Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + SOURCES OF HEMATOPOIETIC STEM CELLS (HSCs) Download Section PDF Listen +++ +++ Marrow ++ Marrow for hematopoietic stem cell transplantation (HSCT) is typically aspirated by repeated placement of large bore needles into the posterior iliac crest, generally 50 to 100 aspirations simultaneously on both sides, while under regional or general anesthesia. The lowest cell dose to ensure stable long-term engraftment has not been defined with certainty, and a standard collection contains more than 2 × 108 nucleated marrow cells/kg recipient body weight. Current guidelines indicate that a volume of up to 20 mL/kg donor body weight should be effective. Seventy percent of donors fully recover by 2 weeks and the risk of serious complications is 1.2 percent. +++ Mobilized Peripheral Blood Stem Cells (PBSC) ++ The most common method to harvest autologous and allogeneic PBSCs is by using granulocyte colony-stimulating factor (G-CSF) with or without chemotherapy. This procedure is safe and in a review of 5930 normal donors, serious side effects were uncommon (< 1%). Splenic rupture has been reported with an estimated incidence of 1 in 10,000. Randomized clinical trials have indicated that engraftment is more rapid with PBSC than with marrow-derived stem cells. The measurement of the absolute number of CD34+ cells/kg recipient body weight collected is a reliable and practical method for determining the adequacy of the PBSC product. A minimum of 2 × 106/kg CD34+ cells is usually recommended, although at this dose, 10 to 20 percent of autologous collections lead to suboptimal (slow or more rarely, no) engraftment. Platelet recovery is most sensitive to borderline collection numbers. Although the number of T cells in PBSC graft is 10-fold greater than in marrow, the incidence of acute graft-versus-host disease (GVHD) does not appear higher, probably because G-CSF influences the proportion of immune tolerizing Treg cells in the apheresis product. However, the risk of chronic GVHD has been found to be about 10 percent higher in PBSC at most major transplant centers. The use of G-CSF to mobilize stem cells in patients with sickle cell anemia is contraindicated, since an acute increase in neutrophil counts can precipitate a catastrophic sickle cell occlusive crisis. +++ Umbilical Cord Blood ++ Umbilical cord blood (UCB) collected from the umbilical vessels in the placenta at the time of delivery is a rich source of HSCs. Because these cells are immunologically relatively naïve, recipients may have satisfactory outcomes, even when crossing major histocompatibility barriers. An analysis of approximately 100 UCB transplants showed that recipients who received < 1.7 × 107 cells/kg body weight had a high rate of graft failure. For adults, this usually requires the use of two closely and suitably matched cord bloods providing a higher CD34+ and CD3+ cell dose. + DEGREE OF MATCHING Download Section PDF Listen +++ +++ HLA Matched Related Donor ++ HLA matched sibling donors were the most common source of HSCT products prior to the establishment of sufficiently diverse unrelated stem cell donor banks. The experience with these transplants for any given disease always serves as the major comparison group for alternative SCT donor sources. +++ HLA Haploidentical Related Donor ++ Because nearly every patient requiring HSCT has a haploidentical family donor (on average half of one's siblings and every parent or child), immune depletion of such stem cell products to reduce the inevitable fatal GVHD has been explored. Numerous studies document the feasibility of this approach, with acceptable rates of a GVHD, and control of the underlying leukemia, the widespread acceptance of haploidentical SCT remains hampered by the prolonged immune reconstitution and a high risk of serious infection experienced in these patients. +++ HLA Matched Unrelated Donor (MUD) ++ The establishment of diverse banks of individuals willing to donate stem cells should their HLA type be required elsewhere in the world has greatly expanded the likelihood of obtaining a donor for the 60 percent or greater proportion of individuals for whom a suitable sibling donor cannot be identified (a percentage that approaches 100% in China). However, the likelihood of obtaining a MUD for persons of African or Hispanic descent is substantially lower. The only drawbacks to MUD transplants are moderately higher rates of GVHD, secondary to minor histocompatibility antigens less likely to match the transplant recipient if derived from an unrelated rather than a sibling donor, the longer time required to identify a suitable MUD, and the greater possibility (than for a family member) that once identified, a MUD might decline to donate. +++ HLA Partially Matched Cord Blood Donor ++ Because of the immunologic naivete of UCB cells, two or greater HLA mismatches are often tolerated for transplantation, resulting in a similar frequency and severity of GVHD as seen using fully matched donors. Compared to adult sources of HSCs, UCB transplants engraft more slowly, especially the slow restitution of platelet counts. +++ Autologous HSCs ++ Autologous HSCT is associated with the lowest rate of nonrelapse morbidity and mortality of any SCT strategy. The purpose of the infusion of autologous HSCs (referred to as autologous HSCT, although not crossing transplantation barriers and is not transplantation in the classic sense) is to permit the administration of very high dose, potentially lethal therapy, to induce remission and cure tumors such as leukemia, myeloma, or lymphoma. The autologous HSC infusion restores hematopoiesis and makes mortality from cytotoxic therapy–induced severe and prolonged marrow aplasia unlikely. One problem with autologous HSCT is the presence in the product of residual tumor cells contaminating the patient's marrow or blood. One approach to this issue is purging tumor cells from the HSC product before infusion. Controversy still exists as to whether purging is a requirement in most cases because the process often reduces the stem cell numbers. A number of ex vivo chemical-based purging strategies for autologous stem cell products failed, mostly because they damaged HSCs and reduced engraftment. A number of immunologic purging methods have been tested, both negative selection of tumor cells and positive selection of stem cells, and have provided mixed results. Perhaps the most common is selection and administration of CD34+ cells. While the administration of CD34+ graft products results in relatively rapid engraftment, with demonstrated reduction in tumor cell contamination by in vitro methods, ultimate relapse rates are not substantially improved and the risk of infection is greater because of immune cell depletion. Instead, in vivo purging has been widely applied to autologous transplantation. The use of chemotherapy and immunotherapy just prior to mobilization of HSCs reduces tumor cell contamination of the collected PBSC product, and simultaneously provides a reduction in total tumor burden in the patient prior to his/her high-dose conditioning regimen. +++ Purification of HSCs from Any Source ++ In humans, the combination of positive selection for CD34, Thy-1, and negative selection for lineage markers, identified a homogenous HSC population. The goal is to purify HSC and thereby reduce the risk of occult malignant cells since marrow or blood mononuclear cells are often contaminated by malignant cells in patients with hematologic malignancies. These efforts present technical challenges primarily because of the rarity of HSC in marrow and G-CSF mobilized blood; however, adequate numbers of HSCs can be isolated free of contaminating tumor cells, in a majority of patients. The time to neutrophil and platelet recovery following purified HSC infusion is comparable to engraftment times using unmanipulated marrow as a graft source, but there is a significant delay in T-cell recovery, especially of CD4+ T cells, of up to 6 months in almost all patients. A number of patients develop unusual infections (i.e., severe cases of influenza, respiratory syncytial virus, cytomegalovirus, and Pneumocystis pneumonia), which raises concern using a "pure" HSC product as the sole source of hematopoietic reconstitution in clinical transplantation. Although too few patients were transplanted to evaluate whether the infusion of a product free of contaminating tumor cells impacted outcomes on event-free and overall survival, results appeared favorable. +++ Graft-versus-Tumor Effect ++ Compared with autologous transplantation, allogeneic HSCT involves more pre-transplantation preparation, poses a greater risk of complications to the patient, is associated with a significantly higher nonrelapse morbidity and mortality, and the period of intensive posttransplantation follow-up is considerably longer. However, unlike autologous stem cell products, there is no risk of tumor contamination in allogeneic HSC products. Since tumor cells are host derived, and allogeneic immune cells recognize them as foreign, the potential exists for the graft to attack the residual tumor cells present in the patient following conditioning therapy. The evidence that allogeneic HSCT outcomes are greatly affected by this graft-versus-tumor effect is summarized in Table 40–1. ++Table Graphic Jump LocationTABLE 40–1EVIDENCE FOR GRAFT-VERSUS-TUMOR EFFECT IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATIONView Table||Download (.pdf) TABLE 40–1 EVIDENCE FOR GRAFT-VERSUS-TUMOR EFFECT IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION Temporal association between immune suppression drug withdrawal and disease remission. Leukemia relapse rate is lower after allogeneic HCT than after syngeneic HCT. Leukemia relapse is lower in patients who develop GVHD than in those who do not. Leukemia relapse rate is lower after allogeneic HCT without GVHD than after syngeneic HCT. Leukemia relapse rate is higher after T-cell–depleted allogeneic HCT than after unmodified HCT. Donor lymphocyte infusions induce remission of leukemia that recurred after allogeneic HCT. Allogeneic HCT after reduced-intensity conditioning induce long lasting remission of leukemia and lymphoma. GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation.Source: Williams Hematology, 8th ed, Chap. 21, Table 21–2, p. 319. + CONDITIONING REGIMENS Download Section PDF Listen +++ ++ A major obstacle to successful allogeneic HSCT is the immune competence of the recipient, providing the ability to reject the graft. This potential to reject infused donor cells is mediated predominantly through residual host T and NK cells. In addition to reducing residual tumor burden in transplant recipients, conditioning regimens must reduce or eliminate this immunologic barrier to successful HSCT. +++ Total Body Irradiation (TBI) ++ TBI has been a primary therapeutic modality included in autologous and allogeneic SCT regimens for patients with hematologic malignancies. TBI has excellent therapeutic effect against a variety of hematolymphoid malignancies, including leukemia that is resistant to chemotherapy, has sufficient immunosuppressive properties, and is able to treat tumor cell sanctuary sites like the testicles and the central nervous system. Most groups employ fractionated dose schedules to a total of 1200–1320 cGy. TBI is almost always used in conjunction with high-dose chemotherapy (e.g., cyclophosphamide) in full-dose conditioning regimens. An alternate form of irradiation is radioimmunotherapy, which involves the use of antibodies to CD33 or CD45 to deliver locally acting radionucleotides to sites of disease, notably in the marrow. Radiation toxicities include later development of cataracts, treatment-related malignancies, and growth impairment in children. +++ High-Dose Chemotherapy ++ A number of chemotherapy regimens that are both effective for the tumor under treatment and are sufficiently immunologically ablative to allow successful HSC engraftment has been tested in patients undergoing autologous and allogeneic SCT for leukemia and lymphoma. For example, BCNU, VP-16 and cyclophosphamide alone, busulfan and cyclophosphamide (BuCy), and adjusted dose BuCy in which monitoring of Bu levels reduces its toxicity. +++ Reduced-Intensity Conditioning (RIC) Regimens ++ The demonstration that immune-mediated mechanisms are critical in controlling minimal residual disease challenged the concept that relatively toxic full-dose chemoradiation is required for cure following allogeneic HSCT. Transplantation regimens that use significantly lower doses of chemoradiation yet that are sufficiently immunosuppressive to allow full donor hematopoietic cell engraftment, have shifted the burden of tumor eradication to graft-versus-tumor effects. RIC is better tolerated than traditional full-dose regimens and is particularly useful in older patients and in those individuals who have comorbid medical conditions that preclude them from aggressive myeloablative regimens, and for patients without malignancy, in whom it is critical only to allow engraftment of a new immune system. One regimen came from detailed studies in a canine model and uses TBI at 2 Gy followed by immunosuppression with mycophenolate mofetil and cyclosporine in an attempt to prevent the recipient T cells from rejecting the graft. The addition of fludarabine to low-dose TBI or cyclophosphamide also reduces the risk of graft rejection to less than 5 percent. The risk of GVHD is not reduced by RIC. Because host hematopoiesis is not ablated when the patient receives his/her donor HSCs, marrow cells are chimeric soon after transplantation with RIC regimens. However, because host HSCs are at a competitive disadvantage, as they have been irradiated or subjected to toxic drugs during conditioning, over time the donor HSCs progressively populate the entire marrow. + EVALUATION AND SELECTION OF CANDIDATES FOR TRANSPLANTATION Download Section PDF Listen +++ ++ Patients considered for transplantation require in-depth counseling by experienced transplantation physicians, nurses, and social workers. Information regarding the prior course, including initial diagnostic studies, previous drug and radiation treatments, and responses to these interventions, as well as a psychosocial assessment of the patient and their caregivers, are important. Table 40–2 highlights the issues and topics that should be addressed during the counseling meetings with transplantation candidates and their families or friends. ++Table Graphic Jump LocationTABLE 40–2TOPICS ADDRESSED DURING COUNSELING MEETINGS WITH TRANSPLANT CANDIDATE AND CARE PROVIDERView Table||Download (.pdf) TABLE 40–2 TOPICS ADDRESSED DURING COUNSELING MEETINGS WITH TRANSPLANT CANDIDATE AND CARE PROVIDER Rationale for why transplantation is a therapeutic option How the transplantation is performed Autologous Allogeneic—choice for full-dose versus RIC Source of cells Marrow versus blood versus other source Risks of procedure Graft failure and graft rejection Risk of GVHD Acute and chronic forms, compatibility of graft Likelihood for long-term immune suppression medication Nonrelapse mortality at 100 days and 1 year Risks of relapse Timing of transplant Projected result Requirement for dedicated care provider Other Financial implications Durable power of attorney Banking of sperm, in vitro fertilized eggs Duration of stay near the transplantation center Return to home and work Sexual activity Quality-of-life issues Habits such as smoking, alcohol, and drug addiction GVHD, graft-versus-host disease; RIC, reduced-intensity conditioning. Source: Williams Hematology, 8th ed, Chap. 21, Table 21–3, p. 321. + DISEASE STATUS AT THE TIME OF TRANSPLANTATION Download Section PDF Listen +++ ++ Disease status at the time of transplantation is the best predictor of long-term disease-free survival following allogeneic and autologous SCT. Attempts at salvaging patients with advanced disease who have failed multiple therapies are rarely successful and if transplantation is to be considered, it is best to consider early in the course of therapy. + AGE AND COMORBID CONDITIONS AT THE TIME OF TRANSPLANTATION Download Section PDF Listen +++ ++ Among adult and pediatric patients, older age at the time of transplantation is an important determinant that adversely affects nonrelapse mortality following autologous and full-dose allogeneic transplant conditioning. Comorbid medical conditions (e.g., diabetes mellitus, renal insufficiency) can have a significant impact on transplantation outcomes. Routine screening of heart and lung function to detect occult abnormalities is important, especially in older patients. Evaluation of liver and kidney function, as well as exposures to potential pathogens such as hepatitis B, hepatitis C, herpes viruses and HIV should be performed in all patients. + DISEASES TREATED WITH STEM CELL TRANSPLANTATION Download Section PDF Listen +++ ++ In general terms, autologous transplantation is recommended for patients whose malignancy exhibits chemosensitivity to conventional dose therapy and does not extensively involve the marrow. In contrast, allogeneic transplantation is generally pursued for hematologic malignancies and disorders that primarily originate in the marrow, such as acute and chronic leukemia, aplastic anemia, and the myelodysplastic and myeloproliferative syndromes. A variety of acquired nonmalignant and congenital disorders can be successfully treated with HSCT. Most notable is allogeneic HSCT for patients with severe aplastic anemia, for which outstanding results have been achieved for those individuals who have an HLA-matched sibling donor; upwards of 80 to 90 percent of these patients have a complete hematologic remission and a long-term disease-free course. HSCT for patients with clinically significant hemoglobin disorders, such as thalassemia major, has been successful, especially in patients without significant liver disease. Likewise, allogeneic HSCT is considered a treatment option for young patients with severe forms of sickle cell disease. Table 40–3 lists disorders commonly treated by transplantation. ++Table Graphic Jump LocationTABLE 40–3LIST OF DISEASES TREATED BY HEMATOPOIETIC CELL TRANSPLANTATIONView Table||Download (.pdf) TABLE 40–3 LIST OF DISEASES TREATED BY HEMATOPOIETIC CELL TRANSPLANTATION Disease/Condition Allogeneic HCT Autologous HCT Malignant disease Acute myelogenous leukemia + + Acute lymphoblastic leukemia + - Chronic myelogenous leukemia + + Chronic lymphocytic leukemia + + Myelodysplastic syndromes + - Myeloproliferative syndromes + - Non-Hodgkin lymphoma + + Hodgkin lymphoma + + Myeloma + + Amyloidosis - + Waldenström macroglobulinemia + + Hairy cell leukemia + - Selected solid tumors (testicular cancer, pediatric tumors) - + Neuroblastoma - + Nonmalignant diseases Acquired aplastic anemia + - Congenital pure red cell aplasia + - Fanconi anemia + - Thalassemia + - Sickle cell anemia + - Paroxysmal nocturnal hemoglobinuria + - Severe combined immunodeficiency + - Wiskott-Aldrich + - Congenital leukocyte dysfunction + - Osteopetrosis + - Familial erythrophagocytic lymphohistiocytosis + - Glanzmann disease + - Hereditary storage diseases + - Selected autoimmune diseases + + Source: Williams Hematology, 8th ed, Chap. 21, Table 21–4, p. 323. + SELECTED RESULTS OF STEM CELL TRANSPLANTATION Download Section PDF Listen +++ +++ Acute Myelogenous Leukemia (AML) ++ Hematopoietic SCT has a significant role in the treatment of AML patients. Many studies have consistently demonstrated that relapse rates are decreased by allogeneic transplantation. In particular, the likelihood of long-term survival is superior in patients with primary refractory disease, de novo AML with unfavorable cytogenetics at any stage of their disease, or with intermediate or favorable cytogenetics at first relapse or subsequent stages. Patients at first presentation with favorable cytogenetics should be treated with subtype specific chemotherapy. Whether patients with intermediate prognosis cytogenetics should be treated with allogeneic transplantation in first remission is controversial. +++ Acute Lymphocytic Leukemia (ALL) ++ Virtually all adults with ALL and standard or high-risk features (including Ph+ ALL) should be treated with allogeneic transplantation in first remission. +++ Myeloma ++ Autologous HSCT within the first year of initiating treatment has been the standard of care for patients younger than 70 years of age with newly diagnosed myeloma. Although neither chemotherapy nor autologous HSCT produces a cure, event-free and overall survival are prolonged following transplantation when compared to treatment with conventional chemotherapy alone. However, with the introduction of lenalidomide and bortezomib, and the ensuing markedly prolonged remissions they induce, the role of HSCT is being reexamined. +++ Non-Hodgkin Lymphoma ++ Patients with chemosensitive moderate- and high-grade lymphoma beyond first complete remission have an improved overall survival with high-dose therapy followed by autologous HSCT compared to best-of-care salvage chemotherapy. Improvement in survival for patients with B-cell non-Hodgkin lymphoma may further be achieved with inclusion of rituximab as an in vivo purging strategy and perhaps in the posttransplantation setting. Relapse of lymphoma after autologous transplantation is the major reason for treatment failure. Several phase II studies reported that patients who suffer a relapse of lymphoma after autologous transplantation could still be salvaged and experience long-term survival of greater than 45 percent using RIC and allogeneic transplantation from matched related and unrelated donors. + COMPLICATIONS OF STEM CELL TRANSPLANTATION Download Section PDF Listen +++ ++ The first 100 days following the cell infusion is typically the time of greatest risk for recipients of autologous and allogeneic HSCT. The most common complications of HSCT are listed in Table 40–4. ++Table Graphic Jump LocationTABLE 40–4COMPLICATIONS OF HEMATOPOIETIC CELL TRANSPLANTATIONView Table||Download (.pdf) TABLE 40–4 COMPLICATIONS OF HEMATOPOIETIC CELL TRANSPLANTATION Vascular access complications Graft failure Blood group incompatibilities and hemolytic complications Acute GVHD Chronic GVHD Infectious complications Bacterial infections Fungal infections Cytomegalovirus infection Herpes simplex virus infections Varicella-zoster virus infections Epstein-Barr virus infections Adenovirus, respiratory viruses, HHV-6, -7, -8, and other viruses Gastrointestinal complications Mucosal ulceration/bleeding Nutritional support Hepatic complications Sinusoidal obstructive syndrome Hepatitis: infectious versus noninfectious Lung injury Interstitial pneumonitis: infectious versus noninfectious Diffuse alveolar hemorrhage Engraftment syndrome Bronchiolitis obliterans Kidney and bladder complications Endocrine complications Drug–drug interactions Growth and development Late onset nonmalignant complications Osteoporosis/osteopenia, avascular necrosis, dental problems, cataracts, chronic fatigue, psychosocial effects, and rehabilitation Secondary malignancies Neurologic complications Infectious, transplant conditioning and immune suppression medication toxicities Thrombotic thrombocytopenic purpura GVHD, graft-versus-host disease; HHV, human herpes virus subtypes. Source: Williams Hematology, 8th ed, Chap. 21, Table 21–5, p. 326. +++ Graft Failure ++ Graft failure is defined as the lack of hematopoietic cell engraftment following autologous and allogeneic HSCT. Criteria are predominantly operational and graft failure is divided into primary (early) and secondary (late) phases. The consequences of graft failure are significant and include a high risk of mortality, often as a consequence of infection and hemorrhage related to cytopenias. +++ Graft Rejection ++ Graft rejection is the immune-mediated rejection of allogeneic donor cells by residual host effector cells that occurs because of the genetic disparity between the recipient and the donor. The determination of graft rejection requires analysis of blood or marrow for chimerism as graft rejection is defined as the inability to detect a meaningful percentage of donor hematopoietic elements. Allogeneic HSCT following RIC is associated with incomplete eradication of host hematopoietic elements. +++ Sinusoidal Obstructive Disease (Veno-occlusive Disease) ++ Sinusoidal obstructive syndrome (SOS) is a clinical syndrome of tender hepatomegaly, fluid retention, weight gain, and elevated serum bilirubin that follows autologous or allogeneic HSCT. The incidence of SOS varies significantly with the intensity of the regimen; from less than 10 percent with RIC to as high as 50 percent following regimens that use cyclophosphamide combined with TBI of greater than 14 Gy. +++ Infections ++ Two important measures for reducing infections in immunocompromised transplant recipients are an effective hand-washing policy, and a strategy for preventing transmission of respiratory infections. Screening the blood supply has reduced the incidence of transfusion-related infections, especially hepatitis C virus and cytomegalovirus in seronegative recipients. The duration of neutropenia and severity of oral and gastrointestinal mucosal damage from the conditioning regimen are risk factors for infection before neutrophil recovery has occurred. Following neutrophil recovery, the persistent B- and T-cell–mediated immune deficiency increases susceptibility to opportunistic infections. Patients who require ongoing immunosuppressive therapy for the control of chronic GVHD are at risk for recurrent bacteremia with encapsulated bacteria and sinopulmonary infections. Fungal infections can be serious complications following HSCT and are more commonly observed in recipients of allografts as a result of the requirement for posttransplantation immunosuppression medication. Fluconazole prophylaxis decreases the incidence of invasive and superficial Candida albicans infections and may decrease the 100-day mortality in allogeneic HSCT recipients. Infection from the herpesvirus family members can cause significant morbidity and mortality and is a common phenomenon following HSCT. Most of the infections are a result of reactivation and the temporal pattern of reactivation follows a relatively predictable course. During the first 100 days after transplantation, patients with viremia are at high risk for developing cytomegalovirus pneumonitis or gastroenteritis. First-line therapy for patients with cytomegalovirus pneumonia or gastroenteritis is ganciclovir combined with intravenous immunoglobulin. +++ Acute GVHD ++ Acute GVHD remains one of the most serious and challenging complications following allogeneic HSCT. The most important risk factor for the development of acute GVHD is the degree of HLA disparity between donor and recipient. Acute GVHD occurs prior to day 100 (although there are clearly exceptions) and primarily affects the skin, gastrointestinal tract, and liver. The severity score ranges between grades 0 and IV and is defined by involvement of each organ system. Acute GVHD, grades II to IV, is considered clinically significant because it is moderately severe, and usually consists of multiorgan disease. Grade II acute GVHD is not typically associated with a poor outcome; however, grades III and IV acute GVHD is associated with a high risk of mortality and decreased patient survival. The mainstay of acute GVHD prevention is prophylaxis with immunosuppressive drugs, and all patients undergoing allogeneic HSCT with a T-cell–replete graft require prophylaxis. Primary prophylaxis with cyclosporine-methotrexate or FK506 (tacrolimus)-methotrexate is the commonly used standard to prevent acute GVHD. The most common agent used to treat acute GVHD is a glucocorticoid, usually methylprednisolone or prednisone at a dose of 1 to 2 mg/kg per day with subsequent tapering once disease activity resolves. Glucocorticoids alone are effective in 50 percent of patients. A variety of other approaches have been explored in the treatment of acute GVHD, including the use of other immunosuppressive agents, antibody-based therapies either to T-cells or cytokines, and photopheresis, all administered in combination with prednisone. +++ Chronic GVHD ++ The clinical manifestations of chronic GVHD are broad and share overlapping features with a variety of autoimmune disorders, such as scleroderma, lichen planus, and dermatomyositis. Chronic GVHD most commonly occurs beyond day 100. If generalized scleroderma occurs, it may lead to joint contractures and debility. Elevations in alkaline phosphatase and serum bilirubin are often the first indication of hepatic involvement with chronic GVHD. Damage to the bile ducts has a similar histopathology to that seen in primary biliary cirrhosis. Liver biopsies are often helpful in establishing a diagnosis. The mainstay of treatment for established chronic GVHD continues to be prednisone. Because of the chronic nature of this disease, long-term treatment is often required. Alternate-day dosing has been found to help reduce some of the toxicity associated with prolonged glucocorticoid use. ++ For a more detailed discussion, see Robert Lowsky and Robert S. Negrin: Principles of Hematopoietic Cell Transplantation. Chap. 21, p. 313 in Williams Hematology, 8th ed.