Current challenges and unmet medical needs in myelodysplastic syndromes

Platzbecker, Uwe; Kubasch, Anne Sophie; Homer-Bouthiette, Collin; Prébet, Thomas

doi:10.1038/s41375-021-01265-7

Cited by 72 publications

(62 citation statements)

References 107 publications

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“…As a consequence of their hydrophobic nature, both DHA and EPA can act as the scaffold in the synthesis of amphiphilic prodrugs [46,47]. In this study, azacitidine was covalently bound to either EPA or DHA, to form N 4 -azacitidine DHA (AzaDHA) and N 4 -azacitidine EPA (AzaEPA) amphiphilic prodrug conjugates through amide linkage (Figure 3). The AzaEPA and AzaDHA prodrugs were then purified via semi-preparative reversed phase high-performance liquid chromatography (RP-HPLC) with a final mean yield of ~10% and a purity of 92% for AzaEPA; AzaDHA was obtained with a mean yield of ~20% and a purity of 97%.…”

Section: Resultsmentioning

confidence: 94%

Azacitidine Omega-3 Self-Assemblies: Synthesis, Characterization, and Potent Applications for Myelodysplastic Syndromes

et al. 2021

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5-Azacitidine, a cytidine analogue used as a hypomethylating agent, is one of the main drugs for the treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) in the elderly. However, after administration, it exhibits several limitations, including restricted diffusion and cellular internalization due to its hydrophilicity, and a rapid enzymatic degradation by adenosine deaminase. The aim of this study was to improve the drug cell diffusion and protect it from metabolic degradation via the synthesis of amphiphilic prodrugs and their potential self-assembly. Azacitidine was conjugated to two different omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The carboxylic acid group of the omega-3 fatty acids was effectively conjugated to the amine group of the azacitidine base, yielding two amphiphilic prodrugs. Nanoprecipitation of the obtained prodrugs was performed and self-assemblies were successfully obtained for both prodrugs, with a mean diameter of 190 nm, a polydispersity index below 0.2 and a positive zeta potential. The formation of self-assemblies was confirmed using pyrene as a fluorescent dye, and the critical aggregation concentrations were determined: 400 µM for AzaEPA and 688 µM for AzaDHA. Additionally, the stability of the obtained self-assemblies was studied and after 5 days their final stable arrangement was reached. Additionally, cryo-TEM revealed that the self-assemblies attain a multilamellar vesicle supramolecular structure. Moreover, the obtained self-assemblies presented promising cytotoxicity on a leukemia human cell line, having a low IC50 value, comparable to that of free azacitidine.

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Section: Resultsmentioning

confidence: 94%

Azacitidine Omega-3 Self-Assemblies: Synthesis, Characterization, and Potent Applications for Myelodysplastic Syndromes

et al. 2021

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“…However, a universal MRD marker for MDS and AML is unlikely because of the genotypic and phenotypic heterogeneity of these diseases [29]. Thus, a more effective strategy may be individualized MRD monitoring using a targeted nextgeneration sequencing panel [30].…”

Section: Minimal Residual Disease Using Liquid Biopsymentioning

confidence: 99%

Minimal Residual Disease Using Liquid Biopsies in Hematological Malignancies

Colmenares¹,

Álvarez²,

Barrio³

et al. 2022

Preprint

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The study of cell-free DNA (cfDNA) and other peripheral blood components (known as “liquid biopsies”) is promising and has been investigated especially in solid tumors. Nevertheless, it is increasingly showing greater utility in the diagnosis, prognosis, and response to treatment of hematological malignancies; in the future, it could prevent invasive techniques, such as bone marrow (BM) biopsy. Most of the studies about this topic have been focused on B cell lymphoid malignancies; some of them have shown that cfDNA can be used as a novel way for diagnosis and minimal residual monitoring in B cell lymphomas, using techniques such as next-generation sequencing (NGS). In myelodysplastic syndromes, multiple myeloma, or chronic lymphocytic leukemia, liquid biopsies may allow for an interesting genomic representation of the tumor clones affecting different lesions (spatial heterogeneity). In acute leukemias, it can be helpful in the monitoring of early treatment response and the prediction of treatment failure. In chronic lymphocytic leukemia, the evaluation of cfDNA permits the definition of clonal evolution and drug resistance in real-time. However, there are limitations such as the difficulty in obtaining sufficient circulating tumor DNA for achieving a high sensitivity to assess minimal residual disease or the lack of standardization of the method and clinical studies to confirm its prognostic impact. This review focuses on clinical applications of cfDNA on minimal residual disease in hematological malignancies.

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“…Indeed, each unit of packed red cells contains 200-250 mg of iron (approximately 100 times the normal daily intake). Moreover, at diagnosis 80% of patients with MDS present already anemia due to ineffective erythropoiesis and requiring blood transfusions (16)(17)(18). Consequently, it is very common that chronic transfusiondependent patients will develop IOL.…”

Section: Mechanisms That Can Favor Iron Toxicity In Patients With Mdsmentioning

confidence: 99%

From Biology to Clinical Practice: Iron Chelation Therapy With Deferasirox

et al. 2021

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Iron chelation therapy (ICT) has become a mainstay in heavily transfused hematological patients, with the aim to reduce iron overload (IOL) and prevent organ damage. This therapeutic approach is already widely used in thalassemic patients and in low-risk Myelodysplastic Syndrome (MDS) patients. More recently, ICT has been proposed for high-risk MDS, especially when an allogeneic bone marrow transplantation has been planned. Furthermore, other hematological and hereditary disorders, characterized by considerable transfusion support to manage anemia, could benefit from this therapy. Meanwhile, data accumulated on how iron toxicity could exacerbate anemia and other clinical comorbidities due to oxidative stress radical oxygen species (ROS) mediated by free iron species. Taking all into consideration, together with the availability of approved oral iron chelators, we envision a larger use of ICT in the near future. The aim of this review is to better identify those non-thalassemic patients who can benefit from ICT and give practical tips for management of this therapeutic strategy.

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Current challenges and unmet medical needs in myelodysplastic syndromes

Cited by 72 publications

References 107 publications

Azacitidine Omega-3 Self-Assemblies: Synthesis, Characterization, and Potent Applications for Myelodysplastic Syndromes

Azacitidine Omega-3 Self-Assemblies: Synthesis, Characterization, and Potent Applications for Myelodysplastic Syndromes

Minimal Residual Disease Using Liquid Biopsies in Hematological Malignancies

From Biology to Clinical Practice: Iron Chelation Therapy With Deferasirox

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