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1.
Front Oncol ; 10: 557643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240808

RESUMO

T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive subtype of leukemia for which important progress in treatment efficiency have been made in the past decades to reach a cure rate of 75%-80% nowadays. It is nevertheless mandatory to find new targets and active molecules for innovative therapeutic strategies as relapse is associated with a very dismal outcome. We designed an experimental workflow to highlight the conserved core pathways associated with leukemogenesis by confronting the gene expression profiles (GEPs) of human T-ALL cases to the GEP of a murine T-ALL representative model, generated by the conditional deletion of the PTEN tumor suppressor gene in T cell precursors (tPTEN-/-). We identified 844 differentially expressed genes, common GEPs (cGEP) that were conserved between human T-ALL and murine signatures, and also similarly differentially expressed, compared to normal T cells. Using bioinformatic tools we highlighted in cGEPan upregulation of E2F, MYC and mTORC1. Next, using Connectivity Map (CMAP) and CMAPViz a visualization procedure for CMAP data that we developed, we selected in silico three FDA-approved, bioactive molecule candidates: α-estradiol (α-E), nordihydroguaiaretic acid (NDGA) and prochlorperazine dimaleate (PCZ). At a biological level, we showed that the three drugs triggered an apoptotic cell death in a panel of T-ALL cell lines, activated a DNA damage response and interfered with constitutive mTORC1 activation and c-MYC expression. This analysis shows that the investigation of conserved leukemogenesis pathways could be a strategy to reveal new avenues for pharmacological intervention.

2.
Hematol Oncol ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32809224

RESUMO

Over the years, the prognosis of adolescents treated for acute lymphoblastic leukemia (ALL) has improved. However, this age group still represents a challenge with an overall survival (OS) of 60% compared to 85% in younger children. Herein, we report the outcome of adolescents treated in the European Organisation for Research and Treatment of Cancer (EORTC) 58951 clinical trial. EORTC 58951 clinical trial included patients with de novo ALL between 1998 and 2008. For this study, we analyzed data of all adolescents between 15 and under 18. Data from 97 adolescents were analyzed, 70 had B-lineage and 27 had T-lineage ALL. The 8-year event-free survival (EFS) and OS for the B-cell precursor ALL cases were 72.3% (59.4%-81.7%) and 80.8% (67.4%-89.1%), respectively. For the T-lineage, the 8-year EFS and OS were 57.4% (36.1%-74.0%) and 59.0% (36.1%-76.2%), respectively. "B-other" ALL, defined as BCP-ALL lacking any known recurrent genetic abnormalities were more frequent in our adolescent population (52.8%) than in younger children (27.1%). Outcome of adolescents in the EORTC 58951 study is supporting the findings that adolescents have better outcome in pediatric compared to adults' trials. Nevertheless, in pediatric studies, adolescents still have a worse prognosis than younger children. Despite the fact that specific unfavorable characteristics may be linked to the adolescent population, a careful study and characterization of adolescents "B-other" genetic abnormalities in ALL is critical to improve the outcome of this population.

3.
Haemophilia ; 26(5): 847-854, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32812322

RESUMO

INTRODUCTION: With current molecular diagnosis, about 1 to 5% of haemophilia A (HA) patients remain genetically unresolved. In these cases, deep intronic variation or structural variation disrupting the F8 gene could be causal. AIM: To identify the causal variation in four genetically unresolved mild-to-severe HA patients using an F8 mRNA analysis approach. METHODS: Ectopic F8 mRNA analysis was performed in four unrelated HA patients. An in vitro minigene assay was performed in order to confirm the deleterious splicing impact of each variation identified. RESULTS: In all probands, mRNA analysis revealed an aberrant splicing pattern, and sequencing of the corresponding intronic region found a deep intronic substitution. Two of these were new variations: c.2113+601G>A and c.1443+602A>G, while the c.143+1567A>G, found in two patients, has previously been reported. The c.1443+602A>G and the c.143+1567A>G variants both led to the creation of a de novo acceptor or donor splice site, respectively. Moreover, the c.143+1567A>G was found in 3/6 patients with genetically unresolved moderate HA registered in our laboratory. Haplotype analysis performed in all patients carrying the c.143+1567A>G variation suggests that this variation could be a recurrent variation. The c.2113+601G>A led to the exonization of a 122-bp antisense AluY element by increasing the strength of a pre-existing cryptic 5' splice site. For each point variation, in vitro splicing analysis confirmed its deleterious impact on splicing of the F8 transcript. CONCLUSION: We identified three deep intronic variations, leading to an aberrant mRNA splicing process as HA causing variation.

4.
J Clin Immunol ; 40(5): 752-762, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32562208

RESUMO

BACKGROUND: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype. METHODS: We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types. RESULTS: The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well. CONCLUSION: This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.

5.
Bull Cancer ; 107(6): 629-632, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32387061

RESUMO

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19.


Assuntos
Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/farmacocinética , Antivirais/uso terapêutico , Criança , Técnicas de Laboratório Clínico , Terapia Combinada , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Gerenciamento Clínico , Síndrome de Down/epidemiologia , Interações Medicamentosas , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/tratamento farmacológico , Neutropenia Febril/prevenção & controle , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro Imunocomprometido , Masculino , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Indução de Remissão , Risco , Medição de Risco , Terapia de Salvação , Avaliação de Sintomas
6.
Am J Hematol ; 95(9): 1057-1065, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32449964

RESUMO

The impact of measurable residual disease (MRD) on cord blood transplantation (CBT) outcomes has remained debated. To address this issue, we assessed the impact of measurable MRD at CBT on outcomes in large cohort of patients with acute leukemia. Inclusion criteria included adult patients with acute myeloid (AML) or acute lymphoblastic leukemia (ALL), CBT as first allo-HCT in first or second complete remission (CR) at transplantation, and known MRD status at the time of CBT. Data from 506 patients were included in the analysis. Among them, 317 patients had AML and 189 had ALL. Positive MRD was reported in 169 (33%) patients while the remaining 337 patients were MRD negative at CBT. At 2 years, relapse incidence was 18% in patients with MRD negativity vs 33% in those with MRD positivity at transplantation (P < .001). Two-year leukemia-free survival (LFS) and overall survival (OS) were 57% and 60%, respectively, in MRD negative patients, vs 38% (P < .001) and 48% (P = .004), respectively, in those with MRD positivity. There was no interaction between the impact of MRD on OS and LFS and diagnosis (ie, ALL vs AML), single or double CBT, and reduced-intensity or myeloablative conditioning. On multivariate analysis, MRD positivity was associated with a higher risk of relapse (HR = 1.8, P = .003), comparable non-relapse mortality (P = .44), worse LFS (HR = 1.4, P = .008) and a trend towards worse OS (HR = 1.3, P = .065). In conclusion, these data suggest that novel strategies that are aiming to achieve MRD negativity at CBT are needed for leukemic patients with positive MRD pre-CBT.

7.
Int J Mol Sci ; 21(1)2019 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-31881723

RESUMO

Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza®), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra®), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra® in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Idoso , Aminoimidazol Carboxamida/farmacologia , Aminoimidazol Carboxamida/uso terapêutico , Apoptose/efeitos dos fármacos , Azacitidina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Recidiva , Ribonucleosídeos/farmacologia , Falha de Tratamento
8.
Viruses ; 11(7)2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284515

RESUMO

Usually self-limited, hepatitis E virus (HEV) infection may evolve to chronicity and cirrhosis in immunosuppressed patients. HEV infection has been described in solid-organ transplantation and hematology patients, but for allogeneic hematopoietic stem cell transplant (alloHSCT) recipients, only small cohorts are available. This retrospective nationwide multi-center series aimed to describe HEV diagnostic practices in alloHSCT French centers, and the course of infection in the context of alloHSCT. Twenty-nine out of 37 centers participated. HEV search in case of liver function tests (LFT) abnormalities was never performed in 24% of centers, occasionally in 55%, and systematically in 21%. Twenty-five cases of active HEV infection were diagnosed in seven centers, all because of LFT abnormalities, by blood nucleic acid testing. HEV infection was diagnosed in three patients before alloHSCT; HEV infection did not influence transplantation planning, and resolved spontaneously before or after alloHSCT. Twenty-two patients were diagnosed a median of 283 days after alloHSCT. Nine patients (41%) had spontaneous viral clearance, mostly after immunosuppressive treatment decrease. Thirteen patients (59%) received ribavirin, with sustained viral clearance in 11/12 evaluable patients. We observed three HEV recurrences but no HEV-related death or liver failure, nor evolution to cirrhosis.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Vírus da Hepatite E/isolamento & purificação , Hepatite E/diagnóstico , Adulto , Idoso , Feminino , França/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatite E/epidemiologia , Hepatite E/imunologia , Hepatite E/terapia , Vírus da Hepatite E/imunologia , Humanos , Imunossupressores/efeitos adversos , Fígado/patologia , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
9.
Biol Blood Marrow Transplant ; 25(9): 1798-1802, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31129355

RESUMO

Prognosis of patients with graft failure is dismal, and retransplantation is the sole option for long-term survival. To address the interest of haploidentical transplantation as a salvage option in this context, we analyzed data from 24 patients with graft failure or loss retransplanted with a haploidentical donor who received post-transplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis (GVHD). Fludarabine-based reduced-intensity conditioning was used in 23 patients and the Baltimore regimen in 14 patients. The median delay between previous and salvage transplantation for graft failure was 63 days (range, 39 to 98). In addition to PTCy, all patients received cyclosporine, and 22 patients also received mycophenolate mofetil for GVHD prophylaxis. With a median follow-up of 353 days (range, 16 to 2010), 1-year overall survival (OS) was 56% (95% confidence interval, 38% to 81%). Transplant complications accounted for 80% of deaths. The cumulative incidence of neutrophil engraftment at day +30 was 79%. Cumulative incidence of grades II to IV acute GVHD at day 100 was 14%, and 1-year cumulative incidence of chronic GVHD was 31%. One-year cumulative incidence of relapse was 13%. Stem cell source did not impact on engraftment, GVHD, relapse, or OS. Salvage haploidentical transplant with PTCy for rescuing graft failure patients leads to an acceptable 1-year OS and might be a valid option in this poor situation.


Assuntos
Transplante de Medula Óssea , Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro , Doença Aguda , Adulto , Aloenxertos , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
10.
Biol Blood Marrow Transplant ; 25(6): e204-e208, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30930192

RESUMO

We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P = .78). Overall, the DIPSS was not significantly predictive of outcome (P = .28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P = .05), whereas groups with intermediate 2 and high risk showed no significant difference (P = .44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P = .04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P = .01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Policitemia Vera/terapia , Mielofibrose Primária/terapia , Trombocitemia Essencial/terapia , Transplante Homólogo/métodos , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Policitemia Vera/mortalidade , Mielofibrose Primária/mortalidade , Prognóstico , Análise de Sobrevida , Trombocitemia Essencial/mortalidade , Resultado do Tratamento
11.
J Allergy Clin Immunol Pract ; 7(6): 1958-1969.e9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30825606

RESUMO

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) germline mutations have been recently described. A comprehensive overview of this early-onset multiorgan autoimmune and lymphoproliferative disease has not yet been compiled. OBJECTIVE: We have conducted a systematic review of published STAT3 GOF cases to describe clinical, diagnostic, and therapeutic aspects of the disease. METHODS: A systematic review including articles published before October 10, 2018, in PubMed, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed. We described cases of patients with STAT3 GOF germline mutations with genetic analysis and a concordant phenotype if functional analyses were not performed for the mutation. RESULTS: The search identified 18 publications describing 42 unique patients. Twenty-eight different mutations were described. Onset of disease was very early with an average age of 3 (0.5-5) years. The most frequent manifestations were autoimmune cytopenias (28 of 42), lymphoproliferation (27 of 42), enteropathy (24 of 42), interstitial lung disease (15 of 42), thyroiditis (13 of 42), diabetes (10 of 42), and postnatal growth failure (15 of 21). Immunodeficiency was not always a predominant feature. Most patients required significant immunosuppressive therapy. Five patients received hematopoietic stem cell transplantation, and 4 died from complications. Improvement of symptoms was observed for 8 of 9 patients who received targeted biotherapies. CONCLUSIONS: STAT3 GOF syndrome is a new clinical entity to consider when confronted with a patient with early-onset polyautoimmunity, lymphoproliferation, and growth failure. At this time, precise therapeutic guidelines are lacking, but use of anti-IL-6 receptor and JAK inhibitor biologics is an attractive possibility.


Assuntos
Fator de Transcrição STAT3/genética , Doenças do Sistema Endócrino/genética , Mutação com Ganho de Função , Gastroenteropatias/genética , Mutação em Linhagem Germinativa , Doenças Hematológicas/genética , Humanos , Doenças do Sistema Imunitário/genética , Pneumopatias/genética
13.
Curr Res Transl Med ; 67(1): 8-15, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30206045

RESUMO

PURPOSE: We developed a prognostic scoring system to evaluate the prognosis of myelodysplastic syndrome (MDS) patients surviving more than 100 days allogeneic hematopoietic cell transplantation after (allo-HCT). PATIENTS AND METHODS: We performed a landmark analysis on a derivation cohort of 393 cases to identify prognostic factors for 3-year overall survival. Potential predictor variables included demographic and clinical data, transplantation modalities and early post-transplant complications. The scoring system was tested against a validation cohort which included 391 patients. RESULTS: Complications occurring before day 100 such as relapse [HR = 6.7; 95%CI, 4.5-10.0] (4 points), lack of platelet recovery [HR, 3.6; 95%CI, 2.2-5.8] (2 points), grade-II acute GVHD [HR = 1.7; 95%CI, 1.2-2.5] (1 point) and grade-III/IV [HR = 2.6; 95%CI, 1.8 -3.8] (2 points) were the only independent predictors of 3-year OS. The 3-year OS associated with low (0), intermediate (1-3) and high (≥4) risk scores was respectively 70%, 46% and 6%. The model performed consistently in both cohorts, with good calibration. CONCLUSION: This post-transplant scoring system is a powerful predictor of outcome after allo-HCT for MDS, and can provide useful guidance for clinicians. Additional studies are required to evaluate this scoring system for other hematologic malignancies.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Adulto , Idoso , Estudos de Coortes , Feminino , França/epidemiologia , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Projetos de Pesquisa , Análise de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/mortalidade , Resultado do Tratamento
14.
Br J Haematol ; 181(4): 523-527, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29676440

RESUMO

This trial explored the efficacy of re-induction chemotherapy including bortezomib in paediatric relapsed/refractory acute lymphoblastic leukaemia. Patients were randomized 1:1 to bortezomib (1.3 mg/m2 /dose) administered early or late to a dexamethasone and vincristine backbone. Both groups did not differ regarding peripheral blast count on day 8, the primary endpoint. After cycle 1, 8 of 25 (32%) patients achieved complete remission with incomplete blood count recovery, 7 (28%) a partial remission and 10 had treatment failure. Most common grade 3-4 toxicities were febrile neutropenia (31%) and pain (17%). Bortezomib was safely combined with vincristine. Bortezomib rarely penetrated the cerebrospinal fluid.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Crise Blástica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Crise Blástica/sangue , Crise Blástica/tratamento farmacológico , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Bortezomib/farmacocinética , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/farmacocinética , Neutropenia Febril/sangue , Neutropenia Febril/induzido quimicamente , Feminino , Humanos , Masculino , Dor/sangue , Dor/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/farmacocinética
16.
Haematologica ; 103(7): 1143-1149, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29599204

RESUMO

In this retrospective study, we evaluate long-term complications in nearly all ß-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 vs 8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Talassemia beta/complicações , Talassemia beta/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , França/epidemiologia , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Inquéritos Epidemiológicos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Adulto Jovem , Talassemia beta/terapia
17.
Biol Blood Marrow Transplant ; 24(8): 1657-1663, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29477777

RESUMO

Usually, after double umbilical cord blood transplantation (DUCBT), only 1 of the transplanted units persists in the long term. The characteristics of the winning cord blood unit (W-CBU) that determine unit dominance and how they influence the outcomes of DUCBT remain unclear. We retrospectively analyzed 347 patients with acute leukemia transplanted with a DUCBT (694 CBU) from 2005 to 2013 who had documented neutrophil engraftment and a W-CBU identified by chimerism analysis, to identify unit characteristics impacting on dominance. Median age at DUCBT was 40 years and median follow-up was 35 months. Among W-CBUs, 41% were ≥5/6 HLA matched to the recipient and 59% were ≤4/6. Multivariate analysis indicated that ≤4/6 HLA-matched W-CBUs led to lower leukemia-free survival (44% versus 56%; hazard ratio [HR], 1.5; P = .032) and overall survival (49% versus 62%; HR, 1.5; P = .028), increased nonrelapse mortality (26% versus 18%; HR, 1.9; P = .027), and acute graft-versus-host disease (46% versus 35%; HR, 1.7; P = .013). We were unable to predict unit dominance, but we demonstrated that outcomes were strongly influenced by the degree of HLA mismatch between W-CBU and recipient. Therefore, selection of both units with the lower number of HLA mismatches with the recipient is indicated.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia/terapia , Doença Aguda , Adulto , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Feminino , Histocompatibilidade , Humanos , Leucemia/mortalidade , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Quimeras de Transplante
19.
Bone Marrow Transplant ; 53(4): 400-409, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29330405

RESUMO

The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N = 61) or MRD (N = 90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR = 2.95, P < 0.001). Disease status at transplant other than CR was also associated with lower GRFS in multivariable analysis (HR = 1.74, P = 0.01). In addition, the administration of ATG was independently linked to higher GRFS (HR = 0.52, P = 0.009). In summary, we observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/terapia , Doadores de Tecidos , Transplante Haploidêntico/métodos , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/complicações , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Adulto Jovem
20.
Leuk Lymphoma ; 59(2): 372-380, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28587506

RESUMO

We performed a prospective multicenter phase 2 study to evaluate the safety and efficacy of prophylactic Extracorporeal Photopheresis (ECP) in adult patients with hematological malignancies early after RIC allo-HSCT on day 21 twice per week during the first two weeks and then once per week for the next four weeks for a total of eight ECP courses. A total of 20 patients were included; 10 were males, median age was 60 years. All patients engrafted, 17 (85%) received the total eight ECP courses. There were no adverse effects related to ECP. Seven patients developed acute graft-versus-host disease (GVHD), with 15% grade ≥ II cumulative incidence at day 100. The cumulative incidence of chronic GVHD at 2 years was 22%. The 2 years probability of overall survival (OS) and progression-free survival (PFS) were 84 and 74%, respectively. This study shows encouraging results with low acute and chronic GVHD incidence and no interference with graft-versus-leukemia (GVL) effect.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fotoferese , Condicionamento Pré-Transplante , Doença Aguda , Idoso , Biomarcadores , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Imunossupressores/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Fotoferese/métodos , Análise de Sobrevida , Quimeras de Transplante , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento
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