Hematopoietic cell transplantation for Chediak-Higashi syndrome.

We reviewed outcomes after allogeneic hematopoietic cell transplantation (HCT) in 35 children with Chediak-Higashi syndrome (CHS). Twenty-two patients had a history of the life-threatening accelerated phase of CHS before HCT and 11 were in accelerated phase at transplantation. Thirteen patients received their allograft from an human leukocyte antigen (HLA)-matched sibling, 10 from an alternative related donor and 12 from an unrelated donor. Eleven recipients of HLA-matched sibling donor, three recipients of alternative related donor and eight recipients of unrelated donor HCT are alive. With a median follow-up of 6.5 years, the 5-year probability of overall survival is 62%. Mortality was highest in those with accelerated phase disease at transplantation and after alternative related donor HCT. Only four of 11 patients with active disease at transplantation are alive. Seven recipients of alternative related donor HCT had active disease at transplantation and this may have influenced the poor outcome in this group. Although numbers are limited, HCT appears to be effective therapy for correcting and preventing hematologic and immunologic complications of CHS, and an unrelated donor may be a suitable alternative for patients without an HLA-matched sibling. Early referral and transplantation in remission after accelerated phase disease may improve disease-free survival.

Role of chest computed tomography at diagnosis in the management of Wilms' tumor: a study by the United Kingdom Children's Cancer Study Group.

PURPOSE: This study sought to determine whether the identification of minimal pulmonary metastatic disease by chest computed tomography (CT) performed at diagnosis in patients with Wilms' tumor and normal chest x-rays (CXR) could predict a subgroup of children at increased risk of pulmonary relapse. PATIENTS AND METHODS: A retrospective analysis was carried out of the records of 449 children entered onto the United Kingdom Childrens' Cancer Study Group Second Wilms' Tumor Study between July 1986 and September 1991. The imaging protocol did not stipulate chest CT at diagnosis, but 141 children who had normal frontal and lateral CXRs and a chest CT scan performed at diagnosis were eligible for analysis. After surgery, children with stage I Wilms' tumor received single-agent chemotherapy (vincristine), whereas children with stages II, III, and bilateral Wilms' tumor received combination chemotherapy. Most children with stage III tumors were also treated with abdominal radiotherapy (20 Gy). RESULTS: In 31 patients (22%), pulmonary nodules were visible on chest CT; eight experienced relapse, four (15%) in the lungs. When only stage I patients were analyzed, there was a significant difference between the pulmonary relapse rate of 43% (three of seven) in the CT-positive group and 10% (five of 48) in the CT-negative group (P =.02). Four of eight patients with stage I disease with pulmonary relapse died. CONCLUSION: CT seemed to identify a subgroup of stage I patients who were at increased risk of pulmonary relapse. These children had received only single-agent chemotherapy. A prospective randomized trial is needed to clarify whether these children would benefit from combination chemotherapy.

Fatal graft-versus-host disease following HLA-mismatched donor lymphocyte infusion.

We report the case of a 10-year-old boy with molecular relapse of CML following unrelated donor BMT who developed fatal grade 4 acute GVHD of the gut and liver following one antigen-mismatched donor lymphocyte infusion. Previous experience of donor lymphocyte infusion in the HLA-mismatched setting is reviewed and the role of adoptive immunotherapy in this situation is discussed.

Improved outcome of alternative donor bone marrow transplantation in children with severe aplastic anaemia using a conditioning regimen containing low-dose total body irradiation, cyclophosphamide and Campath.

The increasing success of human leucocyte antigen (HLA)-matched sibling donor (MSD) transplants and combination immunosuppressive treatments have dramatically improved the prognosis of severe aplastic anaemia (SAA) in children and young adults. For patients who lack a MSD there is a significant minority who fail immunosuppressive therapy or suffer from a severe constitutional aplastic anaemia in which immunosuppression would be ineffective. Alternative donor bone marrow transplantation (AD-BMT) has only had limited success in this context. We report the successful outcome of AD-BMT in eight consecutive patients aged 7 months to 15 years, six of whom had acquired aplastic anaemia who had previously failed to respond to immunosuppression, and two of whom had a severe (non-Fanconi) constitutional aplastic anaemia. All eight patients had received multiple red cell and platelet transfusions. We used a new combination of agents for pretransplant conditioning aiming to maximize immunosuppression and minimize toxicity, consisting of Campath-1G or -1H, cyclophosphamide and low-dose total body irradiation (LD TBI) or fludarabine. Toxicity was minimal and all eight children are alive, well and free of disease at a median follow-up of 32 months. We suggest that this approach could facilitate the successful treatment of children with SAA in whom immunosuppressive therapy has failed or is not appropriate.

Unexpected and variable phenotypes in a family with JAK3 deficiency.

Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vbeta family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.

Clinical course of patients with major histocompatibility complex class II deficiency.

The clinical course of 10 children who have been diagnosed with major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) in the UK over the past eight years is described. They have had a generally poor prognosis, with only two of the 10 still alive despite eight attempts at bone marrow transplantation in six patients. Overwhelming viral infection was the predominant cause of death. Alternative transplant strategies or novel therapies are required for these patients.

Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders.

This was an open study of oral antifungal prophylaxis in 103 neutropenic children aged 0-14 (median 5) years. Most (90%) were undergoing transplantation for haematological conditions (77% allogeneic BMT, 7% autologous BMT, 6% PBSC transplants and 10% chemotherapy alone). They received 5.0 mg/kg itraconazole/day (in 10 mg/ml cyclodextrin solution). Where possible, prophylaxis was started at least 7 days before the onset of neutropenia and continued until neutrophil recovery. Of the 103 who entered the study, 47 completed the course of prophylaxis, 27 withdrew because of poor compliance, 19 because of adverse events and 10 for other reasons. Two patients died during the study and another five died within the subsequent 30 days. No proven systemic fungal infections occurred, but 26 patients received i.v. amphotericin for antibiotic-unresponsive pyrexia. One patient received amphotericin for mycologically confirmed oesophageal candidosis. Three patients developed suspected oral candidosis but none was mycologically proven and no treatment was given. Serious adverse events (other than death) occurred in 21 patients, including convulsions (7), suspected drug interactions (6), abdominal pain (4) and constipation (4). The most common adverse events considered definitely or possibly related to itraconazole were vomiting (12), abnormal liver function (5) and abdominal pain (3). Tolerability of study medication at end-point was rated as good (55%), moderate (11%), poor (17%) or unacceptable (17%). Some patients had poor oral intakes due to mucositis. No unexpected problems of safety or tolerability were encountered. We conclude that itraconazole oral solution may be used as antifungal prophylaxis for neutropenic children.

Haploidentical related transplants and unrelated donor transplants with T cell addback.

Only 30% of children have a matched family donor (MFD). Alternative donors can be found from volunteer unrelated donor (UD) panels, and almost every child has a haploidentical parental donor (Haplo). The outcome of alternative donor BMT has previously been inferior due to increased graft rejection and GVHD. The recent outcome of 121 consecutive children undergoing MFD, UD, and Haplo BMT between 1994 and 1997 was analysed. [table in text] Preparative regimens for MFD/UD/Haplo BMT respectively included TBI in 30%/36%/11%, chemotherapy only in 59%/64%/89%, Campath 1G or none n 14%/ 0%/0%. The balance of GVHD and rejection was addressed by T-cell depletion (Campath 1M) in 2/71 MFD BMTs, T-cell depletion with addback of 5 x 10(4) T cells/kg on day zero in 33/41 UD BMTs, and T cell depletion of purified mobilised peripheral blood CD34+ cells and bone marrow in 9/9 Haplo BMTs. Stable engraftment was achieved in 68/71, and 35/41 (one patient after 2nd BMT) and 7/9 MFD, UD, and Haplo BMTs respectively. Median follow up, survival, disease free survival and, death rates for MFD/UD/Haplo BMT were 12/12/12 months, 74%/77%/78%, 69%/67%/67%, and 27%/23%/23% respectively. Within a wide range of paediatric diseases the outcome of alternative donor BMT now parallels that of MFD BMT.

Agranulocytosis in a patient with thalassaemia major during treatment with the oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one.

Agranulocytosis developed in a 20-year-old Greek patient with beta-thalassaemia major, 11 weeks after commencing chelation with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) and 6 weeks after receiving the drug at a total daily dose of 105 mg/kg. The patient presented with generalised weakness, low-grade fever and sore throat. The total white cell count was 2.0 x 10(9)/l with 0.1 x 10(9)/l neutrophils. The patient was admitted to hospital and successfully treated with intravenous broad-spectrum antibiotics. Neutrophil count recovered 7 weeks later. A number of immunological tests were performed in an attempt to elucidate the cause of agranulocytosis. These investigations gave inconclusive evidence for the presence of a weak IgM antibody to myeloid cells exposed to L1 in this patient. Further studies are required, however, to evaluate the mechanism in any other patient who develops agranulocytosis in association with L1 therapy.

Clinical experience of clozapine-induced neutropenia in the UK. Laboratory investigation using liquid culture systems and immunofluorocytometry.

An incidence of drug-induced neutropenia of 2.5% has been found in the first 1000 patients to be treated with clozapine in the UK. The majority of affected patients experienced mild neutropenia (n = 22) with only 3 patients developing agranulocytosis. Data collected from these 25 patients suggest that the mechanism of neutropenia may be multifactorial. Laboratory investigation using liquid culture systems and immunofluorocytometry has identified clozapine and its major metabolite N-desmethyl clozapine as exhibiting toxic effects against myeloid maturation and myeloid mitotic compartments, respectively. Increased susceptibility to the toxic effects of clozapine was shown in 1 patient who had previously developed clozapine-associated neutropenia. No clinical or laboratory evidence of drug-induced antineutrophil or antimyeloid precursor antibodies was found.

Cellular changes during the infusion of high dose intravenous immunoglobulin.

With the ever widening group of autoimmune conditions that are beneficially affected by infusions of high dose immunoglobulin the possible mechanisms of action of such therapy appear increasingly complex. Fc mediated blockade of the mononuclear phagocyte system is an acknowledged early effect. This is, however, accompanied by a decrease of neutrophil counts which suggests that IgG binding to the neutrophil may be a mechanism of action. The decrease of neutrophil counts is transient but in immune thrombocytopenia is inversely proportional to the platelet response observed. In parallel to the effect on the neutrophil there are changes in the lymphocyte subsets with reversal of the T helper/suppressor ratio and alterations in the individual cellular constituents of each subset that correlate with the clinical response. The observed changes in B cell numbers and function suggest that T dependent and independent antibody production is effected by intravenous immunoglobulin. It is increasingly clear that in ITP at least the clinical response to IV IgG is a summation of several cellular events and their balance reflects the ultimate outcome. It may eventually be possible to use these observations to predict the likely outcome in the individual patient of this mode of therapy.

Pericardial effusion following conditioning for bone marrow transplantation in acute leukaemia.

We report the details of a young woman in whom pericardial tamponade developed acutely following preparation for allogeneic bone marrow transplantation for acute lymphoblastic leukaemia. The aetiology of the effusion, though uncertain, probably relates to the cumulative cardiotoxicity of cyclophosphamide and irradiation upon a myocardium previously sensitised by anthracycline therapy. As the number of transplant procedures increases, this complication may become more common, and might be avoided by a more critical assessment of cardiac function prior to transplantation, with radionuclide angiography.