RESUMO
Febrile neutropenia (FN) is a complication in approximately 90% of autologous stem cell transplant (SCT) patients. Guidelines support early broad-spectrum antibiotics (BSA) to prevent morbidity and mortality. However, in patients who are clinically stable and deemed to have a fever of unknown origin, the optimal duration of BSA is unknown. Accumulating evidence suggests that de-escalation of BSA in select patients may decrease duration of BSA exposure without compromising clinical outcomes such as infection, recurrent fever, and readmission. With this, a de-escalation protocol was implemented at Vanderbilt University Medical Center (VUMC) to identify autologous SCT patients who may benefit from early de-escalation of BSA. The objectives of this study were to analyze the impact of early empiric antibiotic de-escalation on the duration of BSA as well as its impact on the incidence of recurrent fever and documented infection in autologous SCT patients. This was a single-center, retrospective study evaluating patients older than 18 years of age who underwent autologous SCT and experienced an episode of FN from January 2018 to December 2022 at VUMC (Nâ¯=â¯195). The protocol was initiated on January 1, 2020, to de-escalate BSA back to prophylaxis in stable neutropenic patients determined to have a fever of unknown origin. The primary outcome was the number of BSA days within 30 days. Secondary clinical outcomes included recurrent fever, documented infection, readmission, 30-day mortality, and 90-day non-relapsed mortality (NRM). Outcomes were compared across pre- and postprotocol groups with a Wilcoxon rank sum test, Pearson chi-square test, or regression analysis as appropriate. The median BSA duration was 4.7 and 2.7 days in the pre- and postprotocol groups, respectively (P < .001). Recurrent fever (14.2% versus 16.0%, Pâ¯=â¯.726), documented infection (1.7% versus 6.7%, Pâ¯=â¯.068), and readmission (13.3% versus 22.7%, Pâ¯=â¯.091) within 30 days were not significantly different between the two groups. Neither 30-day mortality (0.8% versus 1.3%, Pâ¯=â¯.736) nor 90-day NRM (0.8% versus 1.3%, Pâ¯=â¯.736) differed. The implementation of an early de-escalation protocol for autologous SCT patients who develop FN was associated with a reduction in duration of BSA compared to the preprotocol group without a significant difference in readmission, recurrent fevers, and documented infections. This study adds to existing evidence that early de-escalation of BSA in FN patients with a fever of unknown origin who are afebrile and clinically stable is safe and reduces unnecessary antibiotic use.
RESUMO
The age effect in severe aplastic anemia (SAA) following allogeneic hematopoietic cell transplantation (HCT) favors the use of reduced intensity conditioning (RIC) regimens in older adults. We implemented a non-myeloablative regimen consisting of fludarabine, cyclophosphamide, and rituximab (FCR) to improve HCT outcomes in SAA. Patients who underwent first HCT for SAA utilizing an FCR regimen between January 2016 and May 2022 were included. Outcomes analyzed included time to engraftment, incidence of graft failure, GVHD, viral reactivation, disease recurrence, and GVHD-free, relapse-free survival (GRFS). Among 24 patients included, median age was 43.5 years (22-62) and a variety of donor types and stem cell sources were represented. At median follow-up of 26.9 months (2.4-72.7), no cases of grade III-IV acute (aGVHD) or severe chronic GVHD (cGVHD) were recorded. Viral reactivation was minimal, and there were no cases of graft failure or PTLD, with 100% disease-free and overall survival at last follow up. The estimate of 1-year GRFS was 86.3% (95% CI: 72.8-100%), with moderate cGVHD accounting for all events. The FCR regimen in SAA was well tolerated, even in older adults, with 100% disease-free survival with low GVHD and infection rates. These encouraging findings should be validated in larger prospective trials.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Masculino , Transplante Autólogo , Pessoa de Meia-Idade , FemininoRESUMO
This study aimed to validate the new European Leukemia Net (ELN) 2022 criteria for genetic risk stratification in older adults with acute myeloid leukemia (AML) and to determine the most likely set of clusters of similar cytogenetic and mutation properties correlated with survival outcomes in three treatment groups: intensive chemotherapy (IC), hypomethylating agents (HMA) alone, and HMA plus venetoclax (HMA/VEN). The study included 279 patients (aged ≥60 years) who received IC (N=131), HMA (N=76), and HMA/VEN (N=72) between July 2017 and October 2021. No significant differences were observed in survival among the groups according to ELN 2022 risk stratification. Unsupervised hierarchical clustering analysis identified nine genomic clusters (C1-9) with varying survival outcomes depending on treatment type. For example, C4 (predominant for core binding factor-AML) displayed a favorable prognosis in the IC group, but not in the HMA or HMA/VEN groups. The HMA/VEN group had better outcomes than the HMA group in many clusters (C1, 2, 3, and 5); however, the addition of VEN to HMA or IC did not improve the survival outcomes compared with those of HMA alone in C7 and C9 (predominant for -5, del(5q), -7, -17/abn(17p), complex karyotypes, and mutated TP53). The study highlights the limitations of ELN genetic risk stratification in older adults with AML. It emphasizes the need for a more comprehensive approach that considers co-occurring somatic mutations to guide treatment selection in older adults with AML.
Assuntos
Leucemia Mieloide Aguda , Humanos , Idoso , Prognóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores de Risco , Genômica , Aprendizado de Máquina , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Inibidores de Histona Desacetilases/efeitos adversos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/etiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti-programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.
Assuntos
Evasão da Resposta Imune , Leucemia Mieloide Aguda , Animais , Humanos , Camundongos , Medula Óssea , Imunidade Celular , Imunoterapia , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Effective eradication of leukemic stem cells (LSCs) remains the greatest challenge in treating acute myeloid leukemia (AML). The immune receptor LAIR-1 has been shown to regulate LSC survival; however, the therapeutic potential of this pathway remains unexplored. We developed a therapeutic LAIR-1 agonist antibody, NC525, that induced cell death of LSCs, but not healthy hematopoietic stem cells in vitro, and killed LSCs and AML blasts in both cell- and patient-derived xenograft models. We showed that LAIR-1 agonism drives a unique apoptotic signaling program in leukemic cells that was enhanced in the presence of collagen. NC525 also significantly improved the activity of azacitidine and venetoclax to establish LAIR-1 targeting as a therapeutic strategy for AML that may synergize with standard-of-care therapies.
Assuntos
Leucemia Mieloide Aguda , Animais , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Transdução de Sinais , Modelos Animais de Doenças , Células-Tronco Neoplásicas/metabolismoRESUMO
The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention. In conclusion, we dovetailed on four research areas of interest: 1) microbiome interaction with immune cells after hematopoietic cell and/or solid organ transplantation, graft-versus-host disease (GVHD) and graft rejection, 2) intestinal inflammation and its modification in IBD and cancer, 3) microbiome-neuron-immunity interplay in mental and physical health, and 4) microbiome-micronutrient-immune interactions during homeostasis and infectious diseases. At this VA field-based meeting, we proposed to explore a multi-disciplinary, multi-institutional, collaborative strategy to initiate a roadmap, specifically focusing on host microbiome-immune interactions among those with service-related chronic diseases to potentially identify novel and translatable therapeutic targets.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Síndrome do Intestino Irritável , Microbiota , Veteranos , Humanos , Síndrome do Intestino Irritável/terapiaRESUMO
The skin is the outermost mechanical barrier where dynamic immune reactions take place and is the most commonly affected site in both acute and chronic graft-versus-host disease (GVHD). If not properly treated, pain and pruritis resulting from cutaneous GVHD can increase the risk of secondary infection due to erosions, ulcerations, and damage of underlying tissues. Furthermore, resulting disfiguration can cause distress and significantly impact patients' quality of life. Thus, a deeper understanding of skin-specific findings of GVHD is needed. This review will highlight some promising results of recent pre-clinical studies on the pathophysiology of skin GVHD and summarize the diagnostic and staging/grading procedures according to the clinical manifestations of skin GVHD. In addition, we will summarize outcomes of various GVHD treatments, including skin-specific response rates.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Dermatopatias , Humanos , Qualidade de Vida , Dermatopatias/etiologia , Dermatopatias/terapia , Dermatopatias/diagnóstico , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Pele , Transplante de Medula Óssea/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes.
Assuntos
Síndromes Mielodisplásicas , Neoplasias , Humanos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Medição de Risco , Qualidade de Vida , PrognósticoRESUMO
BACKGROUND: Although most patients with diffuse large B-cell lymphoma (DLBCL) achieve complete remission after first-line rituximab-containing immunochemotherapy, up to 40% of patients relapse and require salvage therapy. Among those patients, a substantial proportion remain refractory to salvage therapy due to insufficient efficacy or intolerance of toxicities. A hypomethylating agent, 5-azacytidine, showed a chemosensitizing effect when primed before chemotherapy in lymphoma cell lines and newly diagnosed DLBCL patients. However, its potential to improve outcomes of salvage chemotherapy in DLBCL has not been investigated. RESULTS: In this study, we demonstrated the mechanism of 5-azacytidine priming as a chemosensitizer in a platinum-based salvage regimen. This chemosensitizing effect was associated with endogenous retrovirus (ERV)-induced viral mimicry responses via the cGAS-STING axis. We found deficiency of cGAS impaired the chemosensitizing effect of 5-azacytidine. Furthermore, combining vitamin C and 5-azacytidine to synergistically activate STING could be a potential remedy for insufficient priming induced by 5-azacytidine alone. CONCLUSIONS: Taken together, the chemosensitizing effect of 5-azacytidine could be exploited to overcome the limitations of the current platinum-containing salvage chemotherapy in DLBCL and the status of cGAS-STING has the potential to predict the efficacy of 5-azacytidine priming.
Assuntos
Retrovirus Endógenos , Linfoma Difuso de Grandes Células B , Humanos , Retrovirus Endógenos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/diagnóstico , Metilação de DNA , Rituximab/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Epigênese GenéticaRESUMO
Although allogeneic hematopoietic cell transplantation (HCT) is the sole potentially curative therapy for patients with poor-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), only a minority of these patients undergo HCT. Patients with TP53-mutated (TP53MUT) MDS/AML are at particularly high risk, yet fewer TP53MUT patients undergo HCT compared with poor-risk TP53-wild type (TP53WT) patients. We hypothesized that TP53MUT MDS/AML patients have unique risk factors affecting the rate of HCT and thus investigated phenotypic changes that may prevent patients with TP53MUT MDS/AML from receiving HCT. In this single-center retrospective analysis of outcomes for adults with newly diagnosed MDS or AML (n = 352), HLA typing was used as a surrogate for physician "intent to transplant." Multivariable logistic regression models were used to estimate odds ratios (ORs) for factors associated with HLA typing, HCT, and pretransplantation infections. Multivariable Cox proportional hazards models were used to create predicted survival curves for patients with and those without TP53 mutations. Overall, significantly fewer TP53MUT patients underwent HCT compared to TP53WT patients (19% versus 31%; P = .028). Development of infection was significantly associated with decreased odds of HCT (OR, .42; 95% CI, .19 to .90) and worse overall survival (hazard ratio, 1.46; 95% CI, 1.09 to 1.96) in multivariable analyses. TP53MUT disease was independently associated with increased odds of developing an infection (OR, 2.18; 95% CI, 1.21 to 3.93), bacterial pneumonia (OR, 1.83; 95% CI, 1.00 to 3.33), and invasive fungal infection (OR, 2.64; 95% CI, 1.34 to 5.22) prior to HCT. Infections were the cause of death in significantly more patients with TP53MUT disease (38% versus 19%; P = .005). With substantially more infections and decreased HCT rates in patients with TP53 mutations, this raises the possibility that phenotypic changes occurring in TP53MUT disease may affect infection susceptibility in this population and drastically impact clinical outcomes.
Assuntos
Deficiência de GATA2 , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adulto , Humanos , Estudos Retrospectivos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Proteína Supressora de Tumor p53/genéticaRESUMO
Biological events that contribute to the pathogenesis of myelodysplastic syndromes/neoplasms (MDS) are becoming increasingly characterized and are being translated into rationally designed therapeutic strategies. Herein, we provide updates from the first International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS) detailing recent advances in understanding the genetic landscape of MDS, including germline predisposition, epigenetic and immune dysregulation, the complexities of clonal hematopoiesis progression to MDS, as well as novel animal models of the disease. Connected to this progress is the development of novel therapies targeting specific molecular alterations, the innate immune system, and immune checkpoint inhibitors. While some of these agents have entered clinical trials (e.g., splicing modulators, IRAK1/4 inhibitors, anti-CD47 and anti-TIM3 antibodies, and cellular therapies), none have been approved for MDS. Additional preclinical and clinical work is needed to develop a truly individualized approach to the care of MDS patients.
Assuntos
Síndromes Mielodisplásicas , Neoplasias , Animais , Humanos , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/terapia , Epigenômica , Terapia Baseada em Transplante de Células e Tecidos , Processamento de Proteína Pós-TraducionalRESUMO
VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T lymphocyte lineages, is upregulated in mouse and human idiopathic pulmonary fibrosis (IPF). However, the significance of VISTA and its therapeutic potential in regulating IPF has yet to be defined. To determine the role of VISTA and its therapeutic potential in IPF, the expression profile of VISTA was evaluated from human single-cell RNA sequencing data (IPF Cell Atlas). Inflammatory response and lung fibrosis were assessed in bleomycin-induced experimental pulmonary fibrosis models in VISTA-deficient mice compared with wild-type littermates. In addition, these outcomes were evaluated after VISTA agonistic antibody treatment in the wild-type pulmonary fibrosis mice. VISTA expression was increased in lung tissue-infiltrating monocytes of patients with IPF. VISTA was induced in the myeloid population, mainly circulating monocyte-derived macrophages, during bleomycin-induced pulmonary fibrosis. Genetic ablation of VISTA drastically promoted pulmonary fibrosis, and bleomycin-induced fibroblast activation was dependent on the interaction between VISTA-expressing myeloid cells and fibroblasts. Treatment with VISTA agonistic antibody reduced fibrotic phenotypes accompanied by the suppression of lung innate immune and fibrotic mediators. In conclusion, these results suggest that VISTA upregulation in pulmonary fibrosis may be a compensatory mechanism to limit inflammation and fibrosis, and stimulation of VISTA signaling using VISTA agonists effectively limits the fibrotic innate immune landscape and consequent tissue fibrosis. Further studies are warranted to test VISTA as a novel therapeutic target for the IPF treatment.
Assuntos
Fibrose Pulmonar Idiopática , Humanos , Camundongos , Animais , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/patologia , Fibrose , Bleomicina/farmacologia , Inflamação/metabolismo , Fibroblastos/metabolismoRESUMO
Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are important sources of morbidity and mortality. Improvements in infection-related complications have made noninfectious pulmonary complications an increasingly significant driver of transplantation-related mortality. Broadly, these complications can be characterized as either early or late complications, with idiopathic pneumonia syndrome and bronchiolitis obliterans syndrome the most prevalent early and late complications, respectively. Outcomes with historical treatment consisting mainly of corticosteroids are often poor, highlighting the need for a deeper understanding of these complications' underlying disease biology to guide the adoption of novel therapies that are being increasingly used in the modern era.
Assuntos
Síndrome de Bronquiolite Obliterante , Bronquiolite Obliterante , Transplante de Células-Tronco Hematopoéticas , Pneumonia , Humanos , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/terapia , Pneumonia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Tumours employ various tactics to adapt and eventually resist immune attack. These mechanisms are collectively called adaptive immune resistance (AIR). The first defined and therapeutically validated AIR mechanism is the selective induction of programmed cell death 1 ligand 1 (PDL1) by interferon-γ in the tumour. Blockade of PDL1 binding to its receptor PD1 by antibodies (anti-PD therapy) has resulted in remission of a fraction of patients with advanced-stage cancer, especially in solid tumours. However, many clinical trials combining anti-PD therapy with other antitumour drugs conducted without a strong mechanistic rationale have failed to identify a synergistic or additive effect. In this Perspective article, we discuss why defining AIR mechanisms at the tumour site should be a key focus to direct future drug development as well as practical approaches to improve current cancer therapy.