RESUMO
OBJECTIVES: To analyse mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis. METHODS: Mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis were analysed in four patients from the French Named Patient Programme by the French National Reference Centre for Herpesviruses. RESULTS: Of three absolute resistance cases, two were associated with treatment interruption or low letermovir concentrations in blood. A fourth case of breakthrough was not associated with resistance. Next-generation sequencing (NGS) genotyping confirmed rapid emergence of resistant mutants, within 3 months of treatment initiation. CONCLUSIONS: Measurement of letermovir concentration and genotyping should be recommended for patient follow-up during letermovir therapy.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Acetatos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Humanos , QuinazolinasRESUMO
OBJECTIVES: To study the management of chronic disseminated candidiasis (CDC) in patients presenting with acute leukemia. PATIENTS AND METHODS: Single-center retrospective study of acute leukemia patients (2006-2015) to investigate three aspects of CDC: its impact on the time interval between diagnosis and hematopoietic stem cell transplantation, when required (non-parametric Wilcoxon-Mann-Whitney test); its impact on overall survival (Cox proportional hazard regression model); antifungal therapeutic strategies implemented. RESULTS: A total of 639 patients presenting with acute leukemia were included; 144 were transplanted and 29 developed CDC. CDC did not significantly increase the time interval between diagnosis and transplantation, nor did it impact the overall survival of recipients. An improved overall survival was observed in non-transplanted acute leukemia patients presenting with CDC. CONCLUSION: CDC should not postpone transplantation if antifungal treatment is optimized.
Assuntos
Candidíase/etiologia , Transplante de Células-Tronco Hematopoéticas , Leucemia/complicações , Infecções Oportunistas/etiologia , Doença Aguda , Corticosteroides/uso terapêutico , Adulto , Aloenxertos , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Candidíase/mortalidade , Neutropenia Febril Induzida por Quimioterapia/complicações , Doença Crônica , Terapia Combinada , Feminino , Humanos , Leucemia/tratamento farmacológico , Leucemia/mortalidade , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/terapia , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/mortalidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Estatísticas não Paramétricas , Tempo para o Tratamento , Condicionamento Pré-Transplante/efeitos adversos , Adulto JovemAssuntos
Cromossomos Humanos Par 2 , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Leucêmica da Expressão Gênica , Hidrazinas/uso terapêutico , Carioferinas/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/genética , Triazóis/uso terapêutico , Apoptose , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Hidrazinas/farmacologia , Leucemia Linfocítica Crônica de Células B/genética , Triazóis/farmacologia , Proteína Exportina 1Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Dermatopatias , Transplante de Pele , Adulto , Aloenxertos , Feminino , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/cirurgia , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Dermatopatias/patologia , Dermatopatias/cirurgiaRESUMO
The outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph- ALL younger adults (18-63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age <45 years (P=0.008) and CR1 duration ⩾18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14-24%) and 13.3% (8-18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21-38%) and 25% (17-33%). In multivariate analysis, CR1 duration ⩾18 months and allo-SCT after relapse were associated with longer DFS (P<0.009 and P=0.004, respectively) and longer OS (P=0.004 and P<0.0001, respectively). In conclusion, although younger adults relapsing after pediatric-inspired ALL therapies retain a poor outcome, some of them may be cured if CR1 duration ⩾18 months and if allo-SCT can be performed in CR2. New therapies are definitely needed for these patients.
Assuntos
Mesilato de Imatinib/administração & dosagem , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Indução de Remissão , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Toxoplasmosis (TXP) is a life-threatening complication of allogeneic haematopoietic stem cell transplantation (AHSCT). Little is known about the risk factors and there is no consensus on prophylactic measures. To investigate the risk factors, we conducted a single-centre, retrospective matched case-control study among adults who underwent AHSCT from January 2006 to March 2015 in our hospital. TXP cases were identified from the prospectively maintained hospital's database. The 1:2 control population consisted of the two patients who received an AHSCT immediately before and after each case with similar donor relationship (related, unrelated) but who did not develop TXP. Risk factors were identified by conditional logistic regression. Clinical features and outcome of TXP were examined. Twenty-three (3.9%) cases of TXP (20 diseases, three infections) were identified among 588 AHSCT recipients. Twenty (87%) cases had a positive pre-transplant Toxoplasma gondii serology. In comparison with 46 matched control patients, risk factors were the absence of effective anti-Toxoplasma prophylaxis (odds ratio (OR) 11.95; 95% CI 3.04-46.88; p <0.001), high-grade (III-IV) acute graft-versus-host-disease (OR 3.1; 95% CI 1.04-9.23; p 0.042) and receipt of the tumour necrosis factor-α blocker etanercept (OR 12.02; 95% CI 1.33-108.6; p 0.027). Mortality attributable to TXP was 43.5% (n = 10). Non-relapse mortality rates during the study period of cases and controls were 69.6% (n = 16) and 17.4% (n = 8), respectively. Lung involvement was the dominant clinical feature (n = 14). Two cases were associated with graft failure, one preceded by haemophagocytic syndrome. Given TXP-related morbidity and attributable mortality, anti-Toxoplasma prophylaxis is essential for optimized management of seropositive AHSCT recipients.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Toxoplasmose/epidemiologia , Transplante Homólogo/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sobrevida , Toxoplasma/isolamento & purificação , Toxoplasmose/patologia , Resultado do TratamentoRESUMO
Actinomycosis is a rare chronic and multifaceted disease caused by Actinomyces species frequently mimicking malignancy or other chronic granulomatous lung diseases. We report 4 original presentations of actinomycosis arising under supposed penicillin prophylaxis in allogeneic stem cell transplantation recipients.
Assuntos
Actinomicose/etiologia , Actinomicose/prevenção & controle , Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pneumopatias/etiologia , Pneumopatias/prevenção & controle , Actinomyces/isolamento & purificação , Actinomicose/diagnóstico por imagem , Actinomicose/microbiologia , Adulto , Antibacterianos/administração & dosagem , Líquido da Lavagem Broncoalveolar/microbiologia , Feminino , Humanos , Pneumopatias/diagnóstico por imagem , Pneumopatias/microbiologia , Masculino , Pessoa de Meia-Idade , Penicilinas/administração & dosagem , Penicilinas/uso terapêutico , Tomografia Computadorizada por Raios X , Transplante Homólogo/efeitos adversosRESUMO
Granulocytic sarcoma, or chloroma, is a rare clinical entity, usually associated with a blood disease, including acute myeloid leukemia. Management strategies are based on the combination of systemic therapy and local therapy (surgery or radiation). Data for radiotherapy dose are derived from retrospective studies and case reports. We conducted a literature review using the Pubmed search engine to clarify the terms and indications for radiotherapy of chloromas.
Assuntos
Sarcoma Mieloide/radioterapia , Antineoplásicos/uso terapêutico , Diagnóstico por Imagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/patologia , Neoplasias Primárias Múltiplas , Prognóstico , Dosagem Radioterapêutica , Sarcoma Mieloide/patologiaAssuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Interleucina-10/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Polimorfismo Genético , Receptores de IgG/genética , Rituximab/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Linfócitos B/patologia , Feminino , Humanos , Masculino , Rituximab/administração & dosagem , Resultado do TratamentoAssuntos
Bioensaio , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia/diagnóstico , Leucemia/genética , Proteínas de Fusão Oncogênica/análise , Doença Aguda , Sequência de Bases , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 21 , Análise Citogenética , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Leucemia/patologia , Dados de Sequência Molecular , Sondas de Oligonucleotídeos/síntese química , Proteínas de Fusão Oncogênica/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Translocação GenéticaAssuntos
Antivirais/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Ganciclovir/uso terapêutico , Herpesvirus Humano 6/patogenicidade , Encefalite Límbica/etiologia , Adulto , Antivirais/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Ganciclovir/administração & dosagem , Humanos , Masculino , Adulto JovemRESUMO
Hormographiella aspergillata is a rare causative agent of invasive filamentous breakthrough infection, mostly arising after echinocandin exposure. We report a neutropenic patient who developed a severe sino-orbito-cerebral H. aspergillata infection while receiving empirical caspofungin, successfully controlled by an aggressive strategy associating surgical debridement and combined high-dose regimen of antifungal drugs.
Assuntos
Agaricales/isolamento & purificação , Antifúngicos/uso terapêutico , Infecções Fúngicas do Sistema Nervoso Central/tratamento farmacológico , Infecções Fúngicas do Sistema Nervoso Central/cirurgia , Leucemia Mieloide Aguda/complicações , Neutropenia/complicações , Encéfalo/microbiologia , Encéfalo/patologia , Caspofungina , Infecções Fúngicas do Sistema Nervoso Central/microbiologia , Terapia Combinada , Desbridamento , Farmacorresistência Fúngica , Equinocandinas/uso terapêutico , Evolução Fatal , Humanos , Lipopeptídeos , Masculino , Dados de Sequência Molecular , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Clorambucila/administração & dosagem , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Estadiamento de Neoplasias , Prognóstico , Rituximab , Taxa de SobrevidaRESUMO
BACKGROUND: The Autorisation Temporaire d'Utilisation (ATU) is an early access program available in France for drugs aimed at treating severe diseases not yet covered by a marketing authorization, for patients without any other therapeutic option and who cannot be included in a clinical trial. PATIENTS AND METHODS: This report presents the use of single-agent ofatumumab in 30 patients with advanced chronic lymphocytic leukemia (CLL) in the French ATU program. RESULTS: These very-high-risk patients had received multiple previous treatments (median = 6), and most had disease that was fludarabine-refractory or alemtuzumab-refractory (or both) or was unsuitable for alemtuzumab treatment. In the intent-to-treat analysis, the overall response rate was 47% (4 of 30, complete response; 10 of 30, partial response). Of 13 patients with 17p deletion, 6 displayed response to ofatumumab, including 2 complete responses. Treatment was well tolerated, with 17 grade 3 or 4 adverse events; 4 cases of grade 3 or 4 infusion reactions were reported, with favorable immediate outcome. Among nonhematologic complications, infections were the most frequent. CONCLUSION: The results confirm the efficacy and acceptable tolerability profile of ofatumumab as a single agent in severely ill patients with CLL. Attention should be paid to possible early infusion reactions to ofatumumab, as well as to the risk of infection.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Diagnosis of AL amyloidosis can be complicated by the diversity and the absence of specificity of symptoms. CASE REPORT: We report a patient who presented with a non-traumatic hepatic hematoma, leading to the discovery of hepatic amyloidosis secondary to probable multiple myeloma. The originality of our report lies in the discovery of two acquired abnormalities of haemostasis: a factor X deficiency and an acquired von Willebrand syndrome, by a likely inhibitor. CONCLUSION: Our case report is a reminder of the importance of haemostasis analysis in AL amyloidosis.
Assuntos
Amiloidose/complicações , Hematoma/etiologia , Hepatopatias/etiologia , Amiloidose/diagnóstico , Deficiência do Fator X/complicações , Deficiência do Fator X/diagnóstico , Feminino , Hematoma/diagnóstico , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina , Hepatopatias/diagnóstico , Pessoa de Meia-Idade , Doenças de von Willebrand/complicações , Doenças de von Willebrand/diagnósticoRESUMO
BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at \[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches.
Assuntos
Vírus BK , Cistite/virologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Polyomavirus/epidemiologia , Infecções Tumorais por Vírus/epidemiologia , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Cidofovir , Cistite/economia , Cistite/epidemiologia , Citosina/análogos & derivados , Citosina/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/economia , Doença Enxerto-Hospedeiro/epidemiologia , Custos de Cuidados de Saúde , Neoplasias Hematológicas/economia , Neoplasias Hematológicas/epidemiologia , Transplante de Células-Tronco Hematopoéticas/economia , Custos Hospitalares , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Infecções por Polyomavirus/tratamento farmacológico , Infecções por Polyomavirus/economia , Fatores de Risco , Transplante Homólogo , Infecções Tumorais por Vírus/tratamento farmacológico , Infecções Tumorais por Vírus/economia , Viremia/complicações , Viremia/tratamento farmacológico , Viremia/imunologia , Adulto JovemRESUMO
The aim of this work was to better understand the importance of the type of experimental setup used to monitor antibiotic release from functionalized hydroxyapatite implants. Microporous hydroxyapatite discs were prepared by sintering and subsequently functionalized with hydroxypropyl-ß-cyclodextrin (HPßCD) polymer crosslinked with butanetetracarboxylic acid. On one hand, polymerization was performed within the implant after its impregnation with the monomers (CD-HA-M implant). On the other hand, a pre-synthesized HPßCD polymer was loaded and fixed onto the HA discs (CD-HA-P implant). Both types of implants were soaked with ciprofloxacin hydrochloride or vancomycin hydrochloride solution and dried at 37°C. The DSC study highlighted that the cyclodextrin polymer could interfere with both drugs, due to the carboxylic groups carried by the crosslinks. Drug release was measured into phosphate buffered saline pH 7.4 in agitated vials, or into agarose gels to more realistically mimic in vivo conditions. Importantly, in all cases, drug release into agarose gels was much slower than into well-agitated phosphate buffer. Non-functionalized discs displayed faster drug release because no complex could be formed and/or due to the absence of the HPßCD polymer network hindering drug diffusion within the implant pores. In the case of ciprofloxacin hydrochloride, drug release from the CD-HA-M implants was faster than drug release from the CD-HA-P implants due to the different polymer structures resulting in different complexation strengths, whereas in the case of vancomycin hydrochloride the release patterns were similar because vancomycin hydrochloride was not included into the cyclodextrin. The agarose gel method seems more biorelevant and discriminatory than the vial method for drug release measurements from bone implants.
Assuntos
Substitutos Ósseos/química , Durapatita/química , Sefarose/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Antibacterianos/química , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Ciprofloxacina/química , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Géis , Cinética , Vancomicina/químicaRESUMO
Maltodextrin (MX) was fixed onto PVDF membranes in order to create a drug delivery Guided Tissue Regeneration (GTR) device with controlled drug delivery properties. PVDF microporous membranes were treated by a mixture of MX and citric acid, resulting to an 18 wt% increase of the supports. MX grafted membrane could capture 103 mg/g chlorhexidin digluconate (DigCHX) instead of 1mg/g for a virgin membrane. A neutralization step was performed before the biological tests. Viability tests confirmed the non-toxicity of the MX polymer coating after neutralisation. In vitro release test in human plasma, and microbiological tests showed that membranes grafted with MX were more performing compared to virgin and beta-CD grafted membranes. The antimicrobial activity was effective during more than 72 h.
Assuntos
Antibacterianos/química , Carboidratos/química , Clorexidina/análogos & derivados , Materiais Revestidos Biocompatíveis/química , Membranas Artificiais , Polivinil/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorexidina/química , Clorexidina/farmacocinética , Clorexidina/farmacologia , Ácido Cítrico/química , Materiais Revestidos Biocompatíveis/farmacologia , Sistemas de Liberação de Medicamentos , Fusobacterium nucleatum/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Polissacarídeos/química , Porosidade , Propriedades de SuperfícieRESUMO
Four chromosomal defects associated with outcome are commonly evaluated by fluorescent in situ hybridization (FISH) in chronic lymphocytic leukemia (CLL), namely deletions of the 13q13-q14, 11q22 and 17p13 regions and trisomy 12. In this study, we compared a quantitative PCR method--quantitative multiplex PCR of short fluorescent fragment (QMPSF)--with FISH for the detection of these acquired aneuploidies in a series of 110 patients with Binet stage A CLL. Genes located in the deleted or gained regions were selected as target genes and amplified using a method based on the simultaneous amplification of short fluorescent genomic fragments under quantitative conditions. A chromosomal imbalance involving one or several of the four loci was detected by either method in 72 patients (65%). A chromosome 13 deletion was present in 61 patients (54%), a 11q22 deletion in nine (8%), a trisomy 12 in nine and a 17p deletion in one. FISH and QMPSF results were identical for 103 out of 110 patients and discrepancies could be explained in most cases. This study demonstrates that a quantitative multiplex PCR represents a cost-effective method that could replace FISH in CLL patients. However, although QMPSF is perfectly adapted to the detection of primary defects, care should be taken when searching for clonal evolutions present in a small proportion of tumor cells.