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.

Self-renewal

Pluripotent Stem Cell

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

LymphoidStem Cell

MyeloidStem Cell

Hematopoietic Stem Cells

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6

Conditioning Therapy

Immune suppression

Hematopoietic stem cells

Treatment Principles

Destroy BM cells and the Host’s

Immune System

Prevention of Graft Failure and GVHD

Myeloablation ImmunosuppressionPrinciples

Bone marrow

Mobilized blood

Umbilical cord blood

02

46

8

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

White Cell Recovery

Days

WB

C C

ounts (x10e9)

Pace of recovery after marrow infusion

Engraftment

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.

> 1.4 X 1023 unique combinations

HLA-A697

HLA-B1010

HLA-C382

HLA-DR603

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

SOURCE: National Marrow Donor Program / Be The Match 2013 fiscal year reports.

75%

19%

34% 30-40%

30-50%

X X XX

X

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

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

High Risk : Benefit Ratio

• No transfusion need

• Avoidance of steroids and subsequent side effects

• Improved iron status

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• 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. – 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??