Treatment of adrenoleukodystrophy with bone marrow transplantation

Three children with adrenoleukodystrophy (ALD) underwent allogeneic bone marrow transplantation (BMT) between 1992 and 1993. The first boy had attention deficits, marked neuropsychological deficits and widespread demyelination in the frontal lobes on MRI before transplantation. Four years later he has mentally deteriorated and the demyelination on MRI has progressed. The second boy had no symptoms but had white matter lesions on MRI when diagnosed. He was regularly followed with MRI and neuropsychological investigations until BMT 18 months later. A progress of the lesions was noted on the initial MRI investigations, and 4 months before BMT a worsening of deficits in attention and kinaesthetic praxis could be observed. He rapidly deteriorated after the transplantation and died 18 months later. Both PCR and in situ hybridization confirmed the presence of donor cells in the brain. The third boy had no symptoms but white matter lesions on MRI when diagnosed. The neuropsychological tests remained normal but a slight progress was observed on MRI just before transplantation. This boy is still healthy 3.5 years after BMT. BMT as treatment for ALD has to be considered very early, even if a child without symptoms but signs of demyelination on MRI, if a suitable donor is available.     

The effect of short-term alloxan-induced diabetes on the activity of drug metabolizing enzymes

A 12 year-old female patient suffering from multifocal Ewing's Sarcoma underwent bone marrow transplantation in March 1992. The donor was the patient's HLA-identical brother. On day 38 following BMT, an occluding catheter thrombosis of the superior vena cava was diagnosed. Lysis therapy using rt-PA was initiated. During therapy, serious bleeding occurred and administration was temporarily discontinued. Normalisation of previously high fibrinogen levels during an acute phase reaction was seen concomitantly with systemic fibrin and probably also fibrinogen fragments as demonstrated using the Western blot technique. Lysis therapy resulted in regained catheter patency, while thrombosis of the superior vena cava persisted. The reduction in the need for the transfusion of packed thrombocytes following lysis was seen as being a positive result. The use of rt-PA following BMT should be carefully weighed against the risks and requires careful patient observation. Due to the systemic fibrinolytic and fibrinogenolytic effects combined with mucositis and thrombocytopenia as a result of transplantation therapy, a high risk of bleeding complications seems likely.     

Transplantation of cord blood progenitor cells can promote bone resorption in autosomal recessive osteopetrosis

Allogeneic BMT has been reported to be the only curative therapy for children with juvenile autosomal recessive osteopetrosis. We report the case of a 14-month-old child in whom bone resorption was observed after cord blood transplantation (CBT). The patient was given CBT from an unrelated newborn matched for five of six HLA antigens. At the time of transplantation, the child presented with neurological symptoms, with feeding problems and visual impairment. A successful engraftment of donor hematopoiesis was demonstrated and the child experienced grade I acute GVHD. Progressive bone clearing was achieved and a bone marrow trephine demonstrated signs of osteoclast function. Despite full engraftment and bone resorption, neurologic deterioration did not improve. This experience documents that CBT can promote the correction of juvenile osteopetrosis. The shorter time needed both to identify an unrelated donor and to perform the transplant, as well as the lower incidence of GVHD make this procedure more appealing than BMT in children lacking an HLA-compatible relative.     

Multiple minor histocompatibility antigen disparities between a recipient and four HLA-identical potential sibling donors for bone marrow transplantation

A patient with acute leukemia and her family including four HLA-identical siblings were analyzed to select a donor who was not only HLA- but also minor histocompatibility (mH) antigen compatible for allogeneic bone marrow transplantation (BMT). The HLA-A2 restricted mH antigen-specific HA-1, -2, -4, and -5 cytotoxic T-lymphocyte (CTL) clones were used to type the family members for expression of these mH antigens. The patient and one HLA-identical sibling were compatible for these mH antigens. This sibling was selected as the bone marrow donor. The patient engrafted promptly but developed acute and chronic graft-versus-host disease. To study the presence of other mH antigen disparities between recipient and donor, host-versus-graft CTL lines and clones were generated by stimulation of recipient peripheral blood lymphocytes (PBLs) with donor bone marrow cells, and graft-versus-host CTL lines were generated after BMT by stimulation of PBLs of donor origin with recipient bone marrow cells. These CTL lines were cytotoxic to cells from the bone marrow donor and from the recipient, respectively, and to cells from several other family members. T-cell lines, generated from the patient after BMT by stimulation of recipient-derived PBLs with donor bone marrow cells, exhibited no specific cytotoxicity to donor or recipient cells. Chimerism studies after BMT revealed that the PBLs and T-cell lines generated after BMT were of donor origin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relative risk and excess rate models in exposure-response analysis

To date, in utero bone marrow transplantation (BMT) has had limited success, largely because of poor donor engraftment. The poor engraftment is probably the result of performing the procedure late in gestation after significant fetal immunocompetence has developed and/or transplanting insufficient numbers of donor hematopoietic stem cells for competing successfully with ongoing fetal hematopoiesis. To overcome these problems, we performed in utero BMT on a fetus with globoid cell leukodystrophy during the first trimester of gestation using selected paternal bone marrow stem (CD34+) cells. CD34 selection allowed a substantially greater number of stem cells to be transplanted. Although the fetus died 7 weeks after the procedure (during the 20th week of gestation), full donor engraftment was established. Moreover, the cause of death appeared to be overwhelming donor engraftment and leukostasis with paternal myeloid cells infiltrating most tissues. The ability of in utero BMT to produce this degree of engraftment provides great promise for the use of this approach in the treatment of a variety of inherited disorders that can be diagnosed prenatally.     

Telomeres and telomerase in normal and malignant haematologic cells

Tumor relapse remains a major obstacle to the success of allogeneic bone marrow transplantation (BMT) as a treatment for leukemia. Due to limited treatment options, the outlook for most patients that relapse following allogeneic BMT has been poor. The infusion of normal immunocompetent leukocytes from the original marrow donor has become a promising new option for treating/preventing leukemia relapse in allogeneic BMT recipients. This form of treatment has often been referred to as donor leukocyte infusion (DLI) therapy. Our laboratory is using murine models of allogeneic BMT to address important unresolved issues regarding DLI therapy in an effort to make the treatment more effective. These include identification of the antileukemic effector cells, augmentation of the antileukemic effect, and understanding why graft-versus-host-disease (GVHD) is less severe than anticipated. This article reviews our work in murine models of DLI and introduces our current working hypotheses concerning DLI therapy.     

Host reactive donor T cells are associated with lung injury after experimental allogeneic bone marrow transplantation

Noninfectious lung injury is common after allogeneic bone marrow transplantation (BMT), but its association with acute graft-versus-host disease (GVHD) is unclear. Using a murine BMT system where donor and host differ by multiple minor histocompatibility (H) antigens, we investigated the nature of lung injury and its relationship both to systemic GVHD and host-reactive donor T cells. Lethally irradiated CBA hosts received syngeneic BMT or allogeneic (B10.BR) T-cell-depleted (TCD) bone marrow (BM) with and without the addition of T cells. Six weeks after BMT, significant pulmonary histopathology was observed in animals receiving allogeneic BMT compared with syngeneic controls. Lung damage was greater in mice that received allogeneic T cells and developed GVHD, but it was also detectable after TCD BMT when signs of clinical and histologic acute GVHD were absent. In each setting, lung injury was associated with significant alterations in pulmonary function. Mature, donor (Vbeta6(+) and Vbeta3(+)) T cells were significantly increased in the broncho-alveolar lavage (BAL) fluid of all allogeneic BMT recipients compared with syngeneic controls, and these cells proliferated and produced interferon-gamma (IFN-gamma) to host antigens in vitro. These in vitro responses correlated with increased IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) in the BAL fluid. We conclude that alloreactive donor lymphocytes are associated with lung injury in this allogeneic BMT model. The expansion of these cells in the BAL fluid and their ability to respond to host antigens even when systemic tolerance has been established (ie, the absence of clinical GVHD) suggest that the lung may serve as a sanctuary site for these host reactive donor T cells. These findings may have important implications with regard to the evaluation and treatment of pulmonary dysfunction after allogeneic BMT even when clinical GVHD is absent.     

Developments in the treatment of patients with chronic myeloid leukemia

In the treatment of chronic myelocytic leukaemia (CML) allogeneic bone marrow transplantation (BMT) from a sibling donor is the treatment of choice in patients younger than 50 years; the overall 5-year survival is about 60%. Donor lymphocyte infusion without chemotherapy may serve as an efficacious therapy for recurrence of CML after allogeneic BMT. Application of allogeneic BMT from a matched unrelated donor is increasing, but the outcome is still inferior to that of sibling BMT, largely due to more severe and more frequent complications. Treatment with interferon-alpha has been shown to prolong the overall median survival, but especially in a subgroup of patients (about 15%) who achieve a major cytogenic response. Combination of interferon-alpha and low-dose cytarabine leads to increased survival and a better cytogenic response than interferon-alpha alone. Current investigations are aimed at further improving survival and cytogenic response by using more intensive chemotherapy, such as high-dose cytarabine, followed by interferon-alpha maintenance therapy.     

Centurion syndrome. Idiopathic anterior displacement of the medial canthus

Bone marrow transplantation (BMT) using HLA-partially matched family donors has produced disappointing results (25-30% of long-term survivors) in patients with severe aplastic anemia. We describe two children affected by severe aplastic anemia, not responsive to immunosuppressive therapy, who underwent allogeneic bone marrow transplantation using a HLA-partially matched family donor. Both cases presented 2 first class HLA-antigens (A and B) disparity between donor and recipient. The pretransplant conditioning regimen consisted of cyclophosphamide, thoracoabdominal irradiation, cytosine-arabinoside, and antilymphocyte globulin. As graft versus host disease (GVHD) prophylaxis, Cyclosporine-A was administered at usual dosages for 6 months. A full marrow engraftment was observed in both cases. Only grade I acute GVHD, promptly responsive to corticosteroid therapy, developed with no chronic GVHD. Five months after transplant, both children progressively developed hypertension, renal function impairment, thrombocytopenia, and severe normochromic anemia, with erythropoietin serum levels lower than expected for the haematocrit. After antihypertension treatment and supportive therapy, the clinical picture progressively improved, while treatment with recombinant human erythropoietin completely corrected the long-lasting anemia. The two children are alive and well 28 months after the transplant, with a Karnofsky score of 100% and a normal peripheral blood count. The authors suggest that, once immunosuppressive therapy has failed, BMT from donors other than HLA-identical sibling is a feasible approach in children affected by severe aplastic anemia, not having an HLA-identical donor.     

Tactical vs. other simulated aerial combat maneuvers

We report here that a patient with relapsed AML after allogeneic bone marrow transplantation achieved and maintained complete remission (CR) after effective donor leukocyte transfusion (DLT), without the occurrence of GVHD and marrow aplasia, for more than 21 months. This continuous CR maintenance is mainly due to the application of DLT at molecular relapse that was diagnosed by monitoring minimal residual disease (MRD) by the quantitation of WT1 (Wilms tumor gene) expression levels (WT1 assay). The present case demonstrates that early application of DLT at molecular relapse is essential for the improvement of the efficacy of DLT for relapsed AML after BMT.     

Outcomes of recipients of both bone marrow and solid organ transplants. A review

In this review we examine the clinical outcomes of patients who have received both bone marrow transplantation (BMT) and solid organ transplantation (SOT) and discuss the possible immunologic consequences of the dual transplants. We collected cases through a comprehensive literature search (MEDLINE database, English literature only) covering the years 1990 through 1997 and correspondence with the International Bone Marrow Transplant Registry. Our study selected case reports of patients who have undergone both bone marrow and solid organ transplants; cases in which bone marrow transplantation was undertaken as an adjunct ot induce or augment donor-specific tolerance in a recipient to the transplanted organ were excluded. Clinical characteristics included patient's demographic information, underlying disorders for each transplant, source of donor organ or tissue, time between transplants, and immunosuppressive regimens used to prevent graft-versus-host disease (GVHD) or graft rejection. Clinical outcomes included patient survival, complications of transplantation, and donor-specific tolerance that was experienced in many cases. Twenty-one cases of SOT after BMT and 7 cases of BMT after SOT were reviewed. Solid organ transplantations included lung, liver, cardiac, and kidney for a variety of BMT-related complications including GVHD, hepatic veno-occlusive disease, chronic renal failure, end-stage pulmonary disease, and severe cardiomyopathy. Bone marrow transplants were performed following SOT for aplastic anemia and hematologic malignancies. Clinical outcomes for patients who received both BMT and SOT were variable and depended on transplant indication and degree of histocompatibility. Prior bone marrow transplantation may tolerize for a subsequent organ transplant from the same donor. Conversely, severe GVHD may follow BMT from human leukocyte antigen (HLA)-matched donors following SOT. The favorable survival in this high-risk group of patients may represent a literature review bias (that is, an undetermined number of unsuccessful cases may not have been reported). Nonetheless, dual transplantation is clearly feasible in selected cases.     

Methylsulfonyl metabolites of PCBs and DDE in human tissues

More than 15 years passed since bone marrow transplantation (BMT) have first introduced to the field of treatment of pediatric cancer. During this period, technology and modality of BMT have been improved steadily and several kinds of hemopoietic stem cell transplantation, for instance, allogeneic BMT from related or unrelated donor, unpurged or purged autologous BMT by 4-hydroperoxycyclophosphamide (4-HC) or magnetic immuno-beads, allogeneic or autologous peripheral blood stem cell transplantation and cord blood stem cell transplantation became available. Now we can choose the most suitable transplantation method for each patient from our repertory according to the patient's condition. In this article, treatment result of allogeneic BMT and 4-HC purged autologous BMT for children with acute leukemia and several kinds of hematopoietic stem cell transplantation for children with solid tumors in my hospital were reported.     

Infusion of donor peripheral blood mononuclear cells to treat relapse after transplantation for chronic myelogenous leukemia

Until recently, the only curative therapy for patients with chronic myelogenous leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT) has been second allogeneic BMT. Recently, donor mononuclear cells have been given to patients with relapsed CML to induce a potent graft-versus-leukemia reaction and re-establish complete remissions in the majority of patients without the need for a second transplant. The extraordinary success of donor mononuclear cell infusions shows that it is possible to manipulate and harness the graft-versus-leukemia (GVL) reaction for clinical benefit. The identity of the effector cells and target antigens is unclear, but intensive investigation is beginning to define the complex cytokine and cellular interactions that mediate GVL reactivity. Current clinical trials are investigating strategies that will retain and enhance the GVL effects while limiting toxicity from this therapy. Ultimately, the ability to harness the GVL potential of allogeneic donor cells without excessive toxicity from graft-versus-host disease will be a central challenge in BMT and cellular immunotherapy.     

Treatment of Ph1-positive chronic myelogenous leukemia in children: comparison between allogeneic bone marrow transplantation and conventional chemotherapy. Spanish Working Party for BMT in Children (GETMON)

BACKGROUND AND OBJECTIVE: To compare the estimated survival and disease-free survival between children with Ph1-positive chronic myeloid leukemia treated with allogeneic bone marrow transplantation or conventional chemotherapy. DESIGN AND METHODS: In this retrospective study we compared the results obtained in a group of 14 children who received allogeneic bone marrow transplantation (BMT) between 1983 and 1993, and another group of 27 children treated with busulfan, hydroxyurea or alpha-interferon during the same time period. Patients were transplanted at a median of 7 months from diagnosis and all except one were in their first chronic phase. Conditioning consisted in total body irradiation and cyclophosphamide in 12 cases, and busulfan was added in two. RESULTS: Of the 14 patients treated with BMT, two died of transplant-related complications and two relapsed 18 and 48 months after the BMT. Ten children remain alive and disease free at a median follow up of 60 months. The probability of DFS at 5 years is 70%. Of the 27 patients treated with chemotherapy, 22 have died at a median of 36 months from diagnosis. The probability of survival at 5 years is 5% versus 83% for the BMT group (p = 0.001). INTERPRETATION AND CONCLUSIONS: Allogeneic BMT is a safe and very effective treatment for Ph-positive CML in children. Patients who have an HLA-identical sibling donor must receive a transplant as soon as possible after being diagnosed.     

Indications, technique and risks in bone marrow transplantation in adulthood

The option of bone marrow transplantation (BMT) significantly improved prognosis of adult patients with hematologic malignancies aged less than 50 years. Allogeneic BMT using the marrow of an HLA-identical family member still provides the most effective method of BMT. Conventional indications for this form of BMT are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk factors, myelodysplastic syndromes and severe aplastic anemia. If performed early in the disease course (e.g. during the chronic phase of CML or first remission of acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die of therapy related complications, e.g. graft versus host disease (GvHD), fatal infections or venoocclusive disease of the liver (VOD) and about 20% of patients succumb to relapse of their hematologic disorder. 80% presenting with severe aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis without previous immunosuppressive therapy and blood transfusions. BMT with the marrow of a matched unrelated donor or autologous BMT are increasingly used as alternative procedures. A rate of lethal complications as high as 50% hinders rapid extension of BMT with unrelated donors. Therefore, this form of BMT should be restricted to young patients with leukemias, who cannot achieve long-term remission with conventional chemotherapy (in case of acute leukemias) or alpha-interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT. Therefore, PBSCT will replace autologous BMT in most cases. Most favourable results of PBSCT have been reported in patients with malignant lymphomas after relapse or inferior response to primary induction therapy. Due to the higher relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients. Trials are required to clarify the potential role of myeloablative therapy with stem cell support in the treatment of patients with solid tumors. Many of the preliminary results already published are unsatisfactory and data of larger trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally for the therapy of patients with solid tumors.     

Psychiatric disorders and consumption of ecstasy drug (MDMA): review of published case reports

We report the result of allogeneic bone marrow transplantation (BMT) in a 14-year-old boy who was neurologically severely involved with the childhood form of adrenoleukodystrophy (ALD) and received marrow from his HLA-A and B nonidentical, MLC-nonreactive paternal donor without T-cell depletion processing. Bone marrow transplantation corrected the excess content of very long chain fatty acid in plasma but did not arrest the deterioration of the neurological status during 3.5-year post-transplant follow-up period. Since partially matched or unrelated donors have been applied to clinical BMT successfully with current new techniques, ALD patients will have a better prognosis when they are transplanted in status of mild and early involvement. Our first experience may be helpful in more trials of BMT for genetic leukodystrophy in Taiwan.     

Self-healing juvenile cutaneous mucinosis in a patient with nephroblastoma

PURPOSE: Enhanced engraftment and reduced viral complications may be achieved in bone marrow transplantation (BMT) by limiting homologous transfusions. We report on limiting donor exposures before and after BMT in a newborn with severe combined immunodeficiency (SCID) using dedicated whole blood and plateletpheresis donors as well as a sterile connecting device (SCD). PATIENTS AND METHODS: A 1-day-old neonate was admitted for an allogeneic, human leukocyte antigen-disparate, T-cell-depleted BMT performed on day 43 of hospitalization. All transfused red blood cells (RBCs) and platelets were cytomegalovirus negative, and were irradiated and leukodepleted (via a Pall filter). Using the SCD, tubing above the filter was connected to the product bag, and the distal tubing was connected to a transfer pack for collection of the filtered product. Additional transfer packs were connected to the filtered product using the SCD to separate small aliquots as needed. RBC aliquots were irradiated individually before each transfusion. RESULTS: During a total of 134 days of hospitalization, only four donor exposures occurred. Eleven RBC transfusions (mean volume 46.4 +/- 12.6 ml) from three donors and five plateletpheresis transfusions (mean volume 74.2 +/- 7.5 ml) from one donor constituted all the patients' transfusion requirements. Evidence of engraftment was seen on day 18 post-BMT with an absolute neutrophil count sustained at > 500 cells/mm3. The last transfusion was received on day 35 post-BMT. CONCLUSIONS: Current blood transfusion technology enables patients undergoing bone marrow transplantation to have limited donor exposures. This practice should decrease viral complications without effecting bone marrow engraftment.     

Allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) after high-dose, marrow-ablative chemoradiotherapy has been established as the treatment of choice for various hematologic, neoplastic, and congenital disorders. The most common type of marrow graft is an allogeneic one from a sibling donor who has compatible human leukocyte antigen (HLA). Only 30% of patients requiring allogeneic BMT have an HLA-compatible sibling donor. Over the past few years, marrows from unrelated HLA-compatible donors have been used with increasing frequency and promising outcome in certain hematologic malignancies. Despite the morbidity and mortality associated with this treatment modality, allogeneic BMT may provide a 20% to 90% chance of long-term, disease-free survival to patients with a wide variety of neoplastic and abnormal marrow disorders.     

Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines

The influence of bone marrow transplantation (BMT) conditioning regimens on the incidence and severity of graft-versus-host disease (GVHD) has been suggested in clinical BMT. Using murine BMT models, we show here an increase in GVHD severity in several donor-recipient strain combinations after intensification of the conditioning regimen by increasing the total body irradiation (TBI) dose from 900 cGy to 1,300 cGy. Increased GVHD was mediated by systemic increases in tumor necrosis factor alpha (TNF alpha). Histologic analysis of gastrointestinal tracts showed synergistic damage by increased TBI and allogeneic donor cells that permitted increased translocation of lipopolysacharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNF alpha from macrophages primed by the GVH reaction. In addition, macrophages isolated within 4 hours of conditioning were primed in proportion to the TBI dose itself to secrete TNF alpha. Thus, the higher TBI dose increased macrophage priming and increased gut damage after allogeneic BMT, causing higher systemic levels of inflammatory cytokines and subsequent severe GVHD. These data highlight the importance of conditioning in GVHD pathophysiology and suggest that interventions to prevent LPS stimulation of primed macrophages may limit the severity of GVHD after intensive conditioning for allogeneic BMT.     

Fatal eosinophilic disease following autologous bone marrow transplantation

A 15-year-old girl developed massive, fatal eosinophilic disease following autologous bone marrow transplantation (BMT) for Hodgkin's disease (HD). Prior to autologous BMT, the erythrocyte sedimentation rate (ESR) was elevated, with active HD, but eosinophilia was absent. Post-autologous BMT, ESR and peripheral eosinophilia were observed to correlate with respiratory symptoms. Initial evaluation revealed no recurrent tumor, infection or other identifiable etiology. A diagnosis of chronic eosinophilic pneumonia was made following lung biopsy. A complete response was initially achieved with steroid therapy; however, when steroid therapy was tapered, the eosinophilia and elevated ESR recurred with worsening respiratory symptoms. Terminally, severe pulmonary disease developed and recurrent HD was found in lung, lymph nodes and bone marrow. During episodes of eosinophilia, the patient's serum stimulated her bone marrow as well as control marrow to produce predominantly eosinophilic colonies. Eosinophilic colony production was not observed with patient's sera obtained prior to or during autologous BMT or with control sera. This patient died of eosinophilic inflammatory disease following autologous BMT. The etiology of this disease was not definitely identified but appeared to be due to an eosinophilic-stimulating factor which developed after autologous BMT.