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Cytomegalovirus (CMV) DNAemia and disease are common complications in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Few studies have compared the efficacy and safety of the HSCT donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in the treatment of CMV DNAemia and disease. In this study, we retrospectively compared the efficacy and safety of HSCT donor and third-party CMV-CTLs in patients with refractory CMV DNAemia or disease after allo-HSCT at our centre from January 2017 to September 2021. Fifty-three patients who received CMV-CTL therapy were enrolled, including 40 in the donor group and 13 in the third-party group, and they were adults aged 18 years or older. Within 6 weeks of treatment, 26 (65.0%) and 9 (69.2%) patients achieved complete response in the donor and third-party groups (p = 1.000). The 2-year overall survival was 59.6% (95% CI 46.1%-77.1%) and 53.8% (32.6%-89.1%) in the donor and third-party groups (p = 0.860). Four (10.0%) patients in the donor group and two (15.4%) patients in the third-party group developed acute graft-versus-host disease within 3 months after CMV-CTL infusions. In conclusion, our data suggest that donor and third-party CMV-CTLs have comparable efficacy and safety for refractory CMV DNAemia and disease.
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Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Citomegalovirus , Linfócitos T Citotóxicos , Infecções por Citomegalovirus/terapia , Infecções por Citomegalovirus/complicações , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
This PASS-ALL study was designed to explore the effect of paediatric-inspired versus adult chemotherapy regimens on survival of adolescents and young adults (AYA) with high-risk Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia (HR PH-ve B-cell ALL) eligible for allogeneic haematopoietic stem cell transplantation (allo-HSCT). The PASS-ALL study is a multicentre, observational cohort study, and 143 patients with HR B-cell PH-ve ALL were enrolled from five centres-77 patients allocated in the paediatric-inspired cohort and 66 in the adult cohort with comparable baseline characteristics. Of the 143 patients, 128 cases underwent allo-HSCT. Three-year leukaemia-free survival (LFS) in the paediatric-inspired cohort was 72.2% (95% CI 60.8%-83.6%) compared with 44.6% (95% CI 31.9%-57.3%; p = 0.001). Furthermore, time-to-positive minimal residual disease (TTP-MRD) post-HSCT was marked different, 3-year cumulative incidence of relapse was 25.9% (95% CI 15.8%-37.2%) in paediatric cohort and 45.4% (95% CI 40.0%-57.9%) in adult cohort (p = 0.026). Finally, the 3-year OS rate was 75.3% (95% CI 64.9%-85.7%) for the paediatric-inspired cohort and 64.1% (95% CI 51.8%-76.4%) for the adult cohort (p = 0.074). On a multivariate analysis, paediatric-inspired regimen is a predictive factor for LFS (HR = 2.540, 95% CI 1.327-4.862, p = 0.005). Collectively, our data suggest that paediatric-inspired chemotherapy pre-HSCT results in deeper and durable MRD response reduces relapse post-HSCT and improves survival in HR B-cell PH-ve ALL patients with allo-HSCT.
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Linfoma de Burkitt , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto Jovem , Humanos , Criança , Cromossomo Filadélfia , Recidiva Local de Neoplasia , Transplante de Células-Tronco Hematopoéticas/métodos , Recidiva , Estudos RetrospectivosRESUMO
BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Metotrexato , Metilprednisolona , Humanos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Feminino , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Adulto , Metilprednisolona/uso terapêutico , Metilprednisolona/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto Jovem , Resultado do Tratamento , Quimioterapia Combinada , Idoso , Adolescente , Doença AgudaRESUMO
BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.
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Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Azacitidina/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Leucemia Mieloide Aguda/terapia , Resposta Patológica Completa , Sorafenibe/efeitos adversos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
The lead-free halide perovskites possess nontoxicity and excellent chemical stability, whereas relatively weak luminescence intensity limits their potential in practical applications. Therefore, strengthening the luminescence intensity and expanding application fields are urgent tasks for the development of lead-free halide perovskites. In this paper, antimony-doped Cs2NaScCl6 crystals synthesized by a solvothermal method emit bright, deep blue photoluminescence at 447 nm. The photoluminescence (PL), photoluminescence excitation (PLE), and absorption spectra demonstrate that Sb3+ doping effectively activate the intrinsic "dark self-trapped exciton (STE)," leading to an impressive photoluminescence quantum yield (PLQY) value of 78.31% for 1% Sb3+ doping. Furthermore, the luminescence intensity remains above 92% compared with the fresh sample without secondary phases detected even after 90 days under environmental conditions. To expand the emission spectra, rare-earth Sm3+ is further incorporated into Cs2NaScCl6:1% Sb3+ crystals. The results show that Sb ions not only enhance intrinsic STE luminescence but also serve as sensitizers to boost the red-light emission of Sm3+, leading to a significant 500-fold increase in red emission intensity. Finally, the PLQY reaches a stunning 86.78%. These findings provide valuable insights in the design of Sb ion-doped lead-free double perovskites, broadening the application fields in various optoelectronic devices.
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BACKGROUND & AIMS: Although the effect of bacterial infection on cirrhosis has been well-described, the effect of non-hepatotropic virus (NHV) infection is unknown. This study evaluated the genome fragments of circulating microorganisms using metagenomic next-generation sequencing (mNGS) in individuals with acute decompensation (AD) of cirrhosis, focusing on NHVs, and related the findings to clinical outcomes. METHODS: Plasma mNGS was performed in 129 individuals with AD of cirrhosis in the study cohort. Ten healthy volunteers and 20, 39, and 81 individuals with stable cirrhosis, severe sepsis and hematological malignancies, respectively, were enrolled as controls. Validation assays for human cytomegalovirus (CMV) reactivation were performed in a validation cohort (n = 58) and exploratory treatment was instituted. RESULTS: In the study cohort, 188 microorganisms were detected in 74.4% (96/129) of patients, including viruses (58.0%), bacteria (34.1%), fungi (7.4%) and chlamydia (0.5%). A NHV signature was identified in individuals with AD, and CMV was the most frequent NHV, which correlated with the clinical effect of empirical antibiotic treatment, progression to acute-on-chronic liver failure, and 90-day mortality. The NHV signature in individuals with acute-on-chronic liver failure was similar to that in those with sepsis and hematological malignancies. CMV was detected in 24.1% (14/58) of patients in the validation cohort. Of the 14 cases with detectable CMV by mNGS, nine were further validated by real-time PCR or pp65 antigenemia testing. Three patients with CMV reactivation received ganciclovir therapy in an exploratory manner and experienced clinical resolutions. CONCLUSIONS: The results of this study suggest that NHVs may play a pathogenic role in complicating the course of AD. Further validation is needed to define whether this should be incorporated into the routine management of individuals with AD of cirrhosis. IMPACT AND IMPLICATIONS: A non-hepatotropic virus (NHV) signature, which was similar to that in individuals with sepsis and hematological malignancies, was identified in individuals with acute decompensation of cirrhosis. The detected viral signature had clinical correlates, including clinical efficacy of empirical antibiotic treatment, progression to acute-on-chronic liver failure and short-term mortality. Cytomegalovirus reactivation, which is treatable, may adversely affect clinical outcomes in some individuals with decompensated cirrhosis. Routine screening for NHVs, especially cytomegalovirus, may be useful for the management of individuals with acute decompensation of cirrhosis.
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Insuficiência Hepática Crônica Agudizada , Infecções por Citomegalovirus , Neoplasias Hematológicas , Sepse , Humanos , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/tratamento farmacológico , Prognóstico , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/complicações , Citomegalovirus/genética , Cirrose Hepática/diagnóstico , Cirrose Hepática/complicações , Sepse/diagnóstico , Sepse/tratamento farmacológico , Sepse/complicações , Neoplasias Hematológicas/complicaçõesRESUMO
Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation; not all patients respond to standard glucocorticoids treatment. This study retrospectively evaluated the effects of ruxolitinib compared with basiliximab for steroid-refractory aGVHD (SR-aGVHD). One hundred and twenty-nine patients were enrolled, 81 in ruxolitinib and 48 in basiliximab group. The overall response (OR) at day 28 was higher in ruxolitinib group (72.8% vs. 54.2%, P = 0.031), as with complete response (CR) (58.0% vs. 35.4%, P = 0.013). Ruxolitinib led to significantly lower 1-year cumulative incidence of chronic GVHD (cGVHD) (29.6% vs. 43.8%, P = 0.021). Besides, ruxolitinib showed higher 1-year overall survival (OS) and 1-year cumulative incidence of failure-free survival (FFS) (OS: 72.8% vs. 50.0%, P = 0.008; FFS: 58.9% vs. 39.6%, P = 0.014). The 1-year cumulative incidence of non-relapse mortality (NRM) was lower in ruxolitinib group (16.1% vs. 37.5%, P = 0.005), and the 1-year relapse was not different. The 1-year cumulative incidence of cytomegalovirus (CMV) viremia, CMV-associated diseases and Epstein-Barr virus (EBV)-associated diseases was similar between the two groups, but EBV viremia was significantly lower in ruxolitinib group (6.2% vs. 29.2%, P < 0.001). Subgroup analyses revealed that OR and survival were similar in ruxolitinib 5 mg twice daily (bid) and 10 mg bid groups. However, ruxolitinib 10 mg bid treatment markedly reduced 1-year cumulative incidence of cGVHD compared with 5 mg bid (21.1% vs. 50.0%, P = 0.016). Our study demonstrated that ruxolitinib was superior to basiliximab in SR-aGVHD treatment and cGVHD prophylaxis, therefore should be recommended.
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Síndrome de Bronquiolite Obliterante , Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Basiliximab/uso terapêutico , Estudos Retrospectivos , Viremia , Herpesvirus Humano 4 , Esteroides/uso terapêutico , Nitrilas/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença AgudaRESUMO
We report a randomized prospective phase 3 study, designed to evaluate the efficacy and tolerability of idarubicin plus busulfan and cyclophosphamide (IDA-BuCy) versus BuCy in autologous hematopoietic stem-cell transplantation (auto-HSCT) for intermediate-risk acute myeloid leukemia (IR-AML) patients in first complete remission (CR1). One hundred and fifty-four patients were enrolled and randomized to receive IDA-BuCy (IDA 15 mg/m2/day on days -12 to -10, Bu 3.2 mg/kg/day on days -7 to -4, and Cy 60 mg/kg/day on days -3 to -2) or BuCy. The 2-year incidence of relapse was 15.6% and 19.5% in IDA-BuCy and BuCy groups (p = 0.482), respectively. There was no significant overall survival (OS) and disease-free survival (DFS) benefit for IR-AML patients receiving IDA-BuCy (2-year OS 81.8% in IDA-BuCy vs. 83.1% in BuCy, p = 0.798; 2-year DFS 76.6% in IDA-BuCy vs. 79.2% in BuCy, p = 0.693). Grade 3 or worse regimen-related toxicity (RRT) was reported for 22 (28.9%) of 76 and 9 (12.0%) of 75 patients in two groups (p = 0.015), respectively. AEs within 100 days with an outcome of death were reported for 4 (5.3%) and 0 patients in two groups. In conclusion, IDA-BuCy has higher RRT and similar anti-leukemic activity compared with BuCy in IR-AML patients in CR1 undergoing auto-HSCT. Thus, caution should be taken when choosing IDA-BuCy for IR-AML patients in CR1 with auto-HSCT. This trial is registered with ClinicalTrials.gov, NCT02671708, and is complete.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Idarubicina , Leucemia Mieloide Aguda/terapia , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/uso terapêutico , Bussulfano/uso terapêutico , Condicionamento Pré-Transplante , Estudos RetrospectivosRESUMO
BACKGROUND: Patients with refractory central nervous system leukemia (CNSL) have a dismal prognosis and lack effective therapy. Case reports have shown that sorafenib is effective against brain metastases, including leukemia. METHODS: To explore the efficacy of sorafenib combined with conventional therapies for refractory CNSL, a phase 2 study was conducted. The primary end point was the complete remission rate (CRR) within 8 weeks of treatment. Secondary end points included the overall response rate (ORR), event-free survival (EFS), overall survival (OS), and adverse events (AEs). RESULTS: Twenty-six patients with refractory CNSL were enrolled; they included 17 with isolated CNSL, 7 with hematological relapse, and 2 with another extramedullary relapse. After 8 weeks of treatment, 21 patients achieved complete remission, 2 achieved partial remission, and 3 achieved no remission for a CRR of 80.8% (95% CI, 62.1%-91.5%) and an ORR of 88.5% (95% CI, 71.0%-96.0%). Twenty patients survived, and 6 died. The 2-year EFS and OS rates were 75.0% (95% CI, 54.5%-88.3%) and 76.9% (95% CI, 54.2%-90.4%), respectively. Six patients experienced grade 3 or 4 treatment-related AEs, including moderate chronic graft-vs-host disease (n = 3), grade 3 or 4 acute graft-vs-host disease (n = 2), and grade 3 skin rash (n = 1). No treatment-related deaths occurred during the therapy of refractory CNSL. CONCLUSIONS: Sorafenib combined with conventional therapies is effective and safe for refractory CNSL. LAY SUMMARY: Sorafenib combined with conventional therapies is effective and safe for refractory central nervous system leukemia.
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Neoplasias do Sistema Nervoso Central , Doença Enxerto-Hospedeiro , Leucemia , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Humanos , Recidiva , Estudos Retrospectivos , SorafenibeRESUMO
BACKGROUND: Use of kinase inhibitors such as dasatinib and imatinib might increase the risk of opportunistic infections, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. However, the effect of sorafenib on EBV and CMV infections remains unclear. The aim of this study was to investigate the effect of sorafenib maintenance post-transplantation on the incidence and mortality of EBV and CMV infections in patients with FLT3-ITD acute myeloid leukemia. METHODS: This was a follow-up of our randomized controlled trial undertaken at seven hospitals in China. The primary endpoint was EBV and CMV infections within 3 years post-transplantation. Secondary endpoints included the cumulative incidences of relapse, non-relapse mortality (NRM), overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) at 3 years. RESULTS: Two hundred two patients were assigned to sorafenib maintenance (n=100) or non-maintenance (control, n=102). Median extended follow-up post-transplantation was 36.8 (range, 2.5-67.1) months. The 3-year cumulative incidences of EBV-DNAemia and EBV-associated diseases were 24.0% (95% CI: 16.1-32.8%) and 5.0% (1.8-10.6%) in the sorafenib group, and 24.5% (16.6-33.2%) and 5.9% (2.4-11.6%) in the control group (P=0.937; P=0.771). The 3-year cumulative incidences of CMV-DNAemia and CMV-associated diseases were 56.0% (45.6-65.1%) and 8.0% (3.7-14.4%) in the sorafenib group, and 52.9% (42.7-62.1%) and 8.8% (4.3-15.3%) in the control group (P=0.997; P=0.826). The 3-year cumulative mortality of EBV- and CMV-associated diseases was 0.0% (0.0-0.0%) and 2.0% (0.4-6.4%) in the sorafenib group, and 1.0% (0.1-4.8%) and 2.0% (0.4-6.3%) in the control group (P=0.322, P=0.980). The 3-year cumulative incidences of relapse, NRM, OS, LFS, and GRFS were 13.0%, 11.1%, 79.0%, 75.9%, and 65.8% in the sorafenib group and 34.8%, 12.7%, 61.4%, 52.5%, and 46.6% in the control group, respectively (P<0.001, P=0.656, P=0.005, P<0.001, P=0.003). The reconstitution of T lymphocyte subsets, B lymphocytes, and natural killer cells was similar between the two groups (all P>0.05). CONCLUSIONS: Sorafenib maintenance post-transplantation does not increase the incidence and mortality of EBV and CMV infections, demonstrating a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02474290 . Registered on June 14, 2015.
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Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Infecções por Citomegalovirus/epidemiologia , Infecções por Vírus Epstein-Barr/epidemiologia , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4/genética , Humanos , Leucemia Mieloide Aguda/terapia , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Intestinal microbiota is an important prognostic factor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its role in predicting survival has not been determined. Here, stool samples at day 15 ± 1 posttransplant were obtained from 209 patients at two centers. Microbiota was examined using 16S rRNA sequencing. The microbiota diversity and abundance of specific bacteria (including Lachnospiraceae, Ruminococcaceae, Erysipelotrichaceae, and Enterobacteriaceae) were assigned a value of 0 or 1 depending on whether they were positive or negative associated with survival, respectively. An accumulated intestinal microbiota (AIM) score was generated, and patients were divided into low- and high-score groups. A low score was associated with a better 3-year cumulative overall survival (OS) as well as lower mortality than a high score (88.5 vs. 43.9% and 7.1 vs. 35.8%, respectively; both P < 0.001). In multivariate analysis, a high score was found to be an independent risk factor for OS and transplant-related mortality (hazard ratio = 5.68 and 3.92, respectively; P < 0.001 and 0.003, respectively). Furthermore, the AIM score could serve as a predictor for survival (area under receiver operating characteristic curve = 0.836, P < 0.001). Therefore, the intestinal microbiota score at neutrophil recovery could predict survival following allo-HSCT.
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Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Microbiota , Firmicutes/genética , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/microbiologia , Humanos , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: Cidofovir (CDV) is a nucleotide analogue with broad antiviral activities. It remains unclear about the CDV administration for anti-cytomegalovirus (CMV) treatment in patients with haploidentical hematopoietic stem cell transplantation (haplo-HSCT). PATIENTS AND METHODS: In this study, 31 out of 101 haplo-HSCT recipients who suffered CMV infection in the CT group (conventional treatment) were enrolled into the CDV-ST group (CDV second-line treatment). These patients were treated with CDV as they failed conventional treatment or they were unavailable to the preemptive antiviral therapy. Nine patients with CMV infection were enrolled into the CDV-FT group (CDV-frontline treatment) and received CDV preemptive therapy. RESULTS: In the CDV-ST group, 23 of 28 (82.1%) patients were observed treatment response with a median time of 9 (2-23) days, and 20 (71.8%) among these patients obtained complete response (CR). In the CDV-FT group, six of eight (75.0%) patients acquired CR with a median of 6 (4-25) days. The treatment response in CDV-treated groups was comparable with those in CT groups. Besides, there was no statistical difference in CMV-related mortality between the three groups (p > .05). During the follow-up period (median follow-up:10 [1-28] months), a total of 8 of 22 (36.4%) patients experienced CMV reactivation in the CDV-ST group versus 23 of 62 (37.1%) in the CT group (p > .05). CDV-related toxicities occurred in 13 of 40 (32.5%) patients, including six (15%) reversible nephrotoxicity. CONCLUSION: Our study suggests that CDV is potentially an option for the salvage treatment of CMV infection in the haplo-HSCT patients.
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Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Antivirais , Cidofovir/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Terapia de SalvaçãoRESUMO
Whether patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) benefit from pretransplant cytoreductive therapy remains controversial. Our study compared the outcomes of upfront transplantation with those of pretransplant cytoreductive therapy in the patients who received transplantation and those who dropped out due to cytoreductive therapy-related adverse effects. Patients with MDS-EB-1 or MDS-EB-2 were enrolled and divided into three groups based on therapy pretransplantation: upfront transplantation (upfront, n = 54), induction chemotherapy (CT, n = 66) and hypomethylating agents (HMA, n = 37) alone. One hundred fifty-seven patients were enrolled and 124 received allo-HSCT, with 5.6%, 28.8% and 29.7% of drop-out rate of transplantation in upfront, CT and HMA groups (P = .030), respectively. Overall therapy-related mortality (TRM), cytoreductive therapy and transplant-related mortality was 13.0%, 32.4% and 28.4% (P = .028), and 5-year overall survival (OS) was 73.6%, 43.4% and 46.9% (P = .033). Multivariate analysis showed that CT and HMA were risk factors for TRM and OS, and transplantation was a protective factor for OS. In transplant patients, 3-year cumulative incidence of relapse was 10.6%, 20.4% and 20.3% (P = .033), 5-year TRM was 14.5%, 20.0% and 17.6% (P = .651), OS was 77.3%, 64.3% and 68.8% (P = .047) and DFS was 74.0%, 63.0% and 65.8% (P = .042). Multivariate analysis showed that CT was a risk factor for DFS, while CT, HMA and poor karyotype were risk factors for relapse. Results suggested that pretransplant cytoreductive therapy was not associated with better outcomes in the patients who had undergone transplantation. Therefore, upfront transplantation may be preferable for MDS patients.
Assuntos
Procedimentos Cirúrgicos de Citorredução/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: Findings of retrospective studies suggest that sorafenib maintenance post-transplantation might reduce relapse in patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. We investigated the efficacy and tolerability of sorafenib maintenance post-transplantation in this population. METHODS: We did an open-label, randomised phase 3 trial at seven hospitals in China. Eligible patients (aged 18-60 years) had FLT3-ITD acute myeloid leukaemia, were undergoing allogeneic haematopoietic stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days post-transplantation. Patients were randomly assigned (1:1) to sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days post-transplantation. Randomisation was done with permuted blocks (block size four) and implemented through an interactive web-based randomisation system. The primary endpoint was the 1-year cumulative incidence of relapse in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02474290; the trial is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were enrolled and randomly assigned to sorafenib maintenance (n=100) or control (n=102). Median follow-up post-transplantation was 21·3 months (IQR 15·0-37·0). The 1-year cumulative incidence of relapse was 7·0% (95% CI 3·1-13·1) in the sorafenib group and 24·5% (16·6-33·2) in the control group (hazard ratio 0·25, 95% CI 0·11-0·57; p=0·0010). Within 210 days post-transplantation, the most common grade 3 and 4 adverse events were infections (25 [25%] of 100 patients in the sorafenib group vs 24 [24%] of 102 in the control group), acute graft-versus-host-disease (GVHD; 23 [23%] of 100 vs 21 [21%] of 102), chronic GVHD (18 [18%] of 99 vs 17 [17%] of 99), and haematological toxicity (15 [15%] of 100 vs seven [7%] of 102). There were no treatment-related deaths. INTERPRETATION: Sorafenib maintenance post-transplantation can reduce relapse and is well tolerated in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. This strategy could be a suitable therapeutic option for patients with FLT3-ITD acute myeloid leukaemia. FUNDING: None.
Assuntos
Doença Enxerto-Hospedeiro/epidemiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Sorafenibe/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , China/epidemiologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases , Indução de Remissão , Sorafenibe/efeitos adversos , Sequências de Repetição em Tandem/genética , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
Central nervous system leukemia (CNSL) relapse is relatively common among Philadelphia chromosome-positive (Ph+) leukemia patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). The prognosis of patients is dismal for those with a BCR-ABL T315I mutation, which is resistant to TKIs including second-generation drugs. We assessed ponatinib for nine patients with recurrent Ph+ CNSL and a T315I mutation after allo-HSCT, including five patients with Ph+ acute lymphoblastic leukemia and four with chronic myelogenous leukemia. Five patients experienced isolated CNSL relapse, and four experienced CNSL with hematologic relapse. All patients received ponatinib combined with intrathecal chemotherapy, and four patients with hematologic relapse received systemic chemotherapy and/or donor lymphocyte infusion. All patients achieved a deep molecular response and central nervous system remission (CNSR) at a median time of 1.5 (range: 0.7-3) months after ponatinib treatment. Two patients experienced a second CNSL relapse due to ponatinib reduction, but they achieved CNSR again after an increase to the standard dosage. Six patients developed graft versus host disease. By April 1, 2019, eight patients were alive, and one died of pneumonia. The median time of survival after the first CNSL relapse posttransplantation was 18 (range: 11.2-48.5) months. Our data from a small number of samples suggests that ponatinib is effective for recurrent Ph+ CNSL patients with a BCR-ABL T315I mutation after allo-HSCT and warrants broader clinical evaluation.
Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Imidazóis/uso terapêutico , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Piridazinas/uso terapêutico , Adulto , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Although studies have reported that intestinal microbiota are associated with acute graft-versus-host disease (aGVHD), they lacked a satisfactory method for predicting aGVHD. We collected stool and blood samples at day 15 posttransplant from 150 patients from two centers who underwent myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT). Stool microbiota were detected by 16S ribosomal RNA gene sequencing; inflammatory factors and T lymphocytes were detected by multiplex immunoassays and flow cytometry, respectively. A gut microbiota score (GMS) from a LASSO (least absolute shrinkage and selection operator) model was developed and validated to predict aGVHD. In the discovery cohort, the GMS could predict II-IV aGVHD (area under the receiver operating characteristic [ROC] curve [AUC] = 0.904, P < .0001). Furthermore, the validation model was consistent with the discovery set (AUC = 0.887, P < .0001). Regulatory T/T-helper 17 (Treg/Th17) cells ratio in the low GMS subgroup was higher compared with the high GMS (P = .012), and the validation set is consistent with the discovery set (P = .003). In addition, high cytokine levels were associated with high GMS. In conclusion, the GMS at neutrophil engraftment could predict aGVHD, and it was a potential and novel method. The GMS was associated with the inflammatory factor and Treg/Th17 balance.
Assuntos
Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Aguda , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfócitos T Reguladores , Condicionamento Pré-TransplanteRESUMO
The optimal therapy for patients with acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) who relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. In this study we retrospectively evaluated the efficacy of sorafenib combined with other therapeutic strategies as salvage therapy for these patients. Eighty-three AML patients with FLT3-ITD relapsing after allo-HSCT were enrolled in this study. Fifty-three patients received salvage therapy containing sorafenib and 30 patients did not. Salvage therapy containing sorafenib was superior to that without sorafenib with respect to complete remission rates, overall survival (OS), and progression-free survival (PFS) (66.0% versus 30.0%, 46.8% versus 20.0%, and 44.9% versus 16.7%, respectively; Pâ¯=â¯.002, Pâ¯=â¯.003, and Pâ¯=â¯.001). Further subgroup analysis revealed that the OS and PFS of patients who received sorafenib combined with chemotherapy followed by donor lymphocyte infusion (DLI) were superior to those receiving other therapeutic regimens, including sorafenib combined with chemotherapy, chemotherapy followed by DLI, and monochemotherapy (Pâ¯=â¯.003, P < .001). Multivariate analysis revealed that salvage therapy including sorafenib was the only protective factor for longer OS (Pâ¯=â¯.035; hazard ratio [HR], .526); salvage therapy including sorafenib and DLI were the protective factors for longer PFS (Pâ¯=â¯.011, HR, .423; Pâ¯=â¯.019, HR, .508). Our data suggest that sorafenib therapy is associated with improved outcomes for FLT3-ITD AML relapsing after allo-HSCT, and whether sorafenib combined with chemotherapy followed by DLI reveals an optimal efficacy merits further study.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Terapia de Salvação , Sorafenibe/administração & dosagem , Sequências de Repetição em Tandem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
The intestinal microbiome plays an important role in the development of acute graft-versus-host disease (aGVHD). However, whether intestinal microbiota can predict the development of aGVHD has been reported only rarely. Here we conducted a prospective study of microbiota in 141 patients after allogeneic hematopoietic stem cell transplantation. We found lower microbiota diversity in the aGVHD group compared with the non-aGVHD group at day 0 and day 15 ± 1 (Pâ¯=â¯.018 and .009, respectively). Diversity was negatively associated with conditioning intensity (Pâ¯=â¯.017, day 0; Pâ¯=â¯.045, day 15) and ß-lactam antibiotic administration (Pâ¯=â¯.004, day 15). Intensified conditioning and ß-lactam antibiotics were associated with a lower regulatory T (Treg)/T helper 17 (Th17) cell ratio at day 15 (Pâ¯=â¯.030 and .047, respectively). At day 15, the levels of the inflammatory factors (tumor necrosis factor α, interleukin [IL]-6, IL-17A, IL-1ß, and lipopolysaccharide) were higher in the intensified conditioning group compared with the standard group (P < .05). The accumulated intestinal microbiota (AIM) score was defined as microbiota diversity and gradient of the 4 bacterials (Lachnospiraceae, Peptostreptococcaceae, Erysipelotrichaceae, and Enterobacteriaceae) at day 15 post-transplantation. The AIM score was positively correlated with aGVHD grade (râ¯=â¯.481, P < .001), and the AIM score could be predictive of the development of aGVHD (grade II-IV aGVHD: area under the curve [AUC], .75, P < .001; grade III-IV aGVHD: AUC, .84, P < .001). These findings suggest that intestinal microbiota and conditioning might induce aGVHD by inflammatory factors and the Treg/Th17 balance. The constitution of the intestinal microbiota at neutrophil engraftment may predict the development of aGVHD.
Assuntos
Microbioma Gastrointestinal/fisiologia , Doença Enxerto-Hospedeiro/fisiopatologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/efeitos adversos , Adolescente , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adulto JovemRESUMO
BACKGROUND: The optimal dose of rabbit antithymocyte globulin (ATG, ImtixSangstat) minimizing infections without increasing graft-versus-host disease (GVHD) is unknown in T cell-replete, G-CSF-primed haploidentical hematopoietic stem cell transplantation (haplo-HSCT). METHODS: Four hundred and eight patients were enrolled in this multicenter study to evaluate the effect of 7.5 mg/kg and 10.0 mg/kg rabbit ATG on viral infections and GVHD prophylaxis after haplo-HSCT. The primary endpoint was EBV DNAemia within 1 year posttransplantation. RESULTS: The 1-year incidence of EBV DNAemia was 20.7% (95% confidence interval, 15.4-26.5) and 40.0% (33.3-46.6) in the 7.5 mg/kg and 10.0 mg/kg groups, respectively (P < 0.001). The 100-day cumulative incidence of grade II to IV aGVHD was 27.1% (21.1-33.4) and 25.4% (19.6-31.5) in the 7.5 mg/kg and 10.0 mg/kg ATG groups, respectively (P = 0.548). The 2-year incidence of chronic GVHD was 34.6% (27.8-41.4) and 36.2% (29.1-43.2) in the 7.5 mg and 10.0 mg groups (P = 0.814). The 1-year incidence of CMV DNAemia was 73.4% (67.2-79.4) and 83.4% (77.5-87.9) in the 7.5 mg/kg and 10.0 mg/kg groups (P = 0.038). The 3-year overall survival posttransplantation was 69.5% (63.2-75.8) and 63.5% (56.2-70.8), and the disease-free survival was 62.2% (55.3-69.1) and 60.3% (53.0-67.6) in the 7.5 mg/kg and 10.0 mg/kg groups, respectively (OS: P = 0.308; DFS: P = 0.660). The counts of EBV- and CMV-specific cytotoxic T cells (CTLs) were higher in the 7.5 mg/kg group than in the 10.0 mg/kg group early posttransplantation. CONCLUSIONS: Compared with 10.0 mg/kg, 7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in haplo-HSCT, probably by affecting EBV- and CMV-specific CTLs. TRIAL REGISTRATION: clinicaltrials.gov, NCT01883180 . Registered 14 June 2013.
Assuntos
Soro Antilinfocitário/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/administração & dosagem , Adolescente , Adulto , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/prevenção & controle , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controleRESUMO
Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have shown that T follicular helper cells (Tfh) contribute to immune pathology in cGVHD, but the function of extrafollicular helper T cells during cGVHD pathogenesis remains largely unknown. In the current study, we identified circulating extrafollicular helper T-like cells (CD44hiCD62LloPSGL-1loCD4+, c-extrafollicular Th-like) in human peripheral blood. We performed phenotypic and functional analyses of c-extrafollicular Th-like cells from 80 patients after allo-HSCT to explore the role of these cells in the development of human cGVHD. Patients with active cGVHD had significantly higher frequencies and counts of c-extrafollicular Th-like cells than those of patients without cGVHD. The expansion of c-extrafollicular Th-like cells was more significant in patients with moderate/severe cGVHD than that of patients with mild cGVHD. C-extrafollicular Th-like cells from patients with active cGVHD exhibited increased functional abilities to induce plasmablast differentiation and IgG1 secretion compared to those of patients without cGVHD. Moreover, c-extrafollicular Th-like cell levels were highly correlated with the generation of autoreactive B cells, plasmablasts and IgG1 antibodies. Our studies provide new insights into human cGVHD pathogenesis and identify c-extrafollicular Th-like cells as a key element in the development of human cGVHD.