William Krivit

Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis.

Nineteen patients whose bone marrow smears showed histiocytic hyperplasia with prominent hemophagocytosis were found to have a clinicopathologic syndrome associated with active viral infection. High fever, constitutional symptoms, liver function, and coagulation abnormalities and peripheral blood cytopenias were characteristic findings. Hepatosplenomegaly, lymphadenopathy, bilateral pulmonary infiltrates, and skin rash were often present. Fourteen of the patients were immunosuppressed. Active infection by herpes group viruses was documented in 14 patients and by adenovirus in 1. The bone marrow of most patients also showed decreased granulopoiesis and erythropoiesis with normal to increased numbers of megakaryocytes. Treatment generally consisted of supportive therapy and withdrawal of immunosuppressive drugs. Thirteen patients recovered. Lymph node biopsy and autopsy material showed generalized histiocytic hyperplasia with hemophagocytosis. The relationship of this disorder to familial hemophagocytic reticulosis, familial erythrophagocytic lymphohistiocytosis, histiocytic medullary reticulosis, and malignant histiocytosis is discussed. Immunosuppressive and cytotoxic therapy may be contraindicated in the treatment of this virus‐associated syndrome.

Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).

Patients with Hurler syndrome (mucopolysaccharidosis type-IH) and metachromatic leukodystrophy (MLD) develop significant skeletal and neurologic defects that limit their survival. Transplantation of allogeneic hematopoietic stem cells results in partial correction of the clinical manifestations. We postulated that some of these defects may be corrected by infusion of allogeneic, multipotential, bone marrow-derived mesenchymal stem cells (MSC). Patients with Hurler syndrome (n = 5) or MLD (n = 6) who previously underwent successful bone marrow transplantation from an HLA-identical sibling were infused with 2–10 × 106/kg MSCs, isolated and expanded from a bone marrow aspirate of the original donor. There was no infusion-related toxicity. In most recipients culture-purified MSCs at 2 days, 30–60 days and 6–24 months after MSC infusion remained of host type. In two patients the bone marrow-derived MSCs contained 0.4 and 2% donor MSCs by FISH 60 days after MSC infusion. In four patients with MLD there were significant improvements in nerve conduction velocities after MSC infusion. The bone mineral density was either maintained or slightly improved in all patients. There was no clinically apparent change in patients’ overall health, mental and physical development after MSC infusion. We conclude that donor allogeneic MSC infusion is safe and may be associated with reversal of disease pathophysiology in some tissues. The role of MSCs in the management of Hurler syndrome and MLD should be further evaluated.

Successful bone-marrow transplantation for infantile malignant osteopetrosis

A five-month-old girl with autosomal-recessive osteopetrosis received a bone-marrow transplant from her five-year-old HLA-MLC-identical brother after preparation with cyclophosphamide and modified total-body irradiation. Engraftment was documented by chromosomal analysis. Anemia, thrombocytopenia, and leukoerythroblastosis corrected within 12 weeks of transplantation. Low serum calcium and elevated serum alkaline and acid phosphatase levels became normal. Serial x-ray studies revealed bony remodeling and new nonsclerotic bone formation. A pretransplantation bone biopsy revealed small marrow spaces, rare marrow elements, increased osteoclasts, and no bony resorption. After transplantation, osteoclasts were actively resorbing bone, and medullary cavities contained normal bone marrow. Fluorescent Y-body analysis after transplantation revealed donor (male) osteoclasts and recipient (female) osteoblasts. Monocyte bactericidal activity, markedly decreased before transplantation, became normal. Vision, hearing, growth, and development were progressively improving 16 months after transplantation. Allogeneic bone-marrow transplantation appears to be the treatment of choice in this fatal disorder.

Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy.

BACKGROUND Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.

Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III.

Over 400 patients with lysosomal and peroxisomal storage diseases have received hematopoietic stem cell transplantation from normal donors. Without treatment, all of these diseases have an inexorable fate leading to central nervous system deterioration and early death. On the other hand, all of the engrafted hosts have had a remarkable positive clinical improvement in response to normalization of previously deficient enzymatic activity. Survival data for those engrafted indicates continued life-span as long as two decades beyond transplantation. The particular diseases treated in this way are included in this article. The specific indications and methods for transplantation are also included in this article.

Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy

BACKGROUND The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3-5 years once clinical symptoms are detectable. The hypothesis to be tested was whether bone-marrow transplantation can over an extended period of time halt the inexorable progressive demyelination and neurological deterioration. METHODS 12 patients with childhood onset of cerebral X-linked adrenoleukodystrophy have been followed for 5-10 years after bone-marrow transplantation. Magnetic resonance imaging (MRI), neurological, neuropsychological, electrophysiological, and plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of this treatment. FINDINGS MRI showed complete reversal of abnormalities in two patients and improvement in one. One patient showed no change from baseline to last follow-up. All eight patients who showed an initial period of continued demyelination stabilised and remained unchanged thereafter. Motor function remained normal or improved after bone-marrow transplantation in ten patients. Verbal intelligence remained within the normal range for 11 patients. Performance (non-verbal) abilities were improved or were stable in seven patients. Decline in performance abilities followed by stability occurred in five patients. Plasma VLCFA concentrations decreased by 55% and remained slightly above the upper limits of normal. INTERPRETATION 5-10-year follow-up of 12 patients with childhood-onset cerebral X-linked adrenoleukodystrophy shows the long-term beneficial effect of bone marrow transplantation when the procedure is done at an early stage of the disease.

Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases.

Human bone marrow contains mesenchymal stem cells (MSCs) that can differentiate into various cells of mesenchymal origin. We developed an efficient method of isolating and culture expanding a homogenous population of MSCs from bone marrow and determined that MSCs express alpha-L-iduronidase, arylsulfatase-A and B, glucocerebrosidase, and adrenoleukodystrophy protein. These findings raised the possibility that MSCs may be useful in the treatment of storage disorders. To determine if donor derived MSCs are transferred to the recipients with lysosomal or peroxisomal storage diseases by allogeneic hematopoietic stem cell (HSC) transplantation, we investigated bone marrow derived MSCs of 13 patients 1-14 years after allogeneic transplantation. Highly purified MSCs were genotyped either by fluorescence in situ hybridization using probes for X and Y-chromosomes in gender mis-matched recipients or by radiolabeled PCR amplification of polymorphic simple sequence repeats. Phenotype was determined by the measurement of disease specific protein/enzyme activity in purified MSCs. We found that MSCs isolated from recipients of allogeneic HSC transplantation are not of donor genotype and have persistent phenotypic defects despite successful donor type hematopoietic engraftment. Whether culture expanded normal MSCs can be successfully transplanted into patients with storage diseases and provide therapeutic benefit needs to be determined.

A Randomized Study of the Prevention of Acute Graft-versus-Host Disease

Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 per cent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants.

Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation

SummaryNeuropsychological assessment is essential in providing documentation of the untreated natural history of storage diseases associated with dementia and quantifying the effectiveness of treatment on central nervous system function. Baseline characterization and outcome of bone marrow transplantation (BMT) for three leukodystrophies and three mucopolysaccharidoses are presented. Results suggests that BMT for Hurler syndrome, adrenoleukodystrophy, and globoid cell leukodystrophy can be effective in preventing dementia if done early enough in the disease. Sanfilippo and Hunter syndromes do not benefit and BMT is not recommended. For metachromatic leukodystrophy, BMT is not recommended for symptomatic early-onset forms of the disease. Further longitudinal follow-up is needed to determine whether the benefits outweigh the risks of BMT for late-onset and preclinical metachromatic leukodystrophy.

The Wiskott-Aldrich syndrome in the United States and Canada (1892-1979).

Information was collected on 301 cases of the Wiskott-Aldrich syndrome in the United States and Canada Examination of available medical records, death certificates and published case reports on these patients showed that they came from a wide geographic area and many diverse ethnic and racial groups. No significant difference was found in the incidence of cases born between 1947 and 1976; the overall rate was 4.0 per million live male births in the United States. Median survival has increased with time from eight months for patients born before 1935 to 6.5 years for those born after 1964. Seventy-six of the 301 patients (25%) were still alive at last follow-up and ranged in age from 1 to 36 years with a median of 10 years. Causes of death were primarily limited to infections or bleeding, but malignancy represented a significant problem. Twelve percent of the group (36 of 301) developed malignancy, the predominant types being lymphorecticular tumors (23 of 36) and leukemia (7 of 36). The overall relative risk for malignancy was found to be greater than 100 times that of the general population and was found to increase with increasing age.