Allogeneic Marrow Transplantation

Preparative RegimensMarrow Harvest and ProcessingTreatment-Related ComplicationsGraft-vs-Host DiseaseOutcomeAlternative Donor Marrow TransplantationHow Old Is Too Old?References Allogeneic marrow transplantation is used to reconstitute hematopoiesis in patients who have received myeloablative therapy for a hematologic malignancy or in patients with irreversible marrow failure, to reconstitute the immune system in patients with severe immunodeficiency, and to normalize metabolism in patients with select inherited metabolic deficiency disorders [1]. Because of the intensity and toxicity associated with allogeneic marrow transplantation, this treatment is generally reserved for patients younger than age 55 whose graft is being provided by a human leukocyte antigen (HLA)-matched related donor; however, in younger patients lacking a compatible related donor, partially matched related and unrelated donors are reasonable alternatives. Improvements in supportive care measures have allowed the successful application of allogeneic marrow transplantation in greater numbers of patients. In 1992, approximately 2,500 allogeneic marrow transplants (BMTs) were reported to the International Bone Marrow Transplant Registry [2]. Preparative Regimens Standard Regimens Eradication of the underlying malignancy and successful engraftment of allogeneic marrow require administration of a preparative regimen of high-dose chemotherapy with or without radiation. Two combinations are well established as preparative regimens for leukemia: cyclophosphamide (Cytoxan, Neosar) plus total-body irradiation (TBI) or busulfan (Myleran) plus cyclophosphamide. TBI has been given as a single dose in the past, but a high incidence of complications, especially interstitial pneumonitis, occurred. Fractionated TBI with lung shielding in combination with cyclophosphamide, 60 mg/kg/d intravenously (IV) for 2 days, has been found to provide adequate antileukemic activity with acceptable toxicity [3]. Fractionation schedules vary and may affect the outcome [4]. Hyperfractionation of TBI also has been investigated, with no apparent benefit reported to date. Busulfan is administered orally at a dose of 1 mg/kg every 6 hours for 16 doses followed by four doses of cyclophosphamide, 50 mg/kg [5], or two doses at 60 mg/kg [6]. Randomized studies comparing these drug regimens have not been performed, and it is unclear whether either regimen is significantly better than the other with regard to efficacy or toxicity. Busulfan/cyclophosphamide has been compared with cyclophosphamide/TBI in randomized studies, but the results remain controversial [7,8]. Successful engraftment of allogeneic bone marrow requires both myeloablation and immunosuppression. Although the dose of busulfan used is myeloablative, it is not sufficiently immunosuppressive to allow engraftment. Cyclophosphamide is immunosuppressive but not myeloablative. TBI is both immunosuppressive and myeloablative. Cyclophosphamide, at 50 mg/kg/d IV for 4 days, is the standard preparative regimen for patients with aplastic anemia who do not require myeloablation [9]. To minimize graft rejection, particularly in previously transfused patients, and to avoid the use of TBI, antithymocyte globulin has been successfully added to cyclophosphamide [10]. Investigational Regimens To reduce the post-transplant relapse rate, the standard regimens have been intensified or modified. Either cyclophosphamide or TBI is always included to ensure engraftment. At M.D. Anderson Cancer Center, etoposide (VePesid) has been added to the cyclophosphamide/TBI regimen, with a slight reduction in the dose intensity of TBI. The modified combination has been well tolerated by patients with high-risk early leukemia, and the long-term survival rate has been approximately 60% [11]. For patients with advanced hematologic malignancies, thiotepa (Thioplex) has been added to the busulfan/cyclophosphamide combination. The tolerability of the modified regimens is similar to that of the standard regimens [12], and, in initial studies, survival was modestly improved compared with that reported for etoposide/cyclophosphamide/TBI [13]. The addition of a bone-seeking radionuclide or a radionuclide conjugated to a monoclonal antileukemia antibody are other potential approaches to improve the antileukemic activity of the preparative regimen without increasing the toxic effect to normal organs [14]. Marrow Harvest and Processing Marrow Transplantation Marrow is harvested from the posterior iliac crests under general anesthesia. At M.D. Anderson, this procedure is routinely performed on an outpatient basis. With approximately 150 aspirations, 10 to 15 mL/kg of bone marrow is removed (approximately 5% of the total marrow volume). Ideally, this amount should contain 100 million to 400 million nucleated cells/kg. The procedure is associated with a very low risk of complications. In a review of 1,270 normal donors in whom marrow harvests were performed [15], all had the expected amount of pain after the aspiration procedure. Six donors (0.5%) experienced life-threatening complications, 10 (0.8%) experienced significant operative-site morbidity (usually transient neuropathies), and 121 (10%) experienced transient postoperative fever. Worldwide, there have been no deaths directly related to this procedure. If there is no blood group (ABO) incompatibility between the patient and the donor, the marrow is filtered to remove bone particles and infused IV. Day 0 is designated as the day of marrow infusion. If there is ABO incompatibility, the red cells, plasma, or both may need to be removed from the donor marrow to prevent a hemolytic reaction during infusion. ABO incompatibility can also lead to hemolytic reactions at the time of engraftment and to prolonged red cell aplasia caused by circulating red cell antibodies. Transfusion support for ABO-incompatible BMT recipients differs from that for nontransplant patients, and the choice of the appropriate ABO for each component is based on blood typing performed on the patient after the transplant and on prior knowledge of the details of the incompatibility [16]. Alternative Sources of Hematopoietic Stem Cells At M.D. Anderson, allogeneic blood stem-cell transplantation has been evaluated as an alternative to allogeneic BMT. The donors receive granulocyte colony-stimulating factor (filgrastim, Neupogen) injections subcutaneously for mobilization, and stem cells are collected by apheresis in a manner similar to that used to collect single-donor platelets. This approach has eliminated the need for general anesthesia and reduced both morbidity and costs for the donor. Despite concerns about the durability of engraftment and the potential adverse effect of infusing large numbers of donor lymphocytes, preliminary results show that engraftment is rapid, and the incidence of graft-vs-host disease (GVHD) is not significantly higher than that in marrow transplant recipients [17]. Allogeneic cord-blood stem cells have also been utilized for transplantation. The relatively small numbers of cells in cord-blood collections have generally limited this approach to pediatric recipients. Current reports indicate, however, that cord-blood stem-cell engraftment is durable and that the risk of GVHD in histo-incompatible recipients may be reduced using this approach [18]. Treatment-Related Complications Regimen-Related Complications Nausea, vomiting, stomatitis, enteritis, alopecia, erythema or rash, and diarrhea occur in most graft recipients and can largely be controlled. Phenytoin is routinely given to prevent seizures from high-dose busulfan. More serious complications, which occur in fewer patients, might include idiopathic interstitial pneumonitis, hemorrhagic cystitis, heart failure and/or pericarditis, hepatic veno-occlusive disease (VOD), and, less commonly, pulmonary hemorrhage. Life-threatening or fatal complications occur in less than 20% of patients. For the standard preparative regimens, regimen-related mortality is approximately 5% [19]. Patients are screened before transplantation for evidence of underlying organ damage that would increase the risk of regimen-related complications. The best studied condition is hepatic VOD, which is seen histologically as occlusion of the central veins of the liver [20]. Toxicity can also lead to centrilobular necrosis without occlusion of the central veins. The VOD liver toxicity syndrome is characterized by fluid retention with weight gain, tender hepatomegaly, ascites, and hyperbilirubinemia. The condition may also result in liver failure. Risk factors for VOD include a history of hepatitis, an elevated transaminase level at the time of transplantation, use of methotrexate as GVHD prophylaxis, cytoreductive therapy with a high-dose regimen, and mismatched or unrelated marrow grafts. VOD management involves maintaining the intravascular volume to minimize further hepatotoxicity and prevent hepatorenal syndrome. There are no established preventive measures and no specific treatments of advanced VOD other than liver transplantation, although prophylaxis with heparin and the early institution of tissue plasminogen activator have been advocated [21,22]. Myelosuppression Engraftment requires a stable absolute neutrophil count of more than 0.5 billion/L and a platelet count of more than 20 billion/L, which are usually achieved around 21 to 24 days after transplantation. Fatal bleeding and infection can occur in 10% of patients. These conditions can be reduced with standard transfusions and the use of prophylactic and empiric antibiotics, as for any patient with prolonged marrow aplasia. Hematopoietic growth factors have been used to shorten the duration of aplasia without increasing the risk of relapse or GVHD [23]. However, the ability of such growth factors to enhance engraftment is limited when methotrexate is used as GVHD prophylaxis. Graft Failure Graft failure occurs in up to 5% of HLA-identical marrow recipients [24] and can be caused by immunologic graft rejection, infection (especially viral), drugs, and insufficient stem cells. An increased risk of graft rejection is associated with a low nucleated marrow cell dose, T-cell depletion, HLA incompatibility, and a positive crossmatch. Under these circumstances, the incidence of graft failure can be as high as 10% to 15% [24]. For patients with aplastic anemia receiving only cyclophosphamide as the preparative regimen, alloimmunization by prior transfusions or pregnancies may also increase the risk of graft rejection [9]. Infection Infectious complications result from the profound neutropenia that can occur early after transplantation and from neutrophil dysfunction and cell-mediated immunodeficiencies, which last for as long as 1 year after transplantation [25]. To reduce the potential for fatal infections, significant restrictions are imposed during this period. Changes in the patient's environment and reconstitution of the immune system with time predispose the patient to develop specific opportunistic infections at different times after transplantation (Table 1). Fluconazole (Diflucan) given prophylactically has reduced the risk of Candida infection [26]. Inhalational amphotericin B is also being evaluated as a means to prevent Aspergillus pneumonia. Trimethoprim-sulfamethoxazole, twice weekly for 1 year, is given to prevent pneumocystic and pneumococcal infections. For patients who are allergic to sulfas, twice weekly doses of penicillin and pentamidine (NebuPent) can be given by inhalation every 3 weeks [27]. Prophylactic IV immunoglobulin may also prevent infectious complications up to 1 year after transplantation [28]. Viral infections have posed a significant challenge. Acyclovir, given during the initial period of neutropenia, is reported to reduce the risk of reactivation of herpes simplex virus (HSV) infections. High-dose acyclovir (Zovirax) was shown to decrease cytomegalovirus (CMV) disease reactivation, but prophylactic use of ganciclovir (Cytovene) through day 100 has nearly eliminated the occurrence of CMV disease after transplantation [29]. Use of ganciclovir has been associated with neutropenia and bacteremia, and the incidence of these conditions has not been remedied by reducing the administration of ganciclovir from 5 days per week to 3 days per week [30]. Surveillance using highly sensitive assays such as the antigenemia test [31] with the preemptive administration of ganciclovir to patients with reactivation of CMV should be considered to reduce both the costs and morbidity of prophylaxis. For patients who are CMV seronegative and have CMV-seronegative donors, CMV-seronegative or CMV-filtered blood products and IV immunoglobulin without ganciclovir are effective in preventing primary CMV infections [32]. With the reduction in morbidity and mortality from CMV disease, problems with respiratory viruses are becoming recognized more commonly and are the subjects of intense investigation [33-35]. Epstein-Barr virus (EBV)-related lymphoproliferative disease (LPD) occurred in 0.6% of patients who received transplants for treatment of leukemia and 0.3% of patients who received transplants for aplastic anemia. The risk of EBV-related LPD was increased in recipients of anti-CD3 monoclonal antibody (for GVHD therapy) and in recipients of T-cell-depleted and HLA-mismatched marrow who developed GVHD [36]. EBV-related LPD, previously uniformly fatal, has been shown to respond to infusion of peripheral blood donor lymphocytes [37]. One year after transplantation, patients may need to be reimmunized with diphtheria, measles-mumps-rubella, polio, influenza, and pneumococcal vaccines as warranted. Prior to that time, immunization with live viruses or exposure to children who have recently received live viral vaccines is discouraged. Immunization with live or attenuated virus preparations should not commence until immunocompetence has been demonstrated. Late Complications Patients are annually evaluated for evidence of regimen-related organ dysfunction. These evaluations include tests for hypothyroidism (often subclinical), primary gonadal failure, pulmonary fibrosis and obstructive lung disease, growth disturbances, cataracts, and leukoencephalopathy [38]. Late (12 to 18 months) infectious complications are possible, particularly in patients who have received T-cell-depleted grafts, long-term steroids, or both. Second malignancies have occurred in 4% to 9% of long-term survivors after allogeneic BMT [39]. The most common malignancy has been EBV-associated lymphoma, which occurs particularly in T-cell-depleted graft recipients. Glioblastoma, melanoma, hepatoma, and epithelial tumors in general also have been reported to occur at an incidence slightly higher than that in the general population. However, it is not clear whether the increase in risk occurs as a result of transplant therapy, an underlying predisposition for malignancies, or the effects of the primary therapy prior to referral for transplantation. With allogeneic BMT, the intensive treatment and prolonged recovery can have a substantial psychosocial effect in the short term. A pretransplant psychosocial evaluation can identify individuals who may require additional intervention after transplantation [40]. Most long-term survivors, however, seem to report good to excellent health and functional ability, with outcomes comparable to those of long-term cancer survivors who receive less intensive treatment [41]. Graft-vs-Host Disease Immunobiology GVHD occurs when the donor's immune system reacts against the marrow recipient's tissue. There is evidence that GVHD is mediated by T-cells, natural killer cells, and inflammatory cytokines [42]. The target antigens are thought to include both major and minor histocompatibility antigens [43]. The incidence and severity of GVHD increase as genetic disparity increases. Thus, patients with HLA-matched related donors have the best outcome. HLA Typing The HLA system is encoded by a series of genes on chromosome 6. For marrow transplantation, HLA-A, HLA-B and HLA-DR are evaluated. A perfect match requires identity at all three loci on both chromosomes (six antigens). HLA-A and HLA-B (class I antigens) are identified serologically. Identity for the class II antigen regions can be established serologically, molecularly, or by the mixed lymphocyte culture. For related patient-donor pairs, serologic typing and mixed lymphocyte culture results are generally concordant. However, either or both of these tests can be difficult to perform on patients with chronic myeloid leukemia (CML), leukemia in relapse, or lymphocytopenia. Molecular typing for HLA-DR is more reliable under these circumstances [44]. For unrelated patient-donor pairs, different tests for class II typing may not be concordant. As a result, molecular typing is now standard procedure for identifying matched unrelated donors. Some reagents used for serotyping can distinguish differences in antigens that were previously undetectable. Antigens identified by this method form cross-reactive antigen groups. With these reagents, patients who were previously identified as HLA-A9 can now be split into HLA-A23 and HLA-A24 groups. Typing from different institutions using different reagents should be interpreted carefully to avoid missing potentially identical patient-donor pairs. Antigen-specificity tables should be used to confirm nonidentity (Table 2)[45]. Mismatching between cross-reactive antigens is considered a minor mismatch, whereas mismatching between non-cross-reactive antigens is considered a major mismatch. For related patient-donor pairs, a single minor mismatch may be of no biologic consequence. Although techniques are available to identify alleles for a number of loci in the HLA-D region, molecular evaluation of the DRbeta1 locus is currently considered sufficient for class II testing for BMT. Molecular typing detects nucleotide sequence differences not distinguishable by serologic methods [45]. For example, 16 related alleles identified serologically as HLA-DR11 can be distinguished by high-resolution molecular typing. Each allele is noted by the two-digit serologic identification followed by the molecular designation. Thus, DRbeta1*1106 refers to an allele of the HLA-DR11 series that is serologically identical to DRbeta1*1105 (also HLA-DR11), but with a different nucleotide sequence. This is referred to as a molecular mismatch. It has not been firmly established whether molecular mismatches at class II loci affect outcome after unrelated donor marrow transplantation. Acute GVHD Patients are monitored for acute GVHD through day 100 after transplantation. Clinical manifestations include skin rash, fever, decreased performance status, nausea, vomiting, diarrhea, and hyperbilirubinemia [46]. These manifestations have been incorporated in a clinical grading system recently reviewed at an international consensus conference [47](Table 3). Risk factors for acute GVHD include older age, a parous or alloimmunized donor, less intense immunosuppression, and increasing genetic disparity [48]. The diagnosis of acute GVHD is frequently made at the bedside with histologic confirmation, especially to exclude infection. Histologic grade I GVHD in the skin can be confused with changes caused by radiation or chemotherapy. Apoptosis or individual cell necrosis is more specific in the skin or gut. With advanced disease, there is confluence of necrosis and eventually complete denudation of the epithelium. In the liver, early GVHD may be confused with viral hepatitis [49]. Prophylaxis: The incidence of acute GVHD in adults varies with the intensity of immunosuppression. Acute GVHD occurs in 100% of patients with no immunosuppression, 40% to 60% of patients with a single agent, and 20% to 30% of patients with a two-drug combination. The combination used most commonly is cyclosporine (Sandimmune) and methotrexate [50]. The former agent prevents the activation of T-cells and the latter inhibits activated T-cells. Methylprednisolone has also been used successfully in combination with cyclosporine [51], but T-cell-targeted immunotoxins, such as the anti-CD5 ricin A chain immunoconjugate, have not been proven useful in eliminating alloreactive T-cells [52]. Cyclosporine is a cyclic polypeptide that acts as a peptidylprolyl cis-trans isomerase inhibitor and prevents T-cell activation at its earliest stage [53]. The agent inhibits interleukin-2 production and interleukin-2 receptor expression. Side effects include hypertension, nephrotoxicity, hypomagnesemia, seizures, hypertrichosis, gum overgrowth, tremors, nausea, and anorexia. Treatment with cyclosporine at 3 to 5 mg/kg/d IV is initiated 1 to 2 days prior to marrow infusion and is changed to a twice-daily oral dose when possible. Many institutions maintain the cyclosporine whole-blood level in a target range, whereas others change the dose only in response to toxicity. There is evidence of an increase in the risk of acute GVHD when cyclosporine blood concentrations remain below a target level [51]. Metronidazole, fluconazole/ketoconazole (Nizoral), and erythromycin-like antibiotics increase cyclosporine blood concentrations, whereas phenytoin and rifampin (Rifadin, Rimactane) decrease such levels [53]. Cyclosporine is given at full dose for at least 180 days after transplantation and is tapered thereafter. Most patients do not require cyclosporine past 1 year after transplantation. Methotrexate is administered IV at 15 mg/m² on day 1 and 10 mg/m² on days 3, 6, and 11. This drug increases the severity of regimen-related mucositis and delays engraftment. The toxicity of the drug frequently precludes administration of the full dose as scheduled. At M.D. Anderson, a modification of the combination using “minidose methotrexate” at 5 mg/m² on days 1, 3, 6, and 11 in combination with cyclosporine appears to be as effective as the full dose without excess toxicity [54]. Tacrolimus (Prograf) is a macrolide lactone with a mechanism of action, immunosuppressive activity, spectrum of toxicities, and pharmacologic interactions nearly identical to those of cyclosporine, but it is about 100 times more potent than cyclosporine. At M.D. Anderson and other institutions, tacrolimus has been evaluated for the prevention of acute GVHD on a schedule similar to that of CSA, with initial doses of 0.03 mg/kg/d IV. For adult recipients of HLA-identical BMT using tacrolimus alone as prophylaxis, the incidence of grades II to IV GVHD was 42% [55]. For adult recipients of matched or one-antigen mismatched unrelated donor marrow grafts using tacrolimus with prednisone or methotrexate as prophylaxis, the incidence of grades II to IV GVHD was 48% [56]. Although these rates are lower than those reported for cyclosporine-based prophylactic regimens, the results of ongoing randomized studies will determine the relative efficacy of tacrolimus. T-Cell Depletion: Removal of alloreactive T-cells from the marrow prior to infusion has been shown to decrease the incidence and severity of GVHD, but it also leads to an increase in graft rejection, infectious complications, and relapse rates [57]. Overall, recipients of T-cell-depleted HLA-identical BMTs had no improvement in long-term outcome compared with patients who received unmanipulated marrow [58]. Partial T-cell depletion or subset depletion also showed no benefit in the whole group, although in an evaluation at M.D. Anderson, CD8 depletion of marrow appears promising for patients with CML when transplanted during the chronic phase [59]. Therapy: Grades II to IV acute GVHD is considered moderate-to-severe and warrants treatment. Some investigators recommend treatment for grade-I GVHD in unrelated donor BMT recipients. First-line therapy for established GVHD is methylprednisolone, at a dose of 2 mg/kg/d or more. Antithymocyte globulin (Atgam) is used as second-line therapy. GVHD of the skin is most responsive, and GVHD of the liver is least responsive. Only about half of patients with moderate-to-severe acute GVHD respond to treatment. The case fatality rate for GVHD can be as high as 50% [60,61]. Chronic GVHD Chronic GVHD occurs in 20% to 50% of long-term survivors. Risk factors for chronic GVHD include older age, prior acute GVHD, use of donor buffy-coat infusions, and prior HSV infection. Patients are at risk for developing chronic GVHD from about 3 months after transplantation to more than 6 months after discontinuing all immunosuppressive therapy. The most common clinical manifestations include the sicca syndrome, lichen planus-like rash, sclerodermatous skin reactions, esophageal and intestinal fibrosis with dysphagia and malabsorption, obstructive lung disease with or without lymphocytic pneumonitis, and elevated alkaline phosphatase level with or without hyperbilirubinemia [62]. Chronic GVHD resembles an autoimmune disease, and with more rare manifestations alone, it can be difficult to diagnose. The histologic manifestations of chronic GVHD are best characterized in the skin, lips, and liver [49,62]. It begins with a cellular inflammatory phase and progresses to widespread fibrosis. In the skin, there is acanthosis, dyskeratosis, and hyperkeratosis with a mononuclear infiltrate at the dermal-epidermal junction and in adnexal structures, which progresses to fibrosis of the reticular dermis and epidermal atrophy. Similarly, a mononuclear infiltrate is seen in the salivary glands on lip biopsy. The liver shows a portal mononuclear infiltrate with damage to the bile ducts and eventually ductopenia. The histologic changes of chronic GVHD can be seen in blind biopsies in the absence of clinical manifestations. When study patients were screened routinely at day 100, detection of subclinical GVHD in two or more organs was predictive of the development of clinical GVHD [63]. Chronic GVHD can present in the absence of (“de novo onset”), following the resolution of (“quiescent onset”) prior acute GVHD or following incompletely resolved acute GVHD (“progressive onset”). Limited chronic GVHD (skin, liver, or both) has a good prognosis (60% to 70% long-term survival), whereas clinical extensive chronic GVHD with multiple-organ involvement has a poorer long-term outcome (20% to 30% long-term survival). Other risk factors for poor outcome include progressive onset, thrombocytopenia, hyperbilirubinemia, and lichen planus histology [62]. Prophylaxis: There are no formal studies of the prevention of chronic GVHD, although it appears that the incidence of chronic GVHD is lower when patients receive full-dose cyclosporine for at least 6 months after transplantation rather than tapering at earlier points in time [64]. Therapy: High-dose prednisone is the first-line therapy for good-risk chronic GVHD. Therapy continues for at least 9 months before tapering. Patients with poor-risk GVHD have been treated with a combination of prednisone and cyclosporine, and this combination has been advocated for patients with good-risk GVHD as well [65,66]. Preliminary studies show that tacrolimus has activity that is at least comparable to that of cyclosporine and has yielded good results in patients resistant to standard management. The most common cause of death for patients with chronic GVHD is infection. All patients should receive prophylactic trimethoprim-sulfamethoxazole or penicillin/pentamidine with or without intravenous immunoglobulin. Outcome Relapse One substantial benefit for allogeneic BMT recipients is the reduction in the relapse rate, compared with the relapse rate following conventional chemotherapy. Relapse rates are clearly higher for patients with advanced leukemia who receive transplants (Table 4). It has become clear that the risk of relapse is markedly lower after allogeneic BMT than after autologous BMT or identical-twin transplants for treatment of leukemia. This is referred to as the graft-vs-leukemia effect [67]. A similar benefit for patients with lymphoma has been reported, although less consistently [68]. Treatment of leukemia relapse after allogeneic BMT represents a major challenge, although the chimeric state of the lymphohematopoietic system at relapse provides the opportunity for testing innovative strategies [69]. Options include chemotherapy, biologic response modifiers, discontinuation of immunosuppression to amplify a possible graft-vs-leukemia effect, and a second transplant. Interferon has proved successful for treatment of relapse of CML during the chronic phase, but infusion of donor buffy-coat cells with or without interferon has a composite clinical response rate of 83% in this group of patients. However, this form of therapy has been complicated by cytopenia, acute GVHD flare-up, and fatalities in a significant percentage (22%) of the patients [70]. The use of CD8-depleted donor lymphocytes appears to be as effective as interferon, and it causes far fewer adverse effects [71]. Second HLA-identical sibling transplantations for leukemia recurrence (usually from the same donor) have been performed in a limited number of patients, and the outcome has been reported to be poorer than after a first BMT [72]. Factors associated with better survival after a second transplantation are a diagnosis of CML or acute myeloid leukemia (AML) in remission, good performance status, and a long duration (more than 6 to 12 months) of initial after-transplantation remission. Survival is 5% to 20% for patients relapsing less than 6 months after the first transplantation and 20% to 40% for patients relapsing later [72]. Long-Term Survival Expected long-term disease-free survival (DFS) rates for HLA-identical BMT recipients vary with disease and disease status (Table 5) [73-80]. For patients with early leukemia, the most common causes of treatment failure were GVHD and CMV. For patients with advanced leukemia, relapse made up a large proportion of failures. Using standard supportive measures, treatment-related mortality averaged 30% at 2 years [81]. New measures for enhancement of engraftment, prevention of GVHD, and prevention of infections are being investigated intensely in an effort to reduce early treatment-related mortality and improve long-term outcome. For patients with AML, the risk of relapse is lower when transplantation is performed in first remission than after first relapse, and long-term DFS is higher in patients who receive transplants during first remission than in patients who receive them later. This must be compared with the outcome of chemotherapy alone when recommending therapy. For patients with CML, the long-term DFS rates are clearly better for patients who receive transplants during the chronic phase than for patients who receive transplants during the accelerated phase or blast crisis. The survival rate appears to be significantly better for patients transplanted within the first year of diagnosis and for patients treated with hydroxyurea as opposed to busulfan [80]. For patients with chronic lymphocytic leukemia, allogeneic transplantation appears to be superior to autologous transplantation [82]. This finding may be comparable to findings in patients with low-grade lymphoma [83]. Experience with allogeneic transplantation for multiple myeloma is limited, although in selected patients it has provided prolonged DFS and probable cure [84]. The role of allogeneic BMT for relapsed or refractory malignant lymphoma and Hodgkin's disease is currently being evaluated [85-87]. Alternative Donor Marrow Transplantation Patients for whom there is no fully compatible related donor can be considered for transplantation from a one-antigen mismatched related donor or a matched unrelated donor [88,89]. In view of the high age-related morbidity and mortality from GVHD with alternative donors, this approach is usually limited to patients younger than 45 years. Even in younger patients, however, the DFS rates associated with this procedure are inferior to the rates for HLA-identical marrow transplant recipients of similar age (Table 6), largely because of the higher incidence of graft failure (primary and secondary) and GVHD-related mortality [24,88,89]. The use of T-cell depletion of marrow has been shown to be beneficial for alternative donor marrow recipients [58], and use of the new immunosuppressive agents may also be beneficial in this group [56,90]. With additional refinements in supportive care measures, long-term outcome is likely to improve for these patients. There are nearly 1.5 million volunteer marrow donors registered with the National Marrow Donor Program. Despite this, the search for an unrelated donor can take 6 months or longer [88]. Currently, only 40% to 50% of searches for Caucasian donors in the United States are successful in locating HLA-A-, HLA-B-, and HLA-DR-matched unrelated donors [91]. Ethnic minorities are underrepresented in the registry, and these patients have a lower probability of success [92]. To utilize this resource most expeditiously, young patients with CML or high-risk acute leukemia should be HLA typed and considered for a preliminary search early in the course of their disease if no HLA-identical sibling is available. How Old Is Too Old? Patients younger than 20 to 30 years of age are usually considered to have a better outcome after allogeneic BMT [2,93], and most transplantation programs do not routinely perform transplants in patients older than 50 to 55 years of age. The age-related difference in outcome is usually ascribed to a higher GVHD-related and treatment-related mortality, although relapse rates have been reported to be higher as well [93]. Patient selection is likely to play an important role in this setting, and in selected patients, advancing age does not necessarily have an adverse impact on relapse, mortality, or DFS rates [94]. It has been suggested that the maximum age at which BMT from a fully HLA-matched sibling donor is recommended could be raised to 60 years, at least for patients with CML [80]. References: References 1. Bortin MM, Horowitz MM, Rimm AA: Increasing utilization of allogeneic bone marrow transplantation. Ann Intern Med 116(6):505, 1992. 2. Bortin MM, Horowitz MM, Rowlings, et al: 1993 progress report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant 12:97, 1993. 3. Thomas ED, Buckner CD, Clift RA, et al: Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med 301:597, 1979. 4. Clift RA, Buckner CD, Appelbaum FR, et al: Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood 76:1867, 1990. 5. Santos GW, Tutschka PJ, Brookmeyer R, et al: Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 309:1347, 1983. 6. Tutschka PJ, Copelan EA, Klein JP: Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 70:1382, 1987. 7. Clift RA, Buckner CD, Thomas ED, et al: Marrow transplantation for chronic myeloid leukemia: A randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 84:2036, 1994. 8. Blaise D, Maraninchi D, Archimbaud E, et al: Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: A randomized trial of busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: A report from the Groupe d'Etudes de la Greffe de Moelle Osseuse. Blood 79:2578, 1992. 9. Storb R, Champlin RE: Bone marrow transplantation for severe aplastic anemia. Bone Marrow Transplant 8:69, 1991. 10. Storb R, Etzioni R, Anasetti C, et al: Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood 84:941, 1994. 11. Giralt SA, Vriesendorp HM, Andersson B, et al: Etoposide, cyclophosphamide, total body irradiation, and allogeneic bone marrow transplantation: An effective treatment for hematologic malignancies. J Clin Oncol 12:1923, 1994. 12. Przepiorka D, Dimopoulos MA, Smith T, et al: Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for marrow transplantation: Risk factors for early regimen-related toxicities. Ann Hematol 68:183, 1994. 13. Przepiorka D, Ippoliti C, Giralt SA, et al: A phase I/II study of high-dose Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for allogeneic marrow transplantation. Bone Marrow Transplant 14:449, 1994. 14. Champlin RE, Dimopoulos M, Bayouth J, et al: Holmium-166 DOTMP, a bone seeking radiochelate for selective marrow radiotherapy with bone marrow transplantation (BMT) for multiple myeloma. Exp Hematol 21:1117, 1993. 15. Buckner CD, Clift RA, Sanders JE, et al: Marrow harvesting from normal donors. Blood 64:630, 1984. 16. Petz LD: Bone marrow transplantation, in Petz LD, Swisher SN(eds): Clinical Practice of Transfusion Medicine, 2nd ed, p 485. New York, Churchill Livingstone, 1989. 17. KÃ¶rbling M, Przepiorka D, Engel H, et al: Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: Potential advantage of blood over marrow allografts. Blood 85:1659, 1995. 18. Bearman SI, Appelbaum FR, Buckner CD, et al: Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 6:1562, 1988. 19. Apperley JF: Umbilical cord blood progenitor cell transplantation. Bone Marrow Transplant 14:187, 1994. 20. Shulman HM, Hinterberger W: Hepatic veno-occlusive disease: Liver toxicity syndrome after bone marrow transplantation. Bone Marrow Transplant 10:197, 1992. 21. Attal M, Huguet F, Rubie H, et al: Prevention of hepatic veno-occlusive disease after bone marrow transplantation by continuous infusion of low-dose heparin: A prospective, randomized trial. Blood 79:2834, 1992. 22. Bearman SI, Shuhart MC, Hinds MS, et al: Recombinant human tissue plasminogen activator for the treatment of established severe veno-occlusive disease of the liver after bone marrow transplantation. Blood 80:2458, 1992. 23. Barge AJ: A review of the efficacy and tolerability of recombinant haematopoietic growth factors in bone marrow transplantation. Bone Marrow Transplant 11(suppl 2):1, 1993. 24. Davies SM, Ramsay NKC, Haake RJ, et al: Comparison of engraftment in recipients of matched sibling or unrelated donor marrow grafts. Bone Marrow Transplant 13:51, 1994. 25. Atkinson K: Reconstruction of the haematopoietic and immune systems after marrow transplantation. Bone Marrow Transplant 5:209, 1990. 26. Goodman JL, Winston DJ, Greenfield RA, et al: A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 326:845, 1992. 27. Przepiorka D, Selvaggi K, Rosenzweig PQ, et al: Aerosolized pentamidine for prevention of pneumocystis pneumonia after allogeneic marrow transplantation. Bone Marrow Transplant 7:324, 1991. 28. Sullivan KM, Kopecky KJ, Jocom J, et al: Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 323:705, 1990. 29. Goodrich JM, Bowden RA, Fisher L, et al: Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 118:173, 1993. 30. Przepiorka D, Ippoliti C, Panina A, et al: Ganciclovir three times per week is not adequate to prevent cytomegalovirus reactivation after T-cell-depleted marrow transplantation. Bone Marrow Transplant 13:461, 1994. 31. Boeckh M, Bowden RA, Goodrich JM, et al: Cytomegalovirus antigen detection in peripheral blood leukocytes after allogeneic marrow transplantation. Blood 80:1358, 1992. 32. Bowden RA, Sayers M, Flournoy N, et al: Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomegalovirus infection after marrow transplantation. N Engl J Med 314:1006, 1986. 33. Whimbey E, Vartivarian SE, Champlin RE, et al: Parainfluenza virus infection in adult bone marrow transplant recipients. Eur J Clin Microbiol Infect Dis 12(9):699, 1993. 34. Whimbey E, Elting LS, Couch RB, et al: Influenza A virus infections among hospitalized adult bone marrow transplant recipients. Bone Marrow Transplant 13(4):437, 1994. 35. Whimbey E, Champlin RE, Couch RB, et al: Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients. Bone Marrow Transplant, September 1995. 36. Zutter MM, Martin PJ, Sale GE, et al: Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood 72: 520, 1988. 37. Papadopoulos EB, Ladanyi M, Emanuel D, et al: Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 330:1185, 1994. 38. Kolb HJ, Bender-GÃ¶tze C: Late complications after allogeneic bone marrow transplantation for leukaemia. Bone Marrow Transplant 6:61, 1990. 39. Lowsky R, Lipton J, Fyles G, et al: Secondary malignancies after bone marrow transplantation in adults. J Clin Oncol 12:2187, 1994. 40. Meyers CA, Weitzner M, Byrne K, et al: Evaluation of the neurobehavioral functioning of patients before, during, and after bone marrow transplantation. J Clin Oncol 12:820, 1994. 41. Wingard JR, Curbow B, Baker F, et al: Health, functional status, and employment of adult survivors of bone marrow transplantation. Ann Intern Med 114:113, 1991. 42. Ferrara JLM, Deeg HJ: Graft-versus-host-disease. N Engl J Med 324:667, 1991. 43. Perreault C, Decary F, Brochu S, et al: Minor histocompatibility antigens. Blood 76:1269, 1991. 44. Howell WM, Evans PR, Spellerberg MB, et al: A comparison of serological, cellular, and DNA-RFLP methods for HLA matching in the selection of related bone marrow donors. Bone Marrow Transplant 4:63, 1989. 45. Bodmer JG, Marsh SGE, Albert ED, et al: Nomenclature for factors of the HLA system, 1994. Hum Immunol 41:1, 1994. 46. Vogelsang GB, Hess AD, Santos GW: Acute graft-versus-host disease: Clinical characteristics in the cyclosporine era. Medicine 67:163, 1988. 47. Przepiorka D, Weisdorf D, Martin PJ, et al: Consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825, 1995. 48. Gale RP, Bortin MM, Van Bekkum DW, et al: Risk factors for acute graft-versus-host disease. Br J Haematol 67:397, 1987. 49. Snover DC: Biopsy interpretation in bone marrow transplantation. Pathol Annu 24:63, 1989. 50. Storb R, Deeg HJ, Pepe M, et al: Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: Long-term follow-up of a controlled trial. Blood 73:1729, 1989. 51. Przepiorka D, Shapiro S, Schwinghammer TL, et al: Cyclosporine and methylprednisolone after allogeneic marrow transplantation: Association between low cyclosporine concentration and risk of acute graft-versus-host disease. Bone Marrow Transplant 7:461, 1991. 52. Przepiorka D, LeMaistre CF, Huh YO, et al: Evaluation of anti-CD5 ricin A chain immunoconjugate for prevention of acute graft-vs-host disease after HLA-identical marrow transplantation. Ther Immunol 1:77, 1994. 53. Ringden O: Cyclosporine in allogeneic bone marrow transplantation. Transplantation 42:445, 1986. 54. Yau JC, Dimopoulos MA, Huan SD, et al: An effective acute graft-vs-host disease prophylaxis with minidose methotrexate, cyclosporine, and single-dose methylprednisolone. Am J Hematol 38:288, 1991. 55. Fay JW, Weisdorf D, Wingard J, et al: FK506 for prevention of graft versus host disease after allogeneic marrow transplantation (abstract). Blood 80:135a, 1992. 56. Fay JW, Nash RA, Wingard J, et al: FK506-based immunosuppression for prevention of graft-versus-host disease (GVHD) after unrelated marrow donor (UMD) transplantation. Transplant Proc 27:1374, 1995. 57. Marmont AM, Horowitz MM, Gale RP, et al: T-cell depletion of HLA-identical transplants in leukemia. Blood 78:2120, 1991. 58. Passweg JR, Champlin RE, Klein JP, et al: Comparison of techniques for T-cell depletion: Effects on leukemia-free survival. Blood 84(suppl):539a, 1994. 59. Champlin RE, Giralt SA, Przepiorka D, et al: Selective depletion of CD8-positive T-lymphocytes for allogeneic bone marrow transplantation: Engraftment, graft-vs-host disease, and graft-vs-leukemia. Prog Clin Biol Res 377:385, 1992. 60. Hings IM, Severson R, Filipovich AH, et al: Treatment of moderate and severe acute GVHD after allogeneic bone marrow transplantation. Transplantation 58:437, 1994. 61. Martin PJ, Schoch G, Fisher L, et al: A retrospective analysis of therapy for acute graft-versus-host disease: Initial treatment. Blood 76:1464, 1990. 62. Atkinson K: Chronic graft-versus-host disease. Bone Marrow Transplant 5:69, 1990. 63. Loughran TP, Sullivan KM, Morton T, et al: Value of day 100 screening studies for predicting the development of chronic graft-versus-host disease after allogeneic bone marrow transplantation. Blood 76:228, 1990. 64. Bacigalupo A, Van Lint MT, Occhini D, et al: Cyclosporin A and chronic graft-versus-host disease. Bone Marrow Transplant 6: 341, 1990. 65. Sullivan KM, Witherspoon RP, Storb R, et al: Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-versus-host disease. Blood 72:555, 1988. 66. Sullivan KM, Gooley T, Nims J, et al: Comparison of cyclosporine (CSP), prednisone (PRED), or alternating-day CSP/PRED in patients with standard and high-risk chronic graft-versus-host-disease (GVHD). Blood 82(suppl):215a, 1993. 67. Horowitz MM, Gale RP, Sondel PM, et al: Graft-vs-leukemia reactions after bone marrow transplantation. Blood 75:555, 1990. 68. Jones RJ, Ambinder RF, Piantadosi S, et al: Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 77:649, 1991. 69. Giralt SA, Champlin RE: Leukemia relapse after allogeneic bone marrow transplantation: A review. Blood 84:3603, 1994. 70. Antin JH: Graft-versus-leukemia: No longer an epiphenomenon. Blood 82:2273, 1993. 71. Giralt SA, Hester J, Huh YO, et al: CD8+ depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation (BMT): Graft vs leukemia without graft vs host disease (GVHD). Blood 84(suppl):538a, 1994. 72. Mrsic M, Horowitz MM, Atkinson K, et al: Second HLA-identical sibling transplants for leukemia recurrence. Bone Marrow Transplant 9:269, 1992. 73. Clift RA, Buckner CD, Thomas ED, et al: Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia. Blood 84:4368, 1994. 74. Anderson JE, Appelbaum FR, Fisher LD, et al: Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome. Blood 82:677, 1993. 75. Ljungman P, de Witte T, Verdonck L, et al: Bone marrow transplantation for acute myeloblastic leukaemia: An EBMT Leukaemia Working Party prospective analysis from HLA-typing. Br J Haematol 84:61, 1993. 76. Reiffers J, Gaspard MH, Maraninchi D, et al: Comparison of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission: A prospective controlled trial. Br J Haematol 72:57, 1989. 77. Horowitz MM, Messere D, Hoelzer D, et al: Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann Intern Med 115:13, 1991. 78. Sebban C, Lepage E, Vernant JP, et al: Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: A comparative study. J Clin Oncol 12: 2580, 1994. 79. Barrett AJ, Horowitz MM, Pollock BH, et al: Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission. N Engl J Med 331:1253, 1994. 80. Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82:1954, 1993. 81. Horowitz MM, Przepiorka D, Champlin RE, et al: Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers? Blood 79:2771, 1992. 82. Khouri IF, Keating MJ, Vriesendorp HM, et al: Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: Preliminary results. J Clin Oncol 12:748, 1994. 83. van Besien K, Khouri IF, Giralt SA, et al: Allogeneic bone marrow transplantation for refractory and recurrent low grade lymphoma: The case for aggressive management. Blood 84(suppl):205a, 1994. 84. Gahrton G, Tura S, Ljungman P, et al: Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 325:1267, 1991. 85. Chopra R, Goldstone AH, Pearce R, et al: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: A case-controlled analysis of the European Bone Marrow Transplant Group Registry Data. J Clin Oncol 10:1690, 1992. 86. Anderson JE, Litzow MR, Appelbaum FR, et al: Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin's disease: The 21-year Seattle experience. J Clin Oncol 11:2342, 1993. 87. van Besien K, Mehra R, Khouri IE, et al: Double intensification and allogeneic or autologous bone marrow transplantation for poor prognosis lymphoma. Blood 82(suppl):146a, 1993. 88. Kernan NA, Bartsch G, Ash RC, et al: Analysis of 462 transplantations from unrelated donors facilitated by the national marrow donor program. N Engl J Med 328:593, 1993. 89. Anasetti C, Beatty PG, Storb R, et al: Effect of HLA incompatibility on GVHD, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol 29:79, 1990. 90. Przepiorka D, von Wolff B, Ippoliti C, et al: Anti-CD5 ricin A chain immunotoxin decreases acute graft-vs-host disease (GVHD) after unrelated donor marrow transplantation (MUD BMT). Exp Hematol 20:709, 1992. 91. Anasetti C, Etzioni R, Petersdorf EW, et al: Unrelated and HLA-partially matched related donor transplants: Advances and controversies in bone marrow transplantation: Keystone symposium on bone marrow transplantation. J Cell Biochem Suppl 18b:48, 1994. 92. Beatty PG, Mori M, Milford E, et al: Racial differences in histocompatibility, implications for unrelated donor BMT: Advances and controversies in bone marrow transplantation: Keystone symposium on bone marrow transplantation. J Cell Biochem Suppl 18b:49, 1994. 93. Gratwohl A, Hermans J, Niederwieser D, et al: Bone marrow transplantation for chronic myeloid leukemia: Long-term results. Bone Marrow Transplant 12:509, 1993. 94. Ringden O, Horowitz MM, Gale RP, et al: Outcome after allogeneic bone marrow transplantation for leukemia in older adults. JAMA 270:57, 1993.