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Treatment with covalent Bruton tyrosine kinase inhibitors (BTKi) represents an important advance in the management of relapsed or refractory mantle cell lymphoma, but these treatments are not curative and many patients ultimately relapse. Pirtobrutinib, a highly selective, non covalent (reversible) BTKi, inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients with poor prognosis B-cell malignancies following prior therapy, including covalent BTKi. This phase III, head-to-head, randomized study (NCT04662255) will evaluate whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naive mantle cell lymphoma.MCL is an uncommon type of B-cell non-Hodgkin lymphoma, a cancer of the immune system. It starts in the part of the lymph node called the mantle zone, where unusual B cells gather and crowd out healthy B cells in the lymph nodes, spleen, bone marrow and/or other organs. MCL can be caused by inappropriate cell signaling. BTK has been identified as a key driver of unusual cell signaling and blocking BTK has been shown to help kill the cancer cells. Covalent (not reversible) BTK inhibitors have advanced the treatment of MCL, but the effectiveness of these treatments is limited by side effects and treatment resistance. Pirtobrutinib, a non covalent (reversible) BTK inhibitor, has been shown to have manageable side effects and to be effective in patients with MCL following previous treatment, including treatment with covalent BTK inhibitors. The BRUIN MCL-321 study compares pirtobrutinib with three currently approved covalent BTK inhibitors (ibrutinib, acalabrutinib or zanubrutinib), in patients with MCL who have never received any form of BTK inhibitor. This trial will look at how many people live with the disease without it getting worse. Like other cancer treatments, pirtobrutinib may affect both healthy cells and tumor cells, which can result in side effects that will also be looked at in this study. This study is active and currently recruiting new patients who have received at least one previous therapy for MCL and have never been treated with a BTK inhibitor.

As microalgas possuem diversas aplicações biotecnológicas e dentro da agricultura podem ser utilizadas como biofertilizantes, bioestimuladoras da germinação de semente, biopesticidas e bioinsetisidas. Para estudar experimentalmente o uso da microalga Chlorella sorokiniana na germinação de sementes, é necessário obter informações na literatura sobre as metodologias de aplicação de microalgas em experimentos de campo que visem este processo. O presente trabalho teve como objetivo coletar informações por meio de uma revisão de literatura, sobre as metodologias e formas de aplicação das microalgas na germinação de sementes. O trabalho de revisão foi realizado na base de dados do Google Acadêmico com os seguintes termos de busca avançada: *seeds germination and biostimulant agent and Chlorella microalgae* -wastewater, nos anos de 2018 a 2022. Foram encontrados 164 artigos científicos dentro da temática estudada e foram selecionados somente aqueles trabalhos que apresentavam em suas metodologias as informações sobre a aplicação de microalgas em experimentos de campo e germinação de sementes, totalizando 5 artigos. As microalgas comprovadamente apresentam efeitos positivos na germinação de sementes de feijão, agrião, beterraba, tomate e pepino. Contudo é evidente a necessidade de se investir em pesquisas que considerem as diferentes variáveis nesta ação bioestimuladora, como espécies de microalgas, tipo de extratos (cultura inteira, sobrenadante, biomassa seca ou úmida), extração dos compostos bioativos da microalga, além de quantidade e método de aplicação. Palavras-chave: Chlorella sorokiniana. Agricultura Sustentável. Compostos Bioativos. Métodos de Extração. Abstract Microalgae have several biotechnological applications and in agriculture it can be used as biofertilizers, seed germination biostimulators, biopesticides and bioinsecticides. In order to study the use of microalgae Chlorella sorokiniana in seed germination, it is necessary to obtain information in the literature regarding methodologies for applying microalgae in field experiments. The present work aimed to collect information through a literature review, on methodologies and forms of microalgae application in seed germination. The review was carried out at Google Scholar database using the keywords: *seeds germination and biostimulant agent and Chlorella microalgae* -wastewater, from 2018 to 2022. 164 scientific articles were found but only studies that presented information about microalgae application in field experiments and seed germination were selected, totalizing 5 articles. Microalgae showed positive effects on germination of beans, watercress, beetroot, tomato and cucumber seeds. However, it is evident the need to invest in research that considers different variables in biostimulating action, such as microalgae species, type of extracts (whole culture, supernatant, dry or wet biomass), extraction of bioactive compounds, in addition to quantity and application method. Keywords: Chlorella sorokiniana. Sustainable Agriculture. Bioactive Compounds. Extraction Methods.

Este trabalho teve como objetivo elaborar um estudo prospectivo de patentes a respeito dos galacto-oligoassacarídeos (GOS) com potencial biotecnológico. Foram analisados e avaliados os documentos depositados na base de dados do WIPO (World Intellectual Property Organization) referentes ao período de 2014 a 2020, utilizando a palavra-chave “galacto-oligosaccharides” totalizando 107 depósitos para a área de interesse do trabalho. No ano de 2017 foi apresentado o maior número de patentes depositadas, em que o Continente asiático apresentou o maior número de depósito, com destaque para a China. Quanto ao perfil dos requerentes, 69% são depósitos feitos por empresas do setor privado, 22% por pessoa física e 9% por universidades. Das patentes depositadas, pelo setor privado, destaca-se a multinacional N.V. Nutrícia localizada na Holanda com 5 depósitos vinculados à necessidade humana. O maior percentual de pedidos com 75% foi destinado para a elaboração de produtos. A concentração foi no setor relacionado à saúde com 70% dos depósitos tendo como destino composições nutricionais, produtos lácteos, fórmulas nutricionais e fórmulas infantis. A área de biotecnologia obteve 19% dos depósitos de patentes, sendo o maior percentual destinado para produção de galacto-oligoassacarídeos. Já a área de alimentos obteve 11%, tendo maior volume destinado aos produtos lácteos. A tendência da utilização e produção de GOS vem sendo de grande interesse em diferentes áreas de interesse e uma das formas de divulgação científica é através de patentes destinadas para estes fins. Palavras-chave: Prebióticos. Galacto-oligossacarídeos. Patentes. Prospecção Tecnológica. Abstract This work aimed to develop a prospective study of patents on galactooligosaccharides (GOS) with biotechnological potential. The documents deposited in the WIPO (World Intellectual Property Organization) database for the period from 2014 to 2020 were analyzed and evaluated, using the keyword “galactooligosaccharides”, totaling 107 deposits for the work area of interest. In 2017, the highest number of patents filed was presented, where the Asian continent had the highest number of filings, especially China. As for the profile of applicants, 69% of them are deposits made by private sector companies, 22% by individuals and 9% by universities. Out of the patents filed by the private sector, the multinational N.V. Nutrícia, located in the Netherlandsstands out, with 5 deposits linked to human needs. The highest percentage of orders, with 75%, were aimed at the elaboration of products. The concentration was in the health-related sector with 70% of the deposits destined for nutritional compositions, dairy products, nutritional formulas and infant formulas. The biotechnology area obtained 19% of patent filings, with the highest percentage aimed at the production of galactooligosaccharides. The food area, on the other hand, obtained 11%, with the largest volume being intended for dairy products. The trend in the use and production of GOS has been of great interest in different areas of interest and one of the forms of scientific dissemination is disclosed through patents for these purposes. Keywords: Prebiotics. Galactooligosaccharides. Patents. Technological Prospecting.

Cheese whey is considered the main by-product obtained by the dairy industry and it is derived from coagulation during cheese production. Half of cheese whey production is used in well-established processes, like production of fresh products, animal feed, and a source of high-added-value compounds, such as whey protein and β-galactosidase. Unfortunately, the use of cheese whey as raw material requires expensive processes. Therefore, a high proportion of this product is wasted and discarded into industrial effluent treatment stations. Different research groups have been studying potential strategies to valorize cheese whey. The goal of this chapter is to present the main characteristics of cheese whey and introduce the possibilities of using this by-product for new biotechnological purposes. The challenge is the arrangement of these processing systems with the players involved in the dairy industry. A joint action between them can turn cheese whey waste into high-added-value products producing zero dairy waste and honoring environmental legislation and public policies.

Patients with myelodysplastic syndromes (MDS) often experience chronic anemia and long-term red blood cell transfusion dependence associated with significant burden on clinical and health-related quality of life (HRQoL) outcomes. In the MEDALIST trial (NCT02631070), luspatercept significantly reduced transfusion burden in patients with lower-risk MDS who had ring sideroblasts and were refractory to, intolerant to, or ineligible for prior treatment with erythropoiesis-stimulating agents. We evaluated the effect of luspatercept on HRQoL in patients enrolled in MEDALIST using the EORTC QLQ-C30 and the QOL-E questionnaire. Change in HRQoL was assessed every 6 weeks in patients receiving luspatercept with best supportive care (+ BSC) and placebo + BSC from baseline through week 25. No clinically meaningful within-group changes and between-group differences across all domains of the EORTC QLQ-C30 and QOL-E were observed. On one item of the QOL-E MDS-specific disturbances domain, patients treated with luspatercept reported marked improvements in their daily life owing to the reduced transfusion burden, relative to placebo. Taken together with previous reports of luspatercept + BSC reducing transfusion burden in patients from baseline through week 25 in MEDALIST, these results suggest luspatercept may offer a treatment option for patients that reduces transfusion burden while providing stability in HRQoL.

O soro de queijo é a porção líquida proveniente da produção de queijoresultante da coagulação ácida ou enzimática das caseínas do leite. Cerca de 40% do soro de queijo produzido no Brasil, é descartado de forma inadequada, apenas 15% dos laticínios no país utilizam toda matéria prima para elaborar novos produtos.Aproximadamente 75% da população mundial apresenta algum tipo de intolerância à lactose que se deve à inatividade ou baixa atividade da enzima intestinal β-galactosidase. A β-galactosidase é uma proteína popularmente conhecida como lactase, classifica-se como uma hidrolase com potencial de hidrolisar a lactose (dissacarídeo), em glicose e galactose (monossacarídeo). É uma enzima de grande importância para a indústria de alimentos, no setor de laticínios e derivados. O objetivo do presente estudo visa fazer um levantamento sobre o potencial biotecnológico de microalga para a produção de compostos bioativos, como por exemplo, a enzima β-galactosidase. Palavras-chave: Biotecnologia. Enzima. Fermentação. Microalgas. Abstract Cheese whey is a proven liquid portion of the production of acidic or enzymatic coagulation of milk caseins. Approximately 40% of the content of cheese produced in Brazil is discarded inappropriately, only 15% of dairy products in the country use all raw materials to make new products. Approximately 75% of the world population has some type of lactose intolerance that should be due to inactivity or low activity of the intestinal β-galactosidase enzyme. Β-galactosidase is a protein popularly known as lactase, classified as a hydrolase with the potential to hydrolyze lactose (disaccharide), into glucose and galactose (monosaccharide). It is an enzyme of great importance for the food industry, no sector of dairy products and derivatives. The objective of the present study is to carry out a survey on the biotechnological potential of microalgae for the production of bioactive compounds, such as an β-galactosidase enzyme. Keywords: Biotechnology. Enzyme. Fermentation. Microalgae.

Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but many patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type and C481-mutated BTK with equal low nM potency.Determine whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naïve MCL.BRUIN MCL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated, BTKi-naïve MCL. Approximately 500 patients will be randomized 1:1. Randomization will be stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2).Global; community hospitals, academic medical centers.Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL who received ≥ 1 prior line of systemic therapy for MCL that did not include a prior BTKi. Patients must have measurable disease per Lugano criteria and must have progressed on or relapsed following the most recent line of therapy prior to study enrollment. Key exclusion criteria include a history of current or prior CNS involvement, significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of randomization, and allogeneic stem cell transplant (SCT), autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization.Pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy.The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee, with the goal of demonstrating the superiority of pirtobrutinib over the investigator's choice of covalent BTKi. Secondary endpoints include overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04662255).Trial in Progress.Trial in Progress.

Luspatercept is an approved therapy for selected patients with lower risk myelodysplasia requiring transfusion despite erythropoiesis-stimulating agents, based on the early results of a randomized trial against placebo. Zeidan and colleagues report that after a median of 26 months follow-up, 27% of patients commencing luspatercept were continuing therapy. Their updated analyses confirm that a significant minority (45%) of eligible patients can achieve transfusion independence, with a median durability of 30 weeks. These longer follow-up data better quantify the incremental benefit of luspatercept over placebo.

O soro do queijo é um subproduto do processo de produção de queijo, sendo este a fração aquosa obtida após a coagulação das caseínas do leite. É rico em lactose, proteínas do soro do queijo (β-lactoglobulina e α-lactoalbumina), vitaminas e minerais. O Soro pode ser utilizado como meio de cultivo por diversos micro-organismos para produção da enzima β-galactosidase, pois estes utilizam a lactose como fonte de carbono. A β-galactosidase é umas das enzimas mais importantes para os laticínios, pois hidrolisa a lactose em glicose e galactose. A β-galactosidase é utilizada para melhorar as características tecnológicas e de textura de produtos lácteos e desenvolvimento de novos produtos isentos de lactose. A β-galactosidase pode ser obtida por diferentes espécies de micro-organismos como fungos, leveduras e bactérias, de animais, frutos e plantas. Porém as de origem microbiana são as de maior interesse para a indústria, uma vez que estas são consideradas seguras para o consumo e possuem maior rendimento. Palavras-chave: Biotecnologia. Enzima. Fermentação. Lactase. Subproduto. Abstract Cheese whey is a by-product of the cheese production process, which is the aqueous fraction obtained after the milk caseins coagulation. It is rich in lactose, cheese whey proteins (β-lactoglobulin and α-lactoalbumin), vitamins and minerals. Cheese whey can be used as a culture by several microorganisms for the enzyme β-galactosidase production, as they use lactose as a carbon source. Β-galactosidase is one of the most important enzymes for dairy products, as it hydrolyzes lactose into glucose and galactose. Β-galactosidase is used to improve the technological and texture characteristics of dairy products and to develop new lactose-free products. Β-galactosidase can be obtained by different species of microorganisms such as fungi, yeasts and bacteria, from animals, fruits and plants. However, those of microbial origin are of greater interest to the industry, since they are considered safe for consumption and have the highest earinings. Keywords: Biotechnology. Enzyme. Fermentation. By-product.

Yeast’s beta-galactosidase is an intracellular enzyme, through which it is possible to determine in vivo its activity as a biocatalyst in the lactose hydrolysis. Permeabilization process was used for transforming the microorganisms cells into biocatalysts with an enhanced enzyme activity. The potential application of this enzyme technology in industrial process depends mainly on the enzyme activity. Beta-galactosidase enzyme that hydrolyzes lactose, for instance, is largely dependent on the reaction time and its stability under different physical conditions, such as pH, temperature and enzyme concentration. The objective of this study was to optimize the cellular permeabilization process of Kluyveromyces marxianus CCT 3172 and Saccharomyces fragilis CCT 7586 cultured in cheese whey for lactose hydrolysis. Box-Behnken design was carried out for cell permeabilization with three independent variables, ethanol concentration, permeabilization time and temperature. The best permeability conditions for K. marxianus CCT 3172 were 27% (v v-1) ethanol, 3 min at 20ºC, with specific enzymatic activity of 0.98 U mg-1. For S. fragilis CCT 7586, a specific enzymatic activity of 1.31 U mg-1 was achieved using 45% (v v-1) of ethanol, 17 min. of reaction under 17ºC. Thus, it was concluded that cellular permeabilization with ethanol is an efficient process to determine beta-galactosidase activity. Yeast’s beta-galactosidase is an intracellular enzyme, through which it is possible to determine in vivo its activity as a biocatalyst in the lactose hydrolysis. Permeabilization process was used for transforming the microorganisms cells into biocatalysts with an enhanced enzyme activity. The potential application of this enzyme technology in industrial process depends mainly on the enzyme activity. Beta-galactosidase enzyme that hydrolyzes lactose, for instance, is largely dependent on the reaction time and its stability under different physical conditions, such as pH, temperature and enzyme concentration. The objective of this study was to optimize the cellular permeabilization process of Kluyveromyces marxianus CCT 3172 and Saccharomyces fragilis CCT 7586 cultured in cheese whey for lactose hydrolysis. Box-Behnken design was carried out for cell permeabilization with three independent variables, ethanol concentration, permeabilization time and temperature. The best permeability conditions for K. marxianus CCT 3172 were 27% (v v-1) ethanol, 3 min at 20ºC, with specific enzymatic activity of 0.98 U mg-1. For S. fragilis CCT 7586, a specific enzymatic activity of 1.31 U mg-1 was achieved using 45% (v v-1) of ethanol, 17 min. of reaction under 17ºC. Thus, it was concluded that cellular permeabilization with ethanol is an efficient process to determine beta-galactosidase activity.

O soro de queijo é o principal subproduto da indústria de laticínios e a alta demanda biológica e química de oxigênio (DBO e DQO) pode causar vários problemas ambientais. Estudos recentes apontam os potenciais usos biotecnológicos do soro de queijo, como o meio de fermentação, para a produção de β-galactosidase. A enzima é muito importante para hidrólise da lactose em galactose e glicose, monossacarídeos mais digeríveis pelo organismo humano. As microalgas podem produzir a β-galactosidase através de processos fermentativos. O objetivo da presente revisão é descrever sucintamente o progresso recente sobre o uso de microalgas na produção de β-galactosidase. No geral, o artigo resume o estado atual do conhecimento sobre microalgas, beta-galactosidase e soro de queijo como fonte de carbono para o crescimento de microalgas e dentro do conceito de economia circular. No entanto, ainda são necessários estudos adicionais sobre as melhores condições de cultivo de microalgas com o objetivo de produzir a enzima em questão. Palavras-chave: Indústria de lacticínio. Biotecnologia. Economia Circular. Valor Agregado. Abstract Cheese whey is the main by-product of dairy industry and due to high biological and chemical oxygen demands (BOD and COD) can cause several environmental problems. Recent studies have pointed the biotechnological potential uses of cheese whey such as fermentation medium to the β-galactosidase production. The enzyme is very important to breakdown the lactose into galactose and glucose, monosaccharide sugars more digestible than lactose. Microalgae can produce β-galactosidase through fermentative processes. The purpose of the current mini-review is to succinctly describe recent progress about the use of microalgae to β-galactosidase production. Overall, the paper summarizes the current state of knowledge about microalgae, beta-galactosidase and cheese whey as carbon source to growing of microalgae and within circular economy concept. However, there is still a need for further studies regarding the best microalgae cultivation conditions with the objective of producing the enzyme in question. Keywords: Dairy industry. Biotechnology. Circular Economy. Added Value.

RESUMEN Se evaluó el efecto de la temperatura sobre la desnaturalización de proteínas y la reacción de Maillard en leche entera y descremada con lactosa hidrolizada. Las leches hidrolizadas se trataron térmicamente a 100, 110, 120 y 130 °C durante un período de 1 hora y se midió la concentración de glucosa, el grado de pardeamiento y la desnaturalización de proteínas. El grado de dorado en la leche entera varió de 14.4 (100 °C) a 42.6 (130 °C). Para la leche descremada fue de 20.2 (100 °C) a 38.0 (130 °C). La concentración de glucosa en leche entera (47% p/v) y en leche descremada (41% p/v) después del tratamiento térmico (130 °C) mostró una reducción significativa en relación con el control (25 °C). El efecto de la temperatura en la desnaturalización de proteínas en leche entera y descremada en relación con el control (25 °C) fue del 100%. La leche tratada térmicamente con lactosa hidrolizada promovió la desnaturalización de proteínas con un aumento del pardeamiento característico de la reacción de Maillard, lo que afectó la calidad nutricional.

Microalgae have been used widely as a biological source for several industries, such as biofuel, pharmaceutical and food. Recently, the agricultural industry has also began using microalgae as an alternative source for sustainable products to replace agrochemicals. Due to the lack of scientific articles in this research area, the objective of this study was to search for applications of microalgae and to characterize its use in agriculture using the patent documents available in three patent databases, World Intellectual Property Organization (WIPO), European Patent Office (EPO) and Brazilian Institute of Industrial Property (INPI). The search was carried out using the keyword “microalgae” and applying the filter for International Patent Classification (IPC) code “A01N” which corresponds to patents related to agriculture and cultivation of microalgae. Our patent database search returned 669 documents and 132 patents were selected for the study based on their abstracts. The first patent was registered in 1982 and described the use of microalgae Chlorella extract as a plant growth promoter. After that, no patent was registered for 15 years. From 2005 to 2014, only seven patents were found. However, the scenario changed from 2015 when the number of patents increased mainly in the United States, China and Europe. The patent analysis showed several applications for microalgae in the agricultural sector, such as plant growth promotion, biofertilization, plant disease control, weed management, and post-harvest quality. This review confirmed the increasing interest in microalgae-derived products in agriculture and the value of using patent documents to assess innovative areas.

Biotechnological processes with microalgae with the aim to achieve high biomass yields must choose the appropriate nutrients and physicochemical parameters, taking into account the specific characteristics of each species to determine the basic needs for its growth. In the present study, the better growth condition of Chlorella sorokiniana IPR 7104 was optimized to reach the maximum beta-galactosidase production. The cheese whey concentration (%), temperature (˚C) and pH were factors investigated and a Box-Behnken Design (BBD) approach was implemented using Statistica 7.0 software. We observed that the cultivation condition to Chlorella sorokiniana IPR 7104 was the heterotrophic, which showed the major enzymatic activity, consequently a lower residual lactose content. Under heterotrophic conditions (without light) the β-galactosidase activity increased linearly until the 8th day. Biomass production grew linearly on the 12th day. The microalgae consumed 89.6% of lactose in 3 days, showing a high capacity to metabolize this disaccharide, through β-galactosidase synthesis. The maximum β-galactosidase production by Chlorella sorokiniana IPR 7104, in heterotrophic conditions and using cheese whey as carbon source, is obtained using the following conditions: 30°C temperature, concentration of ethanol at 20% and time of 4 min. Los procesos biotecnológicos con microalgas con el objetivo de lograr altos rendimientos de biomasa deben elegir los nutrientes y parámetros fisicoquímicos adecuados, teniendo en cuenta las características específicas de cada especie para determinar las necesidades básicas para su crecimiento. En el presente estudio, se optimizó la mejor condición de crecimiento de Chlorella sorokiniana IPR 7104 para alcanzar la producción máxima de beta-galactosidasa. La concentración de suero de queso (%), la temperatura (˚C) y el pH fueron factores investigados y se implementó un enfoque Box-Behnken Design (BBD) utilizando el software Statistica 7.0. Observamos que la condición de cultivo de Chlorella sorokiniana IPR 7104 fue la heterotrófica, la cual mostró la mayor actividad enzimática, consecuentemente un menor contenido de lactosa residual. En condiciones heterótrofas (sin luz), la actividad de la β-galactosidasa aumentó linealmente hasta el octavo día. La producción de biomasa creció linealmente el día 12. Las microalgas consumieron el 89,6% de lactosa en 3 días, mostrando una alta capacidad para metabolizar este disacárido, a través de la síntesis de β-galactosidasa. La producción máxima de β-galactosidasa por Chlorella sorokiniana IPR 7104, en condiciones heterótrofas y utilizando suero de queso como fuente de carbono, se obtiene utilizando las siguientes condiciones: temperatura 30 ° C, concentración de etanol al 20% y tiempo de 4 min. Os processos biotecnológicos com microalgas com o objetivo de alcançar elevados rendimentos de biomassa devem escolher os nutrientes e parâmetros físico-químicos adequados, tendo em conta as características específicas de cada espécie para determinar as necessidades básicas para o seu crescimento. No presente estudo, a melhor condição de crescimento de Chlorella sorokiniana IPR 7104 foi otimizada para atingir a produção máxima de beta-galactosidase. A concentração de soro de queijo (%), temperatura (˚C) e pH foram fatores investigados e um delineamento de Box-Behnken Design (BBD) foi conduzido usando o software Statistica 7.0. Observamos que a condição de cultivo para Chlorella sorokiniana IPR 7104 foi a heterotrófica, que apresentou maior atividade enzimática, conseqüentemente menor teor de lactose residual. Em condições heterotróficas (sem luz) a atividade da β-galactosidase aumentou linearmente até o 8º dia. A produção de biomassa cresceu linearmente no 12º dia. A microalga consumiu 89,6% da lactose em 3 dias, apresentando alta capacidade de metabolizar esse dissacarídeo, por meio da síntese de β-galactosidase. A produção máxima de β-galactosidase por Chlorella sorokiniana IPR 7104, em condições heterotróficas e utilizando soro de queijo como fonte de carbono, é obtida nas seguintes condições: temperatura de 30 °C, concentração de etanol a 20% e tempo de 4 min.

Resumo. O objetivo deste artigo é caracterizar a dinâmica da formação de redes de Pesquisa, Desenvolvimento e Inovação (PD&I) e identificar as principais fontes de atritos e custos de transação relacionados aos processos envolvidos na articulação de Parcerias Público-Privadas (PPP) pela Embrapa Informática Agropecuária. A coleta de dados sobre os processos relativos à PPP da Embrapa foi realizada por meio de pesquisa documental e visitas in loco. Foram identificadas quatro etapas para que a PPP seja formalizada: (i) articulação das parcerias (proposição e submissão de projetos); (ii) implementação/celebração; (iii) gestão e acompanhamento; e (iv) prestação de contas e resultados. Nas duas primeiras etapas, os custos de transação envolvidos são do tipo ex ante. Já na terceira e quarta, são de caráter ex post. Além de descrever os custos e avaliá-los como altos ou baixos, o artigo apresenta iniciativas recentes de aprimoramentos para minimizá-los em âmbito macro, meso e micro institucional. Made available in DSpace on 2022-01-05T15:00:30Z (GMT). No. of bitstreams: 1 ART21104.pdf: 328898 bytes, checksum: a5fa5e7432853a53486ade8403c189f8 (MD5) Previous issue date: 2020 Transaction costs related to the management of public-private partnership networks: case study of brazilian agricultural research institution.

Introduction: Patients with myelodysplastic syndromes (MDS) experience severe anemia, which is commonly managed with frequent red blood cell transfusions (RBCT) in patients refractory to erythropoiesis-stimulating agents. At diagnosis, 85% of patients have anemia and 30-50% depend on RBCT. The administration of RBCT itself provides transient relief in anemia-related symptoms. Per protocol, MEDALIST investigators were advised to transfuse for symptoms related to anemia at the investigators' discretion. Hence, cessation or reduction of RBCT may increase anemia-related symptoms and negatively impact health-related quality of life (HRQoL). Luspatercept is a first-in-class erythroid maturation agent providing clinically meaningful reduction in transfusion burden in patients with transfusion-dependent anemia due to Revised International Prognostic Scoring System (IPSS-R)-defined Very low-, Low-, or Intermediate-risk MDS with ring sideroblasts in the phase 3 MEDALIST trial (NCT02631070). However, the impact of luspatercept on patients' HRQoL has not been evaluated. This analysis aimed to evaluate the effect of luspatercept versus placebo on HRQoL of patients treated for MDS from baseline through Week 25 of the MEDALIST study. Methods: Patients received luspatercept or placebo every 3 weeks for 24 weeks, plus best supportive care (BSC), including tailored amounts of RBCT. Effects of luspatercept versus placebo on HRQoL were evaluated as secondary and exploratory endpoints in the MEDALIST study. In the primary analysis, mean change from baseline to Week 25 (clinical assessment visit) in the European Organisation for Research and Treatment of Cancer's core quality of life questionnaire, version 3.0 (EORTC QLQ-C30) and in the QoL assessment in MDS questionnaire (QOL-E) was determined using mixed-effects repeated measures analysis. Clinically meaningful change within each treatment arm was defined as a ≥ 10-point change in patient-reported outcome (PRO) score from baseline for all EORTC QLQ-C30 domains, and ≥ 0.5 standard deviation of the baseline domain score for all QOL-E domains. Differences between luspatercept and placebo were considered clinically meaningful if the change from baseline between treatment arms exceeded the threshold for a clinically meaningful difference. In an exploratory analysis, patient-reported impact of transfusion dependence and overall side effects on their daily life was estimated using the QOL-E instrument. Results: A total of 229 patients were randomized; 153 patients to luspatercept and 76 to placebo. The HRQoL-evaluable population, consisting of patients with ≥ 1 post-baseline HRQoL score, was 149 patients in the luspatercept arm and 76 patients in the placebo arm. Questionnaire compliance rates among patients remaining on treatment were similar between luspatercept and placebo treatment groups at Week 25 (EORTC QLQ-C30, 88.2% vs 79.4% and QOL-E, 72.5% vs 69.7%). At baseline, MEDALIST patients had a clinically meaningfully worse HRQoL compared with the general population in 5 of 15 EORTC QLQ-C30 domains: physical functioning, role functioning, social functioning, fatigue, and dyspnea. Through Week 25, there was no clinically meaningful difference in change from baseline between and within the luspatercept and placebo arms across all EORTC QLQ-C30 (Global health status shown in Figure A) and QOL-E domains. A greater proportion of patients in the luspatercept arm relative to placebo reported improvements in daily life from the impact of transfusion burden (Figure B). Relative to baseline, the proportion of patients reporting a lower impact of transfusion dependence on their daily life was 39% versus 22% in luspatercept versus placebo at Week 25; in contrast, the proportion of patients reporting a higher impact of transfusion dependence on their daily life was 12% versus 22% in luspatercept versus placebo. Impact of treatment side effects on patients was comparable between luspatercept and placebo. Conclusions: Luspatercept with BSC reduced RBCT burden and patient-reported transfusion impact on their daily life, while maintaining other aspects of HRQoL from baseline through Week 25 in the MEDALIST study. Disclosures Oliva: Alexion: Consultancy; BMS: Consultancy, Honoraria, Patents & Royalties, Speakers Bureau; Novartis: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Apellis: Consultancy. Platzbecker:Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding. Mufti:BMS, Novartis: Research Funding; Abbvie, Novartis: Consultancy. Santini:Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Acceleron, BMS, Menarini, Novartis: Consultancy; BMS, J&J, Novartis: Honoraria. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Komrokji:BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Guo:BMS: Consultancy. Zhang:BMS: Current Employment. Ha:Bristol Myers Squibb: Current Employment. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Lord-Bessen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Fenaux:Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Introduction: Patients (pts) with MDS/MPN-RS-T have limited treatment options for anemia due to ineffective erythropoiesis. Luspatercept, the first-in-class erythroid maturation agent that enhances late-stage erythropoiesis, is approved by the FDA for treatment of anemia in adult pts with lower-risk (LR) MDS with ring sideroblasts (RS) or MDS/MPN-RS-T after erythroid-stimulating agent (ESA) failure. In the randomized, double-blind, phase 3 MEDALIST study, luspatercept significantly reduced transfusion burden vs placebo in pts with LR-MDS (NCT02631070; Fenaux P, et al. N Engl J Med 2020;382:140-51). Here, we assess the efficacy and safety of luspatercept in pts with MDS/MPN-RS-T enrolled in the MEDALIST study. Methods: Eligible pts were ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs (serum erythropoietin > 200 U/L); and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or placebo administered subcutaneously every 3 wks. The primary endpoint was achievement of RBC transfusion independence (RBC-TI) ≥ 8 wks during Wks 1-24. Results: A retrospective analysis identified 23/229 (10.0%) pts enrolled in the MEDALIST trial who had MDS/MPN-RS-T, per WHO 2016 criteria (Arber DA, et al. Blood 2016;127:2391-405); 14 received luspatercept and 9 received placebo. Pts in this subgroup received a median of 4.0 RBC units/8 wks (range 2.0-11.5) during the 16 wks prior to treatment. At baseline, pts had a median hemoglobin (Hb) level of 7.7 g/dL (range 7.0-9.0), a median leukocyte count of 5.1 × 109/L, a median platelet count of 447.0 × 109/L, and 18 (78.3%) pts had serum erythropoietin levels < 200 U/L (Table). In the luspatercept arm, 9/14 (64.3%) pts with MDS/MPN-RS-T achieved the primary endpoint of RBC-TI for ≥ 8 wks during Wks 1-24, compared with 2/9 pts (22.2%) receiving placebo (odds ratio 11.3; 95% confidence interval [CI] 1.19, 106.12; P = 0.028). Pts receiving luspatercept were significantly more likely to achieve clinical benefit (achieving RBC-TI ≥ 8 wks and/or modified hematologic improvement-erythroid [mHI-E] per IWG 2006 criteria [≥ 4 units/8 wks reduction in RBC transfusion in pts with ≥ 4 units/8 wks baseline RBC transfusion burden; Hb increase by ≥ 1.5 g/dL] during Wks 1-24 in pts with < 4 units/8 wks baseline RBC transfusion burden), compared with pts receiving placebo (78.6% vs 33.3%; P = 0.034). Median time from the start of clinical benefit response to end of treatment was 94.6 wks (range 8.0-150.0) in the luspatercept arm and 23.9 wks (range 23.7-57.9) in the placebo arm. During Wks 1-24, mHI-E was achieved by 10 luspatercept pts (6 were high transfusion burden [HTB; defined as baseline transfusion burden ≥ 4 units/8 wks] and 4 were low transfusion burden [LTB; defined as baseline transfusion burden < 4 units/8 wks]) and 1 placebo pt (1/5 HTB). RBC-TI ≥ 8 wks was achieved by 4/8 HTB pts receiving luspatercept (vs 0/5 placebo) and 5/6 LTB pts (vs 2/4 placebo). After 24 wks, pts in the luspatercept arm had a mean Hb increase of +1.7 g/dL compared with an increase of +0.9 g/dL in pts in the placebo arm (least squares [LS] mean difference +0.85 g/dL; 95% CI −1.13, +2.82). Greater reductions from baseline in mean serum ferritin levels were seen with luspatercept (−121.8 μg/L) compared with placebo (−91.9 μg/L) over Wks 9-24 (LS mean difference −90.1; 95% CI −758.4, 578.2). Pts in the luspatercept arm had median platelet counts of 467.5 × 109/L and median leukocyte counts of 6.5 × 109/L post 24 wks of treatment, compared with pts in the placebo arm with 514.0 × 109/L and 6.2 × 109/L, respectively. The incidence of specific TEAEs (occurring in ≥ 1 patient) are as follows: fatigue (1/14 [7.1%] luspatercept vs 1/9 [11.1%] placebo), dizziness (7/14 [50.0%] vs 0/9), dyspnea (3/14 [21.4%] vs 0/9), nausea (6/14 [42.9%] vs 2/9 [22.2%]), arthralgia (1/14 [7.1%] vs 0/9), diarrhea (6/14 [42.9%] vs 1/9 [11.1%]), and hypertension (3/14 [21.4%] vs 0/9). In the luspatercept arm, 1/14 (7.1%) pts experienced ≥ 1 thromboembolic event (transient ischemic attack) and 1/9 (11.1%) pts in the placebo arm progressed to AML (as of July 1, 2019). Conclusions: Luspatercept demonstrated clinical efficacy in pts with MDS/MPN-RS-T with a generally well-tolerated safety profile. These data support the clinical benefits of luspatercept in this patient population with otherwise limited treatment options. Disclosures Komrokji: Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Platzbecker:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Fenaux:BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mufti:Abbvie, Novartis: Consultancy; BMS, Novartis: Research Funding. Santini:Janssen: Research Funding; BMS, J&J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Finelli:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Jurcic:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Research Funding; Astellas: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Kura Oncology: Research Funding; PTC Therapeutics: Research Funding. Greenberg:BMS: Research Funding; Aprea: Research Funding; Notable Labs: Research Funding; H3 Biotech: Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zeidan:Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Leukemia and Lymphoma Society: Other; CCITLA: Other; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; Agios: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. DeZern:Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy; Abbvie: Consultancy. Savona:Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Ryvu: Consultancy; Boehringer Ingelheim: Patents & Royalties; Astex: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:BMS: Current Employment. Ha:BMS: Current Employment. Sinsimer:BMS: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; Medpacto: Research Funding; stelexis: Current equity holder in private company.

In this study, we investigated the outdoor production of a microalga C. vulgaris cultured in two different media under autotrophic cultivation: Bold Basal Medium (BBM) as the control and BBM supplemented with desalination concentrate (BBM + DC) using open raceway ponds (8 m2). Data were collected on the growth, biomass productivity and biochemical composition. The culture developed in BBM + DC showed a biomass productivity of 6.8 g m-2 day-1, while for the BBM control it was 8.5 g m-2 day-1. Intracellular protein was the main algal component (~28.6%), followed by carbohydrate + fiber (~26.0%) and lipids (~5.0%). The predominant fatty acids were mainly α-linolenic (~19.5%), palmitic (~16.5%) and linoleic (~10.0%) acids. This study demonstrates the feasibility of culturing C. vulgaris in an alternative medium based on DC in order to valorize the desalination wastewater through its application to algal mass production.

This chapter presents general aspects regarding microalgae biology and growth under ex situ conditions. Emphasis is given on some aspects of microalgae responses to major environmental and nutritional factors, for example, temperature, light, nutrients, and pH. Then, management of photobioreactor systems where microalgae are grown to achieve the objectives of producing high biomass and bioactive compounds for biotechnological applications is addressed. The feasibility of producing multiproducts has led to more efficient production pathways and use of materials and energy. Most of the studies about microalgae are addressed in an interrelated way with environment and agricultural applications.

RESUMEN Se evaluó el efecto de la temperatura sobre la desnaturalización de proteínas y la reacción de Maillard en leche entera y descremada con lactosa hidrolizada. Las leches hidrolizadas se trataron térmicamente a 100, 110, 120 y 130 °C durante un período de 1 hora y se midió la concentración de glucosa, el grado de pardeamiento y la desnaturalización de proteínas. El grado de dorado en la leche entera varió de 14.4 (100 °C) a 42.6 (130 °C). Para la leche descremada fue de 20.2 (100 °C) a 38.0 (130 °C). La concentración de glucosa en leche entera (47% p/v) y en leche descremada (41% p/v) después del tratamiento térmico (130 °C) mostró una reducción significativa en relación con el control (25 °C). El efecto de la temperatura en la desnaturalización de proteínas en leche entera y descremada en relación con el control (25 °C) fue del 100%. La leche tratada térmicamente con lactosa hidrolizada promovió la desnaturalización de proteínas con un aumento del pardeamiento característico de la reacción de Maillard, lo que afectó la calidad nutricional. ABSTRACT The effect of temperature in protein denaturation and Maillard reaction in whole and skim milk with hydrolyzed lactose was evaluated. Hydrolyzed milk was thermally treated at 100, 110, 120 and 130 °C over a period of 1 hour and glucose concentration, browning degree and protein denaturation were measured. The browning degree in whole milk varied from 14.42 (100 °C) to 42.63 (130 °C) and 20.21 (100 °C) to 38.03 (130 °C) in skim milk. Glucose concentration in whole milk (47% - w/v) and skim milk (41% - w/v) after heat treatment (130 °C) showed a significant reduction in relation to the control (25 °C). The temperature effect in protein denaturation in whole and skim milk in relation to the control (25 °C) was 100%. Thermally treated milk with hydrolyzed lactose promoted protein denaturation with increasing browning characteristic of the Maillard reaction, thus affecting the nutritional quality.

Cheese whey is presented as an alternative for the production of ethanol to be a major source for growth of microorganisms, which catalyze lactose directly to ethanol and other products. Thus the aims of this study were to analyze the influence of nutrients in the cheese whey (15%w/v) fermentation by Saccharomyces fragilis IZ 275, to estimate the ethanol production and verify the repetition of the results of fermentation on a laboratory and pilot scale. Based on the results the nutrients, ammonium sulphate and yeast extract showed no significant difference at 5%, however, a positive ethanol productioin of 5.07% (w/v) and 5.43% (w/v), in laboratory and pilot scale, was respectively observed. In both kinetics, the ethanol yields were 5.6% (v/v), demonstrating that the use of deproteinized cheese whey for industrial fermentations is possible due to repetition of the results from laboratory to pilot scale, presenting as a way to reduce the pollution potential of this by-product, and at the same time to obtain value-added product. Key words: Microorganism biotechnology, industrial whey, bioethanol fermentation, nutrients sources, hydrolysis.

Background: MEDALIST ( NCT02631070 ) is a randomized, placebo-controlled, phase 3 trial evaluating efficacy and safety of luspatercept in patients with anemia due to LR-MDS with RS. Aims: To evaluate long-term transfusion burden reduction with luspatercept in MEDALIST trial patients. Methods: Patients were aged ≥18 years; had IPSS-R-defined LR-MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs; and required RBC transfusions (≥2 units/8 weeks in the 16 weeks before randomization). Two hundred twenty-nine patients were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or placebo subcutaneously every 3 weeks. Results: As of 1 July 2019, 77/153 (50.3%) and 11/76 (14.5%) patients receiving luspatercept and placebo, respectively, achieved ≥50% RBC transfusion burden reduction over at least 24 weeks versus baseline (P Conclusions: Luspatercept demonstrated clinical efficacy in patients with LR-MDS with RS and was associated with significant reductions in RBC transfusions (≥50%) and serum ferritin.

Background: A significant proportion of patients in the MEDALIST trial (randomized, placebo-controlled, phase 3 study evaluating luspatercept, an erythroid maturation agent, for treatment of anemia in LR-MDS patients) achieved RBC transfusion independence (RBC-TI) ≥ 8 weeks (Weeks 1–24) ( NCT02631070 ). Aims: To evaluate the effect of luspatercept dose on efficacy and treatment-emergent adverse events (TEAEs). Methods: Of 229 eligible patients (IPSS-R LR-MDS with RS; age ≥ 18 years; unsatisfactory response to or ineligible for EPO-based therapy; regular RBC transfusions), 153 received luspatercept, starting at 1.0 mg/kg, subcutaneously every 3 weeks. Dose titration to 1.33 and 1.75 mg/kg was allowed in the absence of RBC-TI after ≥2 doses at the same dose level. Dose reductions/delays were used to manage excessive hemoglobin increase and safety. Response was defined as RBC-TI ≥ 8 weeks during Weeks 1–48. Results: As of May 8, 2018, 35 (22.9%), 28 (18.3%), and 90 (58.8%) patients received a maximum dose of 1.0, 1.33, and 1.75 mg/kg, respectively. Median time to dose escalation to 1.33 or 1.75 mg/kg in patients achieving RBC-TI ≥8 weeks was approximately twice (105 and 171 days) that of non-responders (43 and 91 days). Of the 69 luspatercept-treated responders, 47 (68.1%) achieved their first response at 1.0 mg/kg, 5 (7.2%) at 1.33 mg/kg, and 7 (10.1%) at 1.75 mg/kg. The majority of patients with baseline transfusion burden ≤ 6 units/8 weeks were responders (63/108; 58.3%). Of these 63 patients, the maximum dose was 1.0 mg/kg in 24 (38.1%) patients, 1.33 mg/kg in 14 (22.2%), and 1.75 mg/kg in 25 (39.7%); first response occurred at 1.0 mg/kg in 47 (74.6%) patients, at 1.33 mg/kg in 2 (3.2%), and at 1.75 mg/kg in 5 (7.9%); 9 patients received luspatercept at ≥2 dose levels during first response. As of July 1, 2019, 74 (48.4%) and 9 (5.9%) luspatercept-treated patients experienced ≥1 dose delay and ≥1 dose reduction, respectively. New onset of luspatercept-related TEAEs generally did not increase with dose increases from 1.0–1.75 mg/kg. Conclusions: The dose range of 1.0–1.75 mg/kg was well tolerated in LR-MDS patients. Dose escalations contributed to maintenance of response or achievement of multiple response episodes.