Mary C. Territo
I. PRINCIPLES
A. Hematopoietic stem cell transplantation (HSCT) is an important treatment option for an increasing number of malignant and nonmalignant disorders that are listed in Table 37.1. HSCT has been used in malignant diseases for the fol lowing situations:
1. To restore marrow function for the patient following the administration of very high doses (myeloablative/immunoablative) of chemotherapy with or without radiotherapy (CT/RT) to kill off tumor cells. The following requirements apply when using this approach to treat tumors:
a. The tumor must have a steep dose–response curve so that escalating doses of drug results in increased tumor killing.
b. The drugs that give that steep dose–response curve must have the bone marrow as their main dose-limiting toxicity (since HSCT will not protect any of the other organ toxicity).
c. The types of tumors that are usually treated in this manner include primarily the hematologic malignancies (leukemias, lymphomas, myelomas) but also germ cell tumors, neuroblastoma, and selected other solid tumors.
2. To replace deficient or defective hematopoietic cells for diseases such as aplastic anemia and congenital hematologic, immunologic, and metabolic disorders
3. To effectively administer adoptive immunotherapy against tumor cells (the graft-vs.-tumor effect [GVT])
Table 37.1 Uses for Hematopoietic Stem Cell Transplantation
B. The choice of the type of transplant that is performed and the type of conditioning therapy used will depend on the disease being treated, the clinical status of the patient, and the donor cells that are available.
C. Outcomes of transplantation will depend on multiple factors including age of the patient, stage of disease, disease risk factors, prior therapies, comorbid conditions, and the type of conditioning therapy used. For allogeneic transplants, donor relationship, HLA matching, and donor cell dose (for cord blood) are also important variables impacting on outcome.
II. STEM CELL SOURCES. Hematopoietic stem cells (HSCs) normally reside in the bone marrow, with only rare HSCs circulating in the blood. HSCs can be found in increased numbers in the blood during recovery from chemotherapy-induced cytopenias and can also be mobilized from the bone marrow into the blood with agents such as granulocyte colony-stimulating factor (GCSF) or plerixafor, which cause release of the stem cells from their niche in the bone marrow. Umbilical cord blood is a very rich source of HSCs that can also be used for transplantation.
A. Bone marrow (BM) is collected in the operating room under general or spinal anesthesia. Multiple aspirations (of 5 to 10 mL each) are obtained to a desired target dose of about 3 × 108 nucleated cells per kilogram of recipient weight (about 1 to 1.5 L for an adult). The collection is then filtered to remove any bone particles, can be processed to deplete red blood cells (RBCs) or plasma if needed for ABO-incompatible transplants, and can then be cryopreserved for later use or directly infused intravenously into the patient. This was the original product used for HSCT.
B. Peripheral blood stem cells (PBSCs). Donors are first given GCSF to mobilize the HSC into the blood (for autologous donors, chemotherapy is frequently given prior to the GCSF). PBSCs are then obtained in the nucleated cell fraction of the blood by apheresis. Multiple collections may be required to reach the target dose (1 to 5 × 106 CD34-positive cells per kilogram of patient weight). The cells can then be cryopreserved for later use or directly infused intravenously into the patient. This product engrafts a little faster than BM, has a similar incidence of acute graft versus host disease (GVHD) as BM, but has a greater occurrence of chronic GVHD.
C. Umbilical cord blood (UCB) cells are obtained from the umbilical vein of the placenta after the umbilical cord has been severed from the newborn. This blood is rich in HSC, and the lymphocytes are naive. This product results in less GVHD than either BM or PBSC but is slower to engraft.
D. Manipulation. Stem cell sources can be manipulated in a variety of ways depending on the intent of the transplant. Some of the manipulations used include depletion of T cells or lymphocyte subsets, enrichment of CD34-positive cells, and stem cell expansion. Hematopoietic stem cells are also being engineered to augment tumor killing, infection control, or replace genetic deficiencies.
III. TYPES OF HSCT
A. Autologous transplant. The patient’s own cells are used as the HSC source. This approach is primarily used to permit the administration of very high doses (myeloablative) of CT/RT to kill tumor cells. The advantage of this approach is that you do not have to search for an allogeneic donor and there is no GVHD. The disadvantage is that you may have residual tumor cells in the graft and you achieve no graft-versus-tumor effect from the graft.
B. Allogeneic transplant. The HSCs are obtained from someone other than the patient. The donor of the HSCs must be matched by HLA tissue typing with the patient. Genes for the HLA antigen system are found on chromosome 6. HLA typing is performed for the class I antigens (A, B, and C) and the class II DR antigens to identify properly matched donors. The advantage of this approach is that the product has normal stem cells, which are free of tumor or abnormal cells. In addition to allowing recovery after myeloablative CT/RT, allogeneic HSCs can be used to replace deficient or defective stem cells (as used for aplastic anemia or genetic deficiencies). Allogeneic transplantation also provides adoptive immunotherapy against tumor cells of the recipient (GVT effect), and a reduction in the intensity of the conditioning therapy is sometimes used with GVT as the major goal of the transplant. The disadvantages of allogeneic transplantation are that you need to find an appropriately matched donor and that the patient is at risk for GVHD.
1. Related donors. The best donor is usually a sibling with the same two HLA haplotypes as the recipient (matched on both chromosomes for HLA A, B, C, and DR; an “8 of 8 HLA match”). Only about 30% of patients will have an identifiable sibling donor. Identical twin (syngeneic) donors are the best donors immunologically but have a higher risk of relapse (less graft-vs.-tumor effect) after transplant. Rarely, HLA-identical family members other than siblings can be identified. Partially matched or haploidentical related donors (only matched for one of the HLA chromosomes [4 of 8 HLA match]) have been used at some centers. These transplants require additional immunodepletion of the graft and have delayed immune reconstitution.
2. Unrelated donors. There are large registries of individuals around the world who have volunteered to donate HSCs for unrelated patients in need of a transplant. With sensitive DNA-based typing, HLA-matched unrelated donors can be found for many patients. The chances of finding an appropri ate unrelated donor for an individual patient depends on the specific HLA typing of the patient and varies with different ethnic groups. Transplants using unrelated donor HSCs have some increased risk of GVHD but are an appropriate treatment option if no matched related donors are available. The use of unrelated UCB requires less stringent HLA compatibility but may be limited by cell dose.
IV. CONDITIONING THERAPY. Patients are given high doses of CT/RT prior to the transplant. For autologous transplants, the therapy is aimed at getting the greatest tumor killing while ignoring the myeloablative toxicity of the agents but is limited by toxicity to other organs. Immune ablation (to allow for engraftment of the foreign HSCs) is necessary for allogeneic transplants, in addition to tumor killing. Many different “conditioning protocols” have been used with similar outcomes depending on the clinical situation of the patient. Examples of some standard conditioning regimens follow.
A. Total-body irradiation and cyclophosphamide (Cy)
1. Total-body irradiation. Patients receive 12 Gy given in 8 fractions (1.5 Gy each) on days minus 7 to minus 4.
2. Cy, 60 mg/kg/d in normal saline solution, is given IV over 1 hour for 2 days (on days minus 3 and minus 2). Patients also receive mesna, 60 mg/kg/d by constant IV infusion beginning with the start of Cy and continuing until 24 hours following completion of Cy.
3. Rest on day minus 1.
4. HSCT on day 0
B. High-dose busulfan and Cy
1. Busulfan (Busulfex) at a dose of 0.8 mg/kg of ideal body weight or actual body weight (whichever is lower) is administered IV over 2 hours every 6 hours for 4 days for a total of 16 doses on days minus 7 to minus 4. Phenytoin (300 mg/d and adjusted for therapeutic blood levels) should be given prophylactically to prevent seizures beginning on the day prior to starting the busulfan and continued until 2 days after busulfan is completed.
2. Cy (to start after busulfan finishes) at a dose of 60 mg/kg/d is given in normal saline solution IV over 1 hour daily for 2 days (on days minus 3 and minus 2). Patients receive mesna, 60 mg/kg/d by constant IV infusion, beginning with the start of Cy and continuing until 24 hours following completion of Cy.
3. Rest on Day minus 1
4. HSCT on Day 0
C. High-dose BEAM (BCNU/etoposide/cytarabine/melphalan)
1. BCNU (carmustine), 300 mg/m2 in 500 mL normal saline, is given IV over 2 hours on day minus 7.
2. Etoposide, 100 mg/m2, is given IV over 2 hours every 12 hours for 8 doses on days minus 6, minus 5, minus 4, and minus 3.
3. Cytarabine, 200 mg/m2, is given IV over 1 hour every 12 hours for 8 doses on days minus 6, minus 5, minus 4, and minus 3.
4. Melphalan, 140 mg/m2, is given IV over 1 hour on Day minus 2.
5. Rest on day minus 1
6. HSCT on day 0
D. On day 0, donor BM, PBSC, or UCB is administered IV without a filter. Patients should be premedicated with acetaminophen (650 mg PO), diphenhydramine (Benadryl, 50 mg PO or IV), and hydrocortisone (50 mg IV) 30 minutes prior to HSC infusion. Benadryl (50 mg), epinephrine (1:10,000; 10 mL), and hydrocortisone (100 mg) should be at bedside for standby IV use. Oxygen with a nasal cannula setup should also be on standby in the room during the stem cell infusion.
V. SUPPORTIVE CARE
A. All blood products (except the HSC) should be irradiated with 1.5 Gy (to prevent transfusional GVHD) as soon as the conditioning regimen is initiated.
1. RBC transfusions. Packed RBCs should be given to maintain the hematocrit at 27% (or higher if clinically indicated).
2. Platelet transfusions. Platelets should be maintained at 10,000/µL or higher depending on clinical status and evidence of bleeding.
3. For allogeneic transplants when there is an ABO mismatch (of any type) between patient and donor, the patient should be transfused with type O blood for all RBC transfusions starting at the time of admission.
B. Specific supportive care measures
1. Hydration. Patients should receive adequate hydration throughout the preparative regimen, such as 5% dextrose in 0.5 normal saline with 20 mEq normal saline containing potassium chloride per liter at 100 mL/m2/h.
2. Antiemetics. Patients will require intensive antiemetic therapy prior to and during the conditioning CT/RT. They should receive a 5-HT3 (serotonin) antagonist plus dexamethasone, prochlorperazine, and other agents as necessary.
3. Allopurinol (300 mg/d for adults) should be started on admission for transplant for all patients with bulky tumors. The allopurinol should be stopped on day minus 1 or sooner after the transplant, depending on the original tumor burden and the patient’s response.
4. Menstruating females should be started on nonovulatory agents prior to initiation of the conditioning regimen (norethindrone [Aygestin], 5 to 10 mg PO daily) and remain on it until the platelet count exceeds 50,000/µL.
5. Vitamin K1 (AquaMEPHYTON), 10 mg SQ, is given weekly.
6. Growth factors. Depending on the clinical status and the underlying malignancy, GCSF or granulocyte-macrophage colony-stimulating factor can be given starting day plus 2 following transplantation.
C. Protective isolation and prophylaxis
1. Protective isolation should begin when the absolute neutrophil count is ≤500/µL.
a. Hospital rooms should be equipped with air-filtration units. Individuals entering the patient’s room must perform good hand washing or gloving prior to entering the patient area. While in isolation, patients will wash daily with a microbicidal cleaning solution.
b. A low-bacterial diet should be ordered.
c. Antibacterial, antifungal, and antiviral prophylaxis can be initiated at the beginning of the conditioning regimen.
2. Pneumocystis prophylaxis. All allogeneic transplant patients and patients receiving autologous transplants who have had extensive corticosteroid exposure should receive Pneumocystis prophylaxis. Start trimethoprim–sulfamethoxazole (Bactrim DS, one tablet PO every 8 hours) at the onset of the conditioning therapy and stop at day minus 1 before transplantation. Prophylaxis should be restarted after sustained neutrophil engraftment (Bactrim DS, one tablet PO t.i.d. twice a week along with folinic acid 5 mg twice a week) and continued until day 100 after transplant or longer if the patient is receiving immunosuppression (i.e., for GVHD prophylaxis). Dapsone, 50 to 100 mg PO daily; atovaquone (Mepron), 1,500 mg (10 mL) suspension once daily; or pentamidine (aerosolized 300 mg or 4 mg/kg IV) monthly can be used as an alternative for patients with an allergy to sulfa.
3. Cytomegalovirus (CMV) prophylaxis/prevention. Patients who are CMV seronegative prior to transplant should receive only blood products that are CMV seronegative or leukoreduced. CMV seropositive patients undergoing an allogeneic transplant should receive ganciclovir (6 mg/kg IV piggyback [IVPB]/day) starting at the onset of conditioning therapy and stopping at day minus 1 prior to the transplant. After allogeneic transplantation, the ganciclovir (6 mg/kg IVPB/day, 5 d/wk) can be restarted after sustained neutrophil engraftment and continued to day 100 for prophylaxis. Alternatively, after engraftment, patients can be monitored for viremia weekly with evaluation of blood CMV-DNA for antigenemia to determine when preemptive treatment is needed.
D. Prevention and suppression of GVHD. Patients undergoing an allogeneic HSC transplant require immunosuppression treatment to prevent or suppress GVHD.
1. Calcineurin inhibitors. Cyclosporine or tacrolimus should be given to all allogeneic transplant recipients starting on day minus 2. Cyclosporine is initially given at a dose of 3.0 mg/kg IV infusion over 12 hours, followed by 3 mg/kg/d continuous infusion (or 1.5 mg/kg every 12 hours). Doses are adjusted to maintain therapeutic serum cyclosporine levels (between 150 and 350 by Syva EMIT [enzyme multiplied immunoassay technique]). Tacrolimus is given at a dose of 0.03 mg/kg/d continuous IV infusion (or 0.12 mg/kg/d PO in two divided doses). Doses are adjusted to maintain therapeutic whole-blood tacrolimus levels (between 5 and 20 by microparticle enzyme immunoassay). Doses are adjusted for renal failure.
2. Other agents can also be used depending on the GVHD risk of the transplant. These include corticosteroids (i.e., methylprednisolone 1 mg/kg/d IV), antithymocyte globulin (ATG equine [20 to 30 mg/kg/d] or rabbit [Thymoglobulin; 3 mg/kg/d] for 3 to 5 days), mycophenolate (1 g b.i.d.), rapamycin (2 mg/d), or methotrexate (15 mg/m2 IV on day plus 1 and 10 mg/m2 on days plus 3, plus 6, and plus 11).
3. T-cell depletion. GVHD is a T-cell–mediated process. Extensive depletion of T cells from the HSC graft can markedly reduce the incidence and severity of GVHD. Extensive T-cell depletion, however, is accompanied by an increased risk of graft failure, posttransplant lymphoproliferative disease, and an increased risk of tumor relapse so that disease-free survival is not improved. Programs using partial T-cell depletion or adding back of lymphocyte sub-populations at various times posttransplant are used in some centers.
VI. COMPLICATIONS OF HSCT
A. GVHD is a syndrome resulting from the reaction of immunocompetent donor cells against the tissues of an immunocompromised recipient. The immunologic reaction is traditionally divided in an “afferent phase” (antigen presentation) and an “efferent phase” and is favored by the release of proinflammatory cytokines during immune activation and tissue damage associated with the conditioning therapy. Recipient antigen presentation results in activation and proliferation of donor T lymphocytes. Thus, host-specific cytotoxic lymphocytes are generated that mediate tissue damage. During this process, cytokines are secreted and enhance tissue damage by recruiting nonspecific cytotoxic mechanisms (e.g., by direct cytokine damage, natural killer cells, macrophages). Manipulations that include T-cell depletion of the graft, anti–T-lymphocyte agents, and antibodies to certain cytokines have been used to reduce GVHD.
GVHD can be subclassified as acute GVHD (AGVHD), which usually occurs 2 to 8 weeks following allogeneic HSCT, and chronic GVHD (CGVHD), which usually occurs beyond the eighth week. The distinction is not always clear by timing because AGVHD often evolves into CGVHD, and findings characteristic of CGVHD can sometimes occur early. Manifestations of GVHD are shown in Table 37.2.
Table 37.2 Clinical Manifestations of Graft Versus Host Disease (GVHD)
1. Incidence. The incidence of GVHD is influenced by a number of factors including the degree of histoincompatibility, patient age, intensity of conditioning regimen, type of GVHD prophylaxis, and stem cell source.
a. The probability of grade II to IV AGVHD is <30% in HLA-matched siblings but is 60% to 90% with mismatched unrelated transplants. The incidence of grade III to IV AGVHD is about 35% for 7 of 8 HLA mismatched adult donor transplants but only about 10% for mismatched UCB donor transplants.
b. CGVHD occurs in 25% to 60% of patients surviving >4 months after allogeneic transplant. About two-thirds of the patients who develop CGVHD had preceding AGVHD.
2. Diagnosis
a. AGVHD is manifested primarily by the involvement of the skin, liver, and gastrointestinal (GI) tract. Table 37.3 shows the grading system for AGVHD depending on the severity of organ involvement.
(1) Usually, the onset of AGVHD is marked by a maculopapular rash on the face, palms, and soles that can subsequently spread and involve the entire body. Severe cases may go on to develop bullae or desquamation.
(2) Initially, bilirubin levels are elevated with a subsequent rise in alkaline phosphatase; transaminase elevations may occur later.
(3) The presence of secretory watery diarrhea, which can be quite severe, is characteristic of the GI involvement; paralytic ileus can occur. Persistent nausea and vomiting can be seen with upper GI involvement. Radiographically, bowel wall edema, sometimes with a “thumb-printing” appearance, can be demonstrated.
(4) The clinical diagnosis of AGVHD is occasionally confounded by the presence of chemotherapy-related toxicity, infection, allergic reactions, or veno-occlusive disease, which can mimic some of the findings of AGVHD. Biopsy of the involved organ affected by AGVHD typically shows epithelial cell destruction and apoptosis but does not show significant lymphocytic infiltration (suggesting a major role for cytokine destruction in the process).
b. CGVHD is characterized by immune dysregulation and the presence of autoreactive lymphocytes that stimulate a chronic inflammatory process leading to fibrosis and collagen vascular disease–like syndromes. CGVHD can involve the skin, eyes, mouth, lungs, GI tract, liver, genitourinary tract, and musculoskeletal, immune, and hematopoietic systems. Disorders mimicking autoimmune processes such as arthritis, immune cytopenias, polymyositis, and sclerodermatous skin, GI, and lung changes can also be seen.
Table 37.3 Staging and Grading of Acute Graft Versus Host Disease (GVHD)
Adapted from Glicksberg H, Stoub R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 1974;18:295.
3. Treatment. All patients undergoing allogeneic HSCT receive prophylaxis (see Section V.D) to help prevent significant complications from GVHD. Despite this, most patients will develop some degree of GVHD post trans plant. Development of GVHD posttransplant also correlates with a graft-versus-tumor effect so that in some cases GVHD may be beneficial.
a. Patients with grade I AGVHD do not necessarily need to have additional treatment unless they become symptomatic.
b. Patients with grade II to IV AGVHD are usually taking a calcineurin inhibitor when diagnosed. Dose adjustment can be undertaken if serum levels are subtherapeutic. Further T-cell suppression with agents such as corticosteroids, mycophenolate, or rapamycin can be instituted. Treatment with ATG or daclizumab (an anti–interleukin-2R antibody) has also been used. Treatments aimed at specific organ problems, such as topical skin treatments, topical enteric steroids (budesonide), antiperistalsis (loperamide), antisecretory (octreotide), and bile acid (ursodiol) agents can also be instituted.
c. Treatment of CGVHD includes calcineurin inhibitors, corticosteroids, mycophenolate, rapamycin, and thalidomide (100 to 1,600 mg/d). Other treatments that have also been used with success in some patients include extracorporeal photochemotherapy (photopheresis with exposure of blood mononuclear cells to the photosensitizing compound PUVA [psoralen plus ultraviolet A] prior to reinfusion), pentostatin (4 mg/m2every 2 to 4 weeks), alemtuzumab (Campath; anti-CD52 antibody, 10 mg/d for 6 days monthly), or rituximab (Rituxan; anti-CD20 antibody, 375 mg/m2 weekly).
(1) CGVHD patients are at increased risk of infections and thus need prophylaxis and early treatment of infections, monitoring of immunoglobulin G (IgG) levels, and infusion of intravenous IgG (IVIG) for patients with significant hypoglobulinemia.
(2) Supportive care measures include topical steroids, skin lubricants, eye drops, artificial saliva, and nystatin or acyclovir when indicated for oral or skin infections.
(3) Patients with sclerodermatous GVHD and restricted range of motion can benefit from physical therapy.
(4) Patients should use sunscreen and avoid sun exposure.
B. Infections. Although many advances in antimicrobial therapies have improved the overall posttransplant survival, infectious complications remain among the most common causes of morbidity and mortality following allogeneic or autologous HSCT. Treatments of specific microorganisms are discussed in Chapter 35.
1. Conditioning therapy results in severe neutropenia for prolonged periods (2 to 4 weeks and more), and patients are at high risk for infections. Gram-positive and gram-negative bacteria, as well as Candida, Aspergillus, and other fungal infections are common. Patients should receive treatment with broad-spectrum antibiotics and antimycotic agents either prophylactically after the transplant or therapeutically at the earliest signs of fever or infection.
2. Reactivation of herpes viral infections is common. CMV infection is particularly problematic after allogeneic transplantation. Infections usually occur after patients have engrafted. Treatment doses of ganciclovir (5 mg/kg IV every 12 hours for 3 weeks) should be used. Patients with CMV pneumonia should additionally receive IVIG (500 mg/kg every other day for 10 doses).
Infections with adenovirus, respiratory syncytial virus, influenza, and other viruses posttransplant can be quite severe and are associated with a high rate of mortality. Treatment with oseltamivir, ribavirin, vidarabine, IVIG, or other agents should be instituted early.
3. Pneumocystis jirovecii infections can be problematic posttransplant, and patients should receive prophylactic treatment with trimethoprim–sulfamethoxazole as discussed in section V.C.2. Patients who develop Pneumocystisinfections should be treated with therapeutic doses of trimethoprim–sulfamethoxazole (15 to 20 mg/kg/d [trimethoprim component] IV administered in three to four divided doses every 6 to 8 hours).
4. Infections with encapsulated bacteria (Pneumococcus, Meningococcus, Haemophilus) can be seen late in the course (sometimes a year or more) after engraftment has been complete. This complication is related to poor opsonization of the organisms. Patients should receive vaccination for these agents (as well as other primary and booster vaccinations) once their prophylactic GVHD immunosuppressive drugs have been discontinued. Rapid treatment of symptomatic patients is important.
C. Delayed immune reconstitution. HSCT results in profound and protracted immune dysfunction. The type of transplantation (autologous vs. allogeneic, UCB vs. adult source), the conditioning regimen, and the presence of GVHD affect both the severity and the duration of immunodeficiency. After transplant, the entire immune system of the patient will be reconstituted with the donor cells. The development of this new immune system, however, can be a slow process. In addition to quantitative impairment of lymphocytes, loss of skin test reactivity, impaired proliferative responses, and reduced cytokine production by lymphocytes and macrophages can be seen and predispose the patient to infections and posttransplant lymphoproliferative syndromes. Antibody response can also be impaired and may result in poor response to vaccinations as well as susceptibility to bacterial pathogens. Replacement doses of IVIG should be given to patients who fail to normalize their IgG level. The presence of GVHD further delays immunologic recovery as do the therapeutic interventions aimed at treating GVHD.
D. Bleeding. Patients are at risk of bleeding from thrombocytopenia until platelet engraftment occurs. Platelet engraftment usually lags behind neutrophil engraftment, but spontaneous platelet counts of >20,000/µL are attained by most patients by day 21 following autologous transplants and by day 28 following allogeneic transplants (but may require >40 days for UCB transplants). Prophylactic platelet transfusions are usually used to keep platelets above 10,000/µL, but higher levels are needed if patients are febrile or having bleeding symptoms.
E. Nonmarrow organ toxicity. The use of high doses of CT/RT for conditioning patients prior to transplant ignores the marrow toxicity of the agents used, but we must be mindful of the nonmarrow toxicity of these agents.
1. Infections, sepsis, tumor lysis, and other drug exposures can also add to the insult experienced by the nonmarrow organs after transplantation.
2. Toxicity to the lungs, kidneys, heart, liver, GI tract, endocrine glands, and central nervous system can be seen posttransplant.
3. GVHD can also result in toxicity to target organs following allogeneic transplants.
4. Veno-occlusive disease of the liver (VOD), also known as hepatic sinusoidal obstruction syndrome, probably results from injury to the sinusoidal endothelial cells and hepatocytes from the high-dose conditioning therapy. Patients with a history of hepatitis, extensive prior chemotherapy, or certain drug exposures (i.e., gemtuzumab) are at higher risk for development of VOD. VOD is usually seen within the first 1 to 2 months posttransplant and is characterized by hepatomegaly with right upper quadrant pain, unexplained fluid retention, and jaundice. Mild VOD may occur in up to 60% of patients and usually is reversible without treatment. When severe, however, VOD is frequently fatal. Symptomatic treatments should be used, but attempts at treatment with various anticoagulants and antioxidants have been unimpressive. Initial studies using defibrotide have been encouraging.
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