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.     

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.     

Endothelium and bone marrow transplantation

Thrombotic complications may occur early after marrow transplantation and many data suggest that endothelial injury plays a pivotal role in their pathogenesis. Since plasma thrombomodulin and P-selectin are thought to be of value as markers of vascular endothelial cell membrane injury, we investigated their plasma concentration in bone marrow transplant patients aiming better to clarify the degree of endothelial involvement. Plasma thrombomodulin and P-selectin were monitored in 25 patients without thrombotic complications before transplant, on day 0 and weekly for 1 month thereafter, while in three patients who developed VOD monitoring continued until day +52. These proteins were in the normal range in all the uncomplicated patients and in two with reversible VOD, while they were always very high in the only patient who developed very severe and lethal VOD. In conclusion, we suggest that endothelial activation/damage occurs rarely in the course of BMT for hematological malignancies; we were able to document endothelial injury in only one patient with very severe thrombotic complication.     

Autologous bone marrow transplantation in children with advanced neuroblastoma

BACKGROUND: Encouraging results have been reported with high dose chemotherapy and total body radiation followed by bone marrow autotransplantation in children with advanced neuroblastoma; however, relapse remains a significant problem. METHODS: The authors treated 22 children with advanced neuroblastoma with high dose chemotherapy, surgery, intraoperative radiation, and a bone marrow autotransplant (treated in vitro to remove tumor cells) followed by 13-cis-retinoic acid. RESULTS: The 3-year relapse rate was 25% (95% confidence interval [CI], 6-44%). The 3-year disease free survival rate was 72% (95% CI, 52-92%). Toxicities included hemolytic uremic syndrome, herpes infection, and hepatic venoocclusive disease. CONCLUSION: These data suggest that this treatment strategy offers an increased rate of 3-year disease free survival. The nonrandomized nature of this study and its use of multiple modalities precludes the analysis of the specific contribution of each treatment component and comparison with conventional therapy.     

Allogeneic bone marrow transplantation in Japan

Allogeneic bone marrow transplantation (BMT) is being used increasingly to treat diverse diseases in Japan. The distinctive aspects of allogeneic BMT in Japan include the lower incidence of acute graft-versus-host disease, which may be attributable to less disparity in histocompatibility antigens in Japanese. Research in the field of allogeneic BMT in Japan has covered the use of recombinant hemopoietic growth factors, especially granulocyte colony-stimulating factor, and novel immunosuppressive agents.     

Reimmunization after allogeneic bone marrow transplantation

BACKGROUND/AIMS: Patients with cirrhosis and ascites show high plasma concentrations of endothelin. The aim of the current study was to investigate whether this feature is a compensatory response to effective hypovolemia or a consequence of systemic endotoxemia. METHODS: Protocols 1 and 2 assess the effect of acute changes in effective blood volume on plasma endothelin, and protocol 3 investigates the relationship between plasma endotoxin and endothelin in patients with cirrhosis and ascites. Protocol 1 included nine healthy subjects and 26 patients with cirrhosis studied during supine rest, upright tilt (which decreases effective blood volume) and cycloergometric exercise (which activates vasoactive systems by a baroreceptor independent mechanism). Protocol 2 included six patients studied before and 1 and 3 h after the intravenous administration of a plasma expander. In protocol 3, the plasma levels of endothelin and endotoxin were measured in 17 non-infected patients with cirrhosis and also in four patients with spontaneous bacterial peritonitis at diagnosis and following resolution of infection. RESULTS: Plasma endothelin was 3-5 times higher in patients with cirrhosis than in healthy volunteers. In healthy subjects, upright tilt and exercise were associated with a significant activation of the renin-aldosterone and sympathetic nervous systems and an increase in plasma endothelin. In patients with cirrhosis, upright tilt and exercise were associated with a significant increase and plasma volume expansion with a marked suppression of the renin-aldosterone and sympathetic nervous systems. However, in these patients none of these maneuvers affected plasma endothelin levels. In the patients with cirrhosis in protocol 3, there was no correlation between plasma endotoxin and endothelin. Resolution of peritonitis was associated with a marked fall in plasma endotoxin and no changes in plasma endothelin. CONCLUSIONS: These findings suggest that mechanisms other than effective hypovolemia or systemic endotoxemia are involved in the increased plasma endothelin of cirrhosis with ascites.     

Gianotti-Crosti syndrome associated with cytomegalovirus antigenemia after bone marrow transplantation

Gianotti-Crosti syndrome (GCS) is characterized by a distinctive self-limiting acral papular or papulovesicular eruption associated with an underlying viral illness. It has not been previously reported in patients post-bone marrow transplantation. We report a 6-year-old Japanese boy who underwent allogeneic bone marrow transplantation from an unrelated donor for acute lymphoblastic leukemia (ALL) in second remission. He had clinical and histopathologic findings characteristic of GCS and evidence of subclinical infection with cytomegalovirus (CMV) detected by CMV antigenemia assay. It is likely that CMV is the causative agent for the GCS in this case.     

Unrelated donor bone marrow transplantation for children with acute leukemia

PURPOSE: To test the use of unrelated donor bone marrow transplantation (URD BMT) to cure children with high-risk acute leukemias. PATIENTS AND METHODS: Between June 1985 and December 1994, 50 children with acute leukemia (15 acute myelogenous leukemia [AML], 35 acute lymphoblastic leukemia [ALL]; 22 greater than second complete remission [CR]) received BMT from a URD at the University of Minnesota. Ages ranged from 0.9 to 17.5 years (median, 8.8). Median follow-up is 2.1 years (range, 1 to 7.3). Thirty patients (60%) received bone marrow fully matched at HLA-A,B and DRB1; 20 (40%) received bone marrow with a major or minor mismatch at a single HLA-A or B locus. RESULTS: The median time to neutrophil engraftment was day 24 (range, 14 to 42 days) in those receiving matched and day 25 (range, 15 to 32 days) in those receiving mismatched marrow (P = .35). The incidence of grades III to IV graft-versus-host disease (GVHD) was 23% (95% confidence interval [CI], 7% to 39%) in matched and 32% (95% CI, 8% to 52%) in HLA-mismatched patients (P = .57). The incidence of chronic GVHD was 50% (95% CI, 28% to 72%) in matched and 57% (95% CI, 23% to 91%) in mismatched patients (P = .80). Disease-free survival for patients with ALL is 37% (95% CI, 21% to 53%) at 1 year and 30% (95% CI, 15% to 46%) at 2 years; for patients with AML, 53% (95% CI, 28% to 78%) at 1 year and 33% (95% CI, 6% to 60%) at 2 years. CONCLUSION: URD BMT is an effective treatment for children with poor-prognosis acute leukemia and should be considered for all high-risk patients. Early referral of patients is strongly recommended.     

Allogeneic bone marrow transplantation for hypereosinophilic syndrome with advanced myelofibrosis

A 33-year-old man with an atypical course of hypereosinophilic syndrome including malignant hypercalcemia, osteolytic lesions and evolution into severe myelofibrosis was treated by allogeneic bone marrow transplantation after conditioning with cytoxan and total body irradiation. As the transplant was sex-mismatched, chimerism was studied by means of cytogenetic analysis and Y chromosomal DNA amplification by PCR assay. Long-term complete remission has been assessed by normalization of blood cell counts, magnetic resonance imaging and karyotypic analysis. A relapse was observed 40 months after transplantation. The patient remains alive 44 months post-BMT. This case report is compared with those reported in the literature.     

52Fe for additional marrow ablation before bone marrow transplantation

The effectiveness of bone marrow transplantation (BMT) for malignant blood diseases remains limited by the inability of the preparative regimen to eliminate the disease without causing toxicity to normal organs. We have used 52Fe to deliver radiotherapy selectively to the BM. Fourteen patients with hematologic malignancies received 52Fe before a conventional BMT conditioning regimen. The median 52Fe dose was 58 mCi (range, 32 to 85 mCi). As evaluated by quantitative scanning, the median percentage of 52Fe taken up by the BM was 82% (range, 36% to 90%). This resulted in a median radiation-absorbed dose to the BM of 632 rad (range, 151 to 1,144 rad). The median uptake of 52Fe by the liver was 18% (range, 10% to 64%) and the median radiation-absorbed dose to the liver was 239 rad (range, 82 to 526 rad). The median whole body radiation-absorbed dose was 46 rad (range, 22 to 68 rad). No untoward effects were noted after the injections of 52Fe. The patients recovered hematopoiesis without toxicity in excess of that expected with conventional conditioning alone. The median follow-up was 8 months and three patients have relapsed. 52Fe should provide a way to boost the radiation dose to marrow-based diseases before marrow transplantation without increasing toxicity.     

Allogeneic bone marrow transplantation for AL amyloidosis

AL amyloidosis is an infiltrative disorder characterized by the extracellular deposition of insoluble fibrillar immunoglobulin light chains whose production results from a plasma cell dyscrasia. Treatment with melphalan has resulted in an improvement in a few patients. Recently, intensive chemotherapy followed by autologous or syngeneic stem cell support has been shown to offer potential benefit. Allogeneic stem cell support after intensive therapy would retain the benefits of autologous transplantation, with the additional advantages of a tumor-free graft and of a possible graft-versus-tumor effect. We report a patient with AL amyloidosis and significant proteinuria. She improved after an allogeneic bone marrow transplantation.     

Allogeneic bone marrow transplantation for low-grade lymphoma

Advanced low-grade lymphomas are usually incurable with conventional-dose chemotherapy. It is uncertain whether cures are possible with high-dose therapy and bone marrow transplant from a human leukocyte antigen (HLA)-identical sibling. We sought to determine the outcome of HLA-identical sibling bone marrow transplants in advanced low-grade lymphoma in an observational study of 113 patients conducted at 50 centers participating in the International Bone Marrow Transplant Registry (IBMTR). The median patient age was 38 years (range, 15 to 61). Eighty percent had stage IV disease at the time of transplantation. The median number of prior chemotherapy regimens was two (range, 0 to 5). Thirty-eight percent had refractory disease and 29% a Karnofsky performance score (KPS) less than 80%. All patients underwent allogeneic bone marrow transplantation from a HLA-identical sibling donor. The conditioning regimen included total-body irradiation (TBI) in 82% of patients; cyclosporine was used for graft-versus-host disease prophylaxis in 74%. Survival, disease-free survival, recurrence rate, treatment-related mortality, and causes of death were determined. Three-year probabilities of recurrence, survival, and disease-free survival were 16% (95% confidence interval [CI], 9% to 27%), 49% (95% CI, 39% to 60%), and 49% (95% CI, 39% to 59%), respectively. Higher survival was associated with pretransplant KPS >/=90%, chemotherapy-sensitive disease, use of a TBI-containing conditioning regimen, and age less than 40 years. We conclude that high-dose therapy followed by transplantation from a HLA-identical sibling leads to prolonged survival in some patients with advanced low-grade lymphoma. Most mortality is treatment-related, and recurrences are rare.     

Acute renal failure following bone marrow transplantation

The medial preoptic nucleus (MPN) is an essential site for the regulation of male sexual behavior. Previous studies using c-fos as a marker for neural activation have shown that copulation increased c-fos expression in the MPN. Neural activation was also present in brain regions that are connected with the MPN and are involved in male sexual behavior, including the posteromedial bed nucleus of the stria terminalis (BNSTpm), posterodorsal preoptic nucleus (PD), posterodorsal medial amygdala (MEApd), and parvocellular subparafascicular thalamic nucleus (SPFp). The present study investigated whether the copulation-induced, activated neurons in these brain regions are involved in the bidirectional connections with the MPN. Therefore, mating-induced Fos expression was combined with application of anterograde (biotinylated dextran amine) or retrograde (cholera toxin B subunit) tracers in the MPN. The results demonstrated that neurons in the BNSTpm, PD, MEApd, and SPFp that project to the MPN were activated following copulation. However, in males that displayed sexual behavior but did not achieve ejaculation, few double-labeled neurons were evident, although both retrogradely labeled neurons and Fos-immunoreactive cells were present. In addition, retrograde neurons that expressed Fos were located in discrete subdivisions within the brain regions studied, where Fos is induced after ejaculation. Likewise, anterogradely labeled fibers originating from the MPN were not distributed homogeneously but were particularly dense in these discrete subdivisions. These results demonstrate that copulation-induced Fos-positive neurons in specific subdivisions of the BNSTpm, PD, MEApd, and SPFp have bidirectional connections with the MPN. Taken together with previous findings, this supports the existence of a discrete subcircuit within a larger neural network underlying male sexual behavior.     

Hypophosphataemia in patients undergoing bone marrow transplantation

We studied the prevalence of hypophosphataemia (< 0.80 mmol/l) in seventeen patients who had undergone bone marrow transplantation (BMT). Thirteen (77%) of the seventeen patients had hypophosphataemia at some stage during the conditioning phase or after their BMT. Seven (41%) of the seventeen patients had hypophosphataemia in the peri-BMT period that is during the conditioning phase or within one week thereafter. Two of the patients showed severe hypophosphataemia (< 0.30 mmol/l). We suggest that plasma phosphate should be monitored in patients with a bone marrow transplant.