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Transplantation of Hematopoietic Stem Cells. Clinical practice. (Part 2)
Posted on: June 21, 2004

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Hematopoietic stem cell transplantation has been used for many years to treat various malignant and nonmalignant hematologic conditions. However, the high-dose conditioning regimen can lead to major organ dysfunction, life-threatening infection and bleeding. In a previous section, we reviewed allogeneic as well as autologous transplantation aspects. In the allogeneic setting, graft-versus-host disease may develop, making post-transplant management complex. Once a transplant recipient has been discharged from hospital and returns to his or her local community, the primary care physician can play an important role in care. Recipients of stem cell transplants may be severely immunocompromised for many months after transplantation, especially if they are still taking immunosuppressive drugs. Furthermore, endocrine and metabolic deficiencies can develop, and transplant survivors are at risk of a second malignant disease. This review is intended as a basic overview of long0term follow-up issues relevant to primary care providers.

Long-term Follow-up

During the initial 3 months after transplantation, recipients are assessed a minimum of once weekly in the outpatient transplant clinic. Thereafter, long-term survivors without serious complications are seen in the specialty clinic every 3 to 6 months. At this point, the primary care physician begins to play a crucial role in long-term care. The family physician needs to be aware that organ damage from the conditioning regimen, chronic GVHD and immunosuppressive drugs may all lead to an ongoing risk of complications. Infections are of particular concern in allogeneic transplant recipients, may be more severe than in otherwise healthy patients and can involve unusual (or opportunistic) organisms. The use of immunosuppressive agents for many months or years can also predispose allogeneic transplant survivors to a multitude of additional health problems (Table 4).

Table 4. Potential medical complications of long-term immunosuppressive therapy

  • Osteopenia or osteoporosis
  • Avascular necrosis:
    • Hips
    • Shoulders
    • Knees
  • Hypertension
  • Diabetes mellitus
  • Hyperlipidemia
  • Accelerated atherosclerotic vascular disease
  • Renal insufficiency
  • Predisposition to infection:
    • Bacterial
    • Viral
    • Opportunistic
  • Renal insufficiency
  • Myopathy
  • Second malignant disease:
    • Lymphoma
    • Other
  • Depression
  • Cosmetic changes:
    • Obesity
    • Hirsutism
    • Acne
    • Skin striae

With these factors in mind, recommendations for follow-up care of all stem cell transplant recipients are listed in Table 5.

Table 5. Recommendations for follow-up care of stem cell transplant recipients

  • Assess for chronic GVHD (see Table 6) every 3 months*
  • Complete dental examination every 6 months
  • Complete annual physical examination Prostate examination (may include determination of PSA level) (from age 30)
  • Breast examination and mammography (from age 30)
  • Pelvic examination and Papanicolaou smear
  • Thyroid examination
  • Skin examination for premalignant or malignant change
  • Screening for colorectal cancer**
  • Ophthalmologic examination
  • Complete and differential blood count, creatinine level, liver function, TSH level, cholesterol level
  • Serum immunoglobulin levels***
  • Chest radiography
  • Bone densitometry
  • Assess for menopausal symptoms (may include determination of FSH and LH levels)
  • Assess for cardiac risk factors (may include exercise treadmill test, as needed)
* For allogeneic transplant recipients.
** At a minimum, to include digital rectal examination and stool examination for occult blood.
*** Discontinue when patient has been off immunosuppressive drugs for 12 months.
Notes: PSA - prostate-specific antigen;
TSH - thyroid-stimulating hormone;
FSH - follicle-stimulating hormone;
LH - luteinizing hormone;

Chronic GVHD. Chronic GVHD is a syndrome unique to allogeneic stem cell transplantation, with manifestations resembling those seen in autoimmune disease. The highly variable findings may include oral and ocular changes (sicca syndrome), cholestatic hepatic dysfunction and cutaneous scleroderma (Table 6).

Table 6. Manifestations of chronic GVHD

  • Skin changes:
    • Scleroderma
    • Lichenoid rash
  • Lichenoid mucosal reaction:
    • Oral
    • Genital
  • Sicca syndrome:
    • Keratoconjunctivitis sicca
    • Periodontal disease
  • Esophageal dysmotility
  • Hepatic dysfunction
  • Obstructive lung disease (bronchiolitis obliterans)
  • Recurrent infections
  • Malabsorption
  • Weight loss
  • Myositis

Chronic GVHD occurs in at least half of HLA-identical sibling transplants, and its presence is a major risk factor for infection. Treatment of chronic GVHD usually begins with a combination of corticosteroids and cyclosporine for a minimum of 6 months, with the use of immunosuppressive drugs further increasing the risk of infectious complications.
Infections, vaccinations and safe living after transplantation. Although patients surviving for 10 years or more after transplantation have near-normal immunity, persistent hypogammaglobulinemia, impaired cellular immunity and splenic hypofunction all contribute to an increased risk infection for up to 5 years after transplantation, especially in allogeneic transplant recipients with chronic GVHD. Recurrent sinopulmonary infections (e.g., sinusitis, pneumonia, bronchitis) are common in the first 2 years after any stem cell transplant, and reactivation of latent varicella-zoster virus occurs in almost 50% of survivors. The reactivation typically presents as a crusting vesicular dermatomal rash (shingles) 6 to 12 months after transplantation. Prompt treatment with oral antiviral drugs may limit postherpetic neuralgia and can prevent more serious dissemination of disease. Reactivation of cytomegalovirus (CMV), most common in allogeneic recipients who are taking corticosteroids for GVHD, can also be life threatening. Prophylactic ganciclovir is usually administered to CMV antibody-positive patients who require corticosteroid treatment during the first 3 to 6 months after allogeneic transplantation. Pneumocystis jiroveci (formerly carinii) pneumonia can occur in both autologous and allogeneic recipients, and prophylaxis with trimethoprim-sulfamethoxazole or intravenously administered pentamidine is usually recommended until 3 months after transplantation for autologous recipients and until discontinuation of all immunosuppressive drugs in the allogeneic setting.
Antibody titres to vaccine-preventable diseases decline during the first 4 years after transplantation; this decline cannot be prevented by pretransplantation vaccination of either an allogeneic donor or a transplant recipient. Recipients are usually immunocompetent by 2 years after transplantation, and many can begin revaccination as early as 1 year after transplantation. Vaccinations are not suggested (and live vaccines are contraindicated) for allogeneic transplant recipients who are receiving immunosuppressive drugs and those with active chronic GVHD. Recommended guidelines for vaccination of patients after allogeneic and autologous stem cell transplantation are presented in Table 7.
Safe-living practices are a common concern for transplant survivors. Food preparation should be meticulous (including washing hands with soap before and after handling food, using separate utensils for cutting meats and other foods, and careful refrigeration of perishable foods), consumption of fresh water should be avoided and sexual practices may need to be modified during the immunoreconstitution phase. Travel to developing countries is not recommended during the first 2 years after transplantation. Although pets are not strictly prohibited, steps should be taken to minimize contact with the animal's saliva or excrement (e.g., patients should avoid changing litter boxes or cleaning bird cages).
Fertility. Counseling about fertility has become an important issue, given improvements in survival after stem cell transplantation. Infertility in both men and women is the rule after conditioning with TBI-based regimens. Pregnancy has been reported, if rarely, in women who have undergone TBI; however, in one study, 6 (37%) of 16 pregnancies that occurred in 13 TBI recipients terminated in spontaneous abortion. Although generally not occurring until a number of years after transplantation, recovery of spermatogenesis has also been reported in a minority of men treated with TBI3 Counselling of patients who have received non-TBI conditioning is less well defined, since preservation of fertility is possible, even likely, when cyclophosphamide alone is used for patients with aplastic anemia. Contraception should be discussed with the patient as necessary; the younger a female patient is at the time of transplantation, the higher the possibility of a successful pregnancy after high-dose chemotherapy or radiotherapy. One study found a 25% incidence of preterm labour and low-birthweight infants among women who had undergone marrow transplantation but no increased risk of congenital anomalies. Semen analysis in male patients and measurement of follicle-stimulating hormone and luteinizing hormone levels and luteinizing hormone levels in women can be performed to determine menopausal status and the potential for recovery of fertility.
Second malignant disease. Solid cancers are more common in patients who have undergone either autologous or allogeneic stem cell transplantation than in the general population. In patients who have undergone autologous transplantation, greater risks of myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML), lymphoproliferative disorders and solid tumours have all been observed. Although MDS/AML is not a common problem for allogeneic transplant recipients, the observed-to-expected ratio for solid tumours at 10 years was 8.3. The observed-to-expected ratio is significantly greater than that in the general population for cancers of the bone (13.4), oropharynx (11.1), connective tissue (8.0), central nervous system (7.6), liver (7.5) and thyroid (6.6) and for malignant melanoma (5.0). The lifetime risk of a solid tumour is highest among young patients who have received TBI-containing conditioning. These studies highlight the importance of regular screening of all stem cell transplant survivors for the development of a second malignant disease (Table 5).

Long-term Survival

The International Bone Marrow Transplant Registry has reported information on long-term survival and late deaths in 6700 allogeneic transplant recipients. This study found that, for many years after transplantation, the mortality rate in this group was higher than that in the general population, mainly because of recurrent leukemia and complications related to chronic GVHD. Secondary graft failure usually occurs within the first 6 months after transplantation, but very late graft rejection has been reported and may herald disease relapse. Although GVHD is not an issue for autologous transplant recipients, these patients may also experience late complications. Progressive restrictive lung disease, premature atherosclerotic heart disease and endocrine deficiencies have all been reported in survivors of autologous transplantation. Furthermore, although relapse usually occurs within the first transplantation, it has been observed up to 8 usually occurs within the first 2 years after transplantation, it has been observed up to 8 years later.
In long-term follow-up studies, the vast majority of transplant survivors have reported good performance status. In allogeneic recipients, the presence or absence of significant chronic GVHD is the main determinant of performance status. In all survivors of stem cell transplantation, fatigue and sexual dysfunction are common complaints, with fear of relapse and supportive care medications being contributing factors. Physicians caring for survivors need to be aware of these complex medical and psychological issues in order to provide the support required.

Recent Developments: Cord Blood and "Mini" Transplants

Over the past 2 decades, significant medical advances have led to a reduction in morbidity and mortality among recipients of stem cell transplants, and new techniques have further increased the recipient pool. The successful transplantation of unrelated umbilical cord blood cells from central storage facilities was one of the most exciting developments of the 1990s. Part of the interest in umbilical cord blood as a stem cell product is the fact that, before its widespread collection for cryopreservation and banking, it had no known use and was usually discarded. However, cord blood provides an essentially unlimited supply of donors, and these donors appear to possess an immature (and therefore more tolerant) immune system, which allows for a greater degree of mismatching between donor and recipient. A drawback to cord blood transplantation is that the number of stem cells in the product is relatively low for a large recipient (e.g., an older child or an adult). As a result, the vast majority of successful cord blood transplants have been done in small children; nonetheless, some adults have become long-term survivors. In the late 1990s, investigators at the MD Anderson Cancer Center reported success with a new stem cell transplantation procedure referred to as a non-myeloablative or "mini" transplant. This procedure uses a mild conditioning regimen that is more tolerable for older patients and those with concurrent illnesses. The goal of this approach is not to destroy the patient's cancer with the usual high dose treatment but rather to suppress the recipient's immune system enough to allow a donor's stem cells to engraft and slowly generate a "graft-versus-tumour effect." Mini-transplants are now in widespread use, and although their potential to cure some malignant diseases is supported by relatively short-term follow-up, it is clear that the procedure is not without risk. Further investigation of minitransplants is required before their role in stem cell transplantation for the treatment of hematologic disease can be defined.

Table 7. Vaccination schedule for recipients of hematopoeitic stem cell transplants

Vaccine Time after transplantation
12 month 14 month 24 month
Inactivated vaccine or toxoid
Tetanus-diphtheria toxoid + + +
Hemophilus influenzae + + +
Hepatitis B + + +
23-valent pneumococcal polysaccharide + NA +
Influenza Seasonal Seasonal Seasonal
Inactivated polio + + +
Hepatitis A NI NI NI
Meningococcus NI NI NI
Live-attenuated vaccine
Measles-mumps-rubella CI CI []
Varicella vaccine CI CI CI

Hematopoietic stem cell transplantation is commonly used for the treatment of hematologic malignant disease. Primary care physicians should be aware of the potential complications of the procedure. Many changes in stem cell transplantation have occurred over the past 3 decades, and further refinement will occur. Up-to-date information for physicians, patients and donors is available through the Web site of the Leukemia/Bone Marrow Transplant Program of British Columbia (http://www.vch.ca/bmt).

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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