Abnormal Dendritic Cell-poiesis in Patients With Lower-risk Myelodysplastic Syndromes.
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ABSTRACT:
SUBMITTER: Sanchez A
PROVIDER: S-EPMC7000478 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
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Abnormal Dendritic Cell-poiesis in Patients With Lower-risk Myelodysplastic Syndromes.
Sánchez Ángela Á Anguita Eduardo E Chaparro Alberto A Roldán-Etcheverry Juan José JJ López-García Alberto A Ramos-Acosta Carlos C Oancea Raluca R Rodriguez-Muñoz Diego D Alemany Susana S
HemaSphere 20200122 1
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Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis with abnormal blood cell development (dysplasia) leading to cytopenias and an increased risk for progression to acute myeloid leukemia (AML). Patients with MDS can generally be classified as lower- (LR-MDS) or higher-risk (HR-MDS). As treatment goals for patients with LR-MDS and those with HR-MDS differ significantly, appropriate diagnosis, classification, and follow-up are critical for correct disease management. In this review, we focus on the diagnosis, prognosis, and treatment options, as well as the prediction of the disease course and monitoring of treatment response in patients with LR-MDS. We discuss how next-generation sequencing, increasing knowledge on mechanisms of MDS pathogenesis, and novel therapies may change the current treatment landscape in LR-MDS and why structured assessments of responses, toxicities, and patient-reported outcomes should be incorporated into routine clinical practice.
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Project description:Lower-risk myelodysplastic syndromes are defined using prognostic scoring systems that incorporate data on bone marrow blast percentage, degree and numbers of cytopenias, and cytogenetic abnormalities. Increasingly, these are incorporating molecular abnormalities to further refine risk. Therapy is geared toward predominating cytopenias, with erythropoiesis-stimulating agents luspatercept and lenalidomide used to ameliorate anemia, romiplostim and eltrombopag tackling thrombocytopenia, and hypomethylating agents and antithymocyte globulin palliating pancytopenia. Newer agents on the horizon are abrogating the downstream sequelae of specific molecular mutations. One challenge for the future is in further modifying response criteria to align with improvements that are clinically meaningful to patients.
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Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological disorders. Treatment options are classified and defined by prognostic risk based on the International Prognostic Scoring System (IPSS) and, more recently, the revised IPSS (IPSS-R). The treatment goal for lower-risk MDS is to correct cytopenias or their consequences, with the goal of maintaining or improving quality of life. Erythropoiesis-stimulating agents (ESAs) play an important role in treating anemia. Individuals with MDS who have a 5q deletion are particularly sensitive to treatment with lenalidomide; however, this comprises the minority of patients with MDS. Luspatercept was recently approved in the United States and the European Union for the treatment of ESA-refractory MDS with ring sideroblasts. Research into new treatment options, especially after ESA failure, is needed. In this review, we will focus on the current therapeutic options for MDS-related anemia.
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Project description:Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860.
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Project description:Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and an increased risk of transformation. Few effective therapies are available for lower risk MDS patients, especially after the failure of hypomethylating agents. MDS progenitor cells are dependent on the nuclear factor-?B (NF-?B) for survival, which makes it an attractive therapeutic target. As a proteosomal inhibitor, bortezomib is thought to have inhibitory activity against NF-?B. We designed a proof-of-principle study of subcutaneous (SC) bortezomib in lower risk MDS patients with evidence of NF-?B activation in their bone marrow. Fifteen patients were treated, their median age was 71 (range 56-87), 33% were low and 67% int-1 by IPSS, median number of prior therapies was 2, all patients were transfusion dependent. Baseline median pp65 percentage was 31% and 11 patients had evidence of ring sideroblasts (RS). SC bortezomib was safe, well tolerated with no excess toxicity. Three patients out of the 15 (20%) had evidence of response with hematologic improvement (HI-E). Bortezomib caused a decrease in pp65 levels in 7 out of 13 evaluable patients (54%, P?=?.025). Of interest, unexpectedly, we observed a significant decrease in RS in 7 out of 10 (70%) evaluable patients during treatment. In conclusion, this study suggests that NF-?B activation, measured by pp65 levels, may be a useful biomarker in MDS. Bortezomib is safe in this patient population but has modest clinical activity. The role of the proteasome in the genesis of RS needs further study.
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Project description:Patients with myelodysplastic syndromes (MDS) are at risk of early death from cardiovascular complications due to the link between clonal hematopoiesis and endothelial dysfunction. EASIX (Endothelial Activation and Stress Index) has been established to predict endothelial complications after allogeneic transplantation. We investigated the impact of EASIX measured at first diagnosis on survival of patients with lower- and higher-risk MDS (no allogeneic transplantation) in two independent institutions: n = 192 (training cohort) and n = 333 (validation cohort). Serum markers of endothelial cell distress were measured and correlated to EASIX. While no effects of EASIX on survival were observed in higher-risk patients, EASIX was associated with shorter survival in patients with lower-risk MDS in both cohorts (univariate: Cohort I: hazard ratio (HR): 1.46; 95% confidence interval (CI) 1.24-1.71; p-value < 0.001/Cohort II: HR 1.31 [1.17-1.48]; p-value < 0.001). Multivariate Cox regression analysis and prediction error analyses confirmed that EASIX remained a significant predictor of survival after adjustment for age, sex, cytogenetic abnormalities and bone marrow blasts in lower-risk patients. The model of the training cohort could be validated. Serum levels of Angiopioetin-2 correlated significantly with EASIX. We introduce EASIX as an easily accessible and independent predictor for survival in patients with lower-risk MDS.
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Project description:Myelodysplastic syndromes (MDS) are a spectrum of clonal stem-cell disorders characterized clinically by bone-marrow failure. Resultant cytopenias are responsible for significant mortality and decreased quality of life in patients with MDS. In patients with low-risk MDS (LR-MDS), anemia is the most common cytopenia and erythropoiesis-stimulating agents (ESA) are usually used as first-line therapy. Those patients who become refractory to ESA have a poor survival. Available treatment options such as lenalidomide, hypomethylating agents, and immunosuppressive therapy can provide some hematologic response among selected subsets of patients, however durable responses are limited, and these agents can carry significant adverse effects. Chronic transfusions help to alleviate symptoms of anemia but still carry risks associated with transfusion and iron overload. Luspatercept, recently approved for those LR-MDS with ring sideroblasts refractory to ESA, was found to have an improvement in transfusion independence with a well-tolerated safety profile. While anemia is the most common cytopenia, thrombocytopenia and neutropenia management is challenging and the co-occurrence of these cytopenias with anemia may dictate the choice of therapy. In this article, we review LR-MDS and discuss the optimal use of current treatment options and explore new therapeutic options on the horizon.
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Project description:Treatment options are limited for patients with anemia associated with lower-risk myelodysplastic syndromes (LR-MDS). The recent approval of luspatercept for the treatment of anemia associated with very low-to intermediate-risk MDS with ring sideroblasts (RS) or with myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis has provided adult patients and practitioners with a much-needed new therapeutic option. Luspatercept is a first-in-class erythroid maturation agent that exerts its effects on later stages of erythropoiesis. In the phase III MEDALIST trial of patients with LR-MDS with RS, luspatercept (starting dose 1 mg/kg) demonstrated substantial clinical benefit (38% of patients treated with luspatercept vs. 13% of those treated with placebo [p < .001] achieved transfusion independence for ≥ 8 weeks during the first 24 weeks of treatment) and a favorable safety profile. The most common adverse events (AEs), including fatigue, asthenia, dizziness, and diarrhea, were more frequent during the first 4 treatment cycles and subsequently declined. This review provides a comprehensive overview of luspatercept treatment administration, including the mechanism of action, efficacy and safety data, management of dosing, and AEs associated with luspatercept treatment of patients with LR-MDS.
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Project description:Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS (P<1×10-4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.
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