Unique risk factors for bacteraemia in allogeneic bone marrow transplant recipients before and after engraftment

A study of the risk factors associated with bacteraemia in 191 allogeneic bone marrow transplant (BMT) recipients (1991-1996) was performed. In contrast to risk factors commonly cited for cancer chemotherapy, mucositis, degree of conditioning toxicity of the gut and lungs, duration of neutropenia, and severity of neutropenia and monocytopenia were not associated with bacteraemia in the pre-engraftment period, during which the only significant risk factor was late stage underlying disease (P < 0.05). After engraftment, Hickman catheter infection, and severe acute and chronic graft-versus-host disease (GVHD) were found to be independently associated with bacteraemia by multivariate analysis (P < 0.001, <0.05 and <0.05, respectively). This might be explained by intense antimicrobial prophylaxis, early empirical treatment, and non-routine use of haemopoietic growth factors. No significant difference in mortality was detected between bacteraemic and non-bacteraemic patients in both periods. Allogeneic BMT recipients are therefore a group of patients distinct from other cancer patients receiving chemotherapy at risk of developing bacteraemia. The study findings prompt consideration of a management protocol incorporating early and routine use of haemopoietic growth factors before engraftment in high-risk patients with late stage underlying malignancies, routine antimicrobial prophylaxis for acute GVHD with intense immunosuppression, and intravenous immunoglobulin therapy for chronic GVHD. Further cost-benefit analyses are warranted.     

Detection of donor-derived Langerhans cells in MHC class II immunodeficient patients after allogeneic bone marrow transplantation

Barrett's esophagus can progress to dysplasia and adenocarcinoma. Although the incidence of adenocarcinoma of the gastroesophageal junction has increased suddenly in the United States and Europe, we do not know how much of this increase is related to Barrett's esophagus. Interest in mucosal cell abnormalities at the gastroesophageal junction has led researchers to re-examine short-segment Barrett's esophagus. In this recently described condition, specialized columnar epithelium is found in the distal 2 to 3 cm of the esophagus, yet it is not clear how it relates to conventional long-segment Barrett's esophagus, in which the metaplastic epithelium extends higher than 2 to 3 cm above the squamocolumnar junction. The reported prevalence of short-segment Barrett's esophagus found on diagnostic endoscopy varies from 8% to 32%. This wide variation would be lessened by standardized location of biopsy specimens and of endoscopic and histologic staining techniques. Based on the information available, it is apparent that the age range and sex ratios are similar. Although reflux symptoms may be more common in short-segment Barrett's esophagus, disturbances in esophageal motility are less severe and there is less reflux as measured by continuous pH monitoring. Furthermore, recognized complications of Barrett's esophagus, such as ulceration, stricture, high-grade dysplasia, and adenocarcinoma, appear to be uncommon in short-segment Barrett's esophagus.     

Central review of bone marrow biopsy specimens from patients with neuroblastoma

In order to achieve some uniformity in histological detection of bone marrow infiltration by neuroblastoma and to provide a measure of variation in histological opinions, sections from 712 evaluable trephine biopsy cores from children in a European Neuroblastoma Study Group (ENSG) study were reviewed centrally. Biopsy specimens were graded as tumour positive or negative. Discordance between local and central review opinions was found in 5% of specimens. Only five of 165 children at presentation and nine of 256 re-staging procedures in 126 children, affecting one child each, had their diagnosis upgraded to positive. In six re-staging procedures, affecting one child each, the diagnosis was downgraded. The low discordance rate is encouraging and substantially less important than previously documented difficulties in obtaining adequate specimens.     

Intermediate TCR cells can induce graft-versus-host disease after allogeneic bone marrow transplantation

In this study we compared memory performances of 29 probable patients with AD (17 mildly and 12 moderately demented) with those of 39 healthy young subjects, 36 elderly subjects (matched with the AD group for age and years of schooling), and 19 healthy very old subjects. In most of the memory tasks used in the present study, a progressive decline in performance was observed passing from the Young to the Elderly to the Very Old to the AD group. However, patients with AD were selectively impaired in the backward reproduction of verbal and spatial span sequences and in the semantic encoding of verbal material. These data are consistent with the hypothesis of not only quantitative but also a qualitative discontinuity between the process of normal aging and the dementia syndrome.     

Successful engraftment of allogeneic CD34-enriched marrow cell transplantation from HLA-mismatched parental donors

The CD34 antigen is expressed on pluripotent stem cells and the CD34+ cell has been shown to be capable of hematopoietic reconstitution in animal and human autologous grafts. We asked if CD34+ cells could reconstitute hematopoiesis in human allogeneic transplantation from a HLA-mismatched donor. Three pediatric patients with advanced leukemia received allogeneic CD34-enriched marrow cell graft from HLA two (two patients) or three (one patient) loci-mismatched parental donors. CD34+ cell selection was performed with mouse anti-CD34 antibody 9C5 and magnetic beads coated sheep anti-mouse IgG1. 1.53 to 2.48 x 10(9) marrow cells were processed and 2.53 to 7.89 x 10(7) positively selected cells were recovered. The selected population showed 93.7 to 99.0% CD34+ cells and total recovery of CD34+ cells from the starting population was 54.6 to 62.3%. CD34+ cell selection resulted in more than 99.9% depletion of CD5+ cells from the bone marrow. The patients received 2.53 to 7.25 x 10(6) CD34-enriched cells/kg after myeloablative therapy. All patients achieved trilineage engraftment that was confirmed by various genetic markers. Acute graft-versus-host disease (GVHD) was grade 0 (two patients) or grade I (one patient), and hematological recovery was successfully achieved as follows; the days to reach granulocytes over 0.5 x 10(9)/I were 11 to 13 days, reticulocytes over 2% was 18 to 28 days, platelets over 50 x 10(9)/I was 33 to 58 days. One patient is surviving without relapse of leukemia and two patients died after either mixed hematopoietic chimerism or leukemia relapse was observed. These studies suggest that CD34+ marrow cells are capable of hematopoietic reconstitution from HLA two or three loci-mismatched donors even with the lowest dose of mature T cells.     

Keratinocyte growth factor administered before conditioning ameliorates graft-versus-host disease after allogeneic bone marrow transplantation in mice

Keratinocyte growth factor (KGF) is important in tissue repair and wound healing and its administration can abrogate chemical- and radiation-induced tissue damage in rodents. We investigated KGF as a therapeutic agent for the prevention of graft-versus-host disease (GVHD)-induced tissue damage, morbidity, and mortality in an established murine allogeneic bone marrow transplantation (BMT) model. B10.BR (H2(k)) recipient mice were lethally irradiated and transplanted with C57BL/6 (H2(b)) bone marrow (BM) with spleen cells (BMS) as a source of GVHD-causing T cells. KGF-treated mice (5 mg/kg/d subcutaneously days -6, -5, and -4 pre-BMT) receiving BMS exhibited better survival than those not receiving KGF (P =.0027). Cyclophosphamide (Cy), a common component of total body irradiation (TBI)-containing regimens, was administered to other cohorts of mice at a dose of 120 mg/kg/d intraperitoneally on days -3 and -2 before BMT. KGF-treated mice again exhibited a better survival rate than those not receiving KGF (P =.00086). However, KGF-treated recipients receiving TBI or Cy/TBI BMS were not GVHD-free, as shown by lower body weights compared with BM groups. GVHD target tissues were assessed histologically during a 38-day post-BMT observation period. KGF ameliorated GVHD-induced tissue damage in the liver, skin, and lung (completely in some recipients) and moderately so in the spleen, colon, and ileum, even with Cy conditioning. These studies demonstrate that KGF administration, completed before conditioning, has potential as an anti-GVHD therapeutic agent.     

Indications and timing of allogeneic bone marrow transplantation in myelodysplastic syndromes

Allogeneic bone marrow transplantation is an effective treatment for myelodysplastic syndromes, providing a probable cure in about one-third of cases overall. It is generally reserved for patients under 50 years who have an HLA-compatible donor. Post-transplant disease-free survival rates vary according to several prognostic factors, which often overlap with those predicting the spontaneous outcome of the disease. Consequently, it is sometimes difficult to choose the indications and timing of bone marrow transplantation in this setting. Here we review the literature in an attempt to draw up relevant guidelines.     

Oral health of children undergoing allogeneic bone marrow transplantation

BACKGROUND: Mixed bone marrow chimerism reliably produces donor-specific transplantation tolerance for a variety of solid organ and cellular grafts. We used a rat heterotopic tracheal transplant model for chronic rejection to investigate whether mixed chimerism could successfully prevent obstructive airway disease. METHODS: Mixed allogeneic chimeras were prepared by reconstituting lethally irradiated Wistar-Furth (WF) recipients with a mixture of 5 x 10(6) T-cell-depleted syngeneic (WF) and 100 x 10(6) T-cell-depleted allogeneic (ACI) bone marrow cells (ACI + WF --> WF). Mixed chimerism was present in all animals 28 days after bone marrow transplantation. Donor-specific, syngeneic, or major histocompatibility complex (MHC)-disparate allogeneic tracheas were implanted in recipient's omentum and removed for histologic analysis 30 to 150 days after transplantation. RESULTS: At 30 days after implantation, median luminal obstruction grades (0=none, 4=complete) of syngeneic and allogeneic tracheas were 0 and 4, respectively. Donor-specific (ACI) tracheas implanted in chimeric (ACI + WF --> WF) recipients were remarkably free of obstruction (median luminal obstruction grade=0 at 150 days) and had excellent preservation of respiratory epithelium. Third-party F344 tracheas implanted in chimeric recipients developed progressive luminal obstruction (grade 2 at 30 days, grade 3 at 90 days). CONCLUSIONS: Mixed allogeneic chimerism induces donor-specific tolerance and prevents development of the characteristic fibroproliferative obstructive lesion of bronchiolitis obliterans in a rat heterotopic tracheal transplant model. Excellent preservation of tracheal structure and morphology was achieved across major and minor histocompatibility barriers.     

Possible transmission of sarcoidosis via allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) was performed in a 34-year-old man for non-Hodgkin's lymphoma. Two years before bone marrow harvest, pulmonary sarcoidosis was diagnosed in the donor. After steroid therapy, disease of the donor was in clinical remission with only minor radiological signs at the time of BMT. On day 90 after BMT, active sarcoidosis was diagnosed in the recipient. Besides radiologic signs and increased angiotensin converting enzyme levels, diagnosis was proved by characteristic histologic changes in lung and liver biopsies. Immunosuppressive therapy was changed from high dose cyclosporine to high dose methylprednisolone and symptoms promptly resolved within 10 weeks. This case indicates the possibility of transmission of sarcoidosis by marrow transplantation.     

Serum thrombomodulin levels in patients receiving allogeneic bone marrow transplantation

It has been reported that serum levels of thrombomodulin (TM) reflect endothelial damages in various diseases. We measured serum TM levels between day-10 and day 100 in 6 patients receiving allogeneic bone marrow transplantation. Serum TM levels were increased when patients had transplant related complications including graft versus host disease, hemorrhagic cystitis and interstitial pneumonitis. In patient without complications, serum TM levels were within normal limits. These results suggest that the serum TM level serves as a useful marker of treatment related toxicity and a predictor of complications after BMT.     

Busulfan-based regimens and allogeneic bone marrow transplantation in patients with myelodysplastic syndromes

Preparative regimens containing busulfan (BU) followed by allogeneic bone marrow transplantation (BMT) were used in 27 consecutive patients with myelodysplastic syndromes (MDS). The median age was 33 years (range, 4 to 54). Ten were female and 17 male. Sixteen patients had primary MDS, 11 other patients had antecedent hematologic diseases or developed MDS after cytotoxic and/or radiation therapy. Six patients had leukemic transformation and received antileukemic therapy before BMT. Pre-BMT cytogenetic studies showed complex chromosomal abnormalities in 13 patients, a simple abnormality in 5 patients, and normal chromosome in 8 patients. Three BU-based preparative regimens were used: 1 patient received BU 4 mg/kg orally (PO) daily for 4 days and cyclophosphamide (CY) 50 mg/kg intravenously (IV) daily for 4 days (BUCY-4); 24 patients received BU 4 mg/kg PO daily for 4 days, cytosine arabinoside (ara-C) 2 g/m2 IV every 12 hours for 4 doses, and CY 60 mg/kg IV daily for 2 days (BAC); and 2 patients with preceding Fanconi anemia received BU 2 mg/kg PO daily for 4 days followed by total lymphoid irradiation of 5 Gy. Seventeen of 27 patients are alive with no evidence of disease. Ten patients have died: 2 from hepatic veno-occlusive disease, 3 from sepsis, 1 from a cerebral bleed, 1 from a massive gastrointestinal (GI) bleed associated with acute graft-versus-host disease, 1 from hemolytic uremic syndrome with adult respiratory distress syndrome, 1 from bronchiolitis obliterans, and the only patient who did not engraft died from acute myeloid leukemia. Regimen-related toxicities (RRT) include GI tract (diarrhea, 14; stomatitis, 11), liver (9), cardiac (1), and skin (5). Patients who received a genotypically matched marrow graft had a significantly better disease-free survival (DFS) than patients who received a nongenotypic marrow graft (P = .02). The Kaplan-Meier analysis projects an overall DFS of 56% +/- 13% and 78% +/- 10% for patients who received a genotypically matched marrow graft. With the exception of a child who did not engraft, there was no relapse of MDS or leukemia. Excellent DFS, acceptable RRT, and the ease of administration are advantages of this regimen.     

Culture of marrow stromal cells derived from bone marrow specimens formed at fracture site of human long bone

Insult of temporomandibular joints in infancy may result in severe micrognathia with ankylosis. These patients require tracheostomy and a pureed diet for survival. Between July of 1987 and December of 1990, we treated eight patients with severe micrognathia and ankylosis of one or both temporomandibular joints. Preoperative range of motion at the central incisors was 3.2 +/- 2.1 mm (mean +/- SD). Patients underwent functional reconstruction of one (n = 3) or both (n = 5) temporomandibular joints using costochondral grafts and mandibular advancement at 10.4 +/- 1.7 years of age (mean +/- SD). Rigid fixation of bone grafts with early remobilization was achieved in all cases. Average mandibular advancement was 23.8 +/- 3.7 mm (mean +/- SD), and average elongation was 21.4 +/- 3.3 mm (mean +/- SD). Range of motion at the central incisors was 27.4 +/- 4.2 mm (mean +/- SD) 1.7 +/- 0.8 years (mean +/- SD) postoperatively. Seven patients had tracheostomies prior to surgery, and all were successfully decannulated within 6 months postoperatively. One patient was treated with closed capsulotomy under general anesthesia. Two were treated with open capsulotomy and fascial flap transposition. Functional reconstruction of this deformity in mixed dentition offers these unfortunate individuals significant predictable improvement.     

Augmented proliferation of human alveolar macrophages after allogeneic bone marrow transplantation

After allogeneic bone marrow transplantation (allo-BMT), recipient alveolar macrophages (AM) are gradually replaced by AM of the donor origin. An influx of mononuclear phagocytes of donor origin to the lung is responsible for the repopulation, but the detailed kinetics remain unclear. We therefore studied 24 BMT recipients who underwent bronchoalveolar lavage (BAL) from 24 to 83 days after BMT. AM cell number, size, morphology, proliferating ability, and genotype of AM were measured. Before day 50, the number and size of AM in BAL fluid were similar to those of normal nonsmokers. However, after day 50, the mean number of AM increased threefold and the mean cell size decreased due to the increase of small AM. These small cells are presumably of donor origin based on DNA fingerprinting analysis and based on fluorescence in situ hybridization for the Y chromosome in a sex-mismatched case. Immunohistochemistry and cell cycle analysis demonstrated that the increase in AM number coincided with a remarkable increase of AM expressing proliferating cell nuclear antigen, suggesting that small AM are proliferating. This is the first report representing that augmented proliferation of donor AM in situ may contribute to the reconstitution of AM population after BMT.     

Eradication of residual disease by administration of leukemia-specific T cells after experimental allogeneic bone marrow transplantation

Phage display selection strategies rely on the physical link between the displayed heterologous protein ligand and the DNA encoding it. Thus, genes expressing a ligand with a specific binding affinity can be selected rapidly. To improve the specificity and sensitivity of this technology for potential use in identifying ligands to a specific antibody present in a complex mixture, we incorporated a DNA selection step along with the phage display technology. Ligands for hepatitis C virus (HCV) antibodies present in serum were identified by panning a phage-displayed random peptide library against pools of serum HCV antibodies. An additional DNA hybridization screening step using single-stranded DNA isolated from one of the pools increased the specificity and sensitivity, resulting in the selection of an HCV antibody ligand with diagnostic potential.     

Detection of neuroblastoma in the bone marrow: biopsy versus aspiration

OBJECTIVES: To determine the clinical effects of a change from postural drainage (PD) to positive expiratory pressure chest physiotherapy (PEP) in children with cystic fibrosis (CF) and symptoms of gastro-oesophageal reflux (GOR). To measure the effects of PD on GOR in children with CF. METHODS: Study 1: Six adolescents with CF and symptoms of GOR during PD were changed to upright PEP physiotherapy. The effects on lung function, reflux symptom scores and annual hospital days were measured. Study 2: Twenty-four children with CF (mean age 11 years) and symptoms suggestive of GOR underwent 24-h pH monitoring, including periods of chest physiotherapy. RESULTS: Study 1: All six patients reported a reduction in reflux symptoms during PEP therapy (P < 0.001). Lung function parameters improved during the first 6 months of PEP (P < 0.001). This improvement was sustained for a further 18 months. Annual hospital days decreased significantly (P < 0.0005). Study 2: Nine of 24 patients (37.5%) had pathological GOR. Reflux episodes were significantly increased during PD (P < 0.0001), as was fractional reflux time (P < 0.01). CONCLUSIONS: Upright PEP physiotherapy may be more appropriate than PD in selected patients with CF and symptomatic GOR. The role of GOR as a cofactor in the progression of pulmonary disease in CF needs further evaluation.     

Correction of neutropenia and hypogammaglobulinemia in X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation

X-linked hyper-IgM (X-HIM) syndrome is a primary immunodeficiency disease characterized by defects in both cellular and humoral immunity. X-HIM is caused by mutations in the gene for CD40 ligand (CD40L), a T cell membrane protein that mediates T cell-dependent immune functions. We report the case of a 6-year-old male with X-HIM due to an intronic mutation resulting in aberrant CD40L RNA splicing and absence of detectable CD40L protein. The patient had a history of multiple infectious complications and chronic neutropenia requiring treatment with recombinant granulocyte colony-stimulating factor, and underwent allogeneic bone marrow transplantation from an HLA-matched sibling donor. Following successful engraftment, T cell CD40L expression and immunoglobulin isotype switching were reconstituted and neutropenia resolved. Allogeneic bone marrow transplantation can correct neutropenia and reconstitute immune function in X-HIM.     

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings

PURPOSE: To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS: A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS: Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION: Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.     

Efficacy and costs of granulocyte colony-stimulating factor in allogeneic T-cell depleted bone marrow transplantation

Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P < .0001) and time from marrow infusion to discharge (23 days v 17 days, P < .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs.