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1.
Blood ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33171484

RESUMO

Ovarian tissue cryopreservation (OTC) is offered to women treated for acute leukemia to preserve their fertility before hematopoietic stem cell transplantation. The risk of leukemic infiltration in ovarian samples harvested before administration of chemotherapy limits ovarian tissue transplantations. We assessed the minimal residual disease (MRD) by sensitive quantitative polymerase chain reaction in cryopreserved ovarian cortex and medulla samples harvested from 30 patients in complete remission of acute leukemia, including 60 % with negative bone marrow MRD at the time of OTC. Ovarian MRD was undetectable in 21 patients (70%), detectable below 10-4 in 8 patients (27%) and between 10-3 and 10-4 in 1 patient (3%). Twenty patients (67%) had concordant MRD between bone marrow and ovarian samples. Interestingly 4 patients had positive MRD in ovarian samples while undetectable in bone marrow. Our results underline the importance of reaching the best control of the disease with undetectable or low MRD levels before OTC to minimize the risk of ovarian leukemic infiltration. The discordant results between ovarian samples and bone marrow require to test the more ovarian samples available before considering ovarian tissue transplantation.

2.
Bull Cancer ; 107(9): 925-933, 2020 Sep.
Artigo em Francês | MEDLINE | ID: mdl-32921398

RESUMO

Sickle cell disease is associated with severe complications and early mortality in adults. In children, hematopoietic stem cell transplant from HLA-identical sibling can stop the progression of the disease and leads to more than 95% long-term free survival without sickle cell disease. The aim of this workshop was to define indications and modalities of allogeneic hematopoietic stem cell transplant in children and adults with sickle cell disease. Patient and sibling HLA typing should be proposed, early in the course of the disease, when intensification therapies are required. Indications of transplant from HLA-identical sibling in children and adults are, cerebral vasculopathy, occurrence of vaso-occlusive events despite hydroxycarbamide, renal and hepatic diseases related to SCD, chronic anemia<7g/dL despite hydroxycarbamide, need to maintain transfusion programs longer than six months, and major transfusion difficulties related to red blood cell alloimmunization. In children with an HLA-identical sibling donor, we recommend a myeloablative conditioning regimen associating high dose busulfan, cyclophosphamide and ATG, considering the excellent results of this approach In patients over 15 years of age, we recommend the NIH approach consisting of a reduced intensity conditioning regimen by alemtuzumab, and 3Gy total body irradiation, followed by peripheral hematopoietic stem cells and post-transplant immunosuppression by sirolimus In the absence of HLA-identical sibling donor, there is no definitive data for preferring transplant from unrelated versus haplo-identical donors but we recommend to evaluate these approaches in prospective trials.


Assuntos
Anemia Falciforme/cirurgia , Transplante de Células-Tronco Hematopoéticas , Adulto , Criança , Humanos , Transplante Homólogo
3.
Antiviral Res ; 182: 104872, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32768412

RESUMO

OBJECTIVES: Human adenovirus (HAdV) infections are associated with a high morbidity and mortality in transplant patients requiring the use of antiviral treatments. Brincidofovir (BCV), a cytidine analog, inhibits HAdV replication through viral DNA elongation termination and likely through other mechanisms. To elucidate if BCV regulates cellular antiviral pathways, we analyzed its impact on HAdV-infected and non-HAdV-infected lung epithelial cells. METHODS: We assessed the cellular and viral transcriptome of A549 cells infected and non-infected with HAdV C5 and treated or non-treated with BCV by RNAseq after 72 h. RESULTS: BCV treatment of HAdV infected cells resulted in a profound decrease of viral transcription associated with a relative overexpression of the early genes E1A and E4 and of the late gene L1. BCV had also a profound impact on A549 cells' transcriptome. Ontologic analysis revealed an effect of BCV on several pathways known to interact with adenovirus replication as mTor signalling and Wnt pathways. A549 cells treated with BCV demonstrated a significant inhibition of the biological function of "viral replication" including 25 dysregulated genes involved in inflammation pathways. CONCLUSION: We demonstrated that BCV alters viral gene expression and promotes the expression of antiviral cellular pathways in A549 cells. These results provide new insights how to interfere with cellular pathways to control HAdV infections.

4.
Pediatr Blood Cancer ; : e28419, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798263

RESUMO

INTRODUCTION: Our objectives were to assess the quality of life (QoL) of parents of childhood leukemia survivors compared with population norms and to identify the determinants of parents' long-term QoL. METHODS: Parents of minors who had survived childhood leukemia participating in the French LEA cohort (Leucémie de l'Enfant et de l'Adolescent-French Childhood Cancer Survivor Study for Leukemia) were asked to complete the French version of the WHOQOL-BREF. Results were compared with age- and sex-matched values from a French reference population. Parents' and survivors' characteristics likely to be associated with QoL, long after the child's leukemia diagnosis, were explored using multivariate analysis. RESULTS: We included 487 parents (mean age 42.9 ± 6.0 years, mean follow-up time from diagnosis 7.3 ± 3.3 years). Compared with the reference population, scores for physical health and social relationships for parents of childhood leukemia survivors were significantly lower (P < 0.001, effect size = 0.24 and P < 0.001, effect size = 0.29, respectively) contrary to scores for psychological health which were significantly higher (P < 0.001, effect size = 0.29). Even if health- and cancer-related characteristics were associated with parents' QoL in some dimensions, the only factor associated with each of the three dimensions (social relationships, physical health, and psychological) in the multivariate analysis was the parent's financial situation. CONCLUSIONS: Long after leukemia diagnosis, the parents reported lower scores in the physical health and social relationship domains. Despite the difficulties of actually influencing socioeconomic characteristics, it is important to consider the social situation of each family in the long-term care of survivors and their families.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32753706

RESUMO

Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13 ± 2% and 17 ± 4% (p = NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60 ± 2% vs. 42 ± 5%, p < 0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9 ± 1% vs. 23 ± 4%, p < 0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.

7.
Pediatr Blood Cancer ; 67(9): e28233, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32614145

RESUMO

BACKGROUND: We conducted a national multicenter retrospective study in France to evaluate the efficacy and tolerance of ruxolitinib in children with steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplant. PROCEDURE: Patients were recruited from the 15 pediatric transplantation centers. Transplanted patients were eligible if they met the following criteria: aged ≤ 18 years at transplantation, receiving a myeloablative allogeneic hematopoietic stem cell transplant, having an aGVHD of grade ≥2, and treated with ruxolitinib for steroid-refractory aGVHD. RESULTS: Twenty-nine patients received ruxolitinib for steroid-refractory aGVHD. Six patients achieved a complete response at day 28 after the start of treatment but finally 19 patients (65.5%) achieved a complete response (CR) with a median delay of 41 days (5-93 days). Two patients had a partial response. All patients who achieved CR or partial response discontinued corticosteroid treatment. Eight patients showed treatment failure. The overall response rate was 72.4%. Twenty-three of 29 patients were alive at a median follow-up of 685 days (177-1042 days) after the hematopoietic stem cell transplantation. Viral replication was observed in 41.4% of cases. We did not observe severe hematological adverse events and cytopenia requiring a modification of ruxolitinib doses always resolved. The median initial dose of ruxolitinib was 12.6 mg/m2 /day with an important range. We could not demonstrate any relationship between initial dose and effectiveness. CONCLUSION: Ruxolitinib may constitute a promising second-line treatment for children with steroid-refractory aGVHD that should be validated in a prospective large-scale pharmacokinetic and efficacy trial.

8.
Pediatr Blood Cancer ; : e28603, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32706505

RESUMO

BACKGROUND: Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. PROCEDURE: To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. RESULTS: Bu clearance IIV was significantly decreased from 61.3% (covariate-free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children <9 kg. The target AUC was reached for each BW strata, significantly increasing the percentages of patients achieving reaching the targeted AUC as compared to FDA schedule. CONCLUSION: This new model made it possible to propose a novel dosing nomogram that better considered children below 16 kg of BW and allowed better initial exposure as compared to existing dosing schedules. This nomogram, which would be easy to use to determine an optimal dosing schedule in daily practice, will need to be validated in clinical routine. Therapeutic drug monitoring remains strongly advisable for small children and those with specific diseases.

9.
Pediatr Transplant ; 24(6): e13773, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32701220

RESUMO

INTRODUCTION: Myeloablative conditioning before allogeneic HSCT during childhood exposes to serious long-term complications, especially gonadal dysfunction. Pubertal issues are less described than other post-HSCT sequelae in childhood. METHODS: Pubertal development and biological gonadal parameters were assessed in a retrospective monocentric cohort of prepubertal patients who underwent HSCT after myeloablative conditioning with TBI or busulfan between 1981 and 2017. RESULTS: Seventy-four patients (28 girls and 46 boys) were included. No spontaneous pubertal development was found in 50% of girls and 10% of boys (P < .001), and delayed puberty or no spontaneous pubertal development was found in 57% of girls and 24% of boys (P = .009). HRT was used in 82% of girls and 24% of boys (P < .001). In univariate analysis, TBI conditioning (P = .05), female sex (P < .001), acute GVHD (P = .05), extensive chronic GVHD (P = .021), steroid treatment >6 months (P = .016), and malignant diseases (P = .016) were associated with no spontaneous pubertal development, whereas TBI conditioning (P = .003) and extensive chronic GVHD (P = .005) were associated with delayed puberty. In multivariate analysis, factors independently associated with no spontaneous puberty onset were female sex (P = .001) and age >10 years (P = .033). Factors independently associated with delayed puberty were extensive chronic GVHD (P = .041) and age >10 years (P = .031). CONCLUSION: This study highlighted the toxicity of MAC in prepubescent children: TBI did worse, but this was especially true for the most susceptible patients (girls, leukemic patients, and patients older than 10 years). It suggests a possible role of GVHD in delayed puberty.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32594103

RESUMO

Up to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor's RBCs have antigens missing on the recipient's cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.

12.
Hematol Oncol Stem Cell Ther ; 13(2): 58-60, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32380009

RESUMO

Despite huge progress in the fields of newborn screening, encapsulated bacterial infection prophylaxis, immunization, and supportive care in general, people suffering from sickle cell anemia still continue to have a shorter life expectancy and a poorer quality of life due to painful vaso-occlusive events and strokes during childhood, and later, cardiac, pulmonary, and renal injuries, including in Western and high-income countries. From the 2000s, allogeneic stem cell transplantation for severe sickle cell disease from a sibling donor provided the best results-overall as well as disease-free survival-never obtained for any other disease. Nevertheless, this only curative option is proposed to few patient numbers, including in Western countries with high-level medical equipment development, with discrepancies between (i) patients and family, (ii) physicians and care centers dedicated to sickle cell disease, and (iii) hematopoietic stem cell transplant teams. Due to these discrepancies and in order to provide the same quality of discussion and treatment choice for every sickle cell disease patient, we developed a National French multidisciplinary pluri-annual meeting dedicated to sickle cell disease patients and transplantation. We report here our experience of such a meeting.


Assuntos
Anemia Falciforme/terapia , Hematologia/normas , Qualidade de Vida/psicologia , Transplante/normas , Adulto , Humanos
14.
Blood Adv ; 4(8): 1760-1769, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343795

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients.

15.
Bone Marrow Transplant ; 55(8): 1540-1551, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32203263

RESUMO

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.

16.
Transpl Int ; 33(7): 762-772, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32133691

RESUMO

Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

17.
Pediatr Hematol Oncol ; 37(3): 259-268, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32028812

RESUMO

Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.


Assuntos
Ciclosporina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunomodulação , Leucemia Mieloide Aguda , Transfusão de Linfócitos , Doadores de Tecidos , Quimeras de Transplante/sangue , Aloenxertos , Criança , Ciclosporina/efeitos adversos , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/prevenção & controle , Masculino , Estudos Prospectivos , Recidiva
18.
Bone Marrow Transplant ; 55(6): 1126-1136, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32029909

RESUMO

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

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