective with very minimal residual disease

40. Transplant Timeline Evaluation Recovery Consultation Chemotherapy ?
Ascertain Donor Harvest Cells
** Consultation – the earlier the better especially with potential Allo patients as donor identification can take awhile
** Additional chemotherapy as transplant works best with disease under control
**Evaluation – allo prefer to be done at our facility for future comparison
Preparative Therapy
Transplant Day 0

41. Day 0 – Cell Infusion: Hydration Premedication Monitoring
Cryo preserved vs non cryopreserved
**Cells ability to find their way to the marrow after IV infusion

42. Transplant Timeline Evaluation Recovery Consultation Chemotherapy ?
Ascertain Donor Harvest Cells
** Consultation – the earlier the better especially with potential Allo patients as donor identification can take awhile
** Additional chemotherapy as transplant works best with disease under control
**Evaluation – allo prefer to be done at our facility for future comparison
Preparative Therapy
Transplant Day 0

43. Inpatient Recovery Inpatient 2-3 weeks post cell infusion
Monitor for fever/infection
Blood product support
Nutrition support
Activity - PT
Manage toxicities
Mouth sores, electrolyte imbalances, nausea/vomiting

44. Length of Stay in Omaha (Average Time)
Autologous Transplant
Allogeneic Transplant
Evaluation/Work-up: 1-2 days
Collection: 1 week outpatient
Inpatient: 3-4 weeks
Outpatient: 1-2 weeks
Evaluation/Work-up: 1-2 days
Collection from donor: 1 week outpatient
Inpatient: weeks
Outpatient: Until day +100

45. Why 100 Days ? … or Allogeneic Transplants are a big deal!
Balancing act : Graft vs Tumor and Graft vs Host Disease
Acute Graft vs Host can happen fast and can be deadly: Skin, Liver, GI Tract
Management of Acute GVHD is very specialized
Complex medication management with multiple side effects
Immunosuppressant medications increase risk of infections
Patients not allowed to drive, require 24hr caregiver and must be within 30min of NMC

46. Long Term Follow Up Autologous Allogeneic
Immunizations: 3,6,9,12 months and 2 years
Irradiated Blood Products
Day 100 Restaging
Annual Follow Up
Managing Long Term Side Effects
Frequent follow up at NMC during 1st year
Immunizations: 3,6,9,12 months and 2 years
Irradiated Blood Products
Annual Follow Up
Collaborate with referring Oncologist
Managing Long Term Side Effects
Treating Chronic GVHD

47. High Dose Therapy Side Effects - Long Term
Fatigue/Depression
Shingles
Infertility
Slow or Failure to Engraft
Lung Scarring
Heart Damage
Secondary Cancer / Leukemia
Cataracts
Low Thyroid Function

48. Chronic GVHD – Trading one bad disease for another?
Despite having good HLA match, undergoing preparative regimen and compliance with immunosuppressant meds – GVHD can still occur
Months to years later
Skin, Eyes, Mouth, Pulmonary
Early identification and treatment are key
May require long term immunosuppression and steroids
Greatly impacts Quality of Life

49. What’s new – What’s next?
CAR T cells
Alternate Donor Sources: Haplo Related and Unrelated
Preventing and Treating GVHD: Clinical Trials and Multidisciplinary Clinics
Improving Long Term Quality of Life and Survivorship
Selected Stem Cells/Cells for immune reconstitution
Targeted Therapies (antibodies)
Targeted therapy replaces hi dose chemo/radiaiton

50. Questions?

51. Additional Resources
NMC Transplant Education Videos –
Be the Match –
Leukemia and Lymphoma Society –