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Transplantation of Hematopoietic Stem Cells. Clinical practice. (Part 1)
Posted on: June 18, 2004

Bone marrow transplantation was first attempted, albeit unsuccessfully, in 1939, when human bone marrow cells were injected intravenously to treat a patient with aplastic anemia. Since that time, despite uneven progress and problems with entities such as graft-versus-host disease (GVHD), the procedure has become an accepted treatment for various hematologic deficiencies and malignant conditions.
Stem cell transplantation can be performed with cells from a family member or an unrelated volunteer (allogeneic transplantation) or with stem cells previously collected from the patient (autologous transplantation). The choice between the more risky allogeneic transplant and an autologous procedure depends on patient age, the underlying disease, donor availability and institutional preference (Table 1).
The drawbacks of an autologous transplant are possible contamination of the graft with malignant cells and the lack of a graft-versus-tumour effect. Allogeneic transplantation represents 40% of all stem cell transplants performed annually in Canada and requires donor and recipient matching for major histocompatibility (HLA) antigens. The best donor is an HLA-identical sibling; transplants with only partial matching for HLA antigens are associated with a higher risk of post-transplant complications. Only 25% of patients have a suitable sibling donor. At present, a satisfactory unrelated donor can be identified for 80% of white patients, but this figure is lower for patients in other ethnic groups.

Table 1. Common indications for hematopoietic stem cell transplantation.

Allogeneic Autologous
  • Acute leukemia
  • Myelodysplastic syndrome
  • Chronic myeloid leukemia
  • Severe aplastic anemia
  • Indolent lymphoma
  • Chronic lymphocytic leukemia
  • Severe immunodeficiency syndromes
  • Hemoglobinopathies
  • Progressive large-cell lymphoma
  • Progressive Hodgkin's disease
  • Multiple myeloma
  • Relapsed germ cell tumour

Because of the requirement for highly trained medical staff, stem cell transplantation is performed only at specialized centers. Although stem cells can be collected by direct aspiration from the bone marrow, with the patient under general or spinal anesthetic, they are now more commonly harvested from the peripheral blood. Blood stem cell transplantation is accomplished by treating the donor with hematopoietic growth factors, which cause the stem cells to proliferate and circulate freely in the peripheral blood. The blood is then collected by venipuncture and subjected to leukapheresis to obtain the cells for transplantation. The use of blood stem cells is associated with faster recovery of neutrophils and platelets after transplantation (engraftment) than is the case with bone marrow stem cells. Umbilical cord blood harvested at the time of delivery is also used for this purpose.

The actual transplantation of the cells is a simple process involving intravenous infusion of a liquid stem cell product through a large-bore central venous catheter over 1 to 2 hours. The stem cells are then able to travel or "home" to the bone marrow cavity to re-establish hematopoiesis over the next 2 weeks. It is the care of the patient after transplantation that can present much more of a challenge to the multidisciplinary care team, especially in the setting of allogeneic transplant.

Allogeneic Transplantation

This section describes the 4 components of allogeneic transplantation – conditioning, transplantation, engraftment and immunoreconstitution (Fig. 1) – and provides information about the patient's hospital stay and the risks associated with this type of transplantation.
The conditioning regimen: destroying the disease. In preparation for allogeneic stem cell transplantation, the recipient undergoes a conditioning regimen of high dose chemotherapy and, in some cases, radiotherapy to eradicate the underlying malignant disease and to suppress the recipient's immune system so that it will not reject the donor's stem cells.

Table 2. Nonhematologic toxic effects of conditioning.

Early (< 100 days) Late (> 100 days)
  • Alopecia
  • Nausea and vomiting
  • Oropharyngeal mucositis
  • Diarrhea
  • Hepatic veno-occlusive disease
  • Seizures
  • Parotitis
  • Pericarditis
  • Cardiomyopathy
  • Interstitial pneumonitis
  • Hemorrhagic cystitis
  • Rash or hyperpigmentation
  • Hypothyroidism
  • Sterility or premature menopause
  • Growth impairment
  • Dry eyes or mouth
  • Cataracts
  • Osteopenia or osteoporosis
  • Second malignant disease

The first conditioning regimen to be developed – high dose cyclophosphamide combined with total body irradiation (TBI) – remains in common use, and a variety of other TBI and non-TBI preparative regimens have also been developed. Conditioning is administered over approximately 1 week and produces both hematologic (pancytopenia) and nonhematologic side effects. The latter, referred to collectively as regimen-related toxicity, can affect many organ systems (Table 2), but painful organ systems (Table 2), but painful oropharyngeal mucositis is especially difficult for the patient and may necessitate continuous infusion of narcotics and total parenteral nutrition.
Transplantation: countdown to day 0. By convention, pretransplant conditioning days are numbered in a countdown fashion, from day -7 to day 0 (the actual date of transplantation). The days after transplantation are then numbered upward, such that 10 days after the transplant would be day +10. This universal system is useful for describing the timing of events, such as engraftment. From day 0 until engraftment, the patient's protective immunity is reduced, and he or she is vulnerable to infection. In part, this vulnerability is due to breaks in the natural mucosal and skin barriers secondary to mucositis and the necessary indwelling central venous catheter, but neutropenia and other immunodeficiencies also contribute to the risk. Febrile neutropenia, an expected occurrence, requires prompt treatment with broad-spectrum antibiotics. In addition, all patients routinely receive antifungal and antiviral prophylaxis.
Throughout the neutropenic period, the patient is confined to a single room equipped to provide the safest possible environment. A positive-pressure room equipped with high-efficiency particulate air (HEPA) filters remains the "industry standard." Although a strict hand-washing protocol is mandatory, gowns, gloves and masks are rarely required. Restriction to an isolation room is physically and emotionally difficult for patients, and many experience a feeling of isolation, which compounds their natural anxiety.
Engraftment: stem cell function begins. Engraftment is the process whereby the donor cells begin to produce new blood components within the recipient's bone marrow cavity. In practice, engraftment is said to have occurred when the absolute neutrophil count consistently exceeds 0.5 · 109/L. Platelet and red blood cell engraftment generally follows. The patient is supported with blood products until engraftment occurs. Engraftment usually occurs between day +10 and day +20 and is earlier (within this range) when blood stem cells, rather than bone marrow cells, are used. Failure to engraft (primary graft failure or graft rejection) and subsequent irreversible decline of blood counts (secondary graft failure) are serious complications. Fortunately, these conditions develop in less than 5% of recipients, and they are particularly rare after matched-sibling transplant.
Immunoreconstitution: a double-edged sword. Restoration of T-cell and B-cell immunity, which may take 12 months or longer, is critical to the recipient's recovery process. It is only when the donor's immune system is fully functional within the recipient that the risk of opportunistic infection decreases to premorbid levels. However, the presence of immunocompetent donor T cells can also lead to the recognition of host tissue as foreign and hence the development of GVHD.
GVHD is classified as acute when it occurs in the first 100 days after transplantation and chronic when it persists or develops after day +100. Clinically significant acute GVHD occurs in about 40% of matched-sibling and 80% of unrelated-donor transplant recipients. Acute GVHD is characterized by a rash, hepatic dysfunction, diarrhea and vomiting. Certain patients are at greater risk (Table 3).


Fig. 1. Course of events and risks associated with allogeneic transplantation. Blue boxes represent the 4 components of transplantation as outlined in the text; yellow boxes represent the various risks at different stages. RBC = red blood cells.

Table 3. Risk factors for acute graft-versus-host disease (GVHD)

  • HLA* mismatch between donor and recipient
  • Use of an unrelated donor
  • Older age of recipient or donor (or both)
  • Donor allosensitization by pregnancy or transfusion
  • Sex mismatch between donor and recipient
  • Use of T-cell-replete graft
  • Severe regimen-related toxicity
  • Compromised delivery of GVHD prophylaxis**
* HLA - human leukocyte antigen.
** If the patient has renal or liver dysfunction or severe mucositis, the dose of medication may be reduced to minimize any toxic effects.

Grade III and IV acute GVHD is associated with a mortality rate of 80%, although many of these deaths are due to superimposed infection, as a result of both the immunosuppressive effects of GVHD and the medications used to treat the condition (cyclosporine, corticosteroids and antithymocyte globulin). Administration of GVHD prophylaxis is standard practice for transplants involving anyone other than identical twins; a combination of methotrexate and cyclosporine is commonly used.
The graft can also be manipulated to deplete the T-lymphocyte population, but this is associated with a higher risk of infection, graft failure and relapse. If GVHD occurs, it is initially treated with high-dose corticosteroid therapy, which results in a satisfactory response in 50% to 75% of patients. Despite the morbidity and mortality associated with GVHD, its presence may be desirable in some situations because of its association with a lower risk of recurrence of the malignant disease (graft-versus-tumour effect).

The hospital stay and beyond. The average length of hospital stay for allogeneic transplantation is 5 weeks, but the stay can be much longer if complications develop. Furthermore, 25% of patients require at least one readmission during the first 3 months after transplantation. After discharge, the patient's care is continued through the daycare unit, where visits are required for blood work (to assess graft function, late regimen-related toxicity and GVHD), transfusion support and administration of prophylactic antimicrobials.
Risks. Treatment-related mortality in the first 12 months after matched-sibling stem cell transplantation is about 20% to 30%. The figure is higher among recipients of an allograft from an unrelated donor, reaching almost 50% at most adult transplant centers. Patients who do not succumb to transplant-related complications may still have a recurrence of their underlying malignant disease, usually within the first 2 years after the transplant. The risk of relapse depends on the status of disease at the time of transplantation, but even acute leukemia in first complete remission recurs in 25% of patients.

Autologous Transplantation

The rationale for autologous transplantation is that cryopreservation of the patient's own stem cells allows delivery of high-dose chemotherapy and radiotherapy that would otherwise produce lethal bone marrow suppression. The first 3 phases of autologous transplantation are similar to those described above for allogeneic transplantation, except the donor and recipient are the same person. The fourth phase differs, in that the patient's immune recovery is more rapid and there is no potential for GVHD.
Before the collection of autologous stem cells, the patient is usually given chemotherapy to debulk the malignant disease. Thereafter, further chemotherapy or stem cell growth factor (granulocyte colony-stimulating factor) is given to stimulate the stem cells to leave the bone marrow and enter the peripheral blood. The patient then undergoes 1 or 2 (sometimes 3) leukapheresis procedures during which 10 to 20 L of blood are processed; the component containing the stem cells is cryopreserved until it is needed for re-infusion on day 0.
Although stem cells can remain viable after many years of cryopreservation, in practice the patient begins the conditioning regimen within a few days to a few weeks after their collection. As with allogeneic transplantation, conditioning takes about 1 week, after which the cryopreserved stem cells are thawed and infused intravenously. Because immunoreconstitution occurs more quickly than with allografting, autologous transplantation is better tolerated by patients (transplant-related mortality at day +100 is only 5% to 10%). This in turn allows autologous transplantation to be performed in older patients, and some patients are well enough to receive part or all of their treatment in the outpatient setting. Even when admission to hospital is required for autologous transplantation, the stay rarely exceeds 3 weeks.

Continued in Part 2 >>

Source: Chantal S. Léger, Thomas J. Nevill; Hematopoietic stem cell transplantation: a primer for the primary care physician. Canadian Medical Association Journal. MAY 11, 2004; 170 (10), 1569-1579.
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