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1.
Transplant Cell Ther ; 27(3): 274.e1-274.e5, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33781541

RESUMO

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32740936

RESUMO

Medication non-adherence (NA) after allogeneic hematopoietic cell transplantation (allo-HCT) can lead to serious complications. This study assesses NA in French adult and pediatric recipients and identifies factors associated with NA. In accordance with the EMERGE and STROBE guidelines, a cross sectional multicentric survey was conducted. We used a self-reported questionnaire that was adapted to adults and pediatrics, and that could provide a picture of all 3 phases of medication adherence: initiation, implementation, persistence. We enrolled 242 patients, 203 adults (mean age: 51 years old, 50.7% male) and 39 children (mean age: 9 years old, 56.4% female). Reported NA was estimated at about 75% in both populations, adults and pediatrics. In adults, the univariate analysis showed that patients less than 50 years old (p=0.041), (i) treated with cyclosporine (p=0.02), (ii) treated with valacyclovir/acyclovir (p=0.016) and (iii) experiencing side effects (p=0.009), were significantly more non-adherent. In multivariate analysis, only recipient age was significantly associated to NA (p = 0.05). The limited size of the pediatric population did not allow us to draw any statistical conclusion about this population. To the best of our knowledge, this is the first study in France on NA in allo-HCT recipients. Our results highlight the age factor as the only factor related to NA. Further studies are needed to confirm our observations and refine results in pediatric populations, currently most at risk of medication NA.

4.
Bull Cancer ; 2020 Jun 12.
Artigo em Francês | MEDLINE | ID: mdl-32540096

RESUMO

The presence of allo-antibodies in the serum of a recipient awaiting hematopoietic stem cell transplantation (HSCT) may have an impact on transfusion efficiency and/or donor choice, especially in the absence of an identical sibling donor. Prior to transplantation, donor specific anti-HLA (Human Leukocyte Antigen) antibodies (DSA) have a recognized effect on transplant outcome, correlated with the increasing MFI value and with the ability of such antibody to fix the complement fraction. Anti-platelet antibodies (anti-HLA class I and anti-HPA [Human Platelet Antigen]) are better involved in transfusion inefficiency and can be responsible for refractory status. ABO incompatibilities require a specific treatment of the graft in presence of high titer to avoid hemolytic adverse effects. Investigations of these antibodies should be carried out on a regular basis in order to establish appropriate transfusion recommendation, select an alternative donor when possible or adapt the source of cells. After transplantation, in case of delayed recovery or graft rejection, long term aplasia, persistent mixed chimerism or late release, and after elimination of the main clinical causes, a biological assessment targeted on the different type of antibodies will have to be performed in order to orient towards the cause or the appropriate therapy. Further studies should be carried out to determine the impact of anti-MICA antibodies and recipient specific anti-HLA antibodies, on the outcome of the transplantation.

7.
Am J Hematol ; 95(7): 809-816, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32267023

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured.


Assuntos
Anemia de Fanconi , Transplante de Células-Tronco Hematopoéticas , Leucemia , Síndromes Mielodisplásicas , Doença Aguda , Aloenxertos , Intervalo Livre de Doença , Anemia de Fanconi/complicações , Anemia de Fanconi/mortalidade , Anemia de Fanconi/terapia , Feminino , Seguimentos , Humanos , Leucemia/etiologia , Leucemia/mortalidade , Leucemia/terapia , Masculino , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Taxa de Sobrevida
8.
Pediatr Transplant ; 24(4): e13694, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32196861

RESUMO

Antithymocyte globulin is a major drug in transplantation. rATG has been successfully used to prevent graft-versus-host disease in allogeneic HSCT. However, its first infusion is associated with reactions ranging from simple fevers to distributive shocks and may interfere with the transplant conditioning. To evaluate the impact of rATG infusion rate on clinical tolerability, we conducted a retrospective study of all pediatric allogeneic HSCT patients who received rATG (Thymoglobulin®) as part of their conditioning at Lille University Hospital from 2003 to 2018. Until 2012, patients received rATG with a theoretical infusion time of 12 hours (12H group, n = 33). From 2012, they had a theoretical infusion time of 4 hours (4H group, n = 43). Patients from the 12H arm presented more ≥ grade 3 infusion-related reactions at first dose (70% versus 44%, P = .027), had significantly higher fever (median of 39.6°C versus 39.2°C, P = .002), and needed a greater use of symptomatic treatments. However, they received a slightly higher first dose of rATG (median of 2.7 versus 2.3 mg/kg, P = .042). In view of these results, a rATG infusion time of 4 hours can be a relevant option for pediatric transplant centers to avoid interference with the conditioning regimen and facilitate medical surveillance.

9.
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
10.
Bull Cancer ; 107(1S): S72-S84, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31586527

RESUMO

Haploidentical hematopoietic stem cell transplantation has been growing steadily since 2012. The SFGM-TC has twice published guidelines concerning T-cell repleted haploidentical grafts with high dose cyclophosphamide post-transplantation. The 2013 workshop recommended using the non-myeloablative Baltimore protocol with bone marrow and developed prospective protocols to evaluate these transplantations. The 2015 workshop reported improved results of reduced conditioning regimens in Hodgkin's lymphoma and intensive conditioning in myeloid hemopathies, and a similar outcome with 10/10 HLA matched donor with the same disease-risk score thus raising the question of the qualifier "alternative" for haploidentical transplants. The current work concerns the criteria for selecting the donor. The main criterion remains the absence of anti-HLA antibodies directed against the donor present in the recipient sera (DSA - Donor Specific Antibodies). In case of DSA and in the absence of an alternative donor, desensitization protocols exist. The other criteria are impossible to prioritize: age, sex, CMV, and blood type. The degree of relatedness and the number of HLA incompatibilities do not seem to be a criterion of choice. The 'ideal' donor would be a young man, CMV-matched, without major ABO incompatibility with a marrow transplant. There is insufficient data for the KIR-ligand and NIMA/NIPA mismatch. Peripheral stem cell grafts appear to yield more acute GVHD than bone marrow grafts after intensive conditioning, but with comparable survival rates. Based on the literature review, the comparison of haploidentical with unrelated donors encourages inclusion in existing national protocols randomizing these different donors.


Assuntos
Haplótipos , Histocompatibilidade , Doadores de Tecidos , Adulto , Fatores Etários , Aloenxertos , Transplante de Medula Óssea , Ciclofosfamida/uso terapêutico , Infecções por Citomegalovirus/complicações , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Depleção Linfocítica , Masculino , Fatores Sexuais , Linfócitos T , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos
11.
Bull Cancer ; 106(1S): S52-S58, 2019 Jan.
Artigo em Francês | MEDLINE | ID: mdl-30665669

RESUMO

The recommendations of the French Health and Drug Safety Authorities (HAS/ANSM-Haute Autorité de santé/Agence nationale de sécurité du médicament) are known, but there are always new developments underway. With regards to CMV suppression, there is the introduction of platelet glycoprotein Ia and the Intercept (Amotosalem+UVA) inactivation method which addresses bacterial risk. The irradiation of platelets is included in the recommendations to ensure HEV-negative plasma post allograft. In terms of blood transfusion safety, these measures as well as the broader spectrum of Ia, particularly for arboviruses, are a real breakthrough. The survey conducted in clinical services and the services providing blood products for transfusion along with a literature review have shown that several improvements need to be made. The first is a reduction of transfusions of concentrated red blood cells with introduction at a threshold of 7g/dL during hospitalization of patients without a fragile clinical status. The second improvement would address transfusion of refractory thrombocytopenia, encouraging an increase in discussion between clinicians and those conducting the transfusion in order to consider different etiologies and to identify appropriate care protocols. Third would be the need for the transmission of information between the transplantation doctors and blood transfusion specialists in order to define an approach to transfusion care adapted to the patient's situation. It is important to inform and educate patients about transfusion protocols post allotransplant or autotransplant. It must be clearly communicated to patients that they should always have on their person their blood group documentation. This is especially true when receiving care for a hemopathy or an autologous transplant. If undergoing an allogeneic transplant, patients should also carry transfusion guidelines post autotransplant or post allotransplant along with the phone numbers for the stem cell transplantation department and the blood transfusion center responsible for their care.


Assuntos
Autoenxertos , Transfusão de Eritrócitos/normas , Transplante de Células-Tronco Hematopoéticas/normas , Registros Médicos , Transfusão de Plaquetas/normas , Trombocitopenia/terapia , Adulto , Antígenos de Grupos Sanguíneos , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Comunicação Interdisciplinar , Educação de Pacientes como Assunto , Trombocitopenia/etiologia , Transplante Homólogo
12.
Biol Blood Marrow Transplant ; 25(4): 734-742, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30385256

RESUMO

We previously reported in a French prospective randomized study that transplantation of 2 unrelated cord blood (UCB) units instead of 1 unit does not decrease the risk of transplantation failure but may enhance alloreactivity. Here we evaluated the influence of pretransplantation minimal residual disease (MRD) on leukemia relapse and survival after single- versus double-UCB transplantation (UCBT). Among 137 children and young adults who underwent UCBT in this randomized study, 115 had available data on MRD assessment done immediately before initiation of the pretransplantation conditioning regimen. MRD was considered positive at a level of ≥10-4, which was the case of 43 out of 115 patients. Overall, the mean 3-year survival probability was 69.1 ± 4.4%, and it was not significantly influenced by the MRD level: 70.7 ± 5.4% in MRD-negative (<10-4) patients (n = 72), 71.1 ± 9.4% in MRD-positive patients with 10-4 ≤ MRD <10-3 (n = 26) and 58.8 ± 11.9% in MRD-positive patients with ≥10-3 (n = 17). In the MRD-positive group, the mean risk of relapse was significantly lower in the double-UCBT arm compared with the single-UCBT arm (10.5 ± 7.2% versus 41.7 ± 10.4%; P = .025) leading to a higher mean 3-year survival rate (82.6 ± 9.3% versus 53.6 ± 10.3%; P = .031). This difference was observed only in patients who had not received antithymocyte globulin during their conditioning regimen. In the MRD-negative group, there was no differencebetween the single- and the double-UCBT arms. We conclude that even in cases of positive pretransplantation MRD, UCBT in children and young adults with acute leukemia yields a high cure rate, and that a double-unit strategy may enhance the graft-versus-leukemia effect and survival in these patients.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia Mieloide Aguda/terapia , Adulto , Feminino , Humanos , Masculino , Estudos Prospectivos , Adulto Jovem
13.
BMC Pharmacol Toxicol ; 19(1): 81, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522521

RESUMO

BACKGROUND: The use of isavuconazole is approved for the management of invasive aspergillosis and mucormycosis, only in adults, as no paediatric pharmacology studies have been reported to date. Very few paediatric cases have been published concerning the use of isavuconazole. Amphotericin B is the only antifungal agent recommended in paediatric mucormycosis, but adverse effects and especially nephrotoxicity, even with the liposomal formulation, could be problematic. In this context, the use of other antifungal molecules active on Mucorales becomes needful. CASE PRESENTATION: We describe a case of mucormycosis with rapid onset dissemination in a 3-year-old girl recently diagnosed with acute lymphocytic leukaemia. She was successfully treated with isavuconazole alone and then in combination with liposomal amphotericin B. Isavuconazole therapy was guided by therapeutic drug monitoring. CONCLUSIONS: This case offers new perspectives on the potential use of isavuconazole in children with mucormycosis, as an alternative or adjunct to liposomal amphotericin B.


Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Leucemia de Células B/tratamento farmacológico , Mucormicose/tratamento farmacológico , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Doença Aguda , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Resultado do Tratamento
14.
Haematologica ; 103(8): 1278-1287, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724903

RESUMO

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.


Assuntos
Deficiência de GATA2/epidemiologia , Mutação em Linhagem Germinativa , Adulto Jovem , Adolescente , Adulto , Bélgica , Criança , Pré-Escolar , França , Deficiência de GATA2/complicações , Deficiência de GATA2/genética , Deficiência de GATA2/terapia , Neoplasias Hematológicas/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/etiologia , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Inquéritos e Questionários
15.
Blood ; 132(7): 750-754, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-29760162

RESUMO

Outcomes remain poor for refractory severe aplastic anemia (SAA) patients. Alternative donor transplantation may be considered, but results from previous studies are not encouraging. We conducted a prospective nationwide phase 2 study to assess unrelated cord blood (CB) transplantation (CBT) efficacy and safety in refractory SAA patients (Aplastic Anemia and Cord Blood Transplantation protocol). To demonstrate a significant difference in 1-year survival from 20% (null hypothesis) to 50% (alternative hypothesis), we needed to include 25 transplanted patients and therefore included 26 (median age, 16 years). Eligibility criteria required 1 or 2 unrelated CB units, containing separately or together >4 × 107 frozen nucleated cells (NCs) per kilogram of recipient body weight. Conditioning regimen comprised fludarabine (FLU), cyclophosphamide (CY), antithymocyte globulin (ATG), and 2-Gy total body irradiation (TBI). With a median follow-up of 38.8 months, engraftment occurred in 23 patients (88%); cumulative incidences of grade II-IV acute and chronic graft-versus-host disease were 45.8% and 36%, respectively. Twenty-three patients were alive at 1 year, with an 88.5% overall survival (OS) rate, differing significantly from the expected 20% (P < .0001; 84% OS at 2 years). CBT with units containing ≥4 × 107 frozen NCs per kilogram is therefore a valuable curative option for young adults with refractory SAA and no available matched unrelated donors. This trial was registered at www.clinicaltrials.gov as #NCT01343953.


Assuntos
Anemia Aplástica/mortalidade , Anemia Aplástica/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Condicionamento Pré-Transplante , Doadores não Relacionados , Doença Aguda , Adolescente , Adulto , Alanina/administração & dosagem , Alanina/análogos & derivados , Aloenxertos , Soro Antilinfocitário/administração & dosagem , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Taxa de Sobrevida , Irradiação Corporal Total
16.
Pediatr Blood Cancer ; 65(7): e27038, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29528179

RESUMO

BACKGROUND: Etoposide phosphate (EP; single injection, 60 mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo-SCT) conditioning regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context. MATERIALS AND METHODS: A retrospective study was carried out on children hospitalized between 2007 and 2015 for allo-SCT with TBI-based myeloablative conditioning associated with cyclophosphamide (CY, 60 mg/kg/day × 2 days) or EP. The primary endpoint of the study was the occurrence of acute kidney injury (AKI). Additional endpoints were time to recovery for children with AKI, survival, and treatment-related mortality. RESULTS: Thirty-five patients were analyzed (CY: 22 vs. EP: 13). AKI occurred more frequently in the EP group than in the CY one (69% vs. 27%, adjusted odds ratio 6.0, 95% confidence interval [CI] [1.145; 31.445], P = 0.03). The median time to recovery was estimated at 3 days, 95% CI (2; 17), with CY and 11 days 95% CI (5; 18) with EP (adjusted hazard ratio of recovery for EP vs. CY 0.262, 95% CI [0.071; 0.969], P = 0.04). No significant difference was highlighted between the two treatments for survival or for treatment-related mortality. DISCUSSION: This study shows that EP at high dosage or one of its excipients is probably responsible for AKI, as compared to CY. Further studies are required to explore the origin of this adverse effect.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/efeitos adversos , Etoposídeo/análogos & derivados , Doença Enxerto-Hospedeiro/tratamento farmacológico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Compostos Organofosforados/efeitos adversos , Condicionamento Pré-Transplante , Lesão Renal Aguda/mortalidade , Antineoplásicos/administração & dosagem , Criança , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Compostos Organofosforados/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
18.
Blood ; 131(7): 717-732, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29146883

RESUMO

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.


Assuntos
Doenças da Medula Óssea/genética , Mutação em Linhagem Germinativa , Adolescente , Doenças da Medula Óssea/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/genética , Sequenciamento Completo do Exoma
19.
Bull Cancer ; 104(12S): S99-S105, 2017 Dec.
Artigo em Francês | MEDLINE | ID: mdl-29173979

RESUMO

In September 2016 in Lille, France, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th Allogeneic Stem Cell Transplantation Clinical Practices Harmonization Workshop Series. Our work group focused on chemotherapy drug dose adaptation for hematopoietic stem cell transplantation patients presenting a comorbidity. The purpose of this workshop was to provide recommendations on chemotherapy drug dose adaptation for patient populations receiving hematopoietic stem cell transplantation who also had the following comorbidities: obesity, chronic kidney disease and hepatopathy.


Assuntos
Transplante de Células-Tronco Hematopoéticas/normas , Imunossupressores/administração & dosagem , Hepatopatias , Obesidade , Insuficiência Renal Crônica , Condicionamento Pré-Transplante/normas , Adulto , Fatores Etários , Bussulfano/administração & dosagem , Criança , Comorbidade , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , França , Humanos , Hepatopatias/epidemiologia , Melfalan/administração & dosagem , Obesidade/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Sociedades Médicas , Inquéritos e Questionários , Tiotepa/administração & dosagem , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Irradiação Corporal Total
20.
J Hematol Oncol ; 10(1): 102, 2017 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-28482908

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT), the most widely used potentially curable cellular immunotherapeutic approach in the treatment of hematological malignancies, is limited by life-threatening complications: graft versus host disease (GVHD) and infections especially viral infections refractory to antiviral drugs. Adoptive transfer of virus-specific T cells is becoming an alternative treatment for infections following HSCT. We report here the results of a phase I/II multicenter study which includes a series of adenovirus-specific T cell (ADV-VST) infusion either from the HSCT donor or from a third party haploidentical donor for patients transplanted with umbilical cord blood (UCB). METHODS: Fourteen patients were eligible and 11 patients received infusions of ADV-VST generated by interferon (IFN)-γ-based immunomagnetic isolation from a leukapheresis from their original donor (42.9%) or a third party haploidentical donor (57.1%). One patient resolved ADV infection before infusion, and ADV-VST could not reach release or infusion criteria for two patients. Two patients received cellular immunotherapy alone without antiviral drugs as a pre-emptive treatment. RESULTS: One patient with adenovirus infection and ten with adenovirus disease were infused with ADV-VST (mean 5.83 ± 8.23 × 103 CD3+IFN-γ+ cells/kg) up to 9 months after transplantation. The 11 patients showed in vivo expansion of specific T cells up to 60 days post-infusion, associated with adenovirus load clearance in ten of the patients (91%). Neither de novo GVHD nor side effects were observed during the first month post-infusion, but GVHD reactivations occurred in three patients, irrespective of the type of leukapheresis donor. For two of these patients, GVHD reactivation was controlled by immunosuppressive treatment. Four patients died during follow-up, one due to refractory ADV disease. CONCLUSIONS: Adoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a pre-emptive treatment. Our study highlights that third party haploidentical donors are of great interest for ADV-VST generation in the context of UCB transplantation. (N° Clinical trial.gov: NCT02851576, retrospectively registered).


Assuntos
Infecções por Adenovirus Humanos/terapia , Adenovírus Humanos/imunologia , Imunoterapia Adotiva/métodos , Subpopulações de Linfócitos T/transplante , Viremia/terapia , Infecções por Adenovirus Humanos/sangue , Infecções por Adenovirus Humanos/prevenção & controle , Adolescente , Adulto , Aloenxertos , Criança , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Separação Imunomagnética , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Interferon gama/metabolismo , Leucaférese , Masculino , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Doadores de Tecidos , Transplante Haploidêntico , Resultado do Tratamento , Carga Viral , Ativação Viral , Adulto Jovem
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