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Colitis , Infecciones por Citomegalovirus , Citomegalovirus , Hemorragia Gastrointestinal , Humanos , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/terapia , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/inmunología , Hemorragia Gastrointestinal/terapia , Hemorragia Gastrointestinal/etiología , Colitis/virología , Colitis/terapia , Colitis/complicaciones , Citomegalovirus/patogenicidad , Masculino , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Persona de Mediana EdadRESUMEN
INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell therapy, emerging as an efficient treatment option for patients with secondary central nervous system (CNS) lymphoma, is frequently complicated with immune effector cell-associated neurotoxicity syndrome (ICANS). CASE PRESENTATION: We report a case of a 64-year-old woman with transformed follicular lymphoma, developing high-grade ICANS with eosinophilic pleocytosis following third-line therapy with CAR-T cells (tisagenlecleucel). During bridging therapy, she declined neurologically and was diagnosed with secondary CNS lymphoma. She received methotrexate-cytarabine-thiotepa-rituximab regimen with clinical and radiological improvement. Post-CAR-T cell infusion she developed cytokine release syndrome grade II and ICANS grade III. Given the lack of response to steroids, anakinra was initiated with complete ICANS resolution. Cerebrospinal fluid (CSF) analysis, performed only on day +10 due to thrombocytopenia, revealed eosinophils, while infections were excluded. CONCLUSION: This report emphasizes the importance of CSF analysis in individuals with CAR-T-related neurotoxicity for elucidating the role of specific immune cells in such complications.
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Patients with FLT3-mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard-of-care for patients with R/R FLT3-mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt-ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt-ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt-ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem-cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt-ven (12-month OS 58.8% [95% CI 39.5%-87.6%]) versus gilteritinib (42.1% [95% CI 24.9%-71.3%] for gilteritinib). Early salvage with gilt-ven versus any other gilteritinib-based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt-ven did not improve remissions or HSCT-realization rates in patients with R/R FLT3-mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt-ven and a survival benefit was shown for gilt-ven approach when sequenced early for salvage.
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Acute graft-versus-host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem-cell transplantation with limited treatment options. The gut microbiome plays a critical role in aGvHD pathogenesis. Fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach to restore gut microbial diversity. In this prospective pilot study, 21 patients with steroid-resistant or steroid-dependent lower gastrointestinal aGvHD received FMT in capsule form. At 28 days after the first FMT, the overall response rate was 52.4%, with 23.8% complete and 28.6% partial responses. However, sustained responses were infrequent, with only one patient remaining aGvHD-free long-term. FMT was generally well-tolerated. Microbiome analysis revealed dysbiosis in pre-FMT patient stool samples, with distinct microbial characteristics compared to donors. Following FMT, there was an increase in beneficial Clostridiales and a decrease in pathogenic Enterobacteriales. These findings highlight the potential of FMT as a treatment option for steroid-resistant aGvHD. Trial registration number NCT #03214289.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Microbiota Fecal/efectos adversos , Proyectos Piloto , Estudios Prospectivos , Tracto Gastrointestinal , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , EsteroidesRESUMEN
OBJECTIVES: Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to improve long-term survival for early diffuse progressive systemic sclerosis (SSc) compared with cyclophosphamide. Cyclophosphamide, however, does not provide a long-term benefit in SSc. The combination of mycophenolate mofetil (MMF) and rituximab is a potent alternative regimen. We aimed to retrospectively compare the outcomes of SSc patients who underwent AHSCT to patients who met the eligibility criteria for AHSCT but received upfront combination therapy with MMF and rituximab. METHODS: Repeated assessments of modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), and diffusing capacity (DLCO) values were conducted. Clinical improvement was defined as an mRSS decrease > 25% or an FVC increase > 10%. Event-free survival (EFS) was defined in the absence of persistent major organ failure or death. RESULTS: Twenty-one SSc patients in the combination therapy group were compared with sixteen in the AHSCT group. Age, sex and disease duration were similar between the two groups. Clinical improvement at 12 months was seen in 18 (86%) patients in the combination group compared with 13 (81%) in the AHSCT group (p= 0.7). The hazard ratio for EFS at 24 months favored the combination group (HR = 0.09, P= 0.04). During follow-up, both groups exhibited a significant and comparable reduction in mRSS and an increase in FVC values at each time interval up to 24 months. CONCLUSION: MMF and rituximab compared with AHSCT in SSc patients eligible for AHSCT resulted in similar skin and lung clinical improvement with a better safety profile at 24 months.
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COVID-19-related mortality among hematopoietic stem cell transplantation (HSCT) recipients in the pre-vaccine era ranged between 22 and 33%. The Pfizer/BioNTech BNT162b2 vaccine demonstrated significant immunogenicity and efficacy in the healthy population; however, its long-term effects on allogeneic HSCT recipients remained unclear. Our study longitudinally evaluated humoral and cellular responses to the BNT162b2 vaccine in adult allogeneic HSCT patients. A positive response was defined as antibody titers ≥ 150 AU/mL post-second vaccination. Among 77 included patients, 51 (66.2%) responded to vaccination. Response-associated factors were female gender, recent anti-CD20 therapy, and a longer interval between transplant and vaccination. Response rates reached 83.7% in patients vaccinated >12 months post-transplant. At 6 months post-second vaccination, antibody titers dropped, but were significantly increased with the booster dose. Moreover, 43% (6/14) of non-responders to the second vaccination acquired sufficient antibody titers after booster administration, resulting in an overall response rate of 79.5% for the entire cohort. The BNT162b2 vaccine was effective in allogeneic transplant recipients. Although antibody titers decreased with time, the third vaccination led to their significant elevation, with 93% of third-dose responders maintaining titers above 150 AU/mL at 3 months post-administration.
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The severity of T cell-mediated gastrointestinal (GI) diseases such as graft-versus-host disease (GVHD) and inflammatory bowel diseases correlates with a decrease in the diversity of the host gut microbiome composition characterized by loss of obligate anaerobic commensals. The mechanisms underpinning these changes in the microbial structure remain unknown. Here, we show in multiple specific pathogen-free (SPF), gnotobiotic, and germ-free murine models of GI GVHD that the initiation of the intestinal damage by the pathogenic T cells altered ambient oxygen levels in the GI tract and caused dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in a host intestinal HIF-1α- and a microbiome-dependent manner. Regulation of intestinal ambient oxygen levels with oral iron chelation mitigated dysbiosis and reduced the severity of the GI GVHD. Thus, targeting ambient intestinal oxygen levels may represent a novel, non-immunosuppressive strategy to mitigate T cell-driven intestinal diseases.
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Enfermedades Gastrointestinales , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Disbiosis , Intestinos/patología , Enfermedad Injerto contra Huésped/patologíaRESUMEN
Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. Eighty percent were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. Twelve patients (48%) achieved complete response (CR) with gilteritinib. The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3 months, CI 95% 0-36.2 vs. 2.6 months, CI 95% 1.47-3.7; p value = 0.046). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p = 0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p = 0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6 months (CI 95% 2.3-16.8) vs. 7 months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869). In conclusion, in the real-world setting, gilteritinib is effective, including in heavily pre-treated, TKI exposed patients.
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Leucemia Mieloide Aguda , Pirazinas , Compuestos de Anilina/uso terapéutico , Humanos , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Fluoroquinolone prophylaxis during allogeneic hematopoietic stem cell transplantation (allo-HSCT) reduces bloodstream infections. However, this practice affects the gut microbiome and potentially increases dysbiosis, which is closely related to transplantation outcomes, and lower gastrointestinal (GI) tract acute graft-versus-host disease (GVHD). This study assessed the impact of omitting ciprofloxacin prophylaxis on GI GVHD, clinical outcomes, and microbiome composition in patients undergoing allo-HSCT. In this single-center, retrospective study comprising recipients of allo-HSCT performed between 2018 and 2020, routine ciprofloxacin prophylaxis (the exposure variable) was stopped in December 2018. The primary outcome was acute lower GI GVHD within 100 days post-transplantation; secondary outcomes were 1-year overall survival, nonrelapse mortality, relapse, and overall acute GVHD. Outcomes were compared using univariate and multivariate analyses and Kaplan-Meier/competing-risk analyses. Sequential stool samples were collected prospectively from a subpopulation of recipients, and the microbiome composition was analyzed. Seventy-five of the 129 patients (58.1%) received prophylactic ciprofloxacin treatment. Baseline characteristics did not differ between the 2 study groups: patients with ciprofloxacin prophylaxis and those without ciprofloxacin prophylaxis. The rate of lower GI GVHD also did not differ between the 2 groups (24% versus 18.5%; P = .597). None of the secondary outcomes was significantly different between the 2 groups in univariate, multivariate, and time-to-event analyses. In addition, microbiome analysis in a subpopulation of 22 patients did not reveal any significant between-group difference in alpha or beta diversity. Omitting prophylactic ciprofloxacin during allo-HSCT did not affect microbiome composition, lower GI-GVHD rate, or other significant clinical outcomes. The use of prophylactic antibiotics in this setting should be evaluated further.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Microbiota , Ciprofloxacina/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recurrencia Local de Neoplasia/etiología , Estudios RetrospectivosRESUMEN
We observed high rates of bloodstream infections (BSIs) following fecal microbiota transplantation (FMT) for graft-versus-host-disease (33 events in 22 patients). To trace the BSIs' origin, we applied a metagenomic bioinformatic pipeline screening donor and recipient stool samples for bacteremia-causing strains in 13 cases. Offending strains were not detected in FMT donations. Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii could be detected in stool samples before emerging in the blood. In this largest report of BSIs post-FMT, we present an approach that may be applicable for evaluating BSI origin following microbiota-based interventions. Our findings support FMT safety in immunocompromised patients but do not rule out FMT as an inducer of bacterial translocation.
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Bacteriemia , Enfermedad Injerto contra Huésped , Microbiota , Bacteriemia/etiología , Trasplante de Microbiota Fecal , Humanos , Huésped InmunocomprometidoRESUMEN
BACKGROUND: Busulfan (Bu) conditioning used in hematopoietic stem cell transplantation may induce seizures, and prophylactic antiepileptic treatment is recommended. Following updated guidelines, in August 2019, the adult hematopoietic stem cell transplantation department of the Rambam Health Care Campus (Haifa, Israel) switched the antiepileptic prophylaxis protocol from phenytoin to oral levetiracetam during oral Bu conditioning. The aim of this study was to compare the pharmacokinetic parameters of Bu after oral dosing between patients receiving phenytoin and those receiving levetiracetam prophylaxis. METHODS: This study was a retrospective cohort study in adults undergoing myoablative conditioning with oral Bu between August 2018 and August 2020. Bu pharmacokinetic parameters (AUC0-6, C0, Cmax, and Tmax) were compared in patients treated with phenytoin comedication (during the year before the change in policy) and levetiracetam comedication (during the year after the change). Potential confounders were accounted for including age, azole comedication, and body weight. RESULTS: There were no significant differences in demographic and clinical parameters or weight-corrected Bu dose between the phenytoin group (n = 28) and the levetiracetam group (n = 25). There was no difference in the rate of voriconazole comedication, but fluconazole was more common in the phenytoin group (P = 0.026). The median AUC0-6 was significantly lower in the levetiracetam group (949 µM*min; IQR = 806 to 1101 µM*min) than in the phenytoin group (1208 µM*min; IQR = 1087 to 1389 µM*min; P < 0.001). This is a clinically significant difference of 258 µM*min (21%). Azole use was not associated with Bu exposure. CONCLUSIONS: The findings suggest that, after treatment with oral Bu, oral levetiracetam comedication is associated with reduced systemic exposure compared with phenytoin comedication, possibly because of decreased bioavailability.
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Busulfano , Trasplante de Células Madre Hematopoyéticas , Adulto , Anticonvulsivantes , Busulfano/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Levetiracetam/uso terapéutico , Fenitoína , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodosAsunto(s)
Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Huésped Inmunocomprometido/inmunología , Esclerodermia Sistémica/inmunología , Adulto , Anciano , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Vacuna BNT162 , Linfocitos T CD4-Positivos/inmunología , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Esclerodermia Sistémica/terapiaRESUMEN
Pure red cell aplasia (PRCA) can potentially occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT) if recipient and donor ABO blood groups are mismatched, with the recipient having isoagglutinins against the donor blood group. Patient plasma cells that survive transplant conditioning produce anti-ABO isoagglutinins targeting donor erythroid precursors in the bone marrow and thus causing red cell aplasia. Therapeutic options include steroids, discontinuation of immunosuppression, plasmapheresis, donor lymphocyte infusion, rituximab, and bortezomib, all with limited benefit. Daratumumab utilized in the treatment of multiple myeloma is an anti-CD38 monoclonal antibody targeting plasma cells, which makes it a potentially efficient therapy for PRCA. The current case report presents a patient with post-allo-HSCT PRCA cured with daratumumab applied after failure of other therapies. Our findings demonstrate safety and high efficiency of daratumumab, suggesting its applicability as early treatment of post-allo-HSCT PRCA.
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Sistema del Grupo Sanguíneo ABO/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Aplasia Pura de Células Rojas/tratamiento farmacológico , Adulto , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Humanos , Masculino , Neutropenia/terapia , Aplasia Pura de Células Rojas/diagnóstico , Aplasia Pura de Células Rojas/etiología , Trasplante HomólogoRESUMEN
Mechanisms governing allogeneic T cell responses after solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) are incompletely understood. To identify lncRNAs that regulate human donor T cells after clinical HSCT, we performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients that differed in their degree of major histocompatibility complex (MHC) mismatch. We found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT relative to T cells after either MHC-matched or autologous HSCT. Differential expression was validated in an independent patient cohort and in mixed lymphocyte reactions using ex vivo healthy human T cells. We identified Linc00402, an uncharacterized lncRNA, among the lncRNAs differentially expressed between the mismatched unrelated and matched unrelated donor T cells. We found that Linc00402 was conserved and exhibited an 88-fold increase in human T cells relative to all other samples in the FANTOM5 database. Linc00402 was also increased in donor T cells from patients who underwent allogeneic cardiac transplantation and in murine T cells. Linc00402 was reduced in patients who subsequently developed acute graft-versus-host disease. Linc00402 enhanced the activity of ERK1 and ERK2, increased FOS nuclear accumulation, and augmented expression of interleukin-2 and Egr-1 after T cell receptor engagement. Functionally, Linc00402 augmented the T cell proliferative response to an allogeneic stimulus but not to a nominal ovalbumin peptide antigen or polyclonal anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a regulator of allogeneic T cell function.
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Trasplante de Células Madre Hematopoyéticas , ARN Largo no Codificante/genética , Linfocitos T , Animales , Enfermedad Injerto contra Huésped/genética , Histocompatibilidad , Humanos , Ratones , RNA-Seq , Trasplante HomólogoRESUMEN
OBJECTIVES: Midostaurin, a multikinase and FLT3 inhibitor, is the first non-chemotherapy agent approved and widely adopted for the treatment of FLT3-ITD acute myeloid leukemia (AML). Yet, its role in improving survival of patients referred to allogeneic stem cell transplantation (allo-SCT) in first complete remission (CR1) needs to be defined. METHODS: This multicenter study retrospectively evaluated the outcome of 119 FLT3-ITD AML patients [59 (49.6%) males and 60 females] intensively treated between 2015 and 2019 at five Israeli centers. In our cohort, allo-SCT in CR1 was widely implemented (47%) and patient stratification was based on the current allelic ratio (AR) cutoff of 0.5. RESULTS: Ninety-eight patients (82.3%) achieved CR1/CR with incomplete count recovery (CRi). Death during induction was reported in 7 (5.9%) patients. In multivariate analysis, midostaurin use and allo-SCT in CR1 were the most significant factors affecting overall survival (OS). Midostaurin incorporation in chemotherapy regimens significantly improved CR + CRi rates (P = .002), reduced relapse rates (P = .02), and was remarkably advantageous for high-AR patients (2-year OS 82%). In low-AR patients, the midostaurin effect was much less prominent. CONCLUSIONS: Our results demonstrate benefits of midostaurin incorporation in intensive chemotherapy regimens, particularly for high-AR AML patients to whom it should be offered along with allo-SCT in CR1.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Duplicación de Gen , Frecuencia de los Genes , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Estaurosporina/administración & dosificación , Estaurosporina/análogos & derivados , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Outcomes of allogeneic hematopoietic stem cell transplantation (allo- HSCT) have improved in the recent decade; however, infections and graft-versus-host disease remain two leading complications significantly contributing to early transplant-related mortality. In past years, the human intestinal microbial composition (microbiota) has been found to be associated with various disease states, including cancer, response to cancer immunotherapy and to modulate the gut innate and adaptive immune response. In the setting of allo-HSCT, the intestinal microbiota diversity and composition appear to have an impact on infection risk, mortality and overall survival. Microbial metabolites have been shown to contribute to the health and integrity of intestinal epithelial cells during inflammation, thus mitigating graft-versus-host disease in animal models. While the cause-andeffect relationship between the intestinal microbiota and transplant-associated complications has not yet been fully elucidated, the above findings have already resulted in the implementation of various interventions aiming to restore the intestinal microbiota diversity and composition. Among others, these interventions include the administration of fecal microbiota transplantation. The present review, based on published data, is intended to define the role of the latter approach in the setting of allo-HSCT.
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Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Trasplante de Microbiota Fecal , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Trasplante HomólogoRESUMEN
Chronic graft-versus-host disease (cGVHD) remains the main complication of allogeneic hematopoietic stem cell transplantation, limiting its chances for a successful outcome. The over-activity of CD4+ effector T cells and the excessive production of pro-inflammatory cytokines are followed by the development of immune-mediated inflammation and fibrosis of multiple organs. This is the reason for adopting T cell targeting therapies such as cyclosporine A, tacrolimus and mycophenolate mofetil. However, 40% of treated cGVHD patients remain unresponsive, which results in increased morbidity and mortality. Given the complexity of cGVHD pathogenesis, the involvement of B cells as an important player also needs to be explored. Function of aberrant B cells and secretion of relevant cytokines such as B cell activating factor (BAFF) have been found to correlate with cGVHD severity and have therefore become therapeutic targets. Better understanding of the role of B cells and their efficient targeting could improve the outcome of cGVHD.