Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter V.6. Hematopoietic Stem Cell Transplantation and Graft Versus Host Disease
Jocelyn M. Sonson
December 2002

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This is a 7 year old female who presents to the office with a chief complaint of a rash on her head, arms and legs. She has a history of acute lymphoblastic leukemia. She had undergone chemotherapy, went into remission and subsequently received an allogeneic stem cell transplantation from her older brother 20 days ago. The rash started 3 days ago on her ears, palms of her hands and the soles of her feet, progressing further to her arms and legs. It has not progressed to involve her trunk or her extremities and there is no desquamation or bullae formation. She denies any GI discomfort, crampy abdominal pain or diarrhea.

Exam: VS T 38, P 100, R 20, BP 118/65. She is alert and active, in no apparent distress. HEENT negative except for the rash. The rash is an erythematous, maculopapular rash on her palms and soles bilaterally, and on the anterior aspects her arms and legs. The rash is also on the nape of her neck. Neck is supple. Chest is clear. Heart regular without murmurs. Abdomen is soft and non-tender. There might be some slight hepatosplenomegaly, but it is difficult to be certain.

She is diagnosed with early graft versus host disease. She is hospitalized and treated with cyclosporine and methylprednisolone for 10 days until the graft versus host disease (GVHD) is controlled. This was followed by a taper of her corticosteroids.

Hematopoietic stem cell transplantation, commonly called bone marrow transplantation (BMT), is indicated for various hematopoietic disorders (aplastic anemia, hemoglobinopathies), storage diseases, and severe immunodeficiencies. Pediatric malignancies that are candidates for stem cell transplantation include acute myelogenous leukemia, acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CML), lymphomas, neuroblastomas, brain tumors and other solid tumors. Transplantation is recommended only in high-risk situations or when conventional treatment fails. In malignancies such as CML and juvenile myelomonocytic leukemia, hematopoietic stem cell transplantation is used as primary therapy because no other curative treatment exists.

Major sources of stem cells for transplantation include bone marrow, peripheral blood and cord blood. Since the mid-1990s, peripheral blood-derived stem cells have been used with increasing frequency over the traditional marrow cells. Peripheral blood stem cells (PBSC) contain higher numbers of progenitor cells, natural killer cells, and T cells as compared to bone marrow. Studies comparing bone marrow to PBSC transplantation have shown that PBSCs are associated with a shorter period of neutropenia and red blood cell and platelet transfusion dependence, with an equal probability of acute and chronic GVHD. Umbilical cord blood is a new and promising source of hematopoietic progenitor cells with remarkable proliferative potential, which may overcome the limitation of their relatively low absolute cell numbers. Because only a small number of cells are collected, successful transplants are typically limited to smaller sized recipients.

When the stem cells are from an identical twin, the transplant is termed syngeneic. When the stem cells are harvested from the recipient, the transplant is termed autologous. And lastly, when the stem cells are from someone other than the recipient, it is termed allogeneic. The best donors for allogeneic transplantation are siblings who inherit identical human leukocyte antigen (HLA) haplotypes.

Located in the major histocompatibility complex (MHC) on the short arm of chromosome 6, the HLA genes define histocompatibility and determine tolerance of the graft. Although there are over 35 HLA class I and II genes and over 684 alleles, HLA-A, HLA-B (class I), and HLA-DRB1 (class II) genes are used primarily in determining the histocompatibility of donors and recipients for stem cell transplantation. A 6-of-6 match refers to matching these three genes, each of which have two alleles. When none of the 6 alleles match, it is termed a mismatch and the various degrees of mismatch are termed one-antigen mismatch, two-antigen mismatch, etc. When only 3 of 6 alleles mismatch, the term is haploidentical. Graft rejection and graft-versus-host disease (GVHD) are the major immune-mediated complications associated with HLA disparity. The greater the HLA disparity, the higher these risks. Only 25-50% of patients have an HLA-identical sibling, therefore large donor registries have recently been successful in identifying phenotypically matched unrelated donors. In the United States, the National Marrow Donor Program has typed nearly 4 million volunteer donors and uses 118 donor centers and over 57 transplant centers to add 40,000 potential new donors each month.

The initial phase of stem cell transplantation entails the administration of the preparative regimen: chemotherapy and/or radiation therapy. The most common conditioning regimens include total body irradiation (TBI) and cyclophosphamide or busulfan and cyclophosphamide. Other combinations are also used during this conditioning period and include drugs such as etoposide, melphan, carmustine, cytosine arabinoside, thiotepa, ifosfamide, and carboplatin. The combinations are designed to eliminate malignancy, prevent rejection of new stem cells, and to create space for the new cells.

The stem cells infusion takes over an hour, although this time frame depends on the volume infused. Before infusion, the patient is premedicated with acetaminophen and diphenhydramine to reduce the risk of hypersensitivity reaction. The cells are then infused through a central venous catheter. Anaphylaxis, volume overload, and a transient GVHD are the major complications involved.

After stem cell infusion, the primary focus of care is managing the high-intensity preparative regimen. During this period, patients have little or no marrow function and are neutropenic, thus they must depend on transfusions for maintaining erythrocytes and platelets at acceptable levels. Patients are susceptible to life-threatening infections such as herpes simplex virus (HSV) or hospital-acquired nosocomial infections as well as other complications such as veno-occlusive disease, fluid retention, pulmonary edema, and acral erythroderma.

The rate of engraftment is a function of the preparative regimen, the nature and dose of stem cells, and the administration of medications that can suppress recovery. Engraftment, typically defined as a neutrophil count greater than 500 per cubic mm and a platelet count of 20,000 per cubic mm can occur as soon as 10 days to as long as several weeks after infusion. It is during this period that GVHD may occur.

Graft failure and graft rejection of transplanted stem cells, as well as transplanted organs, are influenced by several factors such as HLA disparity, the conditioning regimen, the transplanted cell dose, post-transplant/immunosuppression, donor T cells, drug toxicity and viral infection. Graft rejection may occur immediately, without an increase in cell counts, or may follow a brief period of engraftment. Rejection is usually mediated by residual host T cells, cytotoxic antibodies, or lymphokines and is manifested by a fall in donor cell counts with a persistence of host lymphocytes. Using stem cells from HLA-disparate donors significantly increases the risk for graft rejection/failure.

Transplants for nonmalignant disease generally have more favorable outcomes, with survival rates of 70-90% if the donor is a matched sibling and 36-65% if the donor is unrelated. Transplants for acute leukemias, ALL and AML, in remission at the time of transplant have survival rates of 55-68% if the donor is related and 26-50% if the donor is unrelated . Outcome statistics of autologous transplant for solid tumors are not as good for pediatric malignancies, except for lymphomas.

Graft-versus-host disease (GVHD) is a clinical syndrome that affects recipients of allogeneic stem cell transplants and results in donor T-cell activation against host MHC antigens. There are three requirements for this reaction to occur: 1) the graft must contain immunocompetent cells, 2) the host must be immunocompromised and unable to reject or mount a response to the graft, and 3) there must be histocompatibility differences between the graft and the host.

GVHD can be classified as acute, occurring within the first 100 days after stem cell transplant, or chronic, occurring after the first 100 days. The acute form of GVHD (aGVHD) is characterized by erythroderma, cholestatic hepatitis, and enteritis. aGVHD typically presents about day 19 (median), when patients begin to engraft. It usually starts as either erythroderma or a maculopapular rash that involves the hands and feet and may progress from the top of the scalp down toward the torso, potentially leading to exfoliation or bulla formation. Hepatic manifestations include cholestatic jaundice with elevated values on liver function testing. Intestinal symptoms include crampy abdominal pain and watery diarrhea, often with blood. aGVHD is graded in 5 steps from 0-IV based on involvement of the skin, liver, and GI tract. Grade 0 indicates no clinical evidence of disease. Grade I-IV are graded functionally. Grade I indicates rash on less than 50% of skin and no gut or liver involvement. Grade II indicates rash covering more than 50% of skin, bilirubin 2-3 ml/dL, diarrhea 10-15 ml/kg/d, or persistent nausea. Grade III or IV indicates generalized erythroderma with bulla formation, bilirubin greater than 3 mg/dl, or diarrhea more than 16 mL/kg/d. Survival rates vary from 90% in stage I, 60% in stage II or III, to almost 0% in stage IV.

The development of chronic GVHD (cGVHD), usually occurs after day 100 and resembles a multi-system autoimmune process manifesting as Sjogren's (sicca) syndrome, systemic lupus erythematosus, and scleroderma, lichen planus, and biliary cirrhosis. Recurrent infections from encapsulated bacterial, fungal, and viral organisms are common. The survival rate after onset of chronic GVHD is approximately 42%.

Management of GVHD and graft rejection focuses on both prevention and control of progressive disease. Finding the best HLA matched donor results in the lowest risk of severe disease and rejection. Younger age in either the donor or the recipient is associated with reduced risk. Same gender transplantation is also associated with reduced risk for GVHD. Prophylactic immunosuppression aims to inhibit the host T-lymphocyte activation that mediates rejection and inhibits the donor T-lymphocyte activation that mediates GVHD without altering immunity against infection or malignancy. Because donor T cells are responsible for GVHD, a form of prevention involves depletion of T cells in donor marrows or grafts using monoclonal antibodies or a physical separation technique. Elimination of T cells from the donor graft is an effective approach in some clinical settings, however depletion of T cells allows the persistence of host lymphocytes, which are capable of mediating graft rejection. In addition, loss of donor T cells decreases the benefit of producing a graft-versus-leukemia (GVL) effect and a lower relapse rate.

Treatment of aGVHD focuses on eliminating activated alloreactive T-cell clones. High-dose corticosteroids remain the most effective. Other studied approaches include anti-thymocyte antibodies, anti-TNF and IL-2 receptor antibodies, and immunosuppressive therapy such as cyclosporine, FK506, or mycophenolate mofetil. Treatment for cGVHD should begin with the earliest development of symptoms and requires continued therapy for a minimum of 6 to 9 months, even if symptoms resolve. Therapy for cGVHD includes corticosteroids usually in combination with another agent, often cyclosporine.

Late effects of transplantation can be classified into three basic categories: 1) toxicity from the preparative regimen, 2) toxicity from GVHD, and 3) toxicity from long-term immunosuppression. Clinical conditions include effects on growth and development, neuroendocrine dysfunction, fertility, second tumors, chronic GVHD, cataracts, leukoencephalopathy, and immune dysfunction. The effect of radiation on growth is relatively common and can be a result of a multitude of factors. Disruption of growth hormone production is the most common effect, however thyroid dysfunction, gonadal dysfunction, and bone growth effects also occur due to radiation. Other toxicities include cataracts, azoospermia, and gonadal failure.

Long-term cGVHD effects on the body include disruption of normal glandular function resulting in drying of the eyes, which can lead to corneal injury, and decreased salivary gland production, which can cause severe dental caries. Chronic inflammation of the intestine can lead to strictures and webs. The skin manifestations such as maculopapular rash or a sclerodermatous condition, can extend to all parts of the body and cause fibrosis of the underlying subcutaneous tissues and fascia resulting in contractures.

Continued use of chronic immunosuppressive drugs can cause toxicity that hamper quality of life. These toxicities include hypertension, glucose intolerance, weight gain, growth failure, avascular necrosis of the femoral head, and chronic osteopenia that leads to recurrent fractures. Long-term use of immunosuppressive drugs can lead to recurrent infections, such as bacterial, fungal, cytomegalovirus, adenovirus and varicella zoster.


1. Which of the following is a requirement for a graft-versus-host disease reaction to occur.
. . . . . a. The graft must contain immunocompetent cells.
. . . . . b. The host's T-lymphocytes must be able to mount an immune response against the graft.
. . . . . c. The host must be immunocompromised
. . . . . d. a and b
. . . . . e. a and c

2. True/False: The best predictors for developing GVHD are the age and sex of both the donor and recipient.

3. During the conditioning period prior to stem cell transplantation, which of the following purposes does chemotherapy and/or radiation try to accomplish?
. . . . . a. Prevent rejection of new stem cells
. . . . . b. Create space for new cells
. . . . . c. Eliminate malignancy
. . . . . d. All of the above
. . . . . e. None of the above

4. True/False: A limitation of cord blood as a source for stem cells is the small number of cells collected.

5. During which period does graft-versus-host disease typically occur?
. . . . . a. Conditioning
. . . . . b. Engraftment
. . . . . c. Postengraftment
. . . . . d. All of the above
. . . . . e. None of the above


1. Graham DK, et al. Hematopoietic Stem Cell Transplantation. In: Hay WW, Hayward AR, Levin MJ, et al (eds). Current Pediatric Diagnosis and Treatment, 15th edition. 2001, New York, NY: Lange/McGraw Hill, pp. 1589-1594.

2. Childs RW. Allogeneic Stem Cell Transplantation. In: DeVita VT, Hellman S, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology, 6th Edition. 2001, Philadelphia: Lippincott Williams & Wilkins, pp. 2786-2788.

3. Moore T. Bone Marrow Transplantation. In: Firlit CF, Konop R, Dunn S, et al (eds). eMedicine Journal 2002;3(1).

4. Robertson KA. Bone Marrow Transplantation. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders, pp. 639-641.

5. Hayashi RJ. Stem Cell Transplantation. In: Rudolph CD, Rudolph AM (eds). Rudolph's Pediatric Textbook, 21st edition. 2002, New York, NY: McGraw-Hill, pp. 815-816.

6. Suterwala MS. Graft Versus Host Disease. In: Shigeoka AO, Konop R, Georgitis JW, et al (eds), eMedicine Journal 2001;2(10).

Answers to questions

1. e

2. False. HLA matching is the best predictor.

3. d

4. True

5. b

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