Marie-Françoise Dresse

Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium

Fifty patients affected by sickle cell anaemia underwent transplantation of HLA-identical haematopoietic stem cells (bone marrow, 48; cord blood, 2). Two groups of patients were considered for transplantation. Group 1 included 36 permanent residents of a European country who, retrospectively, met the inclusion criteria accepted at a consensus conference held in Seattle in 1990, wherein children were selected because they already had evidence of a morbid course. Group 2 included 14 patients who were transplanted earlier, had not received more than three blood transfusions and were transplanted because they had decided to return to their country of origin. Kaplan–Meier estimates of overall survival, event-free survival and disease-free survival at 11 years of the whole grafted population are 93, 82 and 85%, respectively. In group 1, overall survival, EFS and DFS were 88, 76 and 80% and in group 2, 100, 93 and 93%, respectively. Clinical manifestations of the disease, as well as disease associated haemolytic anaemia, disappeared in all successfully treated patients. Recovery of spleen function was present in seven out of 10 evaluated patients. Adverse events (death, absence of engraftment, mixed chimerism and relapse) occurred more frequently in group 1 than in group 2 (25% vs 7%, P < 0.001). acute graft-versus-host disease (gvhd) was present in 20 patients (grade i or ii, 19; grade iii, 1), chronic gvhd in 10 (limited, 7; extensive, 3). one patient developed an acute myeloid leukaemia. gonadal dysfunction was present in all patients (six boys and eight girls) transplanted close to or after puberty, although transient in one adolescent girl.

18F-FDG PET in children with lymphomas

PurposeThe aim of this study was to retrospectively evaluate the performance of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) in children with lymphomas, at various stages of their disease.MethodsTwenty-eight children (mean age 12.5 years, 14 girls, 14 boys) with Hodgkin’s disease (HD, n=17) or non-Hodgkin’s lymphoma (NHL, n=11) were evaluated. Patients were investigated at initial staging (n=19), early in the course of treatment (n=19), at the end of treatment (n=16) and during long-term follow-up (n=19). A total of 113 whole-body PET studies were performed on dedicated scanners. PET results were compared with the results of conventional methods (CMs) such as physical examination, laboratory studies, chest X-rays, computed tomography, magnetic resonance imaging, ultrasonography and bone scan when available.ResultsAt initial evaluation (group 1), PET changed the disease stage and treatment in 10.5% of the cases. In early evaluation of the response to treatment (group 2), PET failed to predict two relapses and one incomplete response to treatment. In this group, however, PET did not show any false positive results. There were only 4/75 false positive results for PET among patients studied at the end of treatment (group 3, specificity 94%) or during the systematic follow-up (group 4, specificity 95%), as compared with 27/75 for CMs (specificity 54% and 66%, respectively).Conclusion18F-FDG-PET is a useful tool for evaluating children with lymphomas. Large prospective studies are needed to appreciate its real impact on patient management.

Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment.

To evaluate the survival of patients with sickle cell disease (SCD) recorded in the Belgian SCD Registry and to assess the impact of disease‐modifying treatments (DMT).

The International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped-Study) : Objectives and Preliminary Results

Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9-dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs.

Value of High-Dose Cytarabine During Interval Therapy of a Berlin-Frankfurt-Munster–Based Protocol in Increased-Risk Children With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma: Results of the European Organization for Research and Treatment of Cancer 58881 Randomized Phase III Trial

PURPOSE The European Organization for Research and Treatment of Cancer 58881 study was designed to test in a prospective multicentric randomized trial the value of high-dose (HD) intravenous (IV) cytarabine (Ara-C) added to HD IV methotrexate (MTX) to reduce the incidence of CNS and systemic relapses in children with increased-risk acute lymphoblastic leukemia (ALL) or stage III and IV lymphoblastic lymphoma treated with a Berlin-Frankfurt-Munster (BFM)-based regimen. PATIENTS AND METHODS After completion of induction-consolidation phase, children with increased-risk (risk factor > 0.8 or T-lineage) ALL or stage III and IV lymphoblastic lymphoma were randomized to receive four courses of HD MTX (5 g/m(2) over 24 hours every 2 weeks) and four intrathecal administrations of MTX (Arm A) or the same treatment schedule with additional HD IV Ara-C (1 g/m(2) in bolus injection 12 and 24 hours after the start of each MTX infusion) (Arm B). RESULTS Between January 1990 and January 1996, 653 patients with ALL (593 patients) or lymphoblastic lymphoma (60 patients) were randomized: 323 were assigned to Arm A (without Ara-C) and 330 to Arm B (with Ara-C). A total of 190 events (177 relapses and 13 deaths without relapse) were reported, and the median follow up was 6.5 years (range, 2 to 10 years). The incidence rates of CNS relapse were similar in both arms whether isolated (5.6% and 3.3%, respectively) or combined (5.3% and 4.6%, respectively). The estimated 6-year disease-free survival (DFS) rate was similar (log-rank P =.67) in the two treatment groups: 70.4% (SE = 2.6%) in Arm A and 71.0% (SE = 2.5%) in Arm B. The 6-year DFS rate was similar for ALL and LL patients: 70.2% (SE = 1.9%) versus 76.3% (SE = 5.6%). CONCLUSION Prevention of CNS relapse was satisfactorily achieved with HD IV MTX and intrathecal injections of MTX in children with increased-risk ALL or stage III and IV lymphoblastic lymphoma treated with our BFM-based treatment protocol in which cranial irradiation was omitted. Disappointingly, with the dose schedule used in this protocol, HD Ara-C added to HD MTX, although well tolerated, failed to further decrease the incidence of CNS relapse or to improve the overall DFS.

Neonatal haemoglobinopathy screening in Belgium

Background: A neonatal haemoglobinopathy screening programme was implemented in Brussels more than a decade ago and in Liège 5 years ago; the programme was adapted to the local situation. Methods: Neonatal screening for haemoglobinopathies was universal, performed using liquid cord blood and an isoelectric focusing technique. All samples with abnormalities underwent confirmatory testing. Major and minor haemoglobinopathies were reported. Affected children were referred to a specialist centre. A central database in which all screening results were stored was available and accessible to local care workers. A central clinical database to monitor follow-up is under construction. Results: A total of 191 783 newborns were screened. One hundred and twenty-three (1:1559) newborns were diagnosed with sickle cell disease, seven (1:27 398) with β thalassaemia major, five (1:38 357) with haemoglobin H disease, and seven (1:27 398) with haemoglobin C disease. All major haemoglobinopathies were confirmed, and follow-up of the infants was undertaken except for three infants who did not attend the first medical consultation despite all efforts. Conclusions: The universal neonatal screening programme was effective because no case of major haemoglobinopathy was identified after the neonatal period. The affected children received dedicated medical care from birth. The screening programme, and specifically the reporting of minor haemoglobinopathies, has been an excellent health education tool in Belgium for more than 12 years.

Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years.

Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long‐term use of treatment, pose specific challenges in this age group, which we are only beginning to understand.

3C syndrome: third occurrence of cranio‐cerebello‐cardiac dysplasia (Ritscher‐Schinzel syndrome)

We report a child with an unusual pattern of malformations: severe delay in bone maturation, wide fontanelles and facial dysmorphism (evoking cleidocranial dysplasia), relative macroencephaly with cerebellar vermis hypoplasia, hypertelorism, skeletal abnormalities (1st ribs aplasia, multifocal sternal ossification centers, thin bones), septal defect, muscular waste, hypotonia and developmental delay. Most of these features have been reported previously by Ritscher, Schinzel et al. in two sibs, who suffered more severe cerebellar malformations (Dandy‐Walker cyst or vermis aplasia). We propose 3C syndrome as an easy acronym for this Cranio‐Cerebello‐Cardiac dysplasia.

Donor lymphocyte infusion to eradicate recurrent host hematopoiesis after allogeneic BMT for sickle cell disease

BACKGROUND: Donor lymphocyte infusion (DLI) is currently standard therapy for relapse of malignancies after allogeneic BMT. Several observations suggest that both normal and leukemic progenitor cells of host origin constitute effective target cells for donor‐derived lymphocytes. To prevent relapse of sickle cell disease (SCD), a child with evidence of decreasing mixed chimerism received DLIs 8 months after allogeneic BMT for SCD.

An Estimation of the Incidence and Demographic Picture of the Major Hemoglobinopathies in Belgium (From a Confidential Inquiry)

An estimation of the incidence and demographic picture of the major hemoglobinopathies in Belgium has been approached through a confidential inquiry sent to 228 pediatric and adult hematological departments. Forty-two percent of responses showed that 417 patients are known in Belgium: 83% with sickle cell disease, 13% with β-thalassemia (β-thal) major, 2% with β-thal intermedia, and 1% with Hb H disease. Twenty-five percent of the sickle cell disease patients and 54% of those suffering from a β-thal major were older than 20 years. Three hospitals ensure the follow-up of 70% of the patients and are situated in Brussels, Belgium; a follow-up of less than 20 patients was reported at 21 centers. These results confirm that sickle cell disease is the major hemoglobinopathy in Belgium; it concerns mostly pediatricians but adult hematologists are also confronted with these pathologies. Therefore, it is necessary to implement integrated programs of prevention and treatment.