Imunoterapia com células natural killer : um caminho possível para o tratamento da Leucemia Mielóide Aguda também no Brasil

The allogeneic hematopoietic stem cell transplantation (HSCT) can cure intermediate and high-risk acute myeloid leukemia. Even with the development of strategies to reduce HSCT toxicity, this is still a complex treatment with high morbidity and mortality. Knowledge of the graft versus leukemia effect of HSCT has prepared the way for the development of Adoptive Immunotherapy or in vitro expansion of activated lymphocytes without alloreactivity, with subsequent intravenous infusion. The infusion of genetically modified T lymphocytes and haploidentical natural killer cells has been tested as an alternative to HSCT with very interesting results worldwide and in Brazil, as we not only have the technology of in vitro expansion of clinical grade lymphocytes available, but also do it according to the Good Manufacturing Practices that have been determined internationally.O transplante de células-tronco hematopoéticas (TCTH) alogênico é curativo para leucemia mielóide aguda de risco intermediário e alto. Mesmo com o desenvolvimento de estratégias para minorar a toxicidade do TCTH, este ainda é um tratamento complexo com elevada morbi-mortalidade. O conhecimento sobre o efeito enxerto contra leukemia do TCTH pavimentou o caminho para o desenvolvimento da Imunoterapia Adotiva ou expansão in vitro de linfócitos ativados, sem alo- reatividade, com posterior infusão endovenosa. A infusão de Linfócitos T geneticamente modificados e de células Natural Killer haploidenticas tem sido testada como alternativa ao TCTH com resultados bastante interessantes no mundo e no Brazil já que não apenas dominamos a tecnologia de expansão in vitro de linfócitos em grau clínico, como o fazemos segundo as Boas Práticas de Manufatura determinadas internacionalmente

Peripheral blood persistence and expansion of transferred non-genetically modified Natural Killer cells might not be necessary for clinical activity

Natural killer (NK) cells are innate lymphocytes that react without previous exposition to virus infected or malignant cells and stimulate adaptive immune response to build a long-lasting immunity against it. To that end, tissue resident NK cells are predominantly regulatory as opposed to cytotoxic. In the hematopoietic stem cell transplant (HSCT) setting, which curative potential relies on the graft versus leukemia effect, NK cells are known to play a significant role. This knowledge has paved the way to the active investigation on its anti-tumor effect outside the stem cell transplant scenario. Based on the relevant literature on the adoptive transfer of non-genetically modified NK cells for the treatment of relapsed/refractory acute leukemia and on our own experience, we discuss the role of donor cell peripheral blood persistence and expansion and its lack of correlation with anti-leukemia activity

Distribution of filamentous fungi causing invasive fungal disease at the Haematological Unit, Hospital de Clínicas de Porto Alegre, Brazil

AbstractVery limited data are available in the literature to elucidate the aetiology of invasive mould infections in Latin America. Here we report that Aspergillus species caused only half of such cases in a cohort study conducted over 21 months in a university hospital in Porto Alegre, Southern Brazil. Fusarium spp. were the second most prevalent moulds (20.7%), followed by Zygomycetes (13.8%). The importance of obtaining local epidemiological data for adequately guiding empirical antifungal therapy is reinforced

Distribution of filamentous fungi causing invasive fungal disease at the Haematological Unit, Hospital de Clínicas de Porto Alegre, Brazil

AbstractVery limited data are available in the literature to elucidate the aetiology of invasive mould infections in Latin America. Here we report that Aspergillus species caused only half of such cases in a cohort study conducted over 21 months in a university hospital in Porto Alegre, Southern Brazil. Fusarium spp. were the second most prevalent moulds (20.7%), followed by Zygomycetes (13.8%). The importance of obtaining local epidemiological data for adequately guiding empirical antifungal therapy is reinforced

Bone marrow mesenchymal stem cells in acute-on-chronic liver failure grades 2 and 3 : a phase I-II randomized clinical trial

Introduction: Acute-on-chronic liver failure (ACLF) is an acute liver decompensation in cirrhotic patients, which leads to organ failures and high short-term mortality. The treatment is based on the management of complications and, in severe cases, liver transplantation. Since specific treatment is unavailable, we aimed to evaluate the safety and initial efficacy of bone marrow mesenchymal stem cells (BM-MSC) in patients with ACLF Grades 2 and 3, a population excluded from previous clinical trials. Methods: This is a randomized placebo-controlled phase I-II single center study, which enrolled 9 cirrhotic patients from 2018 to 2020, regardless of the etiology. The control group (n=5) was treated with standard medical therapy (SMT) and placebo infusion of saline. The intervention group (n=4) received SMT plus 5 infusions of 1 × 10^6 cells/kg of BM-MSC for 3 weeks. Both groups were monitored for 90 days. A Chi-square test was used for qualitative variables, and the t-test and Mann–Whitney U test for quantitative variables. The Kaplan–Meier estimator was used to build survival curves. In this study, we followed the intention-totreat analysis, with a significance of 5%. Results: Nine patients with a mean Child–Pugh (CP) of 12.3, MELD of 38.4, and CLIF-C score of 50.7 were recruited. Hepatitis C and alcohol were the main etiologies. )e average infusion per patient was 2.9 and only 3 patients (2 in control and 1 in the BM-MSC group) received all the protocol infusions. There were no infusion-related side effects, although one patient in the intervention group presented hypernatremia and a gastric ulcer, after the third and fifth infusions, respectively. )e survival rate after 90 days was 20% (1/5) for placebo versus 25% (1/4) for the BM-MSC. The patient who completed the entire MSC protocol showed a significant improvement in CP (C-14 to B-9), MELD (32 to 22), and ACLF (grade 3 to 0). Conclusion: BM-MSC infusion is safe and feasible in patients with ACLF Grades 2 and 3

Aspectos Ambientais e Genéticos no Desenvolvimento de Leucemias

The causes of AL are likely to involve an interaction between genetic susceptibility and environment. Polymorphisms in genes coding metabolizing/detoxification enzymes are responsible for this susceptibility. Environmental exposure (occupational or recreational) may also be involved with the etiology of leukemia. Some studies have described that infant leukemia may have the initiation period during in utero development and this may be caused by the parental pre or during the pregnancy period. The aim of this study was to analyze polymorphisms of GSTM1 and GSTT1 genes in order to verify if they have a role in genetic susceptibility to AL and correlate with some environmental aspects. Genomic DNA from 87 patients was analyzed by a multiplex PCR methodology. Material from twenty four families (the patient, the mother and/or the father) were also analyzed and a questionnaire about environmental aspects was applied. Significant increase in the prevalence of GSTT1 null genotype was detected in the patient group comparing to controls (40% X 23%) (P=0.005). No difference was found in the prevalence of GSTM1 null genotype between AL patients and controls (50% X 50%). We detected higher prevalence of occupational exposure to solvents among the fathers, being this an important aspect on leukemia development.A etiologia das LA pode ser explicada pela combinação de fatores genéticos e ambientais. Como exemplo das influências genéticas podem-se citar polimorfismos de genes de metabolização/detoxificação e, como agente ambiental à exposição ocupacional e por lazer. Tem sido descrito que Leucemias infantis poderiam ter a iniciação ocorrendo in útero, devido à exposição parental pré-ou durante a gestação. Este trabalho tem por objetivo analisar os polimorfismos dos genes GSTM1 e GSTT1 em relação à suscetibilidade de desenvolvimento de LA e a relação com alguns fatores ambientais. O DNA genômico de um banco de 87 pacientes foi analisado pela técnica de PCR multiplex. Também foram coletados dados de 24 famílias (pacientes pai e/ou mãe) e aplicado questionário sobre exposição. Foi detectado aumento significativo da freqüência do genótipo GSTT1 nulo quando comparado com uma população controle (40% X 23%) (P=0.005). A freqüência do genótipo nulo para GSTM1 nos pacientes não apresentou diferença significativa com relação aos controles (50% X 50%). Foi detectada uma prevalência alta de pais que relatam exposição a tintas e solventes no período de pré-concepção, podendo este ser um fator importante na origem da doença

Hematopoietic stem cells transplantation and acute myeloid leukemia: Brazilian guidelines

The objective of this work was to define guidelines for the indication of hematopoietic stem cells transplantation (HSCT) in the treatment of acute myeloid leukemia (AML) in Brazil. The role of HSCT in the treatment of AML was discussed by the authors and presented to the Brazilian Society of Bone Marrow Transplantation in a meeting to formulate and ratify the Brazilian Guidelines on HSCT. This consensus was based on a review of international publications and on the Brazilian experience in HSCT for the treatment of AML. The optimal treatment for AML in first complete remission (1CR) has not been defined yet. There is consensus on the indication of allogeneic HSCT with myeloablative conditioning for patients who present high risk cytogenetic changes. Allogeneic HSCT is not indicated for low cytogenetic risk 1RC patients and, apparently, allogeneic and autologous HSCT and consolidation chemotherapy are similar for intermediate risk patients.O objetivo deste trabalho foi definir diretrizes para a indicação do transplante de células-tronco hematopoéticas (TCTH) no tratamento da leucemia mieloide aguda (LMA) no Brasil. O papel do TCTH no tratamento da LMA foi discutido pelosautores e apresentado para a Sociedade Brasileira de Transplante de Medula Óssea na reunião sobre Diretrizes Brasileiras para o TCTH, que o ratificou. Este consenso foi baseado na revisão da literatura internacional e na experiência brasileira em TCTH para o tratamento da LMA. O tratamento ideal para leucemia mieloide aguda em primeira remissão completa (1RC) ainda não está definido. Há consenso na indicação do TCTH alogênico, com condicionamento mieloablativo, para pacientes que apresentem alterações citogenéticas consideradas de alto risco. O TCTH alogênico não está indicado na 1RC para pacientes de baixo risco citogenético e, aparentemente, o TCTH alogênico, autólogo ou a quimioterapia de consolidação são equivalentes para os pacientes de risco intermediário.Hospital de Clínicas de Porto Alegre Serviço de Hematologia e Transplante de Medula ÓsseaUniversidade de São Paulo Hospital das Clínicas Centro de Transplante de Medula ÓsseaHospital de Câncer de Barret HemonúcleoUniversidade Federal de São Paulo (UNIFESP) Hospital Israelita Albert Einstein Centro de Transplante de Medula ÓsseaAssociação de Combate ao Câncer em Goiás Hospital Araújo Jorge Serviço de Transplante de Medula ÓsseaHospital Israelita Albert Einstein Programa de Hematologia e Transplante de Medula ÓsseaUNIFESP, Hospital Israelita Albert Einstein Centro de Transplante de Medula ÓsseaSciEL

Fiberoptic bronchoscopy in the diagnosis and therapeutic decision for respiratory infections in hematological febrile neutropenic patients

Background: Febrile neutropenia is a common complication in patients undergoing chemotherapy or hematopoietic Stem Cell Transplantation (HSCT). Flexible fiberoptic bronchoscopy has been used to aid in the diagnosis of pulmonary diseases. However, there is no consensus regarding the benefit of the exam in establishing diagnosis and in changing the treatment of lung disease in this context. Previous retrospective studies, quite heterogeneous and with non-HIV immunocompromised patients, showed that the yield of fiberoptic bronchoscopy in establishing etiology ranges from 13% to 81%, and in changing therapy, from 5% to 51%.Aim: To evaluate the efficiency of Fiberoptic bronchoscopy and the procedure-related risk for neutropenic patients with hematologic malignancy.Methods: This retrospective cross-sectional study analyzed the medical records of patients with hematologic malignancy with febrile neutropenia who had undergone diagnostic fiberoptic bronchoscopy between January 2011 and December 2012 at the Hospital de Clínicas de Porto Alegre.Results: A total of 45 patients were included: 18 (36%) tested positive for bronchoalveolar lavage, with change in therapeutic management occurring for 95% of them. The procedure-related risk was 2.2%, with one patient showing desaturation immediately after the procedure.Conclusion:  Despite the limited number of patients, our findings indicate that fiberoptic bronchoscopy in neutropenic patients is safe, and the results are similar to those previously reported.