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Mass spectrometry (MS) can detect multiple myeloma-derived monoclonal proteins in peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during post-transplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of post-transplant maintenance with either carfilzomib, lenalidomide, dexamethasone or lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in PB in the post-transplant setting, despite unavailability of pre-treatment calibration samples. There was high agreement between MRD by MS in PB and paired BM MRD results at the 10-5 threshold, assessed by either next generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which in landmark analysis reached statistical significance after 18 cycles post-transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared to MRD negativity by only one modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold. Overall, post-transplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.
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Introduction: Lower-risk myelodysplastic neoplasms (LR-MDS) comprise the majority of MDS. Despite favourable prognoses, some patients remain at risk of rapid progression. We aimed to define the mutational profile of LR-MDS using next-generation sequencing (NGS), Sanger Sequencing (SSeq), and pyrosequencing. Material and methods: Samples from 5 primary LR-MDS (67 exons of SF3B1, U2AF1, SRSF2, ZRSR2, TET2, ASXL1, DNMT3A, TP53, and RUNX1 genes) were subjected to NGS. Next, a genomic study was performed to test for the presence of identified DNA sequence variants on a larger group of LR-MDS patients (25 bone marrow [BM], 3 saliva [SAL], and one peripheral blood [PB] sample/s). Both SSeq (all selected DNA sequence variants) and pyrosequencing (9 selected DNA sequence variants) were performed. Results: Next-generation sequencing results identified 13 DNA sequence variants in 7 genes, comprising 8 mutations in 6 genes (ASXL1, DNMT3A, RUNX1, SF3B1, TET2, ZRSR2) in LR-MDS. The presence of 8 DNA variants was detected in the expanded LR-MDS group using SSeq and pyrosequencing. Mutation acquisition was observed during LR-MDS progression. Four LR-MDS and one acute myeloid leukaemia myelodysplasia-related patient exhibited the presence of at least one mutation. ASXL1 and SF3B1 alterations were most commonly observed (2 patients). Five DNA sequence variants detected in BM (patients: 9, 13) were also present in SAL. Conclusions: We suggest using NGS to determine the LR-MDS mutational profile at diagnosis and suspicion of disease progression. Moreover, PB and SAL molecular testing represent useful tools for monitoring LR-MDS at higher risk of progression. However, the results need to be confirmed in a larger group.
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INTRODUCTION: Chimeric Antigen Receptor (CAR) T-cells and Bispecific Antibodies (BsAb) are the leading platforms for redirecting the immune system against cells expressing the specific antigen, revolutionizing the treatment of hematological malignancies, including multiple myeloma (MM). In MM, drug-resistant relapses are the main therapy-limiting factor and the leading cause of why the disease is still considered incurable. T-cell-engaging therapies hold promise in improving the treatment of MM. However, the effectiveness of these treatments may be hindered by T-cell fitness. T-cell exhaustion is a condition of a gradual decline in effector function, reduced cytokine secretion, and increased expression of inhibitory receptors due to chronic antigen stimulation. AREAS COVERED: This review examines findings about T-cell exhaustion in MM in the context of T-cell redirecting BsAbs and CAR-T treatment. EXPERT OPINION: The fitness of T-cells has become an important factor in the development of T-cell redirecting therapies. The way T-cell exhaustion relates to these therapies could affect the further development of CAR and BsAbs technologies, as well as the strategies used for clinical use. Therefore, this review aims to explore the current understanding of T-cell exhaustion in MM and its relationship to these therapies.
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Anticorpos Biespecíficos , Imunoterapia Adotiva , Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Linfócitos T , Mieloma Múltiplo/terapia , Mieloma Múltiplo/imunologia , Humanos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Anticorpos Biespecíficos/uso terapêutico , Exaustão das Células TRESUMO
Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies have performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations-specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients who had undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to the ATG-G group (7.5% vs. 38.3%, p = 0.001). The negative impact of ATG-G on cGvHD was confirmed by multivariate analysis (HR 8.12, 95% CI 2.06-32.0, p = 0.003). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p < 0.001), with a shorter time between transplant and CMV (<61 days, 77.8% vs. 33.3%, p = 0.008) and a higher median CMV copy number (1000 vs. 0, p = 0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p = 0.005). By multivariate analysis, only aGvHD had an influence on CMV reactivations (HR 0.18, 95% CI 0.04-0.75, p = 0.019). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year relapse-free survival (RFS) while comparing ATG-T and ATG-G (32.0% vs. 40.3%, p = 0.423; 66.7% vs. 60.4%, p = 0.544, respectively).
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Background: Acute myeloid leukemia post cytotoxic therapy (AML-pCT) among breast cancer (BC) survivors represents a life-threatening complication. This study aims to assess the clinical outcomes of AML-pCT post BC. Methods: An analysis of all AML patients treated at a single hematology center (2000-2023) was performed to select patients with AML-pCT post BC. We applied the 2022 ELN criteria to define the genetic risk. Results: Among 847 AML patients, 28 were diagnosed with AML-pCT following BC. Complex karyotype (CK) occurred in 23.8% of patients. The median overall survival (OS) was 40 months. The survival outcomes were better after allogenic hematopoietic stem cell transplantation (alloHCT) treatment compared to chemotherapy alone (median OS: 47 versus 7 months, p = 0.008). Patients demonstrating CK showed lower survival compared to those without CK (2-year OS: 25.0% versus 66.2%, p = 0.0048). The multivariable Cox proportional hazards regression model indicated that treatment with alloHCT emerged as a significant factor associated with improved OS. The treatment was associated with superior OS (HR = 0.07, 95% CI = 0.01-0.86, p = 0.04). Conclusions: Patients with AML-pCT following BC were characterized with the highest frequency of adverse genetic risk profiles and demonstrated worse survival rates. AlloHCT should be performed as early as possible in such patients. The growing need for studies on inherited cancer susceptibility underscores the importance of close AML-pCT development monitoring in BC survivors.
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BACKGROUND: Mim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality. OBJECTIVES: The partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors. METHODS: The MAD part of FRONTIER1 consisted of 42 participants, assigned to 5 cohorts, with participants in cohorts 3 and 4 randomized 1:1 to dosing weekly or every 4 weeks, respectively. Four of the 42 participants (9.5%) had FVIII inhibitors prior to study enrolment. The primary endpoint was treatment-emergent adverse events (TEAEs). PK and PD were evaluated by Mim8 plasma concentration and thrombin generation, respectively. Exploratory efficacy was assessed via the number of treated bleeds. Safety and PD parameters were also evaluated from an exploratory cohort treated with emicizumab. RESULTS: Mim8 was well tolerated, with 1 serious TEAE (anxiety-related chest pain) deemed unrelated to Mim8. There was no dose dependency on the number, causality, type, or severity of TEAEs. PK/PD properties supported weekly to monthly dosing approaches, and few participants experienced treated bleeds beyond the lowest dose cohort (1 in cohorts 2 and 3, and 3 in cohort 5). CONCLUSION: These data support the continued clinical development of Mim8, and FRONTIER1 has proceeded onto an extension phase.
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Hemofilia A , Hemostáticos , Humanos , Fator VIIIa/efeitos adversos , Fator VIIIa/farmacocinética , Fator VIIIa/farmacologia , Hemofilia A/diagnóstico , Hemofilia A/tratamento farmacológico , Hemorragia/tratamento farmacológico , Hemostáticos/efeitos adversos , Hemostáticos/farmacocinética , Hemostáticos/farmacologia , TrombinaRESUMO
Allogeneic hematopoietic cell transplantation (allo-HSCT) stands as an effective treatment method for various hematologic malignancies. However, graft-versus-host disease (GvHD), an intricate immunological phenomenon where donor immune cells target recipient tissues, remains a significant challenge, particularly in mismatched unrelated donors (MMUD). Post-transplant cyclophosphamide (PTCy) has emerged as a promising immunosuppressive strategy, revolutionizing haploidentical transplantation and demonstrating promise in MMUD settings. Background/Objectives: This study aimed to evaluate the impact of PTCy on MMUD allo-HSCT outcomes, specifically its effects on GvHD incidence and overall survival, compared to anthitymocyte globulin (ATG). Methods: One hundred seventy-four patients were classified into three groups based on the type of transplantation: PTCy-haplo (114/174; 65.5%), PTCy-MMUD (23/174; 13.2%), and ATG-MMUD (37/174; 21.2%). Results: Our findings showed that PTCy-MMUD significantly reduced acute GvHD occurrence compared to PTCy-haplo and ATG-MMUD approaches (p = 0.006). The delayed onset of acute GvHD in the PTCy-MMUD group suggests a more controlled immune reconstitution, contributing to the lower incidence. Importantly, PTCy-MMUD exhibited enhanced five-year overall survival rates, aligning with the notion that reduced GvHD correlates with improved patient outcomes (p = 0.032). Conclusions: We believe that this study contributes valuable insights into PTCy-MMUD's management, underscoring its potential to significantly reduce GvHD incidence and enhance survival outcomes. Although further investigations and clinical trials are warranted, this research underscores the promising role of PTCy-based GvHD prophylaxis in improving MMUD allo-HCT success.
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Clostridioides difficile infection (CDI) is the most common cause of infectious diarrhea after allogeneic hematopoietic cell transplantation (allo-HCT). The impact of CDI and its treatment on allo-HCT outcomes and graft-versus-host disease (GVHD), including gastrointestinal GVHD (GI-GVHD) is not well established. This multicenter study assessed real-life data on the first-line treatment of CDI and its impact on allo-HCT outcomes. Retrospective and prospective data of patients with CDI after allo-HCT were assessed. We noted statistically significant increase in the incidence of acute GVHD and acute GI-GVHD after CDI (P = 0.005 and P = 0.016, respectively). The first-line treatment for CDI included metronidazole in 34 patients, vancomycin in 64, and combination therapy in 10. Treatment failure was more common with metronidazole than vancomycin (38.2% vs. 6.2%; P < 0.001). The need to administer second-line treatment was associated with the occurrence or exacerbation of GVHD (P < 0.05) and GI-GVHD (P < 0.001) and reduced overall survival (P < 0.05). In the multivariate analysis, the risk of death was associated with acute GVHD presence before CDI (hazard ratio [HR], 3.19; P = 0.009) and the need to switch to second-line treatment (HR, 4.83; P < 0.001). The efficacy of the initial CDI treatment affects survival and occurrence of immune-mediated GI-GVHD after allo-HCT. Therefore, agents with higher efficacy than metronidazole (vancomycin or fidaxomicin) should be administered as the first-line treatment.
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Infecções por Clostridium , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia , Adulto , Humanos , Vancomicina/uso terapêutico , Metronidazol/uso terapêutico , Estudos Retrospectivos , Polônia , Estudos Prospectivos , Doença Enxerto-Hospedeiro/etiologia , Leucemia/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/etiologiaRESUMO
OBJECTIVES: Nocardiosis is a rare but life-threatening infection after hematopoietic cell transplantation (HCT). We aimed at identifying risk factors for nocardiosis after allogeneic HCT and clarifying the effect of trimethoprim-sulfamethoxazole prophylaxis on its occurrence. METHODS: We performed a retrospective multicenter case-control study of patients diagnosed with nocardiosis after allogeneic HCT between January 2000 and December 2018. For each case, two controls were matched by center, transplant date, and age group. Multivariable analysis was conducted using conditional logistic regression to identify potential risk factors for nocardiosis. Kaplan-Meier survival curves of cases and controls were compared using log-rank tests. RESULTS: Sixty-four cases and 128 controls were included. Nocardiosis occurred at a median of 9 months after allogeneic HCT (interquartile range: 5-18). After adjustment for potential confounders in a multivariable model, Nocardia infection was associated with tacrolimus use (adjusted odds ratio [aOR] 9.9, 95 % confidence interval [95 % CI]: 1.6-62.7), lymphocyte count < 500/µL (aOR 8.9, 95 % CI: 2.3-34.7), male sex (aOR 8.1, 95 % CI: 2.1-31.5), recent use of systemic corticosteroids (aOR 7.9, 95 % CI: 2.2-28.2), and recent CMV infection (aOR 4.3, 95 % CI: 1.2-15.9). Conversely, use of trimethoprim-sulfamethoxazole prophylaxis was associated with a significantly decreased risk of nocardiosis (aOR 0.2, 95 % CI: 0.1-0.8). HCT recipients who developed nocardiosis had a significantly decreased survival, as compared with controls (12-month survival: 58 % and 90 %, respectively; p < 0.0001). CONCLUSIONS: We identified six factors independently associated with the occurrence of nocardiosis among allogeneic HCT recipients. In particular, trimethoprim-sulfamethoxazole prophylaxis was found to protect against nocardiosis.
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Transplante de Células-Tronco Hematopoéticas , Nocardiose , Combinação Trimetoprima e Sulfametoxazol , Humanos , Nocardiose/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Feminino , Estudos de Casos e Controles , Fatores de Risco , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Transplante Homólogo/efeitos adversos , Idoso , Transplantados/estatística & dados numéricos , Nocardia/isolamento & purificação , AntibioticoprofilaxiaRESUMO
The objective of the study was the analysis of clinical types, outcomes, and risk factors associated with the outcome of adenovirus (ADV) infection, in children and adults after allo-HCT. A total number of 2529 patients (43.9% children; 56.1% adults) transplanted between 2000 and 2022 reported to the EBMT database with diagnosis of ADV infection were analyzed. ADV infection manifested mainly as viremia (62.6%) or gastrointestinal infection (17.9%). The risk of 1-year mortality was higher in adults (p = 0.0001), and in patients with ADV infection developing before day +100 (p < 0.0001). The 100-day overall survival after diagnosis of ADV infections was 79.2% in children and 71.9% in adults (p < 0.0001). Factors contributing to increased risk of death by day +100 in multivariate analysis, in children: CMV seropositivity of donor and/or recipient (p = 0.02), and Lansky/Karnofsky score <90 (p < 0.0001), while in adults: type of ADV infection (viremia or pneumonia vs gastrointestinal infection) (p = 0.0004), second or higher HCT (p = 0.0003), and shorter time from allo-HCT to ADV infection (p = 0.003). In conclusion, we have shown that in patients infected with ADV, short-term survival is better in children than adults. Factors directly related to ADV infection (time, clinical type) contribute to mortality in adults, while pre-transplant factors (CMV serostatus, Lansky/Karnofsky score) contribute to mortality in children.