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Cardiovascular and oncological diseases represent the global major causes of death. For both, a novel and far-reaching risk factor has been identified: clonal hematopoiesis (CH). CH is defined as clonal expansion of peripheral blood cells on the basis of somatic mutations, without overt hematological malignancy. The most commonly affected genes are TET2, DNMT3A, ASXL1 and JAK2. By the age of 70, at least 20-50% of all individuals carry a CH clone, conveying a striking clinical impact by increasing all-cause mortality by 40%. This is due predominantly to a nearly two-fold increase of cardiovascular risk, but also to an elevated risk of malignant transformation. Individuals with CH show not only increased risk for, but also worse outcomes after arteriosclerotic events, such as stroke or myocardial infarction, decompensated heart failure and cardiogenic shock. Elevated cytokine levels, dysfunctional macrophage activity and activation of the inflammasome suggest that a vicious cycle of chronic inflammation and clonal expansion represents the major functional link. Despite the apparently high impact of this entity, awareness, functional understanding and especially clinical implications still require further research. This review provides an overview of the current knowledge of CH and its relation to cardiovascular and hematological diseases. It focuses on the basic functional mechanisms in the interplay between atherosclerosis, inflammation and CH, identifies issues for further research and considers potential clinical implications.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/genética , Hematopoyesis Clonal/genética , Hematopoyesis/genética , Mutación , Inflamación/genéticaRESUMEN
Clinical research has resulted in an improvement of treatment options for patients with immune thrombocytopenia (ITP) over the last years. However, only few data exist on the real-life management of patients with ITP. To expand the knowledge, a multicenter, national survey was undertaken in 26 hematology practices distributed all over Germany. All patients with a diagnosis of ITP were documented using questionnaires, irrespective of the diagnosis date over a period of 2 years. Overall, data of 1023 patients were evaluated with 56% of patients being older than 60 years. Seventy-nine percent of the patients had chronic (> 12 months), 16% persistent (> 3-12 months), and 5% newly diagnosed (0-3 months) ITP. In 61% of cases, the disease lasted 3 or more years before survey documentation started. Main strategies applied as first-line therapy consisted of steroids in 45% and a "watch and wait" approach in 41% of patients. During second- and third-line strategies, treatment with steroids decreased (36% and 28%, respectively), while treatment modalities such as TPO-RAs increased (19% and 26%, respectively). As expected, patients with a low platelet count and thus a higher risk for bleeding and mortality received treatment (esp. steroids) more frequently during first line than those with a higher platelet count. Up to a third of patients were treated with steroids for more than a year. Overall, our study provides a cross-section overview about the current therapeutic treatment landscape in German ITP patients. The results will help to improve therapeutic management of ITP patients.
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Manejo de la Enfermedad , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/terapia , Encuestas y Cuestionarios , Adolescente , Adulto , Niño , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/sangre , Estudios Retrospectivos , Esplenectomía/tendencias , Esteroides/uso terapéutico , Adulto JovenRESUMEN
During the last decade, substantial advances have been made in the understanding of the complex molecular, immunological and cellular disturbances involved in the initiation as well as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient population, anemia is present at the time of diagnosis and is thus a major therapeutic challenge. High rates of primary resistance to erythropoiesis-stimulating agents (ESAs), the currently only approved standard therapy to treat anemia in lower-risk MDS, demand the development of novel and efficient drugs with a good safety profile. Luspatercept, a ligand trap of activin receptor II, is able to promote late stage erythropoiesis even in patients failing prior ESA treatment. The presence of ring sideroblastic phenotype defines a subgroup of patients with higher response rates. Additionally, recent developments in clinical research using HIF-1 or telomerase modulation by roxadustat or imetelstat are promising. Other areas of translational research involve targeting the inflammasome by anti-inflammatory drugs in order to improve anemia. These efforts will hopefully pave the way for new targeted treatment options for anemic low-risk MDS patients.
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Resistencia a Medicamentos , Hematínicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Animales , Terapia Combinada , Manejo de la Enfermedad , Hematínicos/administración & dosificación , Hematínicos/efectos adversos , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients. METHODS: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018. FINDINGS: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp≤0·3). With a median follow-up of 13 months (IQR 8·5-22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32-59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82-94; hazard ratio 6·6 [95% CI 3·7-11·8], p<0·0001). The most common (grade 3-4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment. INTERPRETATION: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes. FUNDING: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.
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Antimetabolitos Antineoplásicos/administración & dosificación , Azacitidina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Azacitidina/efectos adversos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Esquema de Medicación , Femenino , Alemania , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Neoplasia Residual , Nucleofosmina , Supervivencia sin Progresión , Estudios Prospectivos , Recurrencia , Medición de Riesgo , Factores de Riesgo , Factores de TiempoAsunto(s)
Anemia Macrocítica/genética , Mutación , Síndromes Mielodisplásicos/genética , Proteína Fosfatasa 2C/genética , Cariotipo Anormal , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Evolución Clonal , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Genes p53 , Humanos , Lenalidomida/farmacología , Lenalidomida/uso terapéutico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteína Fosfatasa 2C/fisiología , Estudios RetrospectivosRESUMEN
Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn's disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn's disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn's disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn's disease patients with "bone pain" and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.
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Enfermedad de Crohn/diagnóstico , Citocinas/sangre , Mediadores de Inflamación/sangre , Osteomielitis/diagnóstico , Adolescente , Algoritmos , Análisis de Varianza , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Juvenil/sangre , Artritis Juvenil/diagnóstico , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Enfermedad de Crohn/sangre , Diagnóstico Diferencial , Análisis Discriminante , Femenino , Humanos , Masculino , Naproxeno/uso terapéutico , Osteomielitis/sangre , Osteomielitis/tratamiento farmacológico , Valor Predictivo de las Pruebas , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoAsunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Lobos , Animales , Azacitidina , VorinostatRESUMEN
Recent developments in high-risk Myelodysplastic Neoplasms (HR MDS) treatment are confronted with challenges in study design due to evolving drug combinations with Hypomethylating Agents (HMAs). The shift from the International Prognostic Scoring System (IPSS) to its molecular revision (IPSS-M) has notably influenced research and clinical practice. Introducing concepts like the MDS/AML overlap complicate classifications and including chronic myelomonocytic leukemia (CMML) in MDS studies introduces another layer of complexity. The International Consortium for MDS emphasizes aligning HR MDS criteria with the 2022 ELN criteria for AML. Differences in advancements between AML and MDS treatments and hematological toxicity in HR MDS underline the importance of detailed trial designs. Effective therapeutic strategies require accurate reporting of adverse events, highlighting the need for clarity in criteria like the Common Terminology Criteria for Adverse Events (CTCAE). We provide an overview on negative clinical trials in HR MDS, analyze possible reasons and explore possibilities to optimize future clinical trials in this challenging patient population.
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Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Síndromes Mielodisplásicos , Humanos , Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8+ CAR T cells is correlated to response, however persistence is not essential for durable remission in RRMM patients. In addition, our data provide evidence, that an increased fraction of CD8+ T cells at day of leukapheresis in combination with successful lymphodepletion positively influence the outcome. We show that patients at risk for higher-grade CRS can be identified already prior to lymphodepletion. Our extensive characterization contributes to a better understanding of the dynamics and effects of BCMA-targeting CAR T cells, in order to predict the response of individual patients as well as side effects, which can be counteracted at an early stage or even prevented.
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Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Mieloma Múltiple/tratamiento farmacológico , Linfocitos T CD8-positivos , Síndrome de Liberación de Citoquinas , Antígeno de Maduración de Linfocitos BRESUMEN
Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma.
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Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.
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The treatment landscape for multiple myeloma (MM) has experienced substantial progress over the last decade. Despite the efficacy of new substances, patient responses tend to still be highly unpredictable. With increasing cognitive burden that is introduced through a complex and evolving treatment landscape, data-driven assistance tools are becoming more and more popular. Model-based approaches, such as digital twins (DT), enable simulation of probable responses to a set of input parameters based on retrospective observations. In the context of treatment decision-support, those mechanisms serve the goal to predict therapeutic outcomes to distinguish a favorable option from a potential failure. In the present work, we propose a similarity-based multiple myeloma digital twin (MMDT) that emphasizes explainability and interpretability in treatment outcome evaluation. We've conducted a requirement specification process using scientific literature from the medical and methodological domains to derive an architectural blueprint for the design and implementation of the MMDT. In a subsequent stage, we've implemented a four-layer concept where for each layer, we describe the utilized implementation procedure and interfaces to the surrounding DT environment. We further specify our solutions regarding the adoption of multi-line treatment strategies, the integration of external evidence and knowledge, as well as mechanisms to enable transparency in the data processing logic. Furthermore, we define an initial evaluation scenario in the context of patient characterization and treatment outcome simulation as an exemplary use case for our MMDT. Our derived MMDT instance is defined by 475 unique entities connected through 438 edges to form a MM knowledge graph. Using the MMRF CoMMpass real-world evidence database and a sample MM case, we processed a complete outcome assessment. The output shows a valid selection of potential treatment strategies for the integrated medical case and highlights the potential of the MMDT to be used for such applications. DT models face significant challenges in development, including availability of clinical data to algorithmically derive clinical decision support, as well as trustworthiness of the evaluated treatment options. We propose a collaborative approach that mitigates the regulatory and ethical concerns that are broadly discussed when automated decision-making tools are to be included into clinical routine.
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Aberrant innate immune signaling has been identified as a potential key driver of the complex pathophysiology of myelodysplastic neoplasms (MDS). This study of a large, clinically and genetically well-characterized cohort of treatment-naïve MDS patients confirms intrinsic activation of inflammatory pathways in general mediated by caspase-1, interleukin (IL)-1ß and IL-18 in low-risk (LR)-MDS bone marrow and reveals a previously unrecognized heterogeneity of inflammation between genetically defined LR-MDS subgroups. Principal component analysis resolved two LR-MDS phenotypes with low (cluster 1) and high (cluster 2) levels of IL1B gene expression, respectively. Cluster 1 contained 14/17 SF3B1-mutated cases, while cluster 2 contained 8/8 del(5q) cases. Targeted gene expression analysis of sorted cell populations showed that the majority of the inflammasome-related genes, including IL1B, were primarily expressed in the monocyte compartment, consistent with a dominant role in determining the inflammatory bone marrow environment. However, the highest levels of IL18 expression were found in hematopoietic stem and progenitor cells (HSPCs). The colony forming activity of healthy donor HSPCs exposed to monocytes from LR-MDS was increased by the IL-1ß-neutralizing antibody canakinumab. This work reveals distinct inflammatory profiles in LR-MDS that are of likely relevance to the personalization of emerging anti-inflammatory therapies.
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Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Células Madre Hematopoyéticas/metabolismo , Médula Ósea/metabolismo , Transducción de Señal , Perfilación de la Expresión GénicaRESUMEN
Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we report how mis-splicing of coenzyme A synthase (COASY), induced by mutations in SF3B1, affects heme biosynthesis and erythropoiesis. Our data revealed that COASY was up-regulated during normal erythroid differentiation, and its silencing prevented the formation of erythroid colonies, impeded erythroid differentiation, and precluded heme accumulation. In patients with MDS-RS, loss of protein due to COASY mis-splicing led to depletion of both CoA and succinyl-CoA. Supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1mut cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the COASY pathway in erythroid maturation and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.
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Anemia , Síndromes Mielodisplásicos , Humanos , Eritropoyesis , Ácido Pantoténico , Calidad de Vida , Factores de Transcripción , Hemo , Factores de Empalme de ARN , FosfoproteínasRESUMEN
Myelodysplastic Syndrome (MDS) with del(5q) represents a unique WHO entity, which is often treated with lenalidomide according to standard clinical practice. Guidelines concerning treatment duration have thus far not been implemented, but rather comprise an indefinite therapy until loss of response. This review presents three red blood cell (RBC) transfusion-dependent MDS with del(5q) cases, starting with one rare case with an unbalanced translocation t(2;5), involving the breakpoint of del(5q) and loss of the 5q15-5q31 region. To the best of our knowledge, no comparable case has been described before with a response to lenalidomide. Strikingly, treatment-induced and maintained cytogenetic complete remission (cCR) in this patient. Furthermore, we report two cases of classical del(5q), in which lenalidomide was interrupted after a short period of lenalidomide therapy at the time cCR was achieved. Despite drug holiday cCR was maintained for seven and nine years, respectively. Then del(5q) re-emerged in the absence of novel molecular aberrations and re-treatment with lenalidomide could again achieve cCR in both cases. Together, this series presents three cases of personalized therapy of MDS with del(5q).
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The EUROPE phase 2 trial investigated the predictive value of biomarkers on the clinical efficacy of single agent romiplostim (ROM) treatment in patients with lower-risk myelodysplastic neoplasms (LR-MDS) and thrombocytopenia within the 'European Myelodysplastic Neoplasms Cooperative Group' (EMSCO) network. A total of 77 patients with LR-MDS and a median platelet count of 25/nl were included, all patients received ROM at a starting dose of 750 µg by SC injection weekly. Thirty-two patients (42%) achieved a hematologic improvement of platelets (HI-P) with a median duration of 340 days. Neutrophil (HI-N) and erythroid (HI-E) responses were observed in three (4%) and seven (9%) patients, respectively. We could not confirm previous reports that HI-P correlated with baseline endogenous thrombopoietin levels and platelet transfusion history, but SRSF2 mutation status and hemoglobin levels at baseline were significantly linked to HI-P. Sequential analysis of variant allelic frequency of mutations like SRSF2 did not reveal an impact of ROM on clonal evolution in both responders and non-responders. In summary, our study confirms the safety and efficacy of ROM in LR-MDS patients and may allow to better define subgroups of patients with a high likelihood of response.
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Síndromes Mielodisplásicos , Neoplasias , Biomarcadores , Hemoglobinas , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Neoplasias/tratamiento farmacológico , Receptores Fc/genética , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/genética , Trombopoyetina/uso terapéutico , Resultado del TratamientoRESUMEN
Luspatercept (Reblozyl) was recently approved for treating patients with transfusion-dependent lower-risk myelodysplastic syndrome (MDS) with ring sideroblasts (RS) and/or SF3B1 mutation who were not eligible for erythropoiesis-stimulating agents (ESAs) or patients for whom those agents failed. Luspatercept acts as an activin receptor type IIB fusion protein ligand trap that targets the altered transforming growth factor beta pathway in MDS, which is associated with impaired terminal erythroid maturation. Treatment with luspatercept results in decreased SMAD signaling, which enables erythroid maturation by means of late-stage erythroblast differentiation and thus improves anemia. ESAs, the current standard first-line therapeutic option for anemic lower-risk patients with MDS, also improve red cell parameters mainly by expanding proliferation of early erythroid progenitor cells. However, erythropoietin (EPO) and its receptor (EPO-R) are also required for survival of late-stage definitive erythroid cells, and they play an essential role in promoting proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. Thus, luspatercept joins the mechanism of ESAs in promoting erythroid maturation. Especially in the subgroup of MDS patients with RS, luspatercept showed high clinical activity for the treatment of anemia in the phase 2 (PACE-MDS) trial and subsequently in the phase 3 (MEDALIST) trial, which resulted in approval by both the US Food and Drug Administration and the European Medicines Agency in April 2020. Additional studies are needed to better understand the mechanism of action and pharmacodynamics of this novel agent in MDS.
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Eritropoyesis , Síndromes Mielodisplásicos , Receptores de Activinas Tipo II , Humanos , Fragmentos Fc de Inmunoglobulinas , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteínas Recombinantes de Fusión , Estados UnidosRESUMEN
Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia. Most patients with MDS are affected by anemia and anemia-related symptoms, which negatively impact their quality of life. While many patients with MDS have lower-risk disease and are managed by existing treatments, there currently is no clear standard of care for many patients. For patients with higher-risk disease, the treatment priority is changing the natural history of the disease by delaying disease progression to acute myeloid leukemia and improving overall survival. However, existing treatments for MDS are generally not curative and many patients experience relapse or resistance to first-line treatment. Thus, there remains an unmet need for new, more effective but tolerable strategies to manage MDS. Recent advances in molecular diagnostics have improved our understanding of the pathogenesis of MDS, and it is becoming clear that the diverse nature of genetic abnormalities that drive MDS demands a complex and personalized treatment approach. This review will discuss some of the challenges related to the current MDS treatment landscape, as well as new approaches currently in development.
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Necesidades y Demandas de Servicios de Salud/normas , Síndromes Mielodisplásicos/terapia , Evaluación de Necesidades/estadística & datos numéricos , Terapia Combinada , Humanos , Síndromes Mielodisplásicos/patologíaRESUMEN
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with heterogeneous presentation, ranging from indolent disease courses to aggressive diseases similar to acute myeloid leukemia (AML). Approximately 90% of MDS patients harbor recurrent mutations , which - with the exception of mutated SF3B1 -have not (yet) been included into the diagnostic criteria or risk stratification for MDS. Accumulating evidence suggests their utility for diagnostic workup, treatment indication and prognosis. Subsequently, in patients with unexplained cytopenia or dysplasia identification of these mutations may lead to earlier diagnosis. The acquisition and expansion of additional driver mutations usually antecedes further disease progression to higher risk MDS or secondary AML and thus, can be clinically helpful to detect individuals that may benefit from aggressive treatment approaches. Here, we review our current understanding of somatic gene mutations, gene expression patterns and flow cytometry regarding their relevance for disease evolution from pre-neoplastic states to MDS and potentially AML.
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Biomarcadores de Tumor/genética , Mutación , Síndromes Mielodisplásicos/patología , Transcriptoma , Progresión de la Enfermedad , Humanos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , PronósticoRESUMEN
Many patients with hematologic malignancies receive RBC transfusion support, which often causes systemic and tissue iron toxicity. Because of their compromised bone marrow function, hematopoietic stem cell transplant (HSCT) recipients are especially vulnerable to excess iron levels. Iron toxicity may compromise transplant engraftment and eventually promote relapse by mediating oxidative and genotoxic stress in hematopoietic stem cells (HSCs) and further impairing the already dysfunctional bone marrow microenvironment in HSCT recipients. Iron toxicity is thought to be primarily mediated by its ability to induce reactive oxygen species and trigger inflammation. Elevated iron levels in the bone marrow can decrease the number of HSCs and progenitor cells, as well as their clonogenic potential, alter mesenchymal stem cell differentiation, and inhibit the expression of chemokines and adhesion molecules involved in hematopoiesis. In vivo, in vitro, and clinical studies support the concept that iron chelation therapy may limit iron toxicity in the bone marrow and promote hematologic improvement and engraftment in HSCT recipients. This review will provide an overview of the current knowledge of the detrimental impact of iron toxicity in the setting of HSCT in patients with hematologic malignancies and the use of iron restriction approaches to improve transplant outcome.