Long-term neurological effects of bone marrow transplantation in a canine lysosomal storage disease

A naturally occurring disease in Plott hound dogs, caused by deficiency of the lysosomal enzyme alpha-L-iduronidase, was used to study the feasibility of bone marrow transplantation therapy in a neurodegenerative storage disease. Three long-term survivors of transplantation with littermate marrow at 5 months of age (before clinical signs) had CNS enzyme activity, glycosaminoglycan storage, and light microscopic and ultrastructural changes evaluated 594, 628, and 740 days after treatment. Iduronidase activity in small amounts (1-3% of donor values) was detectable in brain tissue. Cerebrospinal fluid had higher iduronidase activity after transplantation (7-15% of donor values). Enzyme activity within the CNS resulted in significant reductions in stored glycosaminoglycans and resolution, to a large extent, of light microscopic and ultrastructural lesions observed in affected, untreated littermate control dogs.     

Long-term complications following bone marrow transplantation in children

Abstract Seventeen children who underwent bone marrow transplantation (BMT) between 1975 and 1985 and survived for more than 2 years were evaluated for growth and development. The patients had a follow up of 2.1-13.1 years. Prior to transplant, children with malignancy had received multi-agent chemotherapy and nine had also received central nervous system irradiation. Transplant preparation for malignancy (group 1; n = 13) included high-dose cyclophosphamide (CPA) 120–200 mg/kg and total body irradiation (TBI) 10–13.2 Gy, whereas conditioning for non-malignant disorders (group 2; n = 4) included high-dose CPA 200 mg/kg with or without busulphan. Patients in group 1 showed a steady decline in height velocity following initial chemotherapy and cranial irradiation and the decline was even greater following BMT. Growth hormone (GH) deficiency developed in eight of nine children tested, hypergonadotrophic hypogonadism developed in 11 who reached puberty, thyroid hormone abnormalities were encountered in four out of 10 tested and 11 of 13 developed cataracts. Patients in group 2 did not show decline in linear growth rate, thyroid hormone abnormalities or cataracts after BMT. The only child tested had normal GH levels and the two patients who reached puberty showed delayed but complete gonadal recovery. Our data demonstrate that TBI leads to significant late effects on growth and gonadal function. Contrary to previous reports, a high incidence of cataract formation is observed after fractionated TBI. Conditioning regimens without TBI should be considered in children undergoing BMT.     

Long-term follow-up of a girl with Maroteaux-Lamy syndrome after bone marrow transplantation

Background  Mucopolysaccharidosis type VI (MPS VI or Maroteaux-Lamy syndrome) is a rare autosomal recessive genetic disorder. We treated a 10-year-old girl with Maroteaux-Lamy syndrome successfully with bone marrow transplantation (BMT). Methods  The patient had reconstitution with bone marrow from her HLA-matched brother. One month after BMT, arylsulfatase activity of the recipient’s leukocytes became normal. No graft-versushost disease (GVHD) was observed. Arylsulfatase B activity was maintained and the urinary excretion of glycosaminoglycans (GAGs) became normal. Results  The clinical response of the patient was slow but persistent during 12 years after BMT. Improved motor function included walking alone for a long distance without aid, riding a bicycle, taking a bath by herself, etc. Besides, few infections occurred. Exertional dyspnea, severe snoring, and vertigo were much improved. Conclusions  Early intervention is recommended for BMT. Allogeneic BMT may provide a better life quality as illustrated in the present case.     

MR appearances of bone marrow in children following bone marrow transplantation

Two cases are presented of children who demonstrated complete absence of bone marrow signal on MR imaging of the spine following bone marrow transplantation. The possible causes for these appearances are discussed.     

Long-term effects of bone marrow transplantation for inborn errors of metabolism: A study of four patients with lysosomal storage diseases

Long-term effects of bone marrow transplantation (BMT) were evaluated in patients with I-cell disease, metachromatic leukodystrophy (MLD), Maroteaux-Lamy syndrome or Hunter syndrome (mild form). Donors were human leukocyte antigen (HLA)-matched siblings, and the follow-up periods were 24–71 months after BMT. The enzyme activities were increased in leukocytes, plasma or liver tissues compared with pre-BMT levels. A patient with I-cell disease acquired development of 4–8 month old infants and showed no further progression in cardiac dysfunctions. A patient with MLD showed a decelerated disease progression and an improved peripheral neuropathy, but progressive brain atrophy was not prevented. Patients with Maroteaux-Lamy syndrome or Hunter syndrome showed improvements in hepatomegaly, joint contractures, short stature and tight skin, and this greatly increased their quality of life. These results indicated that the long-term therapeutic effects achieved by BMT were subject to multiple factors including biochemical improvements, a reversibility of affected tissues, or advanced states of disease and central nervous system impairments in inborn errors of metabolism.     

Cardiac involvement in mucopolysaccharidoses: effects of allogeneic bone marrow transplantation.

Echocardiography was performed in 16 children undergoing bone marrow transplantation (BMT) for mucopolysaccharidoses. Cardiac involvement before BMT was detected in seven (44%). One year after BMT (11 patients/five with cardiac involvement), left ventricular restriction resolved in 2/3 patients and hypertrophy in one. In the remainder, at mean follow up of 2.5 years, no progression of preexisting or development of new cardiac involvement was noted. It is concluded that in a significant proportion of patients with mucopolysaccharidoses, cardiac involvement improved after BMT.     

Haploidentical bone marrow transplantation in Mexico

Haploidentical hematopoietic cell transplantation using CD34⁺ cells depleted of T lymphocytes by the CliniMACS is a treatment for hematological malignancy. We report on four Mexican children, three with acute lymphocytic leukemia and one with chronic myelocytic leukemia, who was transplanted with 12 × 10⁶ CD34⁺ stem cells/kg body weight (98% of purity) with a follow‐up of years. The engraftment was successful in three of the four children. All showed cytomegalovirus reactivation, and one died because of graft rejection and infectious complication. The risk of infections was a major problem. Pediatr Blood Cancer 2012; 59: 950–952. © 2012 Wiley Periodicals, Inc.     

Enteral nutrition after bone marrow transplantation

Nutritional insult after bone marrow transplantation (BMT) is complex and its nutritional management challenging. Enteral nutrition is cheaper and easier to provide than parenteral nutrition, but its tolerance and effectiveness in reversing nutritional depletion after BMT is poorly defined. Nutritional status, wellbeing, and nutritional biochemistry were prospectively assessed in 21 children (mean age 7.5 years; 14 boys) who received nasogastric feeding after BMT (mean duration 17 days) and in eight children (mean age 8 years, four boys) who refused enteral nutrition and who received dietetic advice only. Enteral nutrition was stopped prematurely in eight patients. Greater changes in weight and mid upper arm circumference were observed in the enteral nutrition group, while positive correlations were found between the duration of feeds and increase in weight and in mid upper arm circumference. Vomiting and diarrhoea had a similar incidence in the two groups, while fever and positive blood cultures occurred more frequently in the dietetic advice group. Diarrhoea occurring during enteral nutrition was not associated with fat malabsorption, while carbohydrate malabsorption was associated with rotavirus infection only. Enteral feeding did not, however, affect bone marrow recovery, hospital stay, general wellbeing, or serum albumin concentrations. Hypomagnesaemia, hypophosphataemia, zinc and selenium deficiency were common in both groups. In conclusion, enteral nutrition, when tolerated, is effective in limiting nutritional insult after BMT. With existing regimens nutritional biochemistry should be closely monitored in order to provide supplements when required.     

Recent advances in bone marrow transplantation

The major barriers to successful bone marrow transplantation (BMT) are graft-versus-host disease (GVHD), infection, rejection and relapse. The combination of methotrexate and cyclosporin is significantly better than either alone in controlling GVHD. Removal of T cells from donor marrow prior to BMT has also decreased GVHD significantly, but a 5-10% rejection rate occurs and an increased relapse risk is being reported by some centres. Cyclosporin is valuable in the treatment of both acute and chronic GVHD. Interstitial pneumonitis due to cytomegalovirus (CMV) is a major cause of mortality. Protection can be provided with CMV hyperimmune globulin and also by the avoidance of blood donors who are CMV antibody positive. Fractionated total body irradiation is associated with decreased toxicity compared to single dose. There is a 75% 4 year disease-free survival following BMT for acute non-lymphoblastic leukemia in first remission, a 50% survival for acute lymphoblastic leukemia in second remission and an 88% survival for chronic myeloid leukemia in chronic phase. BMT for beta-thalassaemia major in young patients without organ dysfunction cures 80% of patients and identical results are achieved for severe aplastic anaemia when BMT is undertaken prior to blood product transfusion.     

Tube feeding and bone marrow transplantation

BACKGROUND: Children undergoing bone marrow transplantation (BMT) have poor oral intake during the transplant period, caused mainly by the intensive therapy used for their conditioning. Nutritional support (NS) is almost always needed. Whenever possible, tube feeding (TF) is preferred to parenteral nutrition (PN) because its more physiologic and causes fewer complications. However, children undergoing BMT are usually parenterally fed. We, therefore, studied whether TF was tolerated in children undergoing BMT and whether the nutritional intake was adequate in comparison to PN. PROCEDURE: Two groups were compared: TF (n = 12) and PN (n = 22). If intolerance for TF occurred, additional or total PN was given. Nutritional status, intake, complications, and costs were assessed. RESULTS: Both groups had an adequate nutritional status and reached 85% of their nutritional requirements. TF was possible in 62% of the NS days and three children could be exclusively fed with TF. A longer pre-transplant duration of TF seemed to increase the enteral tolerance. Gastrointestinal symptoms were equally frequent in TF as in PN, but cholestasis was less frequent in TF. The mean nutritional cost per child in the TF group was 440 US dollars less than in the PN group. CONCLUSIONS: TF is possible and equal in efficacy to PN in children undergoing BMT, and may have budgetary benefits.     

Haploidentical bone marrow transplantation for osteopetrosis

HLA-matched bone marrow transplantation is an effective form of treatment for some patients with malignant osteopetrosis, a defect of osteoclast function. Following transplant, normal osteoclasts differentiate from donor-derived marrow stem cells and can function normally in some of these patients. For patients without an HLA-matched marrow donor, pharmacologic treatments have not yet proved effective. This article demonstrates that normal osteoclast function can be obtained following the transplantation of HLA-nonidentical marrow that has been purged of T lymphocytes in vitro.     

Recent advances in bone marrow transplantation

The major barriers to successful bone marrow transplantation (BMT) are graft-versus-host disease (GVHD), infection, rejection and relapse. The combination of methotrexate and cyclosporin is significantly better than either alone in controlling GVHD. Removal of T cells from donor marrow prior to BMT has also decreased GVHD significantly, but a 5–10% rejection rate occurs and an increased relapse risk is being reported by some centres. Cyclosporin is valuable in the treatment of both acute and chronic GVHD. Interstitial pneumonitis due to cytomegalovirus (CMV) Is a major cause of mortality. Protection can be provided with CMV hyperimmune globulin and also by the avoidance of blood donors who are CMV antibody positive. Fractionated total body irradiation is associated with decreased toxicity compared to single dose. There is a 75% 4 year disease-free survival following BMT for acute non-lymphoblastic leukaemia in first remission, a 50% survival for acute lymphoblastic leukaemia in second remission and an 88% survival for chronic myeloid leukaemia in chronic phase. BMT for β-thalassaemia major in young patients without organ dysfunction cures 80% of patients and identical results are achieved for severe aplastic anaemia when BMT is undertaken prior to blood product transfusion.     

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 in a child without symptoms but signs of demyelination on MRI, if a suitable donor is available.     

Thyrotoxicosis after matched unrelated bone marrow transplantation

Acquired hyperthyroidism is most commonly autoimmune in etiology. In the setting of allogeneic bone marrow transplantation (BMT), the use of radiotherapy (total body irradiation) as part of the regimen prior to BMT is known to cause endocrine dysfunction, especially hypopituitarism and hypothyroidism, but hyperthyroidism is rare. The authors report this unusual and late complication in a young boy after BMT for relapsed childhood lymphoblastic leukemia and discuss the possible etiologies.     

Stages in pediatric bone marrow transplantation.

Bone marrow transplantation is a relatively new and aggressive procedure that is being used in the treatment of leukemia and aplastic anemia. We observed approximately 30 children and their families at the UCLA Medical Center throughout the procedure. Various psychological responses during the treatment are outlined. Eleven stages are identified, including the patient's and family's first awareness of this procedure, the preadmission evaluation and psychosocial assessment, the introduction into isolation, the donor's hospitalization, the transplantation itself, and the various reactions and interactions of the patient, family, and staff throughout these stages.     

Endocrine complications following pediatric bone marrow transplantation

Pediatric bone marrow transplantation (BMT) for various diseases can lead to endocrine system dysfunction owing to preparative regimens involving chemotherapy and radiation therapy. We assessed the prevalence of post-BMT endocrine complications in children treated at the Alberta Children's Hospital (ACH) from 1991 to 2001. Time of onset of endocrine dysfunction, underlying disease processes, chemotherapy, radiation therapy and age at BMT were characterized. Subjects of <18 years of age at the time of allogeneic or autologous BMT for whom 1-year follow-up through the ACH and a chart were available for review were included in the study. Subjects with a pre-existing endocrine condition were excluded. Of the 194 pediatric BMT procedures performed at the ACH between January 1, 1991 and December 31, 2001, 150 complete charts were available for review. Sixty five subjects received follow-up care at other centers and were excluded. Therefore, a total of 85 subjects were included in the review. The prevalence of endocrine complications identified was: primary hypothyroidism 1.2%, compensated hypothyroidism 7.0%, hyperthyroidism 2.4%, hypergonadotrophic hypogonadism 22.4%, abnormal bone density 2.4%, and secondary diabetes mellitus 1.2%. These findings emphasize the need to screen for endocrine system dysfunction, particularly hypergonadotrophic hypogonadism, in children who have undergone BMT. Children need long-term follow-up so that endocrine complications can be diagnosed and treated promptly.