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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Erythropoiesis-maturing agents (EMAs), which are specific activin fusion proteins that act as ligand traps to neutralize negative regulators of erythropoiesis, have now been tested in patients with LR-MDS. Luspartercept (ACE-536) has shown ability to increase hemoglobin levels in LR-disease and is approved for patients with beta-thalassemia. The Phase II LR-MDS study reveals 63% erythroid responses with 38% achieving red-cell transfusion independence, particularly in patients with ringed sideroblasts or SF3B1-defined LR-MDS. The study met its primary end-points and is anticipated to be approved in 2020.131 Roxadustat (FG-4592) is an oral hypoxia-inducible factor inhibitor being tested in a Phase III study in LD-MDS in an effort to improve anemia.132 Imetelstat, a telomerase inhibitor, is in a Phase II/III study in red-cell transfusion-dependent and ESA-relapsed/refractory LR-MDS patients. Drugs aimed at improving thrombocytopenia, noted in about 50% of all LR-MDS patients, are also being tested. The TPO-receptor agonists romiplostim and elthrombopag have now been tested in Phase III studies and found to have platelet responses associated with survival benefits but are not approved as yet. Several other novel approaches are being tested, including second-generation HMAs, guadecitabine and ASTX727, and combinations of azacytidine with either lenalidomide, vorinostat (a TPO-receptor agonist), or pevonedistat (an NEDD8-activating enzyme).133 Several combination trials of venetoclax with azacytidine, including those adding tagraxofusp, a CD123-targeted drug, in the untreated and relapsed/refractory setting, and studies of immune checkpoint modulation with HMAs are also in progress. Other candidate approaches include vyxeos (CPX-351), a novel liposomal formulation of cytarabine and daunorubicin recently licensed for secondary AML or tMN, targeted IDH1/2 or FLT3 inhibitors, splicesome-modulator H3B-8800, CAR T-cells, and bispecific antibodies.
Thyroid function analysis after roxadustat or erythropoietin treatment in patients with renal anemia: a cohort study
Published in Renal Failure, 2023
Xiaomeng Zheng, Yiyi Jin, Tao Xu, Hongbin Xu, Suyan Zhu
At present, roxadustat is available for the treatment of renal anemia in China. Two early clinical studies published in the New England Journal of Medicine showed that compared with the placebo group, the roxadustat group had a higher frequency of hyperkalemia and metabolic acidosis, but these studies did not evaluate thyroid related adverse reactions [5,6]. Recently, it was noticed that roxadustat might affect thyroid function in dialysis patients, which might be related to interference with the homeostasis of the hypothalamus-pituitary-thyroid axis [13,14]. Thyroid hormone is controlled by the strict feedback regulation of the hypothalamus-pituitary-thyroid axis. Thyroid hormone receptor (THR) plays an important role in the biological activity of thyroid hormone. THR and retinoid X receptor (RXR) form a heterodimer in the gene response element of thyroid hormone, and jointly activate promoter and gene transcription after binding with T3. Roxadustat has a molecular structure similar to that of T3, and the affinity between roxadustat and THR is higher than that between T3 and THR. Therefore, it is speculated that roxadustat, as a THR β agonist, can inhibit the secretion of TSH, resulting in a reduction in serum FT4 and FT3 levels [15]. It is well known that there is a correlation between CKD and thyroid dysfunction related to thyroid hormone and eGFR, age, sex, and immune nephropathy in CKD patients, but substantial data are still lacking. Therefore, we tried to explore the factors influencing the relationship between CKD and thyroid function, specifically, we tried to illustrate the relationship between roxadustat or erythropoietin and thyroid function.
Roxadustat in the treatment of anaemia in chronic kidney disease
Published in Expert Opinion on Investigational Drugs, 2018
Lucia Del Vecchio, Francesco Locatelli
Following the discovery of the HIF, several drugs inhibiting the PHD domain have been developed. They simulate the effect of hypoxia on the HIF system, causing a stimulation of endogenous EPO production and an increase in iron availability. Differing from ESA, they can be administered orally. Roxadustat is one agent of this promising class. Accordingly to the data of phase-II clinical studies, roxadustat is effective and safe in both ND and dialysis patients. Interestingly, it seems to be equally effective in inflamed and non-inflamed CKD patients. As an ancillary effect, it can also decrease serum cholesterol. Differing from traditional ESA, roxadustat does not cause significant rises in blood pressure.
Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease
Published in Expert Opinion on Investigational Drugs, 2018
Lucia Del Vecchio, Francesco Locatelli
Altogether, phase-II clinical trials demonstrated a dose-dependent efficacy of roxadustat in correcting anemia in non-dialysis CKD patients and in adequately maintaining Hb levels compared to epoetin alfa in dialysis patients. The safety profile was good. Only transient liver function abnormalities and one case of acute pancreatitis were described. Nearly from 6% to 20% of the patients treated with roxadustat complained of diarrhea. None of the reported deaths or cardiovascular events occurring during the trials (in total 5) were attributed to roxadustat [50]. One patient developed a first-degree atrio-ventricular block during roxadustat therapy [57].