Stem Cell Transplantation

What are haematopoietic stem cells (HSCs)?

HSCs are pluripotent precursor cells, which means they have the potential to differentiate into all types of blood cells. Stem cells differentiate into either a common myeloid progenitor or a common lymphoid progenitor, which then go on to make the more specialized blood cells including red blood cells, platelets, granulocytes, B cells, T cells and natural killer cells.1

What is Stem Cell Transplantation?

Haematopoietic stem cell transplantation is the introduction of haematopoietic stem cells via the peripheral blood. There are 2 main types of HSCT: allogenic and autologous.

In allogenic transplants, the cells come from a separate donor. In autologous transplants, the patient is their own donor (ie their own cells are re-infused back into their blood). Each type of transplant is used for different purposes.

AUTOLOGOUS

Autologous transplants are used as “rescue therapy” after high dose myeloablative chemotherapy regimens. This means that there are some haematological malignancies that must be treated with chemotherapy regimens that are at high doses. The side effect of these treatments is that it completely destroys the cells in the bone marrow. To replace what has been lost, the patient’s own stem cells are harvested prior to chemotherapy, and then re-infused back into the blood after chemotherapy treatment. The benefit of this method is that it greatly reduces the risk of Graft Versus Host disease (discussed in depth below).1

ALLOGENIC

Allogenic transplants are used when a Graft versus leukemia effects is desirable. This effect is when donor T cells actually play a role in attacking the patient’s leukemic cells. The donor cells also replace the diseased marrow cells with healthy cells. While some level of Graft verus Leukemia effect is desired, the risk with giving a patient someone else’s stem cells is these donor cells include T cells, which recognize the recipient as “foreign”, and try to destroy them - this is called Graft versus Host disease, and poses significant morbidity to transplant patients. GvHD is discussed in greater detail in the “Complications” section.1

HLA Matching in Allogenic Stem Cell Transplants

Stem cells infused into a patient must be as similar to the patient's own cells so that the patient's body is not triggered to reject the foreign cells. The more similar the donor cells to the patients, the lower the chance of rejection. The way to assess the similarity of the donor and patient's cells is through Human Leukocyte Antigen (HLA) matching.

The HLA system involves genes found on chromosome 6. These genes encode for specialized cell surface receptors which can present peptides from antigens to T cells and are therefore essential to the immune system. They have been found to the be most immunogenic in transplant settings, which is why they are used to determine a suitable donor for stem cell transplants. The HLA genes are classified by their region on chromosome 6 into Class 1, Class 2, and Class 3.1,2

Class 1 has 3 genes: HLA-A, HLA-B, and HLA-C.

Class 2 has 3 genes: HLA-DR, HLA-DQ, and HLA-DP.

Each person will inherit one set of these genes from their mother, and one from their father.

When looking for a HLA-compatible donor, many stem cell units will use type for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ (some places do not use DQ). With 2 copies of each of these 5 genes, a desirable donor is a 10/10 match, meaning all 5 gene alleles match.1,2

Types of Stem Cell Donors in Allogenic Transplants

1) Matched Sibling Donor

Siblings who share the same two parents have a 25% chance of having the same HLA genes. The diagram below explains how this occurs:

2) Matched Unrelated Donor

Bone marrow donor registries exist in several countries. These can be used to find unrelated donors who are HLA-compatible. The chance of finding a compatible donor in the UK is lower for ethnic minority groups.

3) Umbilical cord blood cells

Umbilical cord blood cells are multipotent stem cells, which can be stored in cord blood banks. Since they are multipotent, they will be able to differentiate into many types of blood cells.

4) Haploidentical

A haploidentical match means that the donor is a half-match (half the HLA gene alleles are identical to the recipient). This is usually a parent or child of the patient, or a sibling. This option is less suitable than the others because the greater the degree of mismatch, the more likely the body will reject the donor cells as it will recognize them as foreign.

Types of harvest

Stem cells can be obtained from 3 different places:

Peripheral blood stem cells
- Stem cells are mobilised from the bone marrow into the peripheral blood using G-CSF injections
- They are then collected via apheresis (blood is removed from the patient and a machine selects CD34+ cells as this is a surface marker found on stem cells, and returns the rest of the blood back to the donor)
- This is now the most commonly used method of collecting stem cells2
Bone marrow aspiration
- This procedure collects a large volume of stem cells directly from the bone marrow
- This is a surgical procedure which requires general anaesthesia2
Umbilical cord blood
- This is particularly good when an urgent source of stem cells are required
- The HLA matching criteria is less stringent than in bone marrow or peripheral blood stem cell transplants
- The cells obtained through this method take longer to engraft compared to peripheral blood stem cells or bone marrow methods2

Process of Stem Cell Transplantation

In autologous transplants, the process involves removing the patient's stem cells. Chemotherapy to treat lymphoma or myeloma is then given. Chemotherapy in these cases is given at high doses that will destroy the bone marrow. This is known as myeloablation. The collected stem cells are then re-infused into the patient. It will take a while for these stem cells to engraft and start functioning as normal, so during this time, the patient is immunocompromised and at risk of infections.1

The allogenic transplant process is more complicated. In these situations, the patient first receives chemotherapy to destroy the cancer cells in the bone marrow. This also creates empty space in the bone marrow for the incoming donor cells. This process is called CONDITIONING.1,2

The next step is the infusion of the stem cells. These stem cells will form a new immune system for the recipient. It will also attack any remaining leukaemia cells - this is called GRAFT VERSUS LEUKAEMIA (or Graft versus tumor) effect. The mechanism of this phenomenon is that donor cytotoxic (CD8) T cells and Natural Killer (NK) cells recognize the leukaemia cells in the patient's bone marrow and destroy them.2

After the stem cells are infused, it usually takes more than 2 weeks for engraftment to occur. Engraftment is when the infused stem cells in the bone marrow start to produce mature cells in the peripheral blood. Peripheral blood stem cells have the fastest engraftment time compared to umbilical cord and bone marrow stem cells.

Complications

Complications can be categorized into early and late, but there is often overlap of these conditions.2

Acute

Graft Versus Host Disease (GvHD)

Graft versus Host disease is when the donor cells attack the recipient's tissues. The mechanism of this is the donor immune cells recognizing the recipient's as foreign, and therefore mounting an immune response against them. The risk of GvHD is greater is allogenic transplants compared to autologous, and is greater with a higher degree of HLA mismatch. GvHD can either be acute or chronic. In acute GvHD, the most commonly affected sites of the body are: skin, gastrointestinal tract, and liver. Skin involvement presents as rashes. GI involvement presents with diarrhoea. Liver involvement results in hepatitis and jaundice. The principle of treatment for GvHD is suppression of this immune response, which can be achieved with steroids, such as methylprednisolone, or other immunosuppressive medications.3

Infection

While waiting for stem cells to engraft, the recipient is very prone to bacterial, viral, and parasitic infections as they do not have an immune system to fight off pathogens. Additionally, the immunosuppressants that patients are on to prevent Graft Versus Host Disease makes them even more at risk of infections. Striking the balance of immunosuppression for preventing GvHD and the risk of infections is extremely challenging.3

Graft Failure

This is when there is failure of engraftment. The risk of graft failure is higher in HLA-mismatched transplants.2,3

Veno-occlusive disease

This complication occurs as an effect of chemotherapy used in conditioning. Chemotherapy damages the cells in the liver sinusoids, which subsequently lead to inflammation and obstruction of these vessels. It presents with jaundice, abdominal pain, and ascites. It usually occurs approximately 6 weeks post-transplant.2,3

Chronic

Chronic GvHD

Chronic GvHD occurs from 3 months post-transplant onwards. It can affect any part of the body. Examples of manifestations include:

Skin: Lichen planus, sclerosis
Hair: alopecia
Eyes: Sicca (dry, painful)
Mouth: lichen planus, ulcers
Lungs: bronchiolitis obliterans, restrictive lung disease
Liver: derranged liver function
GIT: diarrhoea, anorexia, strictures in the esophagus
Genitalia: lichen planus
Muscle: myositis

Management of chronic GvHD is based on similar principles to acute GvHD and involves steroids and other immunosuppressive agents.2

Late Infections

The immunosuppressive agents that patients are on to prevent GvHD make the patient susceptible to infections. To prevent this from happening, patients are given a vaccination schedule which starts at around 6 months post- transplant and includes all the vaccines routinely given during childhood, and others.2

Endocrine disease

The effect of chemotherapy agents used before and during the transplant process can be toxic to the ovaries and testis, and result in hypogonadism. Women can experience premature menopause as a result. Infertility can also be a consequence of this in both men and women. Before the transplant process, patients are asked about egg and sperm preservation.1,2

Long term steroids used in the transplant process suppress the hypothalamic-pituitary-adrenal axis. These long term steroids can also contribute to development of diabetes mellitus and osteoporosis. Hypo-, hyper-thyroidism, and thyroiditis are all possible consequences of chemotherapy.1,2

Psychosocial impact

Depression, anxiety, and PTSD are all psychiatric effects of stem cell transplantation. Difficulty returning to work, returning to their normal sex life, and overall quality of life are significant complications of stem cell transplants.

Secondary Malignancies

Post transplant lymphoproliferative disorders (mostly EBV-driven lymphomas), haematological cancers (ex. myelodysplastic syndrome, acute myeloid leukaemia), and solid cancers are all complications and possible causes of mortality amongst stem cell transplant survivors.1,2

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References

1. Balassa K, Danby R, Rocha V. Haematopoietic stem cell transplants: principles and indications. British Journal of Hospital Medicine. 2019;80(1):33-39.

2. Hoffbrand V, Moss P. Hoffbrand's Essential Haematology. Oxford: John Wiley & Sons, Ltd; 2016.

3. Dignan F, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P et al. Diagnosis and management of acute graft-versus-host disease. British Journal of Haematology. 2012;158:30–45.