Acute Graft-versus-host Disease Prophylaxis Research Articles

Clinical Outcome by Acute Graft-Versus Host Disease (GVHD) Prophylaxis in Patients Underwent Allogeneic Bone Marrow Transplantation from Unrelated Donors: Nationwide Survey in Japan.

Acute GVHD is one of the most serious complications and the main cause of morbidity and mortality for patients undergoing allogeneic bone marrow transplantation (BMT). So choice of GVHD prophylaxis has great impact on transplant outcome. We performed large-scale retrospective study for acute GVHD by using the data on patients who underwent BMT from unrelated donors (UR-BMT) facilitated by Japan Marrow Donor Program (JMDP). From January 1993 to September 2004, 4,999 patients were registered in the JMDP. The study population consisted of 3,410 out of 4,999 patients who received UR-BMT from HLA A,B,DR genotyping matched or HLA DR DNA allele mismatched donors(2,626 and 784, respectively). We evaluated the effect of age, HLA compatibility, disease status, GVHD prophylaxis (Cyclosporine:CsA+Methotrexate:MTX or Tacrolimus:FK+MTX), severity of acute GVHD and other factors. The Kaplan-Meier estimates of over all survival(OS) were higher for the FK group than for the CsA group in the case of HLA A,B,DR genotyping matched BMT with 5-year survival rates of 54 and 51.4% (P<0.05) and also in the case of HLA DR DNA allele mismatched BMT, 53.2 and 43.4% (P<0.05), respectively. Those of OS were higher for the FK group than for the CsA group in HLA A,B,DR genotyping matched patients with standard-risk leukemia with 5-year survival rates of 65.9 and 60.8% (P<0.05) but in those patients with high-risk leukemia were not different significantly between FK and CsA group (27.4 and 31%: p=0.61). Those of OS in HLA DR DNA allele mismatched patients with standard-risk leukemia were higher for the FK group than for the CsA group with 5-year survival rates of 64.1 and 52.2%(P<0.05) and also in those patients with high-risk leukemia were higher for the FK group than for the CsA group with 5-year survival rates of 42.4 and 27%(P<0.05). Those of OS in patients under 16 years were higher for the FK group than for the CsA group with 5-year survival rates of 78% and 62.2%(P<0.005) and in patients of 16 and over were comparable for the FK and CsA groups with 5-year survival rates of 48.3% and 45.2%(p=0.179). During the first 100 days post-transplant the incidence of grade I- IV acute GVHD was lower in the FK group compared with CsA group (65.8% and 72.7%, respectively: P<0.005), but the incidence of grade II- IV acute GVHD was similar between FK and CsA groups (40.3% and 41.5%, respectively). The incidence of grade I- IV acute GVHD was lower in the HLA A,B,DR genotyping matched group than in the HLA DR DNA allele mismatched group (68.5% and 74.7%, respectively: P<0.001). Multivariate analysis demonstrated that OS was higher for the younger age group (<16 y/o) than for the older age group (≥16 y/o)(HR:1.86, 95%CI:1.58–2.18) and for the standard-risk leukemia group than for the high-risk leukemia group(HR:2.27, 95%CI:1.58–2.59). These findings indicate that the use of FK for acute GVHD prophylaxis is beneficial for patients undergoing UR-BMT, especially for patients under 16 years and with standard-risk leukemia.

Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults

Post transplant immune disorders are problematic in cord blood transplantation (CBT) for adult patients, and optimal prophylaxis has not been established. We investigated whether intensive graft-versus-host disease (GVHD) prophylaxis using short-term methotrexate (MTX) has a prognostic impact on CBT. Post-CBT immune reactions were classified according to time course as pre-engraftment immune reaction (PIR), engraftment syndrome (ES) or acute GVHD. Between March 2001 and November 2005, a total of 77 patients underwent CBT at eight transplantation centers. Median age was 48 years (range, 18-69 years). Preparative regimens comprised myeloablative (n=31) or reduced-intensity (n=46). Acute GVHD prophylaxis included cyclosporine alone (n=23), tacrolimus alone (n=12), cyclosporine plus MTX (n=17), tacrolimus plus short-term MTX (n=23) or cyclosporine plus methylprednisolone (n=2). Cumulative incidences of PIR, ES and grade II-IV GVHD were 36, 12 and 23%, respectively. Short-term MTX exerted significant favorable effects on post-CBT immune reactions (hazard ratio, 0.55; 95% confidence interval (95% CI), 0.31-0.98; P=0.04) in multivariate analysis. Overall survival rates for patients with and without short-term MTX at day 180 were 59% (95% CI, 42-73%) and 16% (95% CI, 6.6-30%) (P=0.0001), respectively. Short-term MTX could offer one optimal regimen to reduce immune reactions and improve outcomes in CBT.

Favorable Impact of Short Term Methotrexate on Early Immune Reaction and Non-Relapse Mortality in Umbilical Cord Blood Transplantation for Adult Patients.

Cord blood transplantation (CBT) represents an attractive alternative for patients with advanced hematological malignancy who lack matched related or unrelated donors. Adult patients receiving myeloablative or reduced-intensity CBT display a 90% chance of engraftment, but also experience a 50% rate of transplant-related mortality. Post-transplant immune disorders including early immune reactions and acute GVHD are problematic in CBT for adult patients. These reactions and/or additional immunosuppressive therapy might increase the risk of infection and organ dysfunction, leading to high rates of transplantation-related mortality. However, optimal prophylaxis and management for immune reactions have not been established in CBT. We investigated retrospectively whether intensive graft-versus-host disease (GVHD) prophylaxis has a prognostic impact on CBT. Post-CBT immune reactions were classified according to time course as pre-engraftment immune reaction (PIR), engraftment syndrome (ES) or acute GVHD. Between March 2001 and September 2003, a total of 77 patients underwent CBT at 8 centers of the Nagoya Blood and Marrow Transplantation Group (NBMTG). Median age of patients was 48 years (range, 18–69 years). Preparative regimens were myeloablative (n=31) or reduced-intensity (n=46). Acute GVHD prophylaxis included cyclosporine alone (n=23), tacrolimus alone (n=12), cyclosporine plus short-term methotrexate (n=17), tacrolimus plus short-term MTX (n=23) or cyclosporine plus methylprednisolone (n=2). Cumulative incidences of PIR, ES and grade I-IV GVHD were 38%, 12% and 29%, respectively. Short-term MTX exerted significant favorable effects on PIR in univariate analysis (hazard ratio, 0.41; 95% confidence interval, 0.19–0.89) and on non-relapse mortality (NRM) in multivariate analysis (hazard ratio, 0.36; 95% confidence interval, 0.16–0.81). On the other hand, PIR occurred in 35% of patients with cyclosporine and 37% with tacrolimus. Short-term MTX appears to offer optimal GVHD prophylaxis to reduce PIR and improve NRM. [Display omitted]

Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genotypes and Risk of Acute Graft-versus-Host Disease Following Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia

Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) play key roles in intracellular folate metabolism. Polymorphisms in these enzymes have been shown to modify toxicity of methotrexate (MTX) after hematopoietic cell transplantation. In this study, we evaluated the risk of acute graft-versus-host disease (GVHD) associated with genetic variation in recipient and donor MTHFR and TS genotypes to assess whether genotype alters the efficacy of MTX in acute GVHD prophylaxis. Data on the transplantation course were abstracted from medical records for 304 adults who received allogeneic hematopoietic cell transplants. MTHFR ( C677T and A1298C) and TS (enhancer-region 28-base pair repeat, TSER, and 1494del6) genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Multivariable logistic regression was used to assess the associations between genotypes and risk of acute GVHD. Compared with recipients with the wild-type MTHFR 677CC genotype, those with the variant 677T allele showed a decreased risk of detectable acute GVHD ( 677CT: odds ratio, 0.8; 95% confidence interval, 0.4-1.6; 677TT: odds ratio, 0.4; 95% confidence interval, 0.2-0.8; P for trend = .01). The variant MTHFR 1298C allele in recipients was associated with an increased risk of acute GVHD compared with the wild-type MTHFR 1298AA genotype ( 1298AC: odds ratio, 2.0; 95% confidence interval, 1.1-3.9; 1298CC: odds ratio, 3.6; 95% confidence interval, 1.0-12.7; P for trend < .01). No association with risk of acute GVHD was observed for donor MTHFR genotypes or for recipient or donor TS genotypes, with the exception of an increase in acute GVHD among recipients whose donors had the TSER 3R/2R genotype (odds ratio, 3.0; 95% confidence interval, 1.3-7.2). These findings indicate that host, but not donor, MTHFR genotypes modify the risk of acute GVHD in recipients receiving MTX, in a manner consistent with our previously reported associations between MTHFR genotypes and MTX toxicity. A direct trade-off between drug toxicity and drug efficacy may play a role. Alternatively, the systemic folate environment, regulated by host tissues, might influence donor T-cell growth and activity.

Assessing the potential role of photopheresis in hematopoietic stem cell transplant

The First International Symposium on Photopheresis in Hematopoietic Stem Cell Transplantation was held in Vienna, Austria with an educational grant from Therakos Inc. from 25 May to 27 May 2005. Three general issues were addressed: (1) pathophysiology of graft-versus-host disease (GvHD), (2) induction of immune tolerance and the immunology of phototherapy and (3) current standard treatment and prevention strategies of acute and chronic GvHD and the use of extracorporeal photopheresis (ECP). The objectives of the meeting were to open a dialogue among leading researchers in photobiology, immunology, and hematopoietic stem cell transplantation; foster discussions and suggestions for future studies of the mechanism of action of ECP in acute and chronic GvHD; and promote collaboration between basic scientists and clinicians. As can be seen from the summaries of the individual presentations, important advances have been made in our understanding of GvHD, including the use of photoimmunology interventions and the development of robust model systems. It is our expectation that data from photoimmunology studies can be used to generate hypotheses in animal models that can further define the mechanism of action of ECP and help translate the findings to clinical trials of ECP for the prophylaxis and treatment of both chronic and acute GvHD.

Oral chronic GVHD in children—treatment with topical tacrolimus ointment

Oral chronic graft versus host disease (GVHD) frequently presents as lichen-type changes, hyperkeratotic plaques, pseudomembranes, or decreased oral range of motion in patients with sclerotic features of skin GVHD and is often associated with significant limitations of oral food intake and a generally decreased quality of life. Decreased oral intake is especially problematic in children with already reduced caloric uptake due to chronic gastrointestinal GVHD. Systemic tacrolimus is well established and efficacious for prophylaxis and treatment of acute and chronic GVHD and topical tacrolimus has shown activity in chronic GVHD skin lesions. We therefore initiated a pilot study to investigate the safety and efficacy of topical tacrolimus ointment in pediatric stem cell transplant recipients with debilitating oral chronic GVHD. Two patients (6 and 13 years) with β-thalassemia were included in the study at 179 and 382 days post transplant respectively. Both suffered from progressive onset, moderate to severe chronic GVHD with involvement of the oral mucosa exhibiting lichen-type changes alongside pain, erythema and small ulcerations of the oral mucosa. One patient additionally presented with progressive sclerosis of the lips limiting opening of the oral cavity. In both patients oral lesions had been refractory to systemic GVHD treatment (cyclosporine 3 and 2 mg/kg respectively). After exclusion of infectious causes for oral lesions, tacrolimus ointment 0.1% (Protopic®, Fujisawa Healthcare) was applied twice daily using a sterile gauze that was inserted into both buccal pouches and left in place for 20 minutes without rinsing the mouth afterwards. At a follow up of 24 and 14 weeks respectively, the only side effect observed was a slight burning discomfort after the first application in one patient. Tacrolimus was absorbed in both patients as exhibited by tacrolimus plasma levels up to 4.2 and 5.6 ng/ml respectively. Pain, erythematous lesions and ulcerations disappeared within 4 weeks of treatment in both. Lichenoid changes markedly improved in both and range of oral opening normalized in the patient affected. Systemic immunosuppression was tapered during treatment with topical tacrolimus in both patients. We conclude that topical application of tacrolimus ointment holds promise as a safe and efficacious treatment for oral chronic GVHD in children. These findings deserve to be affirmed in a larger prospective evaluation. Oral chronic graft versus host disease (GVHD) frequently presents as lichen-type changes, hyperkeratotic plaques, pseudomembranes, or decreased oral range of motion in patients with sclerotic features of skin GVHD and is often associated with significant limitations of oral food intake and a generally decreased quality of life. Decreased oral intake is especially problematic in children with already reduced caloric uptake due to chronic gastrointestinal GVHD. Systemic tacrolimus is well established and efficacious for prophylaxis and treatment of acute and chronic GVHD and topical tacrolimus has shown activity in chronic GVHD skin lesions. We therefore initiated a pilot study to investigate the safety and efficacy of topical tacrolimus ointment in pediatric stem cell transplant recipients with debilitating oral chronic GVHD. Two patients (6 and 13 years) with β-thalassemia were included in the study at 179 and 382 days post transplant respectively. Both suffered from progressive onset, moderate to severe chronic GVHD with involvement of the oral mucosa exhibiting lichen-type changes alongside pain, erythema and small ulcerations of the oral mucosa. One patient additionally presented with progressive sclerosis of the lips limiting opening of the oral cavity. In both patients oral lesions had been refractory to systemic GVHD treatment (cyclosporine 3 and 2 mg/kg respectively). After exclusion of infectious causes for oral lesions, tacrolimus ointment 0.1% (Protopic®, Fujisawa Healthcare) was applied twice daily using a sterile gauze that was inserted into both buccal pouches and left in place for 20 minutes without rinsing the mouth afterwards. At a follow up of 24 and 14 weeks respectively, the only side effect observed was a slight burning discomfort after the first application in one patient. Tacrolimus was absorbed in both patients as exhibited by tacrolimus plasma levels up to 4.2 and 5.6 ng/ml respectively. Pain, erythematous lesions and ulcerations disappeared within 4 weeks of treatment in both. Lichenoid changes markedly improved in both and range of oral opening normalized in the patient affected. Systemic immunosuppression was tapered during treatment with topical tacrolimus in both patients. We conclude that topical application of tacrolimus ointment holds promise as a safe and efficacious treatment for oral chronic GVHD in children. These findings deserve to be affirmed in a larger prospective evaluation.

Reduced Intensity Cord Blood Transplantation Using Mycophenolate Mofetil and Cyclosporine for Adult Patients with Advanced Hematologic Malignancies.

Objectives: To evaluate the feasibility of reduced-intensity unrelated cord-blood transplantation (RI-UCBT) using cyclosporine and mycofenolate mofetil as graft-versus-host disease (GVHD) prophylaxis for adult patients with advanced hematological diseasesMethods: Twenty-one patients (median age, 54; range, 30–76) with advanced hematological diseases underwent RI-UCBT at Metropolitan Fuchu Hospital between July 2002 and September 2004. Underlying disease included AML (n=7), non-Hodgkin lymphoma (n=10), Hodgkin lymphoma (n=2), and aplastic anemia (n=1). Preparative regimen comprised fludarabine (Flu) and total body irradiation (TBI), combined with busulfan (BU) or cyclophosphamide (CY). GVHD prophylaxis was cyclosporine and mycophenolate mofetil. Primary endpoint of this study was engraftment. Secondary endpoints were to describe clinical features of immune reactions following RI-CBT. Immune reactions included high-grade fever (> 38 degree centigrade), elevation of serum C-reactive protein (CRP) levels, skin rash or erythema, diarrhea, hyperbilirubinemia, symptoms of central nerve systems, and body weight gains. They were classified according to their onset after transplant: pre-engraftment immune reactions, engraftment syndrome, and GvHD.Results: Ten patients achieved primary neutrophil engraftment at a median of day 22 (range, 11–33). Five patients died of disease progression before engraftment. Primary graft failure was diagnosed in the remaining 6 patients. Among them, 3 patients received second transplant, and the other 3 patients developed autologous hematopoiesis recovery. Seven of 10 patients who achieved engraftment developed pre-engraftment immune reactions including fever, an increase in CRP, skin rash, diarrhea, and body weight gain. Similar manifestations were observed in six patients who had not achieved primary engraftment. Six patients developed engraftment syndrome. Nine patients developed Grade II to IV GVHD: skin rash (n=9), diarrhea (n=7), and hyperbilirubinemia (n=1). Seven of 10 patients who achieved engraftment survived without disease progression at a median follow-up of 17.5 months (range, 8.4–29.0).Conclusions: This study demonstrated the feasibility of RI-UCBT in adults, indicating that acute GVHD prophylaxis with cyclosporine and mycophenolate mofetil is worth considering for further intense evaluation.

Methotrexate alters hematopoietic recovery and engraftment kinetics when added to cyclosporine for acute GVHD prophylaxis after reduced-intensity stem cell transplantation

Methotrexate (MTX) is a standard drug for graft-versus-host disease (GVHD) prophylaxis, but its effects on hematopoietic recovery and donor engraftment in the setting of reduced-intensity stem cell transplantation (RIST) are not well described. We compared these parameters and acute GVHD in patients with hematologic malignancies undergoing RIST on 2 consecutive clinical trials using identical reduced-intensity conditioning (fludarabine and cyclophosphamide). Group 1 included 50 patients receiving cyclosporine (CSA) alone for GVHD prophylaxis after RIST. Group 2 included 24 patients receiving CSA+ MTX (5 mg/m2 on days +1, +3, +6, +11) for GVHD prophylaxis. The groups were similar with respect to host immune status before RIST, age, and allograft dose of CD34+ and CD3+ cells. All patients in each group received salvage therapy with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus fludarabine (EPOCH-F) prior to RIST. Fourteen patients in the CSA/MTX group also received rituximab with EPOCH-F. Hematopoietic recovery was delayed in the CSA/MTX group, with median neutrophil recovery (>500/μL) and platelet recovery (>100K/μL) occurring 3 and 6.5 days later, respectively, than in the CSA group. Donor engraftment was rapid and complete for most patients in each group (median total mononuclear cell chimerism 100% at day +28 for both groups), and no patient experienced graft rejection. However, full donor chimerism (>95%) was less common for CSA/MTX (75% at day +28, 71% at day +100) than for CSA (90% at day +28, 97% at day +100). Adding MTX to CSA decreased the incidence and severity of acute GVHD. Grade 2–4 acute GVHD occurred in 33/50 (66%) CSA patients, versus 9/24 (38%) CSA/MTX patients. Grade 3–4 GVHD affected 17/50 (34%) CSA patients, including 6 with grade 4 GVHD and 8 with steroid-refractory disease. In contrast, only 5/24 (21%) of CSA/MTX patients had grade 3 GVHD, while none had grade 4 or steroid-refractory GVHD. No treatment-related deaths occurred in the CSA/MTX group, but 14 CSA patients died of treatment-related complications. Thus, the addition of MTX to CSA markedly attenuates the GVH response post RIST, slowing donor engraftment and delaying hematopoietic recovery. These data illustrate the sensitivity of engraftment kinetics to the intensity of GVHD prophylaxis following RIST. Further studies should determine if CSA/MTX will be associated with an increased risk of disease progression after RIST.

Gastrointestinal toxicity from the preparative regimen is associated with an increased risk of graft-versus-host disease

Graft-versus-host disease and disease relapse are the 2 major causes of failure of allogeneic hematopoietic stem cell transplantation (SCT). Ideally, patients who undergo transplantation for malignancies would receive the minimum effective acute graft-versus-host disease (GVHD) prophylaxis to maximize the graft-versus-tumor potential of the allogeneic SCT. Tailoring acute GVHD prophylaxis to the risk for each patient has long been a goal for SCT, but no practical way to adjust acute GVHD prophylaxis has been developed. In murine models of acute GVHD, gut damage from the preparative regimen resulting in the release of many mediators is crucial for initiation of acute GVHD. Using diarrhea as a marker of gut damage, we performed a retrospective study of patients at the Johns Hopkins Hospital given matched sibling transplants for chronic myelogenous leukemia to determine whether gut damage during the preparative regimen is predictive of the development of acute GVHD in humans. Logistic regression models were used to perform the retrospective analysis of the relation of diarrhea during the preparative regimen to a significant acute GVHD grade. This work demonstrated a significant positive correlation between the sum of diarrhea on days 4 to 7 after SCT and acute GVHD and showed a borderline significant positive correlation between the sum of diarrhea on days 1 to 3 and acute GVHD. This is the first correlation demonstrated between gut damage during the preparative regimen and acute GVHD severity in humans. This suggests that damage from the preparative regimen could be used as a marker for the risk of acute GVHD. Prospective trials would have to test whether acute GVHD prophylaxis could be adjusted according to this risk. This may result in a greater graft-versus-tumor effect for patients with less risk of acute GVHD.

Prevention and treatment of epstein–barr virus‐associated lymphoproliferative disorders in recipients of bone marrow and solid organ transplants

Prevention and treatment of epstein–barr virus‐associated lymphoproliferative disorders in recipients of bone marrow and solid organ transplants

Pathogenesis and treatment of graft-versus-host disease after bone marrow transplant.

Stem cell transplantation is being used to treat a number of hematologic malignancies as well as hematologic and immune deficiency states. The ages of patients being offered this therapy and the donor marrow sources have been expanded. One persistent problem has been graft-versus-host disease (GVHD). This article reviews the basic biology of GVHD, clinical manifestations of acute and chronic GVHD, prophylaxis and treatment of acute GVHD, and treatment of chronic GVHD.

Cutaneous manifestations of graft-versus-host disease

Graft-versus-host disease (GvHD) is a severe complication of allogeneic stem cell transplantation. GvHD can arise at various time points: acute GvHD occurs during the first 100 days after transplantation in up to 50% of graft recipients. Chronic GvHD develops less frequently in about 30% after the 3rd month following transplantation involving the skin, the liver, the gastrointestinal tract, the eyes, and the neuromuscular apparatus. Early diagnosis of GvHD can be difficult, as drug reactions, viral infections and cutaneous reactions to radiation therapy may have clinical and histological similarities. In this review, the various cutaneous manifestations of GvHD, the histopathologic features, prophylaxis, and therapies of acute and chronic GvHD are discussed according to the recent literature.

Management of graft-versus-host disease in paediatric bone marrow transplant recipients.

We discuss clinical strategies for the prophylaxis and treatment of both acute and chronic graft-versus-host disease (GVHD) with particular attention to children. Grades II to IV acute GVHD occur in 10 to 50% of patients given an allogeneic transplantation of haemopoietic stem cells (HSCT) from a genotypically HLA-identical donor. A significantly higher incidence and severity of the disease is reported in patients receiving transplants from partially matched family donors or unrelated volunteers. Younger individuals or patients receiving HSCT from younger donors develop GVHD less frequently than do older recipients. Severe acute GVHD is characterised by a significant decrease in survival probability, even though the graft-versus-leukaemia activity associated with both acute and chronic GVHD may reduce the risk of leukaemia relapse. Prophylaxis of acute GVHD usually consists of in vivo post-grafting immunosuppression with cyclosporin alone or in combination with methotrexate; methotrexate alone can be considered in leukaemia patients with a high risk of relapse. In recent years, tacrolimus is increasingly being used instead of cyclosporin, alone or in combination with methotrexate. In vitro T cell depletion in paediatric patients is usually reserved for those with transplants from partially matched family donors or unrelated volunteers. The treatment of patients with grades II to IV acute GVHD should be immediate and aggressive, as the quality and duration of the response directly correlates with survival. The overall response rate to treatment is often unsatisfactory, ranging from 40 to 50% of cases. First-line treatment usually consists of corticosteroids. In patients not responding to corticosteroids, antilymphocyte globulin and monoclonal antibodies directed towards lymphocytes and/or cytokines produced during GVHD are employed, but with variable success. Patients experiencing acute GVHD are also prone to develop chronic GVHD. whose classical treatment is based on the use of cyclosporin and corticosteroids. More recently, encouraging results in the treatment of patients with chronic GVHD have been reported with the use of extracorporeal photochemotherapy. Other drugs, such as ursodeoxycholic acid, etretinate and clofazimine, are under evaluation.

Optimum Use of Tacrolimus in the Prophylaxis of Graft Versus Host Disease

Transplantation of haemopoietic stem cells containing immunocompetent cells invariably leads to the development of graft versus host disease (GVHD) in the recipients unless immunosuppressive prophylaxis is administered for approximately 6 months. Despite the availability of immunosuppressive drugs such as cyclosporin, GVHD remains the most important cause of morbidity and mortality in haemopoietic stem recipients. Tacrolimus (FK506), a macrolide lactone isolated from the fermentation broth of Streptomyces tsukubiensis, has been introduced as an agent with greater activity than cyclosporin for GVHD prophylaxis. Several pilot studies using tacrolimus for prophylaxis of acute GVHD have shown promising results leading to 3 major pivotal trials. These studies were nonblinded randomised trials comparing the combination of tacrolimus and methotrexate with cyclosporin and methotrexate in both matched sibling and unrelated donor transplants for the prevention of acute GVHD. All 3 trials showed a significantly lower incidence of acute GVHD in the tacrolimus arm when compared to the cyclosporin arm. The overall and disease-free survival of patients with non-advanced malignancies was similar between the 2 groups. In one matched sibling study, the overall and disease-free survival in high-risk advanced disease patients who received tacrolimus was poorer than in the cyclosporin recipients. However, a recent matched case controlled study using the International Bone Marrow Transplant Registry database confirmed that the poorer survival outcome of the tacrolimus recipients was due to adverse influence of baseline prognostic factors in the tacrolimus group. The toxicity profile of tacrolimus is similar to that of cyclosporin with the exception that the incidence of hirsutism and hypertension is less frequent in tacrolimus recipients. The nephrotoxicity associated with tacrolimus is dose related. Logistic regression analysis indicated that whole blood tacrolimus concentrations greater than 20 ng/ml were associated with significant nephrotoxicity. The current recommended therapeutic concentration range in whole blood is 10 to 20 ng/ml. Some studies found equal efficacy with a therapeutic range of 5 to 15 ng/ml. This review addresses many details on the practical management of adverse effects, dosage and drug interactions.

Transplantation of Allogeneic CD34+ Blood Cells

Pluripotent stem cells of hematopoiesis and lymphopoiesis are among the CD34+ cells in blood or bone marrow. After granulocyte-colony stimulating factor (G-CSF) treatment, 1% to 2% of the mononuclear cells in blood are CD34+ cells, which can be procured by leukapheresis. We investigated the potential of CD34+ blood cells for reconstituting hematopoiesis and lymphopoiesis after allogeneic transplantation. HLA-identical sibling donors of 10 patients with hematologic malignancies were treated with G-CSF (filgrastim), 5 microgram/kg subcutaneously twice daily for 5 to 7 days. CD34+ cells were selected from the apheresis concentrates by immunoadsorption, concomitantly the number of T cells was reduced 100- to 1,000-fold. After transplantation, five patients received cyclosporine A for graft-versus-host disease (GvHD) prophylaxis (group I); five patients additionally received methotrexate (group II). G-CSF and erythropoietin were given to all patients. Mean numbers of 7.45 x 10(6) CD34+ and 1.2 x 10(6) CD3+ cells per kilogram were transplanted. In group I, the median times of neutrophil recovery to 100, 500, and 1,000 per mm3 were 10, 10, and 11 days, respectively. Group II patients reached these neutrophil levels after 10, 14, and 15 days, respectively. Platelet transfusions were administered for a median of 18 days in group I and 30 days in group II, and red blood cells for 9 and 12 days, respectively. Between day 30 and 60, lymphocytes reached levels of 353 +/- 269 cells per mm3. The median grades of acute GvHD were III in group I and I in group II. Two patients in group I died from acute GvHD. Two leukemic relapses occurred in group II. Complete and stable donor hematopoiesis was shown in all patients with a median follow up of 370 (45 to 481) days. Allogeneic blood CD34+ cells can successfully reconstitute hematopoiesis and lymphopoiesis. Reduction of T cells by CD34+ blood cell enrichment and cyclosporine A alone might not be sufficient for prophylaxis of severe acute GvHD.

Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is caused by immunologic recognition of the patient by the donor marrow graft after allogeneic bone marrow transplantation. Despite advances in understanding and new agents and methods to treat GVHD, the disease and complications related to it and its treatment are the principal causes of death after transplantation. This article reviews the pathogenesis, prediction, prophylaxis, and treatment of both acute and chronic GVHD.