RESUMO
OBJECTIVES: Limited data is available on HCV directly acting agents (DAAs) in haematopoietic stem cell transplant (HSCT) recipients. This study aimed at reporting the characteristics, treatment practices and treatment efficacy in HSCT recipients with chronic HCV. METHODS: Prospective observational study from EBMT Infectious Diseases Working Party (IDWP). Patients with chronic HCV infection were included. RESULTS: Between 12/2015 and 07/2018, 45 patients were included: male in 53%; median age 49 years (range, 8-75); acute leukaemia in 48.9%, lymphoma in 17.7%, non-malignant disorders in 22.3%; allogeneic HSCT in 84%; 77.8% no immunosuppressive treatment. Genotypes 1, 2, 3 and 4 were detected in 54.5%, 20.5%, 13.6% and 11.4%, respectively; advanced fibrosis in 40%, including cirrhosis in 11.4%. Overall, 37 (82.2%) patients received DAAs, at a median of 8.4 years after HSCT (16.2% within 6 months from HSCT). Sofosbuvir-based treatment was given to 62.2%. Thirty-five patients completed planned treatment course, with sustained virological response (SVR) of 89.1%, and 94.3% (33/35) in those who completed the treatment. Side effects possibly related to DAAs were reported in 5 (14%) and did not require treatment discontinuation. CONCLUSIONS: DAAs treatment was effective, safe and feasible in this cohort of mainly allogeneic HSCT recipients with mild/moderate liver damage.
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Transplante de Células-Tronco Hematopoéticas , Hepatite C , Antivirais/efeitos adversos , Quimioterapia Combinada , Estudos de Viabilidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepacivirus , Hepatite C/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Transplantados , Resultado do TratamentoRESUMO
BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). OBJECTIVES: This study sought to characterize HCT outcomes in APDS. METHODS: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. RESULTS: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. CONCLUSIONS: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Doenças da Imunodeficiência Primária/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Rejeição de Enxerto , Humanos , Estimativa de Kaplan-Meier , Inibidores de MTOR/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Doenças da Imunodeficiência Primária/mortalidade , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemAssuntos
Infecções por Adenoviridae , Transplante de Células-Tronco Hematopoéticas , Infecções por Adenoviridae/tratamento farmacológico , Antivirais/uso terapêutico , Citosina/análogos & derivados , Citosina/farmacologia , Citosina/uso terapêutico , Humanos , Organofosfonatos , Estudos RetrospectivosRESUMO
A timely and effective immune reconstitution after hematopoietic stem cell transplantation (HSCT) is of crucial importance to enhance graft-versus-leukemia reaction in hematological malignancies. Several factors can influence the yield of this process, and new mathematical models are needed to describe this complex phenomenon. METHODS: We retrospectively analyzed immune reconstitution in the early post-HSCT period in a multicenter cohort of 206 pediatric patients affected by acute lymphoblastic leukemia, acute myeloblastic leukemia, and myelodysplastic syndrome who received their first allo-HSCT. All patients were in complete morphological remission at transplantation and were followed-up at least 26 mo post-HSCT. Blood samples for analysis of lymphocyte subset numbers were collected at day 100 (±20 d). RESULTS: The 2-y cumulative incidence of relapse was 22.2% (95% confidence interval [CI], 17.3-27). Using principal component analysis, we identified based on 16 input variables a new multivariate model that enables patients' description in a low-dimensional model, consisting of the first 2 principal components. We found that the numbers of CD3+/CD4+/CD8+ lymphocyte subsets at day 100 post-HSCT and acute graft-versus-host disease had the greatest impact in preventing relapse. We ultimately derived a risk score defining high- or medium-low-risk groups with 2-y cumulative incidence of relapse: 35.3% (95% CI, 25.6-45) and 15.6% (95% CI, 10.1-20.7), respectively (P = 0.001*). CONCLUSIONS: Our model describes immune reconstitution and its main influencing factors in the early posttransplantation period, presenting as a reliable model for relapse risk prediction. If validated, this model could definitely serve as a predictive tool and could be used for clinical trials or for individualized patient counseling.
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Ruxolitinib could be considered as an option in the treatment of LONIPCs in children when other treatments are ineffective. Spirometry is a valuable tool for both diagnosis and follow-up of LONIPCs in children. https://bit.ly/3BmOYfb.
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A survey within hematopoietic stem cell transplant (HSCT) centers of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) was performed in order to describe current antiemetic prophylaxis in patients undergoing HSCT. The multicenter survey was performed by a questionnaire, covering the main areas on chemotherapy-induced nausea and vomiting (CINV): antiemetic prophylaxis guidelines used, antiemetic prophylaxis in different conditioning regimens, and methods of CINV evaluation. The survey was carried out in November 2016, and it was repeated 6 months after the publication of the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) specific guidelines on antiemetic prophylaxis in HSCT. The results show a remarkable heterogeneity of prophylaxis among the various centers and a significant difference between the guidelines and the clinical practice. In the main conditioning regimens, the combination of a serotonin3 receptor antagonist (5-HT3-RA) with dexamethasone and neurokin1 receptor antagonist (NK1-RA), as recommended by MASCC/ESMO guidelines, increased from 0 to 15% (before the publication of the guidelines) to 9-30% (after the publication of the guidelines). This study shows a lack of compliance with specific antiemetic guidelines, resulting mainly in under-prophylaxis. Concerted strategies are required to improve the current CINV prophylaxis, to draft shared common guidelines, and to increase the knowledge and the adherence to the current recommendations for CINV prophylaxis in the specific field of HSCT.
Assuntos
Antieméticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Náusea/prevenção & controle , Condicionamento Pré-Transplante/efeitos adversos , Vômito/prevenção & controle , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fidelidade a Diretrizes , Pesquisas sobre Atenção à Saúde , Humanos , Itália , Agonistas Mieloablativos/efeitos adversos , Agonistas Mieloablativos/uso terapêutico , Náusea/induzido quimicamente , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/estatística & dados numéricos , Transplante Autólogo , Vômito/induzido quimicamenteRESUMO
In the present study, we provide the results of a detailed genomic analysis and the growth characteristics of a colistin-resistant KPC-3-producing Klebsiella pneumoniae sequence type 512 (ST512) isolate (the colR-KPC3-KP isolate) with a mutated pmrB and isogenic isolates of colR-KPC3-KP with mcr-1.2 isolated from an immunocompromised patient. From 2014 to 2017, four colR-KPC3-KP isolates were detected in rectal swab samples collected from a pediatric hematology patient at the Azienda Ospedaliero-Universitaria Pisana in Pisa, Italy. Whole-genome sequencing was performed by MiSeq sequencing (Illumina). Growth experiments were performed using different concentrations of colistin. The growth lag phases both of an isolate harboring a deletion in pmrB and of clonal variants with mcr-1.2 were assessed by the use of real-time light-scattering measurements. In the first isolate (isolate 1000-pmrBΔ, recovered in September 2014), a 17-nucleotide deletion in pmrB was detected. In subsequent isolates, the mcr-1.2 gene associated with the plasmid pIncX4-AOUP was found, while pmrB was intact. Additionally, plasmid pIncQ-AOUP, harboring aminoglycoside resistance genes, was detected. The growth curves of the first three isolates were identical without colistin exposure; however, at higher concentrations of colistin, the growth curves of the isolate with a deletion in pmrB showed longer lag phases. We observed the replacement of mutated colR-KPC3-KP pmrB by isogenic isolates with multiple resistance plasmids, including mcr-1.2-carrying pIncX4, probably due to coselection under gentamicin treatment in a patient with prolonged colR-KPC3-KP carriage. The carriage of these isolates persisted in follow-up cultures. Coselection and the advantages in growth characteristics suggest that the plasmid-mediated resistance conferred by mcr has fewer fitness costs in colR-KPC3-KP than mutations in chromosomal pmrB, contributing to the success of this highly resistant hospital-adapted epidemiological lineage.IMPORTANCE Our study shows a successful prolonged human colonization by a colistin-resistant Klebsiella pneumoniae isolate harboring mcr-1.2 An intense antibiotic therapy contributed to the maintenance of this microorganism through the acquisition of new resistance genes. The isolates carrying mcr-1.2 showed fewer fitness costs than isogenic isolates with a pmrB mutation in the chromosome. Coselection and reduced fitness costs may explain the replacement of isolates with the pmrB mutation by other isolates and the ability of the microorganism to persist despite antibiotic treatment.
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Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Colistina/farmacologia , Farmacorresistência Bacteriana , Etanolaminofosfotransferase/metabolismo , Klebsiella pneumoniae/crescimento & desenvolvimento , Proteínas Mutantes/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/genética , Etanolaminofosfotransferase/genética , Aptidão Genética , Hospitais , Humanos , Itália , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Proteínas Mutantes/genética , Deleção de Sequência , Fatores de Transcrição/genética , Sequenciamento Completo do Genoma , beta-Lactamases/metabolismoRESUMO
Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (Pâ¯=â¯.0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P < .001). Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood.
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Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Polidesoxirribonucleotídeos/administração & dosagem , Sistema de Registros , Aloenxertos , Autoenxertos , Pré-Escolar , Intervalo Livre de Doença , Feminino , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/mortalidade , Humanos , Incidência , Lactente , Itália , Masculino , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaAssuntos
Transplante de Medula Óssea , Doença de Chagas/tratamento farmacológico , Doença de Chagas/microbiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doença de Chagas/sangue , Criança , Feminino , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Fatores de Tempo , Transplante HomólogoRESUMO
Immune reconstitution after allogeneic stem cell transplantation protects against opportunistic infections and disease relapse. Identifying the most protective lymphocyte subset would have implications of adoptive immunotherapy. We followed up a case series of 34 allogeneic transplantations for pediatric leukemias, aplastic anemias, or solid tumors. Regardless of baseline hematologic disorder, the speed of reconstitution of cytotoxic CD8 T lymphocytes and the achieving of the 10th percentile of normal CD4 T lymphocytes (but not B lymphocytes or natural killer cells) conditioned overall survival. The source of hematopoietic stem cells (peripheral blood vs bone marrow) and the occurrence of graft-versus-host disease (either acute or chronic) did not impact on immune reconstitution. Larger case series are needed to confirm the pivotal role of cytotoxic CD8 T lymphocytes in overall survival.