Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita.

Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre-existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged.

Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience.

Although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for patients with Fanconi anemia (FA), published series mostly refer to single-center experience with limited numbers of patients. We analyzed results in 795 patients with FA who underwent first HSCT between May 1972 and January 2010. With a 6-year median follow-up, overall survival was 49% at 20 years (95% confidence interval, 38-65 years). Better outcome was observed for patients transplanted before the age of 10 years, before clonal evolution (ie, myelodysplastic syndrome or acute myeloid leukemia), from a matched family donor, after a conditioning regimen without irradiation, the latter including fludarabine. Chronic graft-versus-host disease and secondary malignancy were deleterious when considered as time-dependent covariates. Age more than 10 years at time of HSCT, clonal evolution as an indication for transplantation, peripheral blood as source of stem cells, and chronic graft-versus-host disease were found to be independently associated with the risk for secondary malignancy. Changes in transplant protocols have significantly improved the outcome of patients with FA, who should be transplanted at a young age, with bone marrow as the source of stem cells.

Immunological profile of Fanconi anemia: a multicentric retrospective analysis of 61 patients.

In this study, the immunological status of 61 patients with Fanconi anemia (FA) with advanced marrow failure before hematopoietic stem cell transplantation was analyzed by assessing the phenotype of peripheral blood lymphocytes, serum immunoglobulin (Ig) levels, and inflammatory cytokines. In patients with FA, total absolute lymphocytes (P < 0.0001), B cells (P < 0.0001), and NK cells (P = 0.003) were reduced when compared with normal controls. T cells (CD3), that is, cytotoxic T cells, naïve T cells, and regulatory T cells, showed a relative increase when compared with controls. Serum levels of IgG (P < 0.0001) and IgM (P = 0.004) were significantly lower, whereas IgA level was higher (P < 0.0001) than in normal controls. TGF-ß (P = 0.007) and interleukin (IL)-6 (P = 0.0007) levels were increased in the serum of patients when compared with controls, whereas sCD40L level decreases (P < 0.0001). No differences were noted in the serum levels of IL-1ß, IL-2, IL-4, IL-10, IL-13, IL-17, and IL-23 between FA subjects and controls. This comprehensive immunological study shows that patients with FA with advanced marrow failure have an altered immune status. This is in accordance with some characteristics of FA such as the proinflammatory and proapoptotic status. In addition, B lymphocyte failure may make tight and early immunological monitoring advisable.

Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004).

BACKGROUND: A population-based cohort of children aged 1-18 years with acute lymphoblastic leukaemia (ALL) was treated with a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). We aimed to confirm the results of the most effective DCOG ALL protocol for non-high-risk (NHR) patients to date (ALL-6), compare results with ALL-7 and ALL-8, and study prognostic factors in a non-randomised setting. METHODS: From Jan 1, 1997, until Nov 1, 2004, patients with ALL were treated according to the ALL-9 protocol in eight Dutch academic centres with their affiliated peripheral hospitals. Patients were stratified into NHR and high risk (HR) groups. HR criteria were white-blood-cell count of 50,000 cells per microL or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement; patients who did not fulfil these criteria were deemed to be NHR. The NHR group was treated with a three-drug induction (dexamethasone, vincristine, and asparaginase) for 6 weeks, medium-dose methotrexate for 3 weeks, then maintenance therapy. HR patients received a four-drug induction (as for the NHR patients plus daunorubicin) for 6 weeks, high-dose methotrexate for 8 weeks, and two intensification courses before receiving maintenance therapy. Triple intrathecal medication was given 13 times in NHR patients, 15 times in HR patients (17 times for patients with initial CNS involvement). No patient received cranial irradiation. Maintenance therapy was given until 109 weeks for all patients and consisted of mercaptopurine and methotrexate for 5 weeks, alternated with dexamethasone and vincristine for 2 weeks. Kaplan-Meier analysis was done on an intention-to-treat basis with event-free survival as the primary endpoint. This trial is registered at trialregister.nl, number NTR460/SNWLK-ALL-9. FINDINGS: 859 patients were recruited to the study. Complete remission was achieved in 592 (98.5%) of the 601 patients in the NHR group and 250 (96.9%) of the 258 in the HR group. Five patients in the NHR group and four in the HR group died during induction. Median follow-up for patients alive was 72.2 (range 4.8-132.7) months as of August, 2008. 5-year event-free survival was 81% (SE 1%) in all patients: 84% (2%) in NHR patients, and 72% (3%) in HR patients. Isolated CNS relapses occurred in 22 (2.6%) of 842 patients. In a multivariate analysis, DNA index was the strongest predictor of outcome (<1.16 vs >or=1.16; relative risk 0.42, 95% CI 0.22-0.78), followed by age (1-9 vs >or=10 years; 2.23, 1.60-3.11) and white-blood-cell count (<50,000 vs >or=50,000 cells per microL; 1.60, 1.13-2.26). INTERPRETATION: The overall results of the dexamethasone-based DCOG ALL-9 protocol are better than those of our previous Berlin-Frankfurt-Münster-based protocols ALL-7 and ALL-8. The results for NHR patients were achieved with high cumulative doses of dexamethasone and vincristine, but without the use of anthracyclines, etoposide, cyclophosphamide, or cranial irradiation, therefore minimising the risk of side-effects. FUNDING: Dutch Health Insurers.

Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT).

BACKGROUND AND OBJECTIVES: The treatment of acquired aplastic anemia (AA) is based on allogeneic bone marrow transplantation (BMT) and immunosuppressive therapy. The aim of this study was to assess the outcome of children and adults with AA treated in the last decade, and to determine whether results have improved in two sequential time periods,1991-1996 and 1997-2002. DESIGN AND METHODS: Two-thousands and seventy-nine consecutive patients with AA, classified according to first-line treatment: BMT (n=1567) or immunosuppressive therapy (n= 912), the patients for the two sequential time periods were studied. Analyses included variables related to patients, disease and transplant. RESULTS: The actuarial 10-year survival was 73% and 68% for BMT or immunosuppressive treatment, respectively (p=0.002). BMT outcome improved significantly with time (69% and 77%, p=001) for both matched sibling donor (MSD) (74% and 80%; p=0.003 ), alternative donor (38% and 65% p=0.0001), and was better in children (79% versus 68%, p<0.0001). Multivariate analysis: favorable predictors (p<0.001) were younger age, transplant beyond 1996, MSD, a short interval diagnosis-transplant , no irradiation. IS: no significant improvement over time (69% and 73% p=0.29). Survival was significantly better in children (81% versus 70%, p=0.001), especially in vSAA(83% versus 62%, p=0.0002). Combined IS was superior to single drug treatment (77% versus 62%, p=0.002). Multivariate analysis: significant predictors of survival: age > or =16 years (p=0.0009), longer interval between diagnosis -treatment (p=0.04), single drug versus combined IS (p=0.02). INTERPRETATION AND CONCLUSIONS: Outcome has improved in subsets of AA patients: those receiving first- line BMT and children with vSAA treated with IS. Age remains a major predictor for both treatments. Early intervention is associated with a significantly better outcome and is strongly recommended, whatever the first-line therapy.

Influence of donor/recipient sex matching on outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia.

BACKGROUND: Increased risk of transplant related mortality in male recipients of female hematopoietic stem cell grafts and in vitro reactivity of lymphocytes against H-Y encoded gene products in females with rejected male grafts have been documented. An increased rejection of male grafts in female recipients is not reported for solid organ or stem cell transplants and the role of H-Y as transplantation antigen has been controversial. METHODS: Data from 1481 patients with a hematopoietic stem cell transplant for aplastic anemia reported from 154 centers in 28 countries were analyzed. Outcome was compared between patients with donors of the same or opposite sex. RESULTS: Survival at 5 years was significantly better in patients with donors from the same sex: 68% vs. 60% (P = 0.001). Male patients with female donors had a decreased survival (relative risk of death 1.52, P < 0.001) and an increased risk of severe graft-versus-host disease (relative risk 1.33, P = 0.03) compared to recipients of sex-matched grafts. Female patients with male donors had a decreased survival (relative risk of death 1.44, P = 0.01) and an increased risk of rejection (relative risk 2.20, P = 0.01) compared to recipients of sex-matched grafts. In a subgroup analysis, the negative effects of donor/recipient sex-mismatching appeared confined to patients receiving conditioning regimens not containing antithymocyte globulin. CONCLUSIONS: These data confirm H-Y as a clinically relevant transplantation antigen, in both the graft-versus-host and the host-versus-graft direction. Wherever possible, donor-recipient sex-matching should be integrated into donor selection algorithms.

SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype.

DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4. These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway.

Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively. The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively. Splenectomy had been performed before HSCT in 24 children. The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13% and 35%, respectively. Age older than 4 years predicted an increased risk of disease recurrence. The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55% and 49%, respectively (P = NS), with median observation time of patients alive being 40 months (range, 6 to 144). In multivariate analysis, age older than 4 years and female sex predicted poorer outcome. Results of this study compare favorably with previously published reports. Disease recurrence remains the major cause of treatment failure. Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling.