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Contains fulltext : 96501.pdf (publisher's version ) (Closed access), The aim of our study was to evaluate, through the Eurocord and European Group for Blood and Marrow Transplantation (EBMT) registries, outcomes and risk factors for outcomes in adult patients who underwent single or double unrelated cord blood transplantation (UCBT) for myelodysplastic syndrome (MDS) or secondary acute myeloblastic leukemia (sAML). A total of 180 adults with MDS (n=39) or sAML (n=69) were analyzed. Risk factors for outcomes were analyzed using the Fine and Gray method and the Cox model. Median age was 43 (18-72) years. In all, 77 patients (71%) received a single UCBT. Myeloablative conditioning regimen (MAC) was given to 57 (53%) patients. Median numbers of nucleated and CD34(+) cells at freezing were 3.6 x 10(7) and 1.1 x 10(5) kg. At 60 days, cumulative incidence of neutrophil recovery was 78+/-4% and was independently associated with the number of CD34(+) cells per kg (>1.1 x 10(5); P=0.005) and advanced disease status (blasts <5% at time of UCBT, P=0.016). A 2-year non-relapse mortality (NRM) was significantly higher after MAC (62 vs 34%; P=0.009). A 2-year disease-free-survival (DFS) and overall survival (OS) were 30 and 34%, respectively. In multivariate analysis, patients with high-risk disease (blasts >5% and International Prognostic scoring system (IPSS) intermediate-2 or high in MDS) had significant poorer DFS (hazard ratio (HR): 1.76; P=0.047). In spite of high NRM, these data indicate that UCBT is an acceptable alternative option to treat adults with high-risk MDS or sAML, without a suitable human leukocyte antigen (HLA)-matched donor.

This report assessed the results of allogeneic stem cell transplantation (allo-SCT) in 26 patients with Shwachman-Diamond disease (SDS) and severe bone marrow abnormalities. The conditioning regimen was based on busulphan (54%), total body irradiation (23%), fludarabine (15%) or other chemotherapy combinations (8%). Standard prevention of graft versus host disease (GVHD) with ciclosporin +/- methotrexate was adopted in 54% of the patients whilst in vivo or in vitro T-cell depletion was used in 17 and four patients respectively. Neutrophil and platelet engraftment were achieved in 21 (81%) and 17 (65%) of 26 patients after a median time of 18 days and 29 days respectively. The incidence of grade III and IV acute GVHD was 24% and of chronic GVHD 29%. Nine patients died after a median time of 70 d, post-SCT. After a median follow-up of 1.1 years, the transplant-related mortality was 35.5% (95% CI 17-54) whilst the overall survival was 64.5% (95% CI 45.7-83.2). Allo-SCT was found to be successful in more than half of SDS patients with severe bone marrow dysfunction. Further improvements would be anticipated by a better definition of the optimum time in the course of disease to transplant and by the adoption of less toxic conditioning regimens.

Diamond-Blackfan anemia (DBA) is a constitutional disease characterized by a specific maturation defect in cells of erythroid lineage. We have assembled a registry of 229 DBA patients, which includes 151 patients from France, 70 from Germany, and eight from other countries. Presence of malformations was significantly and independently associated with familial history of DBA, short stature at presentation (before any steroid therapy), and absence of hypotrophy at birth. Two hundred twenty-two patients were available for long-term follow-up analysis (median, 111.5 mo). Of these individuals, 62.6% initially responded to steroid therapy. Initial steroid responsiveness was found significantly and independently associated with older age at presentation, familial history of DBA, and a normal platelet count at the time of diagnosis. Severe evolution of the disease (transfusion dependence or death) was significantly and independently associated with a younger age at presentation and with a history of premature birth. In contrast, patients with a familial history of the disease experienced a better outcome. Outcome analysis revealed the benefit of reassessing steroid responsiveness during the course of the disease for initially nonresponsive patients. Bone marrow transplantation was successful in 11/13 cases; HLA typing of probands and siblings should be performed early if patients are transfusion dependent, and cord blood should be preserved. Incidence of DBA (assessed for France over a 13-y period) is 7.3 cases per million live births without effect of seasonality on incidence of the disease or on malformative status. Similarly, no parental imprinting effect or anticipation phenomenon could be documented in families with dominant inheritance.

We determined the proportion of survival variability explained by the usual prognostic factors in childhood acute lymphoblastic leukaemia (ALL) during a prognostic study of 1552 patients enrolled in three consecutive Fralle group protocols (Fralle 83, Fralle 87 and Fralle 89). The event-free survival rates at 5 years were 54.8% (SD 1.9), 43.1%) (SD 2.7) and 55.6% (SD 2.2), respectively. In the univariate analysis the following variables were predictive of poor outcome: male gender, elevated leucocytosis (> 50 x 10(9)/l), circulating blastosis. haemoglobin >12 g/dl, platelet count <100 x 10(9)/l, age under 1 year or over 9 years, enlarged mediastinum, nodes, spleen and liver, T phenotype, absence of CD10+ cells; testicular and meningeal involvement, poor response to induction therapy (CCSG M3), and LDH >400 U/l. Among the cytogenetic features, hyperdiploidy had a protective effect, whereas hypodiploidy, translocation and other structural abnormalities had a negative influence, particularly in cases of t(9;22) or t(4;11). Multivariate analysis summarized the prognostic information in terms of four variables: age, gender, leucocytosis and cytogenetic features. Missing data had little influence on the results. However, despite their significance in the multivariate analysis, these four variables each had very low predictive power (1.1% for gender, 2.0% for age, 3.5% for leucocytosis, and 1.6% for cytogenetic features). Thus, the most significant prognostic factors in childhood ALL each explain no more than 4% of the variability in prognosis. This may explain the disappointing practical value of these factors and underlines the need for prognostic tools in childhood ALL.

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean +/- SE) of disease-free survival (DFS) at 7 years was 59.5 +/- 9% (95% confidence interval). The estimated chance of relapse was 22.5 +/- 15% with a median follow-up of 88.5 months (range 51-132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD. site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 +/- 12.6%, 37.5 +/- 19.8% and 774 +/- 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3-4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.

From September 1988 to December 1995 forty-four children (age < 17 years) with Ph1 Chronic Myelogenous Leukemia (CML) received unrelated donor marrow transplantation in 8 European Countries. Thirty-three evaluable children were typed by serological testing on HLA-A, B, and DR loci. Thirty of them were further DR subtyped by DNA techniques. Twenty-four pairs were 6 antigen matched. Seven were mismatched at 1 locus (2 pairs at A and B loci respectively and 3 at DR locus). Two out of 30 pairs evaluated by molecular biology had one antigen mismatched at DRB1 locus. Thirty-two (96%) out of 33 evaluable children reached a sustained granulocyte count higher than 0.5 x 10(9)/l at a median of 21 (range 14-88) days after transplantation. The remaining child failed to engraft. Two children developed secondary graft failure. A platelet count greater than 50 x 10(9)/l sustained for at least seven consecutive days without transfusion support was reached at a median of 25 (range: 20-144) days by 24 out of 33 evaluable children and 9 children never recovered to above 50 x 10(9)/l. Twenty-one out of 33 evaluable children developed grade I (n = 7), grade II (n = 8), grade III (n = 2) or grade IV (n = 4) acute GvHD (63%). Seven of the 30 evaluable children surviving more than 100 days developed chronic GvHD (20%) which was limited in 4 cases and extensive in 3. Relapse occurred in 3 of the 44 (7%) children at 2 to 24 months (median 14). Twenty-four month relapse rate was 14%. Seventeen out of 44 children (38%) died of transplant related mortality (TRM), 4 (9%) of secondary tumor, 4 (9%) of infections, 3 (7%) of organ failure, 1 (2%) of interstitial pneumonia, 5 (11%) of unknown causes. Actuarial TRM was 61% for children grafted before December 1991 and 33% for children grafted after January 1992 (p = .01). EFS was 49.7%; it was 65% for children receiving more than 3.5 x 10(9)/Kg MNC.

Patients with lysosomal storage disorders have visceral, skeletal, and neurological abnormalities and a limited life expectancy. Bone marrow transplantation has been used to correct the metabolic defects and leads to metabolic improvements in most patients. However, the long-term effect of such therapy is uncertain. We analysed the data from 63 patients transplanted for lysosomal storage diseases. The transplant-related mortality was 10% if an HLA-identical sibling marrow donor was available (n = 40) and 20-25% if mismatched tissue was used. Data on the effect of bone marrow transplantation on biochemical and clinical disease variables were available in 29 of the 63. 28 had a follow-up duration of 1.0-10.2 years; 1 patient died of disease progression in the first year after stable engraftment. 13 patients who had severe neurological symptoms at the time of transplantation showed disease progression. Engraftment of bone marrow in 5 patients with non-neuronopathic Gaucher's disease led to complete disappearance of symptoms. 11 patients had skeletal symptoms because of various mucopolysaccharidoses (MPSs). There was stabilisation of the skeletal lesions during the observation period of 1.4-6.4 years, but none of the patients showed significant regression of the skeletal symptoms. The visceral features (hepatosplenomegaly, cardiac hypertrophy, and upper airway obstruction) in these patients abated after transplantation. We could not evaluate the biochemical and clinical variables in 34 patients because of graft rejection, transplant-related mortality, or follow-up of less than 1 year. There were significant beneficial effects of bone marrow transplantation in patients with non-neuronopathic Gaucher's disease. Stabilisation of disease was observed in patients with MPS-I and MPS-II; this potential benefit needs to be confirmed by longer follow-up. Bone marrow transplantation was not effective if severe neurological symptoms were already present at the time of transplantat

A subgroup of children with ALL remains at high risk of relapse despite the administration of intensive chemotherapeutic protocols and may benefit from allogeneic BMT. The cytoreductive regimen used most often combines TBI with cyclophosphamide. Nevertheless, miscellaneous long-term sequelae have been consequent upon radiotherapy, especially in young children. This retrospective multicentric study analyzes the outcome of children with ALL under 4 years of age receiving an HLA-genoidentical BMT following a radiation-free preparative regimen. A busulfan-based regimen with cyclophosphamide or melphalan +/- etoposide +/- cytarabine was given to 21 children (median age: 28 months, range 6-48). Sixteen patients with initial poor prognostic factors were transplanted in first complete response (CR) and five patients in relapse or second CR. With a median follow-up of 47 months, the results show an overall 4-year DFS of 61.1%. Leukemic recurrence was observed in eight patients. The preparative regimen was well-tolerated and there were no transplant-related deaths. A busulfan-based BMT preparative regimen may be a therapeutic alternative to TBI-containing regimens in young children. Efforts are currently aimed at reducing the relapse rate in these children by optimizing the tumoricidal potential of chemotherapy and the graft-versus-leukemia effect of allogeneic BMT.