Thrombotic microangiopathy after allogeneic blood and marrow transplantation is associated with dose-intensive myeloablative conditioning regimens, unrelated donor, and methylprednisolone T-cell depletion

BACKGROUND: Allogeneic blood and marrow transplantation (BMT)-associated thrombotic microangiopathy (TM) contributes to transplant-related morbidity and mortality. This report examines the incidence of and risk factors for allogeneic BMT-associated TM in two patient cohorts treated before and after changes in myeloablative conditioning regimen intensity (high vs. standard intensity). METHODS: Cohort 1 includes 153 consecutive allogeneic BMT patients who underwent transplantation between April 1994 and October 1997 with an allogeneic BMT-associated TM crude incidence of 12%. Cohort 2 includes 75 consecutive allogeneic BMT patients who underwent transplantation from November 1997 to November 2000 with an allogeneic BMT-associated TM crude incidence of 1%. RESULTS: In cohort 1, matched unrelated donor transplant and methylprednisolone (MP) T-cell depletion (TCD) of donor bone marrow were significantly associated with allogeneic BMT-associated TM by univariate analysis; therefore, a logistic model incorporating these effects was constructed to calculate the expected number of allogeneic BMT-associated TM cases in cohort 2. Seven cases would have been expected, but only one was observed (P = 0.003; bayesian predictive test). The multivariate analysis of both cohorts yielded MP-TCD (P<0.001), high-intensity myeloablative conditioning regimens used in cohort 1 (P = 0.02), and matched unrelated donor (P = 0.03) as significant predictors of time to allogeneic BMT-associated TM. CONCLUSION: Avoidance of high-intensity conditioning regimens may decrease the incidence of allogeneic BMT-associated TM.     

Bone Marrow Cell Transplant From Donors With Cardiovascular Risk Factors Increases the Pro‐atherosclerotic Phenotype in the Recipients

Improvement of long‐term survival after hematopoietic stem cell transplantation has revealed that these patients have an increased appearance of de novo cardiovascular risk factors. Even though in these clinical studies no relation to transplant‐related factors has been found, no attention has been paid to the influence of cardiovascular risk factors affecting the bone marrow donors on the cardiovascular risk of the recipients. Thus, the aim of this study was to analyze, using an animal model, whether transplantation of bone marrow from donors with cardiovascular risk factors increases cardiovascular risk in healthy recipients. Results from transplantation experiments have shown that bone marrow from donors with cardiovascular risk factors induced pro‐atherogenic modifications in the cholesterol profile of healthy recipients, increasing the low‐density lipoprotein cholesterol fraction in comparison to those transplanted with control bone marrow. Moreover, bone marrow from donors with cardiovascular risk factors induced significant alterations in liver pro‐inflammatory state and lipid metabolism–related gene expression that could contribute to alter cholesterol homeostasis. Altogether, these results suggest that cardiovascular risk factors in the donor confer a cardiometabolic alteration to their bone marrow cells that is transferred to noncardiovascular disease transplant recipients, affecting their liver function and increasing their cardiovascular risk.     

Changes of clotting factors (7, 9 and 10) and hepatocyte growth factor in patients with thrombotic microangiopathy after bone marrow transplantation

To investigate risk factors for thrombotic microangiopathy (TMA) after bone marrow transplantation (BMT), the levels of three clotting factors (7, 9 and 10) and hepatocyte growth factor (HGF) were measured. Among 46 consecutive patients who underwent BMT, six developed TMA and 40 did not. The levels of the clotting factors and HGF did not differ significantly between the six patients with TMA and the 40 patients without it. In two patients who developed TMA during the earlyperiod after BMT, however, the levels of the three clotting factors were significantly decreased even before BMT, along with a significant increase of HGF. These findings suggest that patients with severe hepatic dysfunction before BMT, especially those with impaired protein synthesis, had an increased risk of developing TMA soon after BMT. It was also suggested that measurement of clotting factors (7, 9 and 10) and HGF may be useful to predict the occurrence of TMA in the early period after BMT.     

Osteonecrosis of the femoral head after allogeneic bone marrow transplantation

A comparative retrospective analysis of 100 consecutive patients after bone marrow transplantation was performed with magnetic resonance imaging in addition to plain radiography for the development of osteonecrosis of the femoral head. The incidence and risk factors for osteonecrosis of the femoral head were identified, comparing various parameters concerning bone marrow transplantation between the groups with and without evidence of osteonecrosis. Nineteen (19%) of 100 patients had osteonecrosis of the femoral head develop. Four factors were found to be statistically significantly different between patients who had osteonecrosis develop and those who did not: younger age at the time of bone marrow transplantation, chronic graft-versus-host disease, cumulative dose of steroid, and intravenous pulse therapy with methylprednisolone. It was concluded that a low rate of complications and low dose steroid administration would reduce the incidence of osteonecrosis after bone marrow transplantation.     

Late pulmonary sequelae after childhood bone marrow transplantation

BACKGROUND: Respiratory function in transplanted children is important because of the long life expectancy of bone marrow transplant recipients, particularly children. Attention is now being focused on the late sequelae of treatment on organ system function. A few papers have been published but available data are somewhat conflicting. METHODS: A cross sectional study aimed at evaluating the late effects of transplantation on lung function was performed in a group of 52 young patients who were given autologous or allogeneic bone marrow transplants during childhood for haematological malignancies. RESULTS: No patients reported chronic respiratory symptoms. The distribution of respiratory function patterns showed that only 62% of patients had respiratory function within the normal limits; 23% had a restrictive pattern and 15% had isolated transfer factor impairment. The percentage of patients with lung function abnormalities was higher in those who (1) received a bone marrow transplant after two or three complete remissions compared with those who were transplanted immediately after the first remission (54% vs 21%; p < 0.02), (2) underwent allogeneic bone marrow transplantation rather than an autologous transplantation (45% vs 26%; p = 0.06), and (3) had a pulmonary infection compared with those without (56% vs 26%; p = 0.07). CONCLUSIONS: In spite of the absence of chronic respiratory symptoms there is a high prevalence of children with late pulmonary sequelae after bone marrow transplantation. Regular testing is recommended after transplantation, in particular in subjects at higher risk of lung injuries, such as those receiving transplants after more than one remission, those receiving allogeneic transplants, and those having suffered from pulmonary infections. When lung function abnormalities become apparent, long term follow up is necessary to see whether they become clinically relevant. All patients should remain non-smokers after transplantation and should have active early and aggressive treatment for respiratory illnesses.     

Can lung function measurements be used to predict which patients will be at risk of developing interstitial pneumonitis after bone marrow transplantation?

BACKGROUND: Lung function often deteriorates after bone marrow transplantation for haematological malignancies. Whether pulmonary function measurements are useful for monitoring patients' progress after transplantation and for alerting clinicians to the development of pneumonitis is uncertain. METHODS: Serial pulmonary function measurements were made in 39 patients with a haematological malignancy, and the values from 18 recipients of T cell depleted allogeneic (n = 17) or autologous (n = 1) bone marrow transplants who developed interstitial pneumonitis were compared retrospectively with values from 21 recipients of allogeneic (n = 17) or autologous (n = 4) transplants who did not develop pneumonitis. Lung function was measured at the onset of a further 18 episodes of pneumonitis. RESULTS: Measurements made before transplantation showed no difference in forced expiratory volume in one second (FEV1), transfer factor for carbon monoxide (TLCO), or total lung capacity between the two groups, but the forced vital capacity (FVC) was slightly higher in those who developed pneumonitis (mean (SD)% predicted 104 (12)) than in those who did not (93 (17%)). Six weeks and three months after transplantation all pulmonary function measurements had fallen slightly in both groups but TLCO had fallen considerably more in those who later developed pneumonitis, being 71% (SD 11%) and 77% (7%) of pretransplant values in patients who later developed pneumonitis compared with 109% (38%) and 96% (26%) in those who did not. All lung function measurements were significantly lower at the onset of pneumonitis than three months after transplantation, even in patients with no abnormal signs and a normal chest radiograph. CONCLUSIONS: Serial measurements of gas transfer before and after bone marrow transplantation may be useful for predicting which patients will be at risk of developing pneumonitis and may help to diagnose pneumonitis in breathless patients with no abnormal signs.     

Nonbacterial nonfungal pneumonia following marrow transplantation in 100 identical twins

Pneumonia attributable to causes other than bacterial or fungal infection is a major complication of allogeneic marrow transplantation. In this study, the incidence, mortality, and possible risk factors for the development of nonbacterial, nonfungal pneumonia after 100 syngeneic marrow transplants for hematological malignancy are reviewed and compared with the results found in 351 allogeneic marrow transplants performed during the same time period. Both the incidence and mortality of pneumonia were far lower among syngeneic patients, especially for pneumonia associated with cytomegalovirus. Idiopathic pneumonia, however, occurred with about equal frequency in the two populations. Among twins, an increased incidence of pneumonia was seen in older patients and in those who received chemotherapy in addition to cyclophosphamide and total body irradiation as part of the preparative regimen for transplantation.     

Immunoglobulin levels in dogs after total-body irradiation and bone marrow transplantation

The influence of total-body irradiation (TBI) and autologous or allogeneic bone marrow transplantation on serum immunoglobulin subclasses was determined in a dog model. Only IgG1 levels decreased after low-dose (+/- 4.5 Gy) TBI, but levels of all immunoglobulin classes fell after high-dose TBI (8.5 GyX1 or 2X6.0 Gy). After autologous bone marrow transplantation IgM levels were the first and IgE levels were the last to return to normal. After successful allogeneic bone marrow transplantation prolonged low IgM and IgE levels were found but IgA levels increased rapidly to over 150% of pretreatment values. A comparison of dogs with or without clinical signs or graft-versus-host disease (GVHD), revealed no differences in IgM levels. Dogs with GVHD had higher IgA but lower IgE levels. Dogs that rejected their allogeneic bone marrow cells showed significant early rises in IgE and IgA levels in comparison with dogs with GVHD. These results differ from the observations made on Ig levels in human bone marrow transplant patients. No significant differences in phytohemagglutinin stimulation tests were found between dogs with or without GVHD or dogs receiving an autologous transplant for the first four months after TBI and transplantation. An early primary or secondary involvement of humoral immunity in GVHD and graft rejection in dogs is postulated.     

Thrombotic nephropathy and pulmonary hypertension following autologous bone marrow transplantation in a patient with acute lymphoblastic leukemia: case report

Thrombotic microangiopathy is a severe and life-threatening complication following allogeneic or autologous bone marrow transplantation (BMT). Herein we describe a case of microangiopathic hemolytic anemia with progressive renal failure and pulmonary hypertension subsequent to autologous BMT due to acute lymphoblastic leukemia.     

Hemostatic complications in bone marrow transplantation: a retrospective analysis of 447 patients

BACKGROUND: Hemostatic complications are not uncommon after bone marrow transplantation (BMT). However, little is known about the frequency, localization, determinants, and outcome of hemostatic events in autologous and allogeneic BMT. METHODS: Four hundred forty-seven patients (364 allogeneic, 83 autologous transplants) were evaluated retrospectively for the presence of hemostatic complications (bleeding, thrombosis, hepatic veno-occlusive disease [VOD], microangiopathic hemolytic anemia) from the start of conditioning therapy until June 2000. RESULTS: A total of 83.2% of the patients presented with at least one hemostatic complication during the investigational period. Most bleeding episodes occurred within the first 4 weeks after transplantation and were relatively mild. However, 27.1% of the patients hemorrhaged severely, generally doubling the overall mortality of the BMT recipients. Fatal gastrointestinal or intracerebral hemorrhages contributed to 1.1% of the events. Bleeding was strongly associated with prolonged thrombocytopenia and graft-versus-host disease (GVHD). Hemorrhagic cystitis may additionally have been triggered by the preceding conditioning regimens containing cyclophosphamide. Thromboembolic events occurred most frequently in allogeneic transplant recipients, for whom the incidence was 14.6%. Chronic GVHD and treatment with steroids were the major determining factors. The incidence of hepatic VOD in 4.7% of the allogeneic transplant recipients was associated with a high fatality rate. Busulfan conditioning increased the VOD risk 2.6-fold. Moderate or severe microangiopathic hemolytic anemia was associated with GVHD and occurred in 14.6% of the allogeneic transplant recipients, leading to an increased overall mortality. CONCLUSION: Hemostatic disturbances, commonly found in the course of transplantation, are associated with a high transplantation risk and closely related to thrombocytopenia and immunologic complications.     

Bone marrow transplantation. Overview and personal results]

Main indications for allogeneic bone marrow transplantation are severe aplastic anemia, severe combined immunodeficiency, acute leukemia and chronic myeloid leukemia. In standard risk situations survival rates are 50 to 80%. The probability of disease-free survival after bone marrow transplantation is depending on the stage of disease. If possible bone marrow transplantation should be performed early, not in advanced disease when conventional measures failed. Main problems are therapy-related organ toxicity, rejection, graft-versus-host disease and a long lasting risk of infection. Usually histocompatible relatives of the patients are selected as marrow donors. Bone marrow transplantation using unrelated donors is under investigation. Autologous transplantations with cryopreserved marrow are performed in acute leukemia, malignant lymphomas and some solid tumors, but prospective studies comparing transplantation and conventional therapeutic procedures are still missing.     

Manipulation of graft-versus-host disease for a graft-versus-leukemia effect after allogeneic bone marrow transplantation in AKR mice with spontaneous leukemia/lymphoma

Graft-versus-host (GVH) disease can result in a beneficial graft-versus leukemia (GVL) effect after bone marrow transplantation in patients with malignant disease. In this report, we used bacteria-free AKR (H-2k) mice bearing advanced spontaneous T cell leukemia/lymphoma as a moel to evaluate the GVH and GVL effects of bone marrow transplantation using fully incompatible SJL (H-2s) donors. A therapeutic GVL effect, accompanied by increased leukemia-free survival, was obtained only when 0.5 X 10(6) allogeneic lymphocytes (lymph node cells) were added to the marrow inoculum. Transplantation of allogeneic bone marrow without added lymph node cells (or use of syngeneic cells) resulted in a significant increase in leukemia relapse; increasing the dose of allogeneic lymph node cells to 2.0 X 10(6) resulted in significantly higher GVH-associated mortality. Survival and therapeutic benefits were obtained only when the intensity of the GVH reaction was carefully controlled by manipulation of alloreactive lymphocytes present in the marrow. These results suggest, indirectly, that T cell depletion may abolish any GVL effect of marrow transplantation, even if the donor is mismatched with the host at the major histocompatibility complex. The frequency in the spleen of cytotoxic T lymphocytes (CTL) reactive against host alloantigens was estimated using limiting-dilution microcytotoxicity assays at various times after transplantation of allogeneic bone marrow with and without added lymph node cells. The average frequency of CTL was highest in mice that were given marrow plus lymph node cells and tested within the first four weeks after transplantation. The level of CTL activity measured in vitro was dependent on the dose of lymphocytes injected and correlated with both the GVL and GVH effects in vivo. Down-regulation of CTL activity against host, but not third-party, alloantigens in vitro was observed under limiting dilution assay conditions, leading to the suggestion that host-specific regulatory cells may be present in these allogeneic bone marrow chimeras.     

Adult respiratory distress syndrome-like disorders after allogeneic bone marrow transplantation

BACKGROUND: Adult respiratory distress syndrome-like respiratory disorders are a serious, but uncommon, complication of bone marrow transplantation. METHODS: We measured various cytokines in 2 patients with respiratory disorders and 11 patients without respiratory problems after allogeneic bone marrow transplantation. RESULTS: The patients with respiratory disorders had elevated levels of interferon-gamma and interleukin-2 in the aplastic phase, and elevation of tumor necrosis factor-alpha, intercellular adhesion molecule-1, and interleukin-8 at the time of leukocyte recovery. Both patients with respiratory disorders developed fever during the aplastic phase, whereas none of the patients without fever had respiratory disorders. Among patients who had fever during the aplastic phase but no respiratory disorders, there was no elevation of cytokines from the aplastic phase to the recovery phase. CONCLUSIONS: Respiratory disorders may occur after bone marrow transplantation when an inflammatory response during the aplastic phase stimulates cytokines that cause vascular endothelial damage and increases the levels of chemokines and adhesive molecules along with elevation of the leukocyte count.     

Megakaryocytic colony-stimulating activity in patients receiving a marrow transplant during hematopoietic reconstitution

Megakaryocytic colony formation is dependent upon growth-stimulating activities present in human serum or plasma. Factors with diverse biological activities including megakaryocytic colony-stimulating activity (Mk-CSA) are provided by the medium of mitogen stimulated peripheral mononuclear cells or subsets of peripheral T cells. In this communication we describe the stimulatory activity of plasma collected from allogeneic and autologous bone marrow transplant recipients on the growth of megakaryocytic colonies. Mk-CSA was found to increase after transplantation as bone marrow regenerated. The stimulatory activities for CFU-M were greater in plasma from allogeneic bone marrow transplant patients receiving T cell-depleted donor marrow than in patients receiving unmodified donor marrow. Growth-promoting activities derived from mitogen-stimulated lymphocytes of T4 phenotype, a potent source of Mk-CSA, did not increase the frequency of CFU-M when cultured in plasma collected from transplant patients receiving a T cell-depleted donor marrow. However, a further increase in the number of CFU-M was observed when exogenous Mk-CSA was added to the cultures supplemented with plasma from patients receiving unmodified donor marrow. Plasma of patients who received autologous marrow displayed similar Mk-CSA activity when compared with the activity of plasma obtained from transplant recipients receiving an unmodified allogeneic donor marrow. Stimulatory activities supporting multilineage colonies (CFU-GEMM), erythroid bursts (BFU-E), and granulocytic colonies (CFU-C) derived from plasma of the three different transplant groups revealed no statistical difference with respect to the frequency of CFU-GEMM, BFU-E, or CFU-C colonies when compared with pretransplant plasma. The results suggest that MK-CSA may play an important role in the regulation of megakaryopoiesis in vivo. Moreover the data suggest the presence of humoral regulators that appear to be different with respect to the processing of the donor marrow.     

Serum levels and receptor expression of tumor necrosis factor-alpha following human allogeneic and autologous bone marrow transplantation.

We have investigated tumor necrosis factor-alpha levels in serum samples of patients before and after allogenic (16 patients) or autologous (8 patients) bone marrow transplantation. A sensitive immunoradiometric assay for monitoring levels of endogenous tumor necrosis factor-alpha was used. The serum levels of tumor necrosis factor-alpha were found to be relatively low (ranging from less than 15 to 77 pg/ml). Among 13 patients having graft-versus-host disease following allogeneic bone marrow transplantation 8 patients did not have detectable tumor necrosis factor-alpha (less than 15 pg/ml) while 4 out of 8 patients undergoing autologous bone marrow transplantation had detectable tumor necrosis factor-alpha levels (15 pg/ml), indicating a lack of correlation between tumor necrosis factor-alpha serum levels and the occurrence of graft-versus-host disease. Because the tumor necrosis factor-alpha levels detected in patient sera could be regulated by TNF-receptor expression, the presence of TNF-receptor on patients' peripheral blood mononuclear cells was also studied using fluorescent liposome-conjugated tumor necrosis factor-alpha and immunofluorescence analysis. Our data indicate that peripheral blood mononuclear cells of some patients receiving either autologous or allogeneic bone marrow transplantation expressed significant levels of TNF-receptors, suggesting a lack of correlation between TNF-receptor expression and graft-versus-host disease development.     

Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation as a late complication of chronic graft-versus-host disease

BACKGROUND: This study aims to determine the incidence and outcome of nephrotic syndrome in patients who underwent allogeneic stem cell transplantation in a single center. METHODS: Records of 279 adult patients with hematological diseases who underwent allogeneic hematopoietic stem cell transplantation were analyzed to evaluate the incidence and outcome of nephrotic syndrome. The diagnosis of chronic graft-versus-host disease was based on clinical evidence with histological confirmation whenever possible. RESULTS: Of the 279 patients, 105 with a minimum follow-up of 100 days developed chronic graft-versus-host disease: six of these had nephrotic syndrome. The cumulative incidence of nephrotic syndrome was 8% at day +1,681. Patients grafted with peripheral blood stem cells had a higher probability of developing nephrotic syndrome than did those grafted with bone marrow: 24% and 3%, respectively. The pathological diagnosis was membranous glomerulonephritis in four patients, and minimal change disease in one; the diagnosis could not be histologically confirmed in the sixth patient. All patients had extensive chronic graft-versus-host disease and were receiving treatment with cyclosporine A and steroids (four patients). Response to immunosuppressive therapy with cyclosporine A and steroids was achieved in all patients at a median time of 12 weeks after transplantation. CONCLUSION: Patients with chronic graft-versus-host disease may be considered to be at risk of nephrotic syndrome: careful monitoring of renal function is advisable, particularly in patients receiving allogeneic peripheral stem cell grafts.     

Nephrotic syndrome after stem cell transplantation

Nephrotic syndrome occurs rarely after bone marrow transplantation. We describe three patients with myeloid malignancy who developed nephrotic syndrome from 5, 22 and 25 months after allogeneic stem cell transplantation (SCT), confirmed by electron microscopy as membranous glomerulonephritis in two and minimal change glomerulonephritis in one. Proteinuria was initially severe in all and clinically distinct from prior graft-vs.-host disease in two patients. While all responded initially to prednisolone and cyclosporine therapy, two recipients with high-risk leukemia developed late solid organ and bone marrow relapse of their disease, which ultimately proved fatal. The third patient remains alive and disease-free with minimal proteinuria off immunosuppressive therapy. Hence, the onset of de novo high-grade proteinuria after allogeneic SCT should prompt renal histological confirmation, and a trial of immunosuppressive therapy after other causes of nephritic syndrome have been excluded.     

Epstein-Barr-virus-related malignant B cell lymphoplasmacytic lymphoma following allogeneic bone marrow transplantation for aplastic anemia

The development of B cell lymphoma has been reported to occur in recipients of a variety of organ transplants, including some patients who have received an allogeneic bone marrow graft. In this report, we describe a patient with severe aplastic anemia who developed a malignant B cell lymphoplasmacytoid proliferation 48 days after undergoing allogeneic marrow transplantation from her HLA-matched MLC-nonreactive brother. Immunologic studies showed this malignancy to be a mixed polyclonal and monoclonal proliferation in donor cells. Virologic studies documented Epstein Barr infection of the cells. A review of the literature suggests that graft-versus-host disease and treatment of this complication by antithymocyte globulin are related to the development of the EBV-related malignancy in the EBV-infected B cells of the developing bone marrow graft.     

异基因造血干细胞移植后白血病髓外复发的临床分析

目的 探讨异基因造血干细胞移植(allo-HSCT)后髓外复发的发病机理、危险因素、治疗方法及临床转归.方法 回顾分析164例allo-HSCT受者的临床资料,选择受者性别、年龄、原发病、移植前疾病状态、是否有髓外浸润、预处理方案、供者类型、HLA相合程度、术后移植物抗宿主病(GVHD)发生情况等10个临床参数做单因素分析,对P＜0.1的单因素进行多因素分析.髓外复发的治疗方法包括局部放疗、单纯手术切除,全身化疗、供者淋巴细胞输注和二次移植.结果 164例受者均顺利重建造血功能.术后发生白血病髓外复发9例(5.5%),髓外复发的中位时间为7.5个月(2.3～42.6个月);术后发生急性GVHD 94例次(57.3%),慢性GVHD 83例次(50.6%).复发后有4例受者死亡.单因素分析表明,受者性别、移植前疾病进展期、移植前髓外浸润、供者类型及术后发生慢性GVHD等因素与白血病髓外复发显著相关(P＜0.1).经Cox回归多因素分析发现,移植前疾病处于进展期(P＜0.05)、白血病髓外浸润(P＜0.01)及术后发生慢性GVHD(P＜0.01)为alloHSCT后白血病髓外复发的独立危险因素.结论 多种因素参与了髓外复发的发病机理,免疫逃逸可能在其中起主要作用.疾病进展期、移植前伴髓外浸润和慢性GVHD是白血病髓外复发的独立危险因素.白血病髓外复发常伴随骨髓复发,预后较差,因此预防白血病细胞由髓外向髓内扩散对长期存活非常重要.     

Heterotopic sternum transplant in rats: A new model of a vascularized bone marrow transplantation

We introduced the heterotopic vascularized sternum transplant as a more simple and pure alternative to allogeneic hind limb transplantation for the study of bone marrow transplantation. We report the clinical and histopathological manifestations after transplantation of syngeneic and allogeneic sternal grafts with and without immunosuppression with FK-506. Syngeneic grafts maintained normal histology, whereas allografts showed rejection, which was prevented by FK-506. FK-506-treated allografts developed chimerism that was present throughout the observation period. Transplantation of the sternum may be a valuable model to study vascularized bone marrow transplantation and its effects on repopulation of bone marrow of the host, chimerism, and tolerance.