28. Haematopoietic Stem Cell Transplantation

There are two types of haematopoietic stem cell transplantation, autologous and allogenous.

Autologous stem cell transplantation

Autologous stem cell transplantation refers to removing and storing the patient’s own hematopoietic stem cells, which are later re-transfused back into the patient after high dose myeloablative chemotherapy. It’s a very safe procedure. However, relapse occurs in 40 – 75% of patients.

Nowadays 98% autologous transplants are performed by harvesting stem cells from peripheral blood, with only 2% being bone marrow transplants. 20 years ago, bone marrow transplants were used almost exclusively.

Indications:

  • Lymphomas
    • Hodgkin lymphoma
    • Non-Hodgkin lymphoma
      • Mantle cell lymphoma
      • Peripheral T-cell lymphoma
      • DLBCL
  • Multiple myeloma and other plasma cell disorders
  • Certain solid tumours

Certain solid tumours, like Ewing sarcoma, require such a high dose of chemotherapy or irradiation to be cured that the bone marrow would be eliminated. By giving these patients autologous stem cell transplant they can receive this high dose of antineoplastic therapy and still keep their bone marrow.

Autologous stem cell transplant is often curative for lymphomas but rarely curative for multiple myeloma. Thus, multiple myeloma patients should continue to receive supportive therapy after the transplant.

Advantages vs allogenous transplant:

  • There is no need for a donor
  • There is no need for post-transplant immunosuppression
  • There is low risk for rejection and graft-versus-host disease

Disadvantages vs allogenous transplant:

  • There is no graft-versus-tumor effect
  • There is a higher risk for relapse
  • There is a higher risk for early post-transplant infections
  • Tumor cells can contaminate the graft

Efforts were put in to try to invent techniques to purge tumor cells from the grafts, but these turned out to not improve the outcome of the patient.

Allogenous stem cell transplantation

Allogenous stem cell transplantation refers to using haematopoietic stem cells harvested from a sibling or unrelated donor. Relapse occurs in 10 – 40% of patients.

Indications:

  • Acute leukaemias
    • ALL
    • AML
  • Aplastic anaemia
  • Thalassaemia
  • Bone marrow failure
  • CML (although nowadays better treatment options for CML exist, so it’s rarely performed on this indication)

Advantages vs autologous transplant:

  • There is a graft-versus-tumor effect
  • There is a lower risk for early post-transplant infections

The graft-versus-tumor (GvT) effect refers to how the donor lymphocytes may recognize and kill the tumor cells of the patient to a higher degree than the patient’s own lymphocytes would. The T-cells of the graft recognize the donor recipient’s antigens on the tumor cells and attack them. It is debated whether the graft-versus-tumor effect can be separated from graft-versus-host disease or if the two are actually the same phenomena.

Disadvantages vs autologous transplant:

  • There is a higher risk of graft-versus-host disease
  • There is a higher risk of rejection
  • The patient needs post-transplant life-long immunosuppression
  • A matching donor is needed

Outcome:

A scoring system called EGMT or Gratwohl can be used to estimate the survival and mortality rate of a person receiving an allogenous stem cell transplant, based on risk factors like age, disease stage, donor type, etc. A higher score gives a poorer prognosis with a higher mortality.

Stem cell harvesting

Haematopoietic stem cells express CD34 and are therefore sometimes referred to as CD34+ cells.

Haematopoietic stem cells (HSCs) are found in the peripheral blood in extremely low levels. Administration of haematopoietic growth factors like G-CSF (filgrastim) increases the number of HSCs in the peripheral blood more than 1000-fold. In some patients G-CSF alone doesn’t yield enough peripheral HSCs. In these patients G-CSF can be combined with chemotherapy or the CXCR4 inhibitor plerixafor. These combinations give higher yields than G-CSF alone.

The blood then undergoes apheresis, the process where the cells and the soluble elements of the blood are separated. These cells are then cryopreserved by adding DMSO, which prevents ice crystals from forming, and freezing them with liquid nitrogen at -196 C. After a few weeks the patient will receive what’s called a conditioning regimen (more about this later) and will thereafter get the reinfusion of the cryopreserved HSCs.

For 60% of patients a peripheral venous access suffices, but for the rest a central venous access or both are necessary.

Some factors appear to increase the risk that the stem cell harvest will be unsuccessful (that the patient will be a “poor mobilizer”):

  • Older age
  • Few circulating CD34+ cells
  • Decreased total blood volume

The following factors may also play a role:

  • Certain diagnoses, like AML
  • Prior irradiation
  • More than 3 prior lines of chemotherapy
  • Bone marrow involvement of the malignancy
  • Advanced stage of the disease
  • Use of alkylating agents like cisplatin
  • If the malignancy has already relapsed once
  • Low platelet count (< 150 000)

However, despite these risk factors it is difficult to predict who will be poor mobilizers and who won’t. There are no validated algorithms that predict poor mobilizers.

Drake et al created a scoring system to assess the effect of previous chemotherapy on the yield of stem cell mobilization but it turned out to not be useful.

Conditioning regimen

After stem cells have been harvested and around 10 – 5 days before the HCTs are transplanted back into the patient, the patient will receive a so-called conditioning regimen. The goals of this conditioning regimen are to:

  • Suppress the immune system to decrease the risk for graft rejection
  • Make room in the bone marrow for the donor HCTs to grow
  • Destroy any residual cancer cells

Previously the goals of the conditioning were to give the patient extremely high doses of total body irradiation and chemotherapeutic agents to try to eradicate as many tumor cells and be as myeloablative as possible. Nowadays we have recognized that the graft-versus-tumor effect contributes substantially to the effectiveness of the haematopoietic stem cell transplant, and that a lower dose, non-myeloablative conditioning regimen is also viable. This is called nonmyeloablative conditioning regiments (NM) or reduced-intensity conditioning (RIC) and have allowed for weaker populations to receive stem cell transplant, like older people.

The conditioning regimen involves one or more of the following: chemotherapeutic drugs, monoclonal antibody therapy and/or radiation. The specific regimen used depends on the exact malignancy and whether it is myeloablative, nonmyeloablative or reduced-intensity.

  • Myeloablative conditioning regimens
    • BEAM
      • Carmustine (BCNU), etoposide, aracytin, melphalan
      • Used for non-Hodgkin and Hodgkin lymphoma
    • Bu-CY
      • Busulfan, cyclophosphamide
    • TBI-CY
      • Total body irradiation, cyclophosphamide
    • Melphalan
      • Used for multiple myeloma
      • Excreted by liver -> viable for renal failure, which is common in MM
  • Nonmyeloablative/RIC regimens
    • Flu/TBI
    • Flu/Cu

Isolation during conditioning:

During the treatment with a conditioning regimen the patient must be isolated to prevent infections. Patients will be placed in an isolation room with everything they need. The room will be fitted with a HEPA filter and there will be positive air pressure. All sources of water must have pseudomonas and legionella filters installed. High standards of hygiene must be upheld.

Antimicrobial prophylaxis:

It’s often necessary for patients to receive antimicrobial prophylaxis during the conditioning.

Antibacterial prophylaxis, more specifically with a fluoroquinolone like levofloxacin has been shown to reduce infection and mortality. However, it is not given to all transplant patients.

Antifungal prophylaxis is recommended for all transplant patients. Fluconazole and posaconazole are often used.

Antiviral prophylaxis is recommended for patients who are seropositive. The most important viruses are HSV, VZV and CMV. If the patient is seropositive for any of these, they should receive acyclovir or another antiviral.

Adverse effects:

Conditioning therapies can cause many adverse effects:

  • Mucositis
    • Very common
    • Often with ulcers
  • Pneumonitis
  • Veno-occlusive disease of the liver
  • Nausea, vomiting
  • Alopecia
  • Rash
Donor lymphocyte infusion

Donor lymphocyte infusion (DLI) refers to transfusing lymphocytes from the donor into a person who has received a haematopoietic stem cell transplant. The donor should be the same as the donor of the graft in the stem cell transplant. Lymphocytes can be stored from the time when the stem cells are harvested, or the donor can be asked to donate blood once more.

After a stem cell transplant, the so-called chimerism will be measured regularly. Chimerism refers to how much of the patient’s bone marrow consists of the patient’s own cells and how much of it consists of the donor’s cells. The closer to 100% donor, the better.

Mechanism of action:

DLI takes advantage of the graft-versus-tumor effect. The donor lymphocytes recognize and kill the tumor cells of the patient.

Indications:

DLI is recommended in people who experience relapse after an allogenous haematopoietic stem cell transplantation. The DLI can be enough to put the patient back into remission.

A drop in chimerism increases the risk for relapse or graft rejection. A DLI can increase the chimerism and prevent this.


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