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In this study we have identified frequent human leukocyte antigen (HLA)-A, -B, -C,-DRB1, and -DQB1 alleles, frequent HLA-B/C, HLA-DRB1/DQB1 two-allele associations, and the most common HLA-A/B/C/DRB1/DQB1 five-locus haplotypes in a population residing in the Paris, France, area. The study was carried out in 356 families of children awaiting hematopoietic stem-cell transplantation (HSCT), with the selection criterion that haplotypes could be assigned with certainty to both the patient and at least one parent. Parental haplotypes were HLA-A, -B serologically typed, and HLA-C, -DRB1, -DQB1 broadly typed by polymerase chain reaction-sequence-specific oligonucleotide probe. The alleles of the most frequent haplotypes were subsequently defined at a high-resolution level by polymerase chain reaction-sequence-specific primer. The results on the distribution of common alleles and common allele associations demonstrated similarities with the previously published data in Caucasian populations, as expected from the geographic origin of the studied population. More importantly, this study provides the largest listing of common B/C and DRB1/DQB1 associations and of common five-allele haplotypes defined with certainty in a Caucasian population to date. These results can be used to help estimate the likelihood of finding a suitable donor in unrelated HSCT and to delineate search strategies for potential donors.

Adenovirus infection remains an important cause of mortality after bone marrow transplantation (BMT). Currently no efficient antiviral treatment is known. Thus, testing new modalities of early diagnosis and treatment is a crucial objective. Adenovirus infection is defined by the combination of symptoms and the isolation of virus from the source of clinical symptoms. The involvement of two or more organs and the presence of virus in blood cultures define disseminated disease. Seven children with a median age of 7 years received bone marrow transplantation for leukemia. All received an unrelated graft without T cell depletion. Adenovirus was sought in blood, urine and biopsy specimens using PCR and culture. Analysis of biopsy specimens included systematic immunohistochemistry. Cidofovir treatment was initiated as soon as biopsy revealed the histopathological signs of adenovirus. Cidofovir was given at 5 mg/kg once weekly for 3 weeks then every 2 weeks. Six patients had diarrhoea and one patient had cystitis. Adenovirus infection and disseminated disease were diagnosed in four cases and three cases, respectively. In six cases, serotype A31 was isolated from gastrointestinal biopsy and in two cases serotypes B2 and C6 were detected in blood and urine. Cidofovir treatment was associated with clinical improvement of diarrhoea, cystitis and fever in five patients, in whom the virus became undetectable in cultures and PCR analyses despite the persistence of immunodeficiency. The median follow-up was 360 days after BMT (240-570). One child died of invasive aspergillosis and another of disseminated adenovirus after interruption of cidofovir therapy. Further studies in immunocompromised patients will be needed to extend these promising results concerning the role of cidofovir in adenovirus infection.

Improvements in HLA-typing by DNA-based methods now allow accurate genotyping of unrelated bone marrow (UBM) donors and recipients and also definition of haplotypes. In this regard, B*5002 has been predicted in linkage disequilibrium with Cw*0602, DRB1*0406 and DQB1*0402 based on the frequency of allele coexistence. Here, we confirm this assumption by HLA genotyping of four informative families and three unrelated individuals. In the four families, the extended haplotype HLA-B*5002, -Cw*0602, -DRB1*0406, DQB1*0402 can be definitely assigned by the mode of heritance. Furthermore, this association of alleles was also found in the three B*5002 unrelated individuals. Knowledge of the frequent linkage disequilibrium of these rare alleles can improve UBM donor search strategies.

The spontaneous proliferation and the effects of 8 various growth factors (GF) were evaluated on leukemic cells from 27 patients with B-lineage ALL. Two groups of ALLs were distinguished. ALLs from group I (21 patients) exhibited a low spontaneous proliferative rate and were stimulated by IL-3 + IL-7 +/- SCF and/or LIF, while ALLs from group II (6 patients) had a high spontaneous proliferative rate and did no longer require this combination of GFs for proliferation. No effect of bFGF, IGF-I, IL-10 and IL-11 alone or in combination, was observed. Such differences in the behaviour of B-ALLs indicated that the GF requirement of ALL blasts was not related to the presence of serum in the culture nor to the pattern of reactivity of ALL blasts for B lymphoid markers or CD34 antigen. Furthermore, we showed in 1/9 cases that high proliferation might be due to an overexpression of the bcl-2 proto-oncogene and to the acquisition of an autocrine secretion.

Post-transplant lymphoproliferative disorder (PTLD) after haemopoietic stem cell transplantation is a serious complication that occurs in 8-22% of patients with high-risk factors. We retrospectively investigated tolerance and efficacy of humanized anti-CD20 monoclonal antibody (rituximab) as first-line treatment in 12 children with B-cell PTLD. At diagnosis, eight patients had tumoral involvement. The other four patients had fever, associated with raised Epstein-Barr virus (EBV) viral load and monoclonal gammopathy. Rituximab was given at the dose of 375 mg/m2 once a week by intravenous infusion (1-9 infusions). Only 1/48 infusions was associated with a grade 2 clinical adverse event. Eight out of 12 (66%) patients responded to the treatment and were in complete remission. All patients without tumoral involvement responded to the treatment. A rapid decrease in fever within 1 week was observed in all responders. Non-responders did not show any clinical response during the first week. Tumoral involvement and immunodepression seemed to be more marked in non-responders. Rituximab was an effective and well-tolerated treatment of B-cell PTLD. Early treatment before tumoral involvement seemed to be the most effective approach. Lack of rapid response should lead to intensification of PTLD treatment. Pre-emptive treatment should be considered and evaluated in further longitudinal multicentre studies.

Bone marrow transplantation (BMT) from matched sibling donors has been useful for the treatment of acute lymphoblastic leukaemia in children with a poor prognosis but is not available to more than two-thirds of patients who do not have a matched allogeneic donor. This study was undertaken to assess one strategy of marrow graft rejection prevention when alternative marrow sources such as HLA-phenoidentical unrelated volunteers and HLA-partially incompatible relatives were used. Results have been compared with two matched groups of children with the same risks factors and disease status who underwent HLA-genoidentical or autologous BMT. The conditioning regimen was the same for the three groups of patients; in the study group anti-LFA-1 and anti-CD2 monoclonal antibodies combined with T-cell depletion of the marrow was added to prevent graft rejection and graft-versus-host disease. Nineteen patients were included and followed for a median of 25 months (14 months to 3 years). Bone marrow engraftment occurred in 83% of the evaluable patients. Post-transplantation infectious diseases were the most frequent causes of death in the study group, occurring in 31% of patients. No fatal infections occurred in the two control groups. Post-transplantation relapse of leukaemia occurred in 26% of study group's patients, in 58% of autologous BMT control group's patients and 5% of HLA-genoidentical allogeneic group's patients. The event-free survival was 83% in the HLA-genoidentical control group, and 30% and 24% in the study group and in the autologous control group, respectively. In conclusion, a high rate of engraftment was achieved by the use of anti-LFA-1 and anti CD2 antibodies. Occurrence of a long-lasting immunodeficiency, however, led to a high incidence of lethal infections and relapses. Combined approaches are therefore to be investigated accelerating immune reconstitution after transplantations of T-depleted HLA partially incompatible marrow.

A nationwide, longitudinal study of infants born to human immunodeficiency virus-seropositive mothers has been under way in France since 1986. After 7 years of follow-up observations, we will update our assessment of the transmission rate in France and analyze, on a larger number of mother-infant pairs, the influence of maternal factors. Among the 848 pairs included in this analysis, the transmission rate was 20.2 +/- 2.7%. The transmission rate has remained stable with time and was not influenced by the mode of delivery, the mode of maternal infection, or the mother's ethnic origin. It was twice as high among the breast-fed infants as among the bottle-fed infants (40 vs. 19%, p0.04). Two factors were identified in a multivariate analysis (that did not include lymphocyte subset counts and the mode of feeding) as being associated with an increased risk of maternofetal transmission: p24 antigenemia (odds ratio = 3.1, confidence interval, = 1.5-6.2; p0.003) and elevated maternal age (p0.05). In the subgroup of 277 women whose absolute CD4+ lymphocyte counts at the time of delivery were available, the risk of transmission increased gradually from 15% of counts of600 CD4+ cells to 43% at counts of200. The risk of transmission was also related to the percentage of CD8+ cells, but each of the two factors seemed to play an independent role: the risk was lowest (12%) when the CD4+ cell count was500 and the proportion of CD8+ cells wasor = 40%, and was highest (50%) for values200 and40%.(ABSTRACT TRUNCATED AT 250 WORDS)

The treatment of children with acute lymphoblastic leukaemias (ALL) according to EORTC 58951 protocol is divided into 3 phases (induction, consolidation, maintenance). During the induction phase, patients are randomly assigned to receive either prednisone or dexamethasone (associated with anticancer drugs). The response to corticotherapy is evaluated by the quantification of the residual disease (RD) at day 35 of treatment and has an major impact on prognosis and treatment: patients with an RD lower than 10−2/100 000 cells. The distribution of CYP3A genotypes was : *1/*1: 2,7%, *1/*3: 18,8% and *3/*3: 78,5%, in aggrement with already published data. CYP3A5*2 and *6 mutations were not found There was no difference in the response to corticosteroid treatment according to individual CYP3A5 genotypes or to the type of corticosteroid. Our results did not evidence an impact of CYP3A5 on the initial response to corticosteroids. Clinical Pharmacology & Therapeutics (2004) 75, P20–P20; doi: 10.1016/j.clpt.2003.11.075