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El mieloma múltiple es una enfermedad neoplásica que constituye aproximadamente el 10% de todos los tumores hematológicos y el 1,8% de todas las neoplasias. Se caracteriza por la proliferación clonal de células plasmáticas patológicas, acumuladas principalmente en MO, enfermedad lítica ósea y una severa inmunosupresión, sobre todo en etapas avanzadas de la enfermedad. A pesar de los avances en el tratamiento del mieloma en la última década, el MM sigue siendo una enfermedad incurable, donde la mayoría de pacientes recaen con periodos de respuesta cada vez más cortos. Por esta razón, existe la necesidad de encontrar nuevas opciones terapéuticas basadas en distintos mecanismos de acción para superar este escenario de recaídas y refractariedad a los tratamientos actuales.La terapia T CAR autóloga es una terapia innovadora que ha logrado resultados impresionantes en neoplasias de células B, incluido MM/RR, que ha llevado a la aprobación de dos productos en el mercado. La experiencia con células T CAR comerciales revelan limitaciones como toxicidades graves, producción larga y costosa, y con un control de la enfermedad subóptimo en muchos pacientes. Por otra parte, pacientes que recaen a las terapias aprobadas T CAR BCMA no tienen muchas más opciones terapéuticas. Por tanto, se requieren estrategias alternativas o secuenciales a las terapias T CAR BCMA. Las células NK-CAR emergen como un abordaje terapéutico a menor coste y mucho más seguro, sin generar EICH, citopenias prolongadas, CRS o neurotoxicidades graves..., Multiple myeloma is a neoplastic disease that constitutes approximately 10% of all hematologic tumors and 1.8% of all neoplasms. It is characterized by clonal disease of pathological plasma cells, accumulated mainly in bone marrow, lytic bone lesions, and severe immunosuppression, especially in advanced stages of the disease. Despite advances in the treatment of myeloma in the last decade, MM remains incurable, where most patients relapse with increasingly shorter response periods. For this reason, there is an unmet need to find new therapeutic options based on different mechanisms of action to overcome this scenario of relapses and refractoriness to current treatments.Autologous CAR T therapy is an innovative therapy that has achieved impressive results in B-cell neoplasms, including RR/MM, leading to the approval of two products on the market. Experience with commercial CAR T cells reveals limitations such as severe toxicities, time-consuming and expensive production, and suboptimal disease control in many patients. On the other hand, patients receiving the approved BCMA CAR T therapies do not have many other therapeutic options. Therefore, alternative or sequential strategies to BCMA CAR T therapies are required. CAR NK cells are emerging as a lower cost and much safer therapeutic approach, without generating GVHD, prolonged cytopenias, CRS or severe neurotoxicity...

El mieloma múltiple (MM) es una neoplasia caracterizada por la proliferación clonal de células plasmáticas patológicas, principalmente en la médula ósea. constituye el 10% de los todos los tumores hematológicos y el 1,8% de todas las neoplasias. La sintomatología clásica se engloba en las siglas CRAB, hipercalcemia, fallo renal, anemia y enfermedad lítica ósea..., Multiple myeloma (MM) is a neoplasm characterized by the clonal proliferation of pathologic plasma cells (PC), mainly in the bone marrow (BM). It constitutes 10% of hematologic tumors and 1,8% of all neoplasms. Classic symptomatology is included in CRAB acroyn, hypercalcemia, renal failure, anemia and bone lytic lesions...

The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease., Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Universidad de Sevilla, Junta de Andalucía, Universidad Complutense de Madrid, Depto. de Química Orgánica, Fac. de Ciencias Químicas, TRUE, pub

This HEMATO-MADRID COVID-19 study assessed COVID-19 outcomes in 1818 hematologic cancer patients from February 2020 to October 2022 across different phases, including the Omicron period. Severe cases were more common in patients over 70 years with comorbidities or chronic lymphocytic leukemia. However, during the Omicron period, rates of severe illness reduced notably, especially among vaccinated individuals. Hospitalization, intensive care admissions, and overall mortality decreased in the Omicron phase compared to pre-Omicron, yet mortality rates in hospitalized patients remained high. Older age consistently correlated with higher mortality risk in both phases. Factors like prior stem cell transplantation, vaccination, and specific treatments were linked to improved survival rates among hematologic cancer patients facing COVID-19., A greater understanding of clinical trends in COVID-19 outcomes among patients with hematologic malignancies (HM) over the course of the pandemic, particularly the Omicron era, is needed. This ongoing, observational, and registry-based study with prospective data collection evaluated COVID-19 clinical severity and mortality in 1818 adult HM patients diagnosed with COVID-19 between 27 February 2020 and 1 October 2022, at 31 centers in the Madrid region of Spain. Of these, 1281 (70.5%) and 537 (29.5%) were reported in the pre-Omicron and Omicron periods, respectively. Overall, patients aged ≥70 years (odds ratio 2.16, 95% CI 1.64–2.87), with >1 comorbidity (2.44, 1.85–3.21), or with an underlying HM of chronic lymphocytic leukemia (1.64, 1.19–2.27), had greater odds of severe/critical COVID-19; odds were lower during the Omicron BA.1/BA.2 (0.28, 0.2–0.37) or BA.4/BA.5 (0.13, 0.08–0.19) periods and among patients vaccinated with one or two (0.51, 0.34–0.75) or three or four (0.22, 0.16–0.29) doses. The hospitalization rate (75.3% [963/1279], 35.7% [191/535]), rate of intensive care admission (30.0% [289/963], 14.7% [28/191]), and mortality rate overall (31.9% [409/1281], 9.9% [53/536]) and in hospitalized patients (41.3% [398/963], 22.0% [42/191]) decreased from the pre-Omicron to Omicron period. Age ≥70 years was the only factor associated with higher mortality risk in both the pre-Omicron (hazard ratio 2.57, 95% CI 2.03–3.25) and Omicron (3.19, 95% CI 1.59–6.42) periods. Receipt of prior stem cell transplantation, COVID-19 vaccination(s), and treatment with nirmatrelvir/ritonavir or remdesivir were associated with greater survival rates. In conclusion, COVID-19 mortality in HM patients has decreased considerably in the Omicron period; however, mortality in hospitalized HM patients remains high. Specific studies should be undertaken to test new treatments and preventive interventions in HM patients., Depto. de Medicina, Fac. de Medicina, TRUE, pub, Descuento UCM

En un contexto de creciente escasez, el nuevo paradigma en la gestión eficiente del agua se apoya en la digitalización de las infraestructuras hidráulicas con objeto de optimizar la gestión del recurso en todas sus posibles dimensiones. Uno de los factores claves para afrontar los nuevos retos que deben afrontar las empresas del ciclo urbano del agua es la escasez de personal técnico cualificado. La formación profesional está llamada a desempeñar un papel fundamental en proporcionar una formación de calidad actualizada técnicamente y alineada con las necesidades de los sectores productivos y de servicios buscando para ello el diálogo y la colaboración con las empresas. Esta misión conlleva la adopción de estrategias y métodos de enseñanza-aprendizaje innovadores y la elaboración de recursos didácticos novedosos. En este artículo se presenta el proyecto Digital Water Learning Hub cuyo objeto es generar una plataforma en la nube que permita al alumnado de formación profesional el manejo y operación de plantas piloto físicas en remoto simulando un telecontrol como recurso para la adquisición de competencias en digitalización del agua. El proyecto propuesto por el IES Beatriu Fajado de Mendoza, el Institut Pere Martell con la colaboración de la empresa Fomento Agrícola de Castellón, SA (FACSA) ha sido seleccionado en la convocatoria de ayudas destinadas a la realización de proyectos de innovación e investigación aplicadas y transferencia del conocimiento en la formación profesional en el año 2023.

This phase Ib, non-randomized, open-label study evaluates the safety and tolerability of ruxolitinib in combination with nilotinib and prednisone in patients with naïve or ruxolitinib-resistant myelofibrosis (MF). A total of 15 patients with primary or secondary MF received the study treatment; 13 patients had received prior ruxolitinib treatment (86.7%). Eight patients completed seven cycles (53.3%) and six patients completed twelve cycles of treatment (40%). All the patients experienced at least one adverse event (AE) during the study (the most common AEs were hyperglycemia, asthenia, and thrombocytopenia), and 14 patients registered at least one treatment-related AE (the most common treatment-related AEs were hyperglycemia (22.2%; three grade 3 cases). Five treatment-related serious AEs (SAEs) were reported in two patients (13.3%). No deaths were registered throughout the study. No dose-limiting toxicity was observed. Four out of fifteen (27%) patients experienced a 100% spleen size reduction at Cycle 7, and two additional patients achieved a >50% spleen size reduction, representing an overall response rate of 40% at Cycle 7. In conclusion, the tolerability of this combination was acceptable, and hyperglycemia was the most frequent treatment-related AE. Ruxolitinib in combination with nilotinib and prednisone showed relevant clinical activity in patients with MF. This trial was registered with EudraCT Number 2016-005214-21., Instituto de Salud Carlos III (España), Instituto de Investigación Hospital 12 de Octubre (España), Centro de Investigación Biomédica en Red de Cáncer, Novartis, Depto. de Medicina, Fac. de Medicina, TRUE, pub, Descuento UCM

The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease.

Subsets of multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS) present with a monoclonal immunoglobulin specific for hepatitis C virus (HCV), thus are presumably HCV-driven, and antiviral treatment can lead to the disappearance of antigen stimulation and improved control of clonal plasma cells. Here we studied the role of hepatitis B virus (HBV) in the pathogenesis of MGUS and MM in 45 HBV-infected patients with monoclonal gammopathy. We analysed the specificity of recognition of the monoclonal immunoglobulin of these patients, and validated the efficacy of antiviral treatment (AVT). For 18/45 (40%) HBV-infected patients, the target of the monoclonal immunoglobulin was identified: the most frequent target was HBV (n=11), followed by other infectious pathogens (n=6), and glucosylsphingosine (n=1). Two patients whose monoclonal immunoglobulin targeted HBV (HBx and HBcAg), implying that their gammopathy was HBV-driven, received AVT and the gammopathy did not progress. AVT efficacy was then investigated in a large cohort of HBV-infected MM patients (n=1367), who received anti-HBV treatments, or not, and compared to a cohort of HCV-infected MM patients (n=1220). AVT significantly improved patient probability of overall survival (p=0.016 for the HBV-positive cohort, p=0.005 for the HCV-positive cohort). Altogether, MGUS and MM disease can be HBV- or HCV-driven in infected patients, and the study demonstrates the importance of antiviral treatment in such patients., Ligue Nationale contre le Cancer, Spanish Society of Hematology, Depto. de Bioquímica y Biología Molecular, Fac. de Farmacia, TRUE, pub

In cases of treatment failure in acute myeloid leukemia (AML), the utility of mutational profiling in primary refractoriness and relapse is not established. We undertook a perspective study using next-generation sequencing (NGS) of clinical follow-up samples (n=91) from 23 patients with AML with therapeutic failure to cytarabine plus idarubicin or fludarabine. Cases of primary refractoriness to treatment were associated with a lower number of DNA variants at diagnosis than cases of relapse (median 1.67 and 3.21, respectively, p=0.029). The most frequently affected pathways in patients with primary refractoriness were signaling, transcription and tumor suppression, whereas methylation and splicing pathways were mainly implicated in relapsed patients. New therapeutic targets, either by an approved drug or within clinical trials, were not identified in any of the cases of refractoriness (0/10); however, 8 potential new targets were found in 5 relapsed patients (5/13) (p=0.027): 1 IDH2, 3 SF3B1, 2 KRAS, 1 KIT and 1 JAK2. Sixty-five percent of all variants detected at diagnosis were not detected at complete response (CR). Specifically, 100% of variants in EZH2, RUNX1, VHL, FLT3, ETV6, U2AF1, PHF6 and SF3B1 disappeared at CR, indicating their potential use as markers to evaluate minimal residual disease (MRD) for follow-up of AML. Molecular follow-up using a custom NGS myeloid panel of 32 genes in the post-treatment evaluation of AML can help in the stratification of prognostic risk, the selection of MRD markers to monitor the response to treatment and guide post-remission strategies targeting AML, and the selection of new drugs for leukemia relapse., Instituto de Salud Carlos III, CRIS against Cancer foundation, Spanish Ministry of Economy and Competitiveness, Depto. de Bioquímica y Biología Molecular, Fac. de Farmacia, TRUE, pub

Purpose: The gut microbiota plays important roles in health and disease. We questioned whether the gut microbiota and related metabolites are altered in monoclonal gammopathies and evaluated their potential role in multiple myeloma and its response to treatment. Experimental Design: We used 16S rRNA sequencing to characterize and compare the gut microbiota of patients with monoclonal gammopathy of undetermined significance (n ¼ 11), smoldering multiple myeloma (n ¼ 9), newly diagnosed multiple myeloma (n ¼ 11), relapsed/refractory multiple myeloma (n ¼ 6), or with complete remission (n ¼ 9). Short-chain fatty acids (SCFA) were quantified in serum and tested in cell lines. Relevant metabolites were validated in a second cohort of 62 patients. Results: Significant differences in alpha- and beta diversity were present across the groups and both were lower in patients with relapse/refractory disease and higher in patients with complete remission after treatment. Differences were found in the abundance of several microbiota taxa across disease progression and in response to treatment. Bacteria involved in SCFA production, including Prevotella, Blautia, Weissella, and agathobacter, were more represented in the premalignant or complete remission samples, and patients with higher levels of Agathobacter showed better overall survival. Serum levels of butyrate and propionate decreased across disease progression and butyrate was positively associated with a better response. Both metabolites had antiproliferative effects in multiple myeloma cell lines. Conclusions: We demonstrate that SCFAs metabolites and the gut microbiota associated with their production might have beneficial effects in disease evolution and response to treatment, underscoring its therapeutic potential and value as a predictor., MCIN/AEI/10.13039/501100011033, Ministry of Science, Innovation and Universities of Spain, Instituto de Investigación Hospital 12 de Octubre, CIBERONC, AECC, Sociedad Espanola de Hematología y Hemoterapia, Depto. de Bioquímica y Biología Molecular, Fac. de Farmacia, TRUE, pub

Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and serine-arginine-rich (SR) proteins phosphorylation were altered during cytarabine resistance. Moreover, phosphorylation of SR proteins at diagnosis were significantly lower in responder than non-responder patients, pointing to their utility to predict response. These changes correlated with altered transcriptomic profiles of SR protein target genes. Notably, splicing inhibitors were therapeutically effective in treating sensitive and resistant AML cells as monotherapy or combination with other approved drugs. H3B-8800 and venetoclax combination showed the best efficacy in vitro, demonstrating synergistic effects in patient samples and no toxicity in healthy hematopoietic progenitors. Our results establish that RNA splicing inhibition, alone or combined with venetoclax, could be useful for the treatment of newly diagnosed or relapsed/refractory AML., Depto. de Bioquímica y Biología Molecular, Fac. de Farmacia, TRUE, pub

Refractoriness to induction therapy and relapse after complete remission are the leading causes of death in patients with acute myeloid leukaemia (AML). This study focussed on the prediction of response to standard induction therapy and outcome of patients with AML using a combined strategy of mutational profiling by next-generation sequencing (NGS, n = 190) and ex vivo PharmaFlow testing (n = 74) for the 10 most widely used drugs for AML induction therapy, in a cohort of adult patients uniformly treated according to Spanish PETHEMA guidelines. We identified an adverse mutational profile (EZH2, KMT2A, U2AF1 and/or TP53 mutations) that carries a greater risk of death [hazard ratio (HR): 3 29, P < 0 0001]. A high correlation was found between the ex vivo PharmaFlow results and clinical induction response (69%). Clinical correlation analysis showed that the pattern of multiresistance revealed by ex vivo PharmaFlow identified patients with a high risk of death (HR: 2 58). Patients with mutation status also ran a high risk (HR 4 19), and the risk was increased further in patients with both adverse profiles (HR 4 82). We have developed a new score based on NGS and ex vivo drug testing for AML patients that improves upon current prognostic risk stratification and allows clinicians to tailor treatments to minimise drug resistance., Instituto de Salud Carlos III, CRIS against Cancer foundation, Spanish Ministry of Economy and Competitiveness, Depto. de Bioquímica y Biología Molecular, Fac. de Farmacia, TRUE, pub