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Acute megakaryoblastic leukaemia (AMkL) is a rare subtype of acute myeloid leukaemia (AML) representing 5% of all reported cases, and frequently diagnosed in children with Down syndrome. Patients diagnosed with AMkL have low overall survival and have poor outcome to treatment, thus novel therapies such as CAR T cell therapy could represent an alternative in treating AMkL. We investigated the effect of a new CAR T cell which targets CD41, a specific surface antigen for M7-AMkL, against an in vitro model for AMkL, DAMI Luc2 cell line. The performed flow cytometry evaluation highlighted a percentage of 93.8% CAR T cells eGFP-positive and a limited acute effect on lowering the target cell population. However, the interaction between effector and target (E:T) cells, at a low ratio, lowered the cell membrane integrity, and reduced the M7-AMkL cell population after 24 h of co-culture, while the cytotoxic effect was not significant in groups with higher E:T ratio. Our findings suggest that the anti-CD41 CAR T cells are efficient for a limited time spawn and the cytotoxic effect is visible in all experimental groups with low E:T ratio.
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Nowadays, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become the main subject of the scientific medical world and all World Organizations, causing millions of deaths worldwide. In this review, we have highlighted the context of the Coronavirus disease 2019 (COVID-19) pandemic, how the virus spreads, the symptoms and complications that may occur, and, especially, the drug treatment of viral infection, with emphasis on monoclonal antibodies. While well-known strains such as Alpha, Beta, Gamma, and, especially, Delta have shown an accelerated transmission among the population, the new Omicron variant (discovered on 24 November 2021) indicates more significant infectiousness and the poor efficacy of monoclonal antibody therapy due to mutations on the spike protein receptor-binding domain. With these discoveries, the experiments began, the first being in silico and in vitro, but these are not enough, and in vivo experiments are needed to see exactly the cause of neutralization of the action of these drugs. Following the documentation of the latest medical and scientific research, it has been concluded that there are many chemical molecules that have the potential to treat SARS-CoV-2 infection, but more detailed clinical trials are needed for their use in therapy. In addition, it is important to consider the structure of the viral strain in the administration of treatment.
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Tratamento Farmacológico da COVID-19 , Preparações Farmacêuticas , Anticorpos Antivirais , Humanos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
BACKGROUND: In autologous stem cell transplant (ASCT)-eligible myeloma patients, prolonged induction does not necessarily improve the depth of response. METHOD: We analyzed 1222 ASCT patients who were classified based on (a) the interval between induction and stem cell collection, (b) the type of induction regimen: BID (Bortezomib, IMiDs, and Dexamethasone), Bortezomib-based, or CTD (Cyclophosphamide, Thalidomide, and Dexamethasone), and (c) the time to best response (Early ie, best response within 4 or 5 months, depending on the regimen vs Late; Good ie, VGPR or better vs Poor). RESULTS: The length of induction treatment required to achieve a Good response did not affect PFS (P = .65) or OS (P = .61) post-ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (P = .31), and median OS 81.7, 92.7, and 77.4 months, respectively (P = .83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, P-value = .02). However, achieving a Good response at induction was associated with a better response (≥VGPR) post-transplant. CONCLUSION: The kinetics of response did not affect outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Duração da Terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Prognóstico , Indução de Remissão , Fatores de Tempo , Transplante Autólogo , Resultado do TratamentoRESUMO
Although the cause for bone marrow fibrosis in patients with myelofibrosis remains controversial, it has been hypothesized that it is caused by extensive fibroblast proliferation under the influence of cytokines generated by the malignant megakaryocytes. Moreover, there is no known drug therapy which could reverse the process. We studied the fibroblasts in a novel system using the hanging drop method, evaluated whether the fibroblasts obtain from patients are part of the malignant clone of not and, using this system, we screen a large library of FDA-approved drugs to identify potential drugs candidates that might be useful in the treatment of this disease, specifically which would inhibit fibroblast proliferation and the development of bone marrow fibrosis. We have found that the BM fibroblasts are not part of the malignant clone, as previously suspected and two immunosuppressive medications-cyclosporine and mycophenolate mophetil, as most potent suppressors of the fibroblast collagen production thus potentially inhibitors of bone marrow fibrosis production in myelofibrosis.
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Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Ciclosporina/farmacologia , Descoberta de Drogas/instrumentação , Fibroblastos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Ácido Micofenólico/farmacologia , Mielofibrose Primária/tratamento farmacológico , Linhagem Celular , Relação Dose-Resposta a Droga , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Cinética , Mutação , Mielofibrose Primária/genética , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Chronic lymphocytic leukemia (CLL) is a malignancy defined by the accumulation of mature lymphocytes in the lymphoid tissues, bone marrow, and blood. Therapy for CLL is guided according to the Rai and Binet staging systems. Nevertheless, state-of-the-art protocols in disease monitoring, diagnostics, and prognostics for CLL are based on the assessment of minimal residual disease (MRD). MRD is internationally considered to be the level of disease that can be detected by sensitive techniques and represents incomplete treatment and a probability of disease relapse. MRD detection has been continuously improved by the quick development of both flow cytometry and molecular biology technology, as well as by next-generation sequencing. Considering that MRD detection is moving more and more from research to clinical practice, where it can be an independent prognostic marker, in this paper, we present the methodologies by which MRD is evaluated, from translational research to clinical practice.
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Leucemia Linfocítica Crônica de Células B , Neoplasia Residual , Antineoplásicos/uso terapêutico , Consenso , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Técnicas de Diagnóstico Molecular , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/fisiopatologiaRESUMO
Even if considered a cumulative and not a proliferative CD5+ B-cell neoplasm, chronic lymphocytic leukemia (CLL) has a proliferation rate higher than that recognized earlier, especially in the lymphoid tissues. Some patients with CLL develop a clinical syndrome entitled Richter syndrome (RS). Understanding CLL genetics and epigenetics may help to elucidate the molecular basics of the clinical heterogeneity of this type of malignancy. In the present project we aimed to identify a microRNA species that can predict the evolution of therapy-resistant CLL towards RS. In the first phase of our study, microRNA-19b was identified as a possible target, and in the second phase, we transfected three different CLL cell lines with microRNA-19b mimic and inhibitor and assessed the potential role on leukemia cells in vitro. The mechanism by which miR-19b acts were identified as the upregulation of Ki67 and downregulation of p53. This was further supported through RT-PCR and western blotting on CLL cell lines, as well as by next generation sequencing on two patients diagnosed with CLL that evolved into RS.
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Transformação Celular Neoplásica , Exossomos , Leucemia Linfocítica Crônica de Células B , MicroRNAs , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Exossomos/química , Exossomos/metabolismo , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , MicroRNAs/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Síndrome , Células Tumorais CultivadasRESUMO
Melphalan at a dose of 200 mg/m2 is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m2 and melphalan 140 mg/m2 are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m2 (n=245) and melphalan 200 mg/m2 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m2 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m2versus melphalan 140 mg/m2: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m2 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m2 and melphalan 140 mg/m2 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m2 or melphalan 140 mg/m2 for key transplant outcomes (NCT01362972).
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Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Resultado do TratamentoRESUMO
Haploidentical stem cell transplantation is a therapeutic option for patients without an HLA-matched donor. It is increasingly being used worldwide due to the application of posttransplantation cyclophosphamide and is associated with lower incidence of graft-versus-host disease and treatment-related mortality. Haploidentical donors are generally available for most patients and stem cells can be rapidly obtained. Delays in transplantation while waiting for unrelated donor cells can be potentially problematic for patients with advanced disease at risk for progression; thus, the use of haploidentical donors, especially in this setting, can be life-saving. Here we reviewed the literature on haploidentical stem cell transplantation performed with posttransplantation cyclophosphamide.
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Doença Enxerto-Hospedeiro/tratamento farmacológico , Teste de Histocompatibilidade , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Incidência , Condicionamento Pré-Transplante , Transplante Homólogo , Doadores não RelacionadosRESUMO
Allogeneic hematopoietic stem cell transplantation (HCT) is a well-established treatment for many malignant and non-malignant hematological disorders. As frequent complication in up to 50 % of all patients, graft-versus-host disease (GVHD) is still the main cause for morbidity and non-relapse mortality. Diagnosis of GVHD is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally recognized consensus has yet been established. Here, microRNAs (miRs) represent an interesting tool since miRs have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we could assume that miRs play a key role in the pathogenesis of acute GVHD, and their detection might be an interesting possibility in the early diagnosis and monitoring of acute GVHD. Recent studies additionally demonstrated the implication of miRs in the pathogenesis of acute GVHD. In this review, we aim to summarize the previous reports of miRs, focusing on the pathogenesis of acute GVHD and possible implications in diagnostic approaches.
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Doença Enxerto-Hospedeiro/metabolismo , MicroRNAs/biossíntese , Transplante de Células-Tronco/efeitos adversos , Animais , Biomarcadores/metabolismo , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/genética , Humanos , MicroRNAs/genética , Transplante de Células-Tronco/tendências , Transplante Homólogo/efeitos adversos , Transplante Homólogo/tendênciasAssuntos
Transplante de Rim , Mieloma Múltiplo/terapia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/cirurgia , Injúria Renal Aguda/terapia , Adulto , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/uso terapêutico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Indução de Remissão , Diálise Renal , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Transplante AutólogoRESUMO
AIMS AND OBJECTIVES: To establish the availability of High Efficiency Particulate Air (HEPA)- and nonHEPA-filtered rooms in eastern European transplant centres and to investigate the impact on incidence of pneumonia and mortality after haematopoietic stem cell transplantation (HSCT). BACKGROUND: Barrier nursing in HEPA-filtered rooms is generally recommended for patients undergoing HSCT. There are only limited data on the availability of HEPA-filtered rooms and the impact on incidence of pneumonia and mortality. DESIGN: A prospective, observational, international study. METHODS: Monitoring cards were distributed within the East Forum EBMT-Nurses Group cooperating centres, and 689 consecutive patients were registered in 1/2010-6/2012. Patients were monitored for 100 days post-transplant. RESULTS: In patients undergoing autologous HSCT, pneumonia developed in 14/400 (3·5%) and was the cause of death in 2/14 (14%) of patients. There was no significant difference in mortality between HEPA-filtered and nonHEPA-filtered groups (4·5% vs. 4·9%, respectively). 239/400 (59%) transplantations were performed in single-bed rooms [190/239 (79%) HEPA-filtered] and 161 (41%) in two-bed rooms [28/161 (17%) HEPA-filtered]. In allogeneic transplantation, pneumonia developed in 24/289 (8·3%) and was the cause of death in 11/24 (45%) of patients. There was no significant difference in mortality between HEPA-filtered and non-HEPA-filtered groups (14% vs. 17%, respectively). 281/289 (97%) of allogeneic transplantations were performed in single-bed rooms [254/281 (90%) HEPA-filtered], and pneumonia was more frequent in patients on corticosteroids and in rooms without HEPA. CONCLUSION: The incidence of pneumonia in the autologous transplantation setting is low. More pneumonia was observed in the allogeneic HSCT group, especially in patients on corticosteroids. There was a trend towards a lower incidence of pneumonia in allogeneic HSCT patients treated in HEPA-filtered rooms. RELEVANCE TO CLINICAL PRACTICE: Autologous HSCT transplantation may safely be performed without HEPA filtration. HEPA filtration might be preferable in patients undergoing allogeneic transplantation.
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Transplante de Células-Tronco Hematopoéticas , Isolamento de Pacientes , Quartos de Pacientes , Pneumonia/epidemiologia , Adolescente , Adulto , Idoso , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pneumonia/etiologia , Pneumonia/enfermagem , Pneumonia/prevenção & controle , Estudos Prospectivos , Adulto JovemRESUMO
In Europe, most HTLV-1-infected individuals originate from highly endemic regions such as West Indies, sub-Saharan Africa, and South America. The only genuine endemic region for HTLV-1 in Europe is Romania where ATL series have been reported among Romanian patients. Our objective is to better understand the origin of this endemic focus based on a study of the genetic diversity of HTLV-1 in Romanians. DNA was obtained from PBMCs/buffy coats of 11 unrelated HTLV-1-infected individuals of Romanian origin. They include 9 ATL cases and 2 asymptomatic carriers. LTR sequences were obtained for all specimens. Complete genomic HTLV-1 sequences were obtained using four PCR series on 10 specimens. Phylogenetic trees were generated from multiple alignments using HTLV-1 prototypic sequences and the new generated sequences. Most of the complete LTR sequences (756-bp) showed low nucleotide diversity, ranging from 0% to 0.8% difference, and were closely related (less than 0.8% divergence) to the only previously characterized Romanian strain, RKI2. One strain, ROU7, diverged slightly (1.5% on average) from the others. Phylogenetic analyses both on partial LTR and the complete genome demonstrate that the 11 sequences belong to the HTLV-1a cosmopolitan genotype and 10 of them belong to the previously denominated a-TC Mozambique-Southern Africa A subgroup. In this study, we demonstrated that the HTLV-1 present in Romania most probably originated in Southern Africa. As most Romanian HTLV-1 strains are very closely related, we can assume that HTLV-1 has been introduced into the Romanian population recently. Further studies are ongoing to decipher the routes of arrival and dissemination of these HTLV-1 strains, and to date the emergence of this endemic focus in Central Europe.
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Variação Genética , Infecções por HTLV-I , Vírus Linfotrópico T Tipo 1 Humano , Filogenia , Sequências Repetidas Terminais , Romênia/epidemiologia , Humanos , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/classificação , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Infecções por HTLV-I/virologia , Infecções por HTLV-I/epidemiologia , Sequências Repetidas Terminais/genética , Masculino , Feminino , Análise de Sequência de DNA , DNA Viral/genética , Pessoa de Meia-Idade , Adulto , África Austral/epidemiologia , IdosoRESUMO
Despite the numerous advantages of allogeneic hematopoietic stem cell transplants (allo-HSCT), there exists a notable association with risks, particularly during the preconditioning period and predominantly post-intervention, exemplified by the occurrence of graft-versus-host disease (GVHD). Risk stratification prior to symptom manifestation, along with precise diagnosis and prognosis, relies heavily on clinical features. A critical imperative is the development of tools capable of early identification and effective management of patients undergoing allo-HSCT. A promising avenue in this pursuit is the utilization of proteomics-based biomarkers obtained from non-invasive biospecimens. This review comprehensively outlines the application of proteomics and proteomics-based biomarkers in GVHD patients. It delves into both single protein markers and protein panels, offering insights into their relevance in acute and chronic GVHD. Furthermore, the review provides a detailed examination of the site-specific involvement of GVHD. In summary, this article explores the potential of proteomics as a tool for timely and accurate intervention in the context of GVHD following allo-HSCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Biomarcadores , Condicionamento Psicológico , ProteômicaRESUMO
Prospective randomized trials have reported a benefit for anti-thymocyte globulin (ATG)-based graft-versus-host disease (GvHD) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with unrelated donors (UD). However, the optimal GvHD prophylaxis strategy has been recently challenged by the increasing use of post-transplant cyclophosphamide (PTCY). We report from the EBMT registry the outcomes of 960 patients with myelodysplastic neoplasms (MDS) undergoing allo-HSCT from UD with PTCY or ATG as GvHD prophylaxis. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Disease characteristics were similar in both groups. Day 28 neutrophil engraftment was significantly better with ATG (93% vs 85%, p<0.001). With a median follow-up of 4.4 years (95% confidence interval [CI] 4.2 - 4.8), 5-year OS was 58% (95% CI 50-65) with PTCY and 49% (95% CI 46-53%) in the ATG group, p=0.07. 5-year PFS was higher for PTCY with 53% (95% CI 45-60) vs 44% (95% CI 40-48) for ATG, p=0.043. Grade II-IV aGvHD incidence was lower using PTCY (23% [95% CI 17-29%] vs 30% [95% CI 27-33%]), p=0.044 while there was no difference in incidence of cGvHD at 5 years. Multivariable analyses confirmed better OS and PFS with PTCY, with a HR for ATG of 1.32 (1 - 1.74), p=0.05, and a better PFS for PTCY with a HR for ATG of 1.33 (1.03 - 1.73), p=0.03. This study suggests that GvHD prophylaxis using PTCY instead of ATG in this setting remains a valid option. Further prospective randomized studies would be essential to confirm these results.
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Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B-tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01-telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice.
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Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Receptores KIR , Humanos , Pessoa de Meia-Idade , Genótipo , Transplante de Células-Tronco Hematopoéticas/normas , Leucemia Mieloide Aguda/terapia , Ligantes , Prognóstico , Receptores KIR/genética , Síndromes Mielodisplásicas/terapiaRESUMO
Invasive fungal disease (IFD), predominantly aspergillosis, is associated with significant morbidity and mortality in immunocompromised patients, especially those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. There has been a great deal of scientific debate as to the effectiveness of antifungal prophylaxis in preventing infection in different patient groups and in which patients it is an appropriate management option. Deciding on an appropriate prophylaxis regimen for IFD is challenging as the incidence varies among different patient groups, due to the varied nature of their underlying haematological disease, and in different regions and centres. Attempts have been made to define risk factors and include them in treatment protocols. Impaired immune status of the patient, especially neutropenia, is a key risk factor for IFD and can sometimes be related to specific polymorphisms of genes controlling innate immunity. Risk factors also vary according to the type of fungal pathogen. Consequently, prophylaxis needs to be tailored to individual patient groups. Furthermore, the choice of antifungal agent for prophylaxis depends on the potential for drug-drug interactions with the patients' concomitant medications. Additional challenges are optimal timing of antifungal prophylaxis, when to change from prophylaxis to antifungal treatment and how to prevent recurrence of IFD. This article considers the use of antifungal prophylaxis for patients at risk of IFD in daily clinical practice, with clinical profiles that may be distinct from those covered by guidelines, and aims to provide practical advice for treatment of these patient groups.
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Antifúngicos/uso terapêutico , Administração de Caso/organização & administração , Quimioprevenção/métodos , Neoplasias Hematológicas/complicações , Hospedeiro Imunocomprometido , Micoses/prevenção & controle , Medicina de Precisão/métodos , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Micoses/diagnóstico , Micoses/tratamento farmacológico , Medição de Risco , Transplante Homólogo/efeitos adversosRESUMO
Tumor growth and metastasis are reliant on intricate interactions between the host immune system and various counter-regulatory immune escape mechanisms employed by the tumor. Tumors can resist immune surveillance by modifying the expression of human leukocyte antigen (HLA) molecules, which results in the impaired presentation of tumor-associated antigens, subsequently evading detection and destruction by the immune system. The management of chronic lymphocytic leukemia (CLL) is based on symptom severity and includes various types of targeted therapies, including rituximab, obinutuzumab, ibrutinib, acalabrutinib, zanubrutinib, idelalisib, and venetoclax. These therapies rely on the recognition of specific peptides presented by HLAs on the surface of tumor cells by T cells, leading to an immune response. HLA class I molecules are found in most human cell types and interact with T-cell receptors (TCRs) to activate T cells, which play a vital role in inducing adaptive immune responses. However, tumor cells may evade T-cell attack by downregulating HLA expression, limiting the efficacy of HLA-dependent immunotherapy. The prognosis of CLL largely depends on the presence or absence of genetic abnormalities, such as del(17p), TP53 point mutations, and IGHV somatic hypermutation status. These oral targeted therapies alone or in combination with anti-CD20 antibodies have replaced chemoimmunotherapy as the primary treatment for CLL. In this review, we summarize the current clinical evidence on the impact of HLA- and cytokine-type responses on outcomes after targeted therapies currently used to treat CLL.
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Acute promyelocytic leukemia (APL) currently represents one of the malignant hemopathies with the best therapeutic responses, following the introduction of all-trans retinoic acid (ATRA) and subsequently of arsenic trioxide (ATO) treatment. As a result, a large proportion of patients with APL achieve long-term responses after first-line therapy, so performing a hematopoietic stem cell transplant as consolidation of first complete remission (CR) is no longer necessary. Even in the case of relapses, most patients obtain a new remission as a result of therapy with ATO and ATRA, but an effective consolidation treatment is necessary to maintain it. The experience accumulated from studies published in the last two decades shows the effectiveness of hematopoietic stem cell transplantation (HSCT) in improving the outcome of patients who achieve a new CR. Thus, the expert groups recommend transplantation as consolidation therapy in patients with a second CR, with the indication for autologous HSCT in cases with molecular CR and for allogeneic HSCT in patients with the persistence of minimal residual disease (MRD) or with early relapse. However, there is a variety of controversial aspects related to the role of HSCT in APL, ranging from the fact that outcome data are obtained almost exclusively from retrospective studies and historical analyses to questions related to the type of transplantation, the impact of minimal residual disease, conditioning regimens, or the role of other therapeutic options. All these questions justify the need for controlled prospective studies in the following years.
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INTRODUCTION: Emerging immunotherapies are pushing the boundaries of cancer treatment, with chimeric antigen receptor (CAR)-T cell therapy being one of the most advanced. Due to the increasingly crowded CAR-T cell field, patenting and protecting the intellectual property of these CAR-T cells implies a good knowledge of the legal landscape. AREAS COVERED: The present manuscript focuses on the challenges regarding the patenting process of CAR-T technology, beginning with a description of the main characteristics of CAR-T cells and their functionalities, continuing with the legal landscape applicable to patenting processes, and concluding by presenting the potential strategies to overcome the impediments that can appear when trying to patent CAR-T cells. It is meant to offer insights for those who are exploring possible patenting options in CAR-T cells territory. PubMed and Patenscope databases were used for patent and literature searching (2013-2023). EXPERT OPINION: There is no one-size-fits-all solution in this matter and the medical evolution of this therapy will certainly bring out even more challenges. Comprehensive knowledge of the intellectual property, exposure to potential litigation, growing competition, and the high price of therapy, are strikingly relevant in the broader landscape. Future endeavors would be to take steps toward the harmonization of the CAR-T patenting procedure.
Assuntos
Receptores de Antígenos Quiméricos , Humanos , Patentes como Assunto , Imunoterapia Adotiva/métodos , Linfócitos T , Imunoterapia/métodosRESUMO
Multiple myeloma (MM) is a malignant plasma cell disorder accounting for around 1.8% of all neoplastic diseases. Nowadays, clinicians have a broad arsenal of drugs at their disposal for the treatment of MM, such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, bispecific antibodies, CAR T-cell therapies and antibody-drug conjugates. In this paper we briefly highlight essential clinical elements relating to proteasome inhibitors, such as bortezomib, carfilzomib and ixazomib. Studies suggest that the early use of immunotherapy may improve outcomes significantly. Therefore, in our review we specifically focus on the combination therapy of proteasome inhibitors with novel immunotherapies and/or transplant. A high number of patients develop PI resistance. Thus, we also review new generation PIs, such as marizomib, oprozomib (ONX0912) and delanzomib (CEP-18770) and their combinations with immunotherapies.