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Off-label tocilizumab and adjuvant iron chelator effectiveness in a group of severe COVID-19 pneumonia patients: A single center experience.
Birlutiu, V, Birlutiu, RM, Chicea, L
Medicine. 2021;(18):e25832
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Abstract
Tocilizumab (TCZ), a monoclonal recombinant antibody against IL-6 receptor, is currently used in managing the cytokine release syndrome (CRS) that occurred in coronavirus disease 2019 (COVID-19) selected cases. The primary objective of our study was to establish the effectiveness of TCZ in patients with severe or critical severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia.We retrospectively analyzed 25 consecutive patients, admitted in the Academic Emergency Hospital Sibiu, Romania from April 1, 2020 until May 25, 2020, all with confirmed SARS-CoV-2 infection and severe pneumonia. All patients were treated off-label with TCZ, beside their standard care. Adjuvant iron chelator was associated in 11 patients.Six female and 19 male patients admitted in our hospital all with confirmed SARS-CoV-2 infection and severe pneumonia as defined by Chinese Centers for Disease Control and Prevention were enrolled in this study. Seventeen of the 25 enrolled patients (68%) were seriously ill requiring noninvasive ventilation or oxygen mask, and 8 cases (32%) were critically ill requiring invasive mechanical ventilation. All patients received TCZ, and also received hydroxychloroquine, and lopinavir/ritonavir 200/50 mg for 10 days. Adjuvant iron chelator (deferasirox - marketed as Exjade) was associated in 11 patients who had ferritin serum levels above 1000 ng/mL. No side effects were encountered during infusions or after TCZ. We observed a rapid increase in arterial oxygen saturation for 20 of the 25 cases (80%) with a favorable evolution toward healing. Survivors were younger than 60 years old (80%), had less comorbidities (10% no comorbidities, 70% with 1 or 2 comorbidities), lower serum ferritin levels (30% under 1000 ng/mL), and 50% had no serum glucose elevation. Our patients with CRS had no response to corticosteroid therapy. Five out of the 25 patients had an unfavorable evolution to death. The off-label use of TCZ in patients with severe or critically ill form of SARS-CoV-2 infection had good results in our study.Off-label use of TCZ in severe and critical cases of COVID-19 pneumonia is effective in managing the "cytokine storm." Better outcomes were noted in younger patients. Associated adjuvant iron chelators may contribute to a good outcome and needs to be confirmed in larger studies.
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Tolerability and efficacy of deferasirox in patients with transfusional iron overload: results from a German 2-year non-interventional study.
Nolte, F, Nückel, H, Schmidt, B, Geer, T, Rubanov, O, Hebart, H, Jarisch, A, Albrecht, S, Johr, C, Schumann, C, et al
Journal of cancer research and clinical oncology. 2018;(8):1531-1538
Abstract
BACKGROUND Iron overload (IOL) due to repetitive transfusions of packed red blood cells (pRBC) has a major impact on morbidity and mortality in patients with inherited bone marrow failure syndromes and hemoglobinopathies such as thalassemia and sickle cell disease. However, whether IOL influences the outcome of elderly patients with myeloid malignancies is not yet clear. Moreover, clinical trials have reported high drop-out rates during treatment with the oral iron chelator deferasirox (DFX). AIM: Here we report the results of a 2-year prospective observational study that aimed at describing the routine use of DFX in patients with hematological malignancies with regard to safety, efficacy and handling of the drug in a routine setting. RESULTS A total of 406 patients were included. 58% of the patients were male. Most of the patients had myelodysplastic syndromes (MDS) (68%) and myeloproliferative neoplasms (MPN) (14%). Median time from first transfusion to study enrollment was 1.1 years (0-25.5 years) and most patients were chelation naive (91%) at enrollment. With regard to transfusion burden, most of the patients were moderately or mildly transfusion-dependent with 53% receiving 2-4 and 27% receiving less than 2 units of pRBC per month. Serum ferritin decreased from a mean of 2305 μg/l (± 1449 μg/l) to a mean of 1910 μg/l (± 1529 μg/l) at 24 months. There was no substantial change in transfusion-dependence during the observation period. Dose adjustments were reported in 48% of the patients with dose-escalation strategies being the most frequent reason for dosage increases (49%). The median observation time was 355 days (5-1080 days). Median duration of exposure to DFX was 322 days (2-1078 days). Two-hundred and ninety (72%) patients discontinued the trial prematurely after a median time of 235 days (1-808 days). Death (29%) and adverse events (23%) were the main reasons for discontinuation. Eleven percent of the patients discontinued treatment due to sufficient decrease in serum ferritin. Most frequent adverse events were decrease in creatinine clearance (22%), increase in serum creatinine (18%) and diarrhea (16%). CONCLUSION This descriptive trial confirms the efficacy of DFX in decreasing the serum ferritin. Moreover, the high drop-out rates seen in prospective trials are recapitulated in this study, which can be attributed to adverse events in a substantial proportion of patients.
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The effect of desferrioxamine chelation versus no therapy in patients with non transfusion-dependent thalassaemia: a multicenter prospective comparison from the MIOT network.
Ricchi, P, Meloni, A, Pistoia, L, Spasiano, A, Spiga, A, Allò, M, Gamberini, MR, Lisi, R, Campisi, S, Peluso, A, et al
Annals of hematology. 2018;(10):1925-1932
Abstract
We prospectively assessed by magnetic resonance imaging (MRI) the advantages of desferrioxamine (DFO) with respect to the absence of chelation therapy in non transfusion-dependent thalassaemia (NTDT) patients. We considered 18 patients non-chelated and 33 patients who received DFO alone between the two MRI scans. Iron overload was assessed by the T2* technique. Biventricular function parameters were quantified by cine sequences. No patient treated with DFO had cardiac iron. At baseline, only one non-chelated patient showed a pathological heart T2* value (< 20 ms) and he recovered at the follow-up. The percentage of patients who maintained a normal heart T2* value was 100% in both groups. A significant increase in the right ventricular ejection fraction was detected in DFO patients (3.48 ± 7.22%; P = 0.024). The changes in cardiac T2* values and in the biventricular function were comparable between the two groups. In patients with hepatic iron at baseline (MRI liver iron concentration (LIC) ≥ 3 mg/g/dw), the reduction in MRI LIC values was significant only in the DFO group (- 2.20 ± 4.84 mg/g/dw; P = 0.050). The decrease in MRI LIC was comparable between the groups. In conclusion, in NTDT patients, DFO therapy showed no advantage in terms of cardiac iron but its administration allowed an improvement in right ventricular function. Moreover, DFO reduced hepatic iron in patients with significant iron burden at baseline.
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Two-year observational study of deferiprone in superficial siderosis.
Kessler, RA, Li, X, Schwartz, K, Huang, H, Mealy, MA, Levy, M
CNS neuroscience & therapeutics. 2018;(3):187-192
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INTRODUCTION Superficial siderosis is a rare, neurodegenerative disease caused by toxic accumulation of hemosiderin on the surface of the brain and the spinal cord, most commonly from chronic subarachnoid hemorrhage. AIMS The aim of this study was to assess the clinical and radiological outcomes of superficial siderosis patients using deferiprone, a cell permeant iron chelator. Subjects obtained pre- and post-treatment brain MRIs and weekly laboratory tests. Osirix software was used to develop a method of quantifying hemosiderin deposition. Three-dimensional whole brain images of gradient echo images were rendered and compared by dividing the mean T2 hyperintensity to the maximal cerebrospinal fluid signal. RESULTS A total of 38 subjects completed the study, of which clinical and radiological data were available for 30. The average age was 64 years (range 37-86), 53% were male, 94% were white. Nineteen subjects (63%) reported either no progression of disease or an improvement in at least one neurological domain, with 40% of patients reporting a stabilization in hearing function and 30% reporting stable or improved coordination and walking. By MRI, there was an overall mean increase in T2 hyperintensity of the whole brain of 1%-13% over the 2-year time period in half of patients, indicating a reduction hemosiderosis. There were no cases of agranulocytosis, and declines of white blood cells counts and neutrophils averaged <10%. Fatigue was the most common side effect. CONCLUSION This is the first long-term prospective study of superficial siderosis on the iron chelator, deferiprone. MRI quantification of hemosiderin appears to demonstrate a measurable reduction in half of patients and this correlated with a stabilized or improving disease course. A future placebo-controlled trial is necessary to determine whether deferiprone is an effective therapy for superficial siderosis.
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MRI multicentre prospective survey in thalassaemia major patients treated with deferasirox versus deferiprone and desferrioxamine.
Pepe, A, Meloni, A, Pistoia, L, Cuccia, L, Gamberini, MR, Lisi, R, D'Ascola, DG, Rosso, R, Allò, M, Spasiano, A, et al
British journal of haematology. 2018;(5):783-795
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We prospectively assessed the efficacy of deferasirox versus deferiprone or desferrioxamine as monotherapy in thalassaemia major (TM) patients by magnetic resonance imaging (MRI). We selected the patients enrolled in the Myocardial Iron Overload in Thalassaemia network who received only one chelator between two MRIs (deferasirox = 235, deferiprone = 142, desferrioxamine = 162). Iron overload was measured by T2* technique and biventricular function by cine images. Among the patients with baseline myocardial iron, in all three groups there was a significant improvement in global heart T2* values. The deferiprone and desferrioxamine groups showed a significant improvement in left ventricular ejection fraction (LVEF). Only the deferiprone group showed a significant improvement in right ventricular ejection fraction (RVEF). The improvement in global heart T2* was significantly lower in the deferasirox versus the deferiprone group. The improvement in the LVEF was significantly higher in the deferiprone and desferrioxamine groups than in the deferasirox group and the improvement in the RVEF was significantly higher in the deferiprone than in deferasirox group. Among the patients with baseline hepatic iron, the changes in hepatic iron were comparable in deferasirox versus the other groups. Deferasirox monotherapy was less effective than deferiprone in improving myocardial siderosis and biventricular function and less effective than desferrioxamine in improving the LVEF.
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Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST).
Vichinsky, E, El-Beshlawy, A, Al Zoebie, A, Kamdem, A, Koussa, S, Chotsampancharoen, T, Bruederle, A, Gilotti, G, Han, J, Elalfy, M
Pediatric blood & cancer. 2017;(9)
Abstract
BACKGROUND Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. PROCEDURE Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter. RESULTS In total, 267 patients (mean age 3.2 years) predominantly with β-thalassemia (n = 176, 65.9%) were enrolled. Mean ± standard deviation deferasirox dose was 25.8 ± 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years' treatment. The proportion of patients with two or more consecutive postbaseline measurements (≥7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval [CI]: 2.1-7.9) and 4.0% (95% CI: 1.8-7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. There were no new safety signals. CONCLUSIONS Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.
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Multidisciplinary evaluation at baseline and during treatment improves the rate of compliance and efficacy of deferasirox in elderly myelodysplastic patients.
Del Corso, L, Biale, L, Parodi, EL, Russo, R, Filiberti, R, Arboscello, E
International journal of clinical oncology. 2017;(2):380-386
Abstract
BACKGROUND Deferasirox (DFX) is used to reduce iron levels in patients with myelodysplastic syndrome (MDS) who develop iron overload after chronic red blood cell infusions. However, DFX can be associated with renal and gastrointestinal toxicities, which may cause treatment interruption or discontinuation. This study aimed to determine the effectiveness and safety of DFX in patients with MDS. METHODS This multicenter, retrospective, observational study was conducted at two hospitals in Italy. Elderly patients with transfusion-dependent MDS received DFX for up to 12 months and were divided into two groups: group A comprised patients who were not under multidisciplinary assessment; group B comprised patients under multidisciplinary control. Treatment effectiveness was estimated by monitoring the serum ferritin (SF) levels throughout the study. Any treatment-related adverse events (AEs), clinically relevant analytical alterations, and reasons for treatment discontinuation were monitored. RESULTS The study included 44 patients (13 female, 31 male; median age 77.0 years). At 3 months, SF levels decreased by ≥20 % in 29 and 31 % of patients in groups A and B, respectively, in 17 and 36 % of patients at 6 months, and in 22 and 58 % at 12 months. The most common AEs were diarrhea and increased serum creatinine, which were more frequent in group A. The discontinuation rate after renal AE was 15 and 5 % in groups A and B, respectively. CONCLUSION Multidisciplinary evaluation can be an effective strategy for monitoring renal function in patients on DFX therapy, to improve treatment adherence and overall efficacy in elderly patients with MDS.
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Effect of iron chelator desferrioxamine on serum zinc levels in patients with beta thalassemia major.
Sultan, S, Irfan, SM, Kakar, J, Zeeshan, R
The Malaysian journal of pathology. 2015;(1):35-8
Abstract
UNLABELLED β-thalassemia is the most common genetic disorder worldwide with an increased prevalence around the Mediterranean, Indian subcontinent and in South-East Asia. Various siderotic and non-siderotic complications significantly impact the quality of life. Thalassemic patients are also at risk of zinc deficiency due to diverse causes including desferrioxamine chelation. This study sought to investigate the prevalence of zinc deficiency in beta thalassemia major patients on desferrioxamine for iron chelation. STUDY DESIGN This was a descriptive, prospective, cross-sectional study over a 6-month period. 63 cases of beta thalassemia major within the age group of 5-15 years on desferrioxamine for at least 1 year, were included. Basic patient demographics such as age, gender and duration of disease were recorded. Serum zinc levels were determined by atomic absorption spectrophotometry. RESULTS The mean age of patients was 10.84±3.47 (5 to 15) years. There were 35 (55.6%) males and 28(44.4%) females. The prevalence of zinc deficiency (zinc levels>50 µg/dl) was 22.2%. Proportions of deficiency were higher in males with a duration of disease beyond 10 years. CONCLUSIONS Zinc deficiency is not uncommon in beta thalassemia patients on desferrioxamine. We suggest that zinc levels be regularly monitored in these patients.
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MRI guided iron assessment and oral chelator use improve iron status in thalassemia major patients.
Nichols-Vinueza, DX, White, MT, Powell, AJ, Banka, P, Neufeld, EJ
American journal of hematology. 2014;(7):684-8
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Oral iron chelators and magnetic resonance imaging (MRI) assessment of heart and liver iron burden have become widely available since the mid 2000s, allowing for improved patient compliance with chelation and noninvasive monitoring of iron levels for titration of therapy. We evaluated the impact of these changes in our center for patients with thalassemia major and transfusional iron overload. This single center, retrospective observational study covered the period from 2005 through 2012. Liver iron content (LIC) was estimated both by a T2* method and by R2 (Ferriscan® ) technique. Cardiac iron was assessed as cT2*. Forty-two patients (55% male) with transfused thalassemia and at least two MRIs were included (median age at first MRI, 17.5 y). Over a mean follow-up period of 5.2 ± 1.9 y, 190 MRIs were performed (median 4.5 per patient). Comparing baseline to last MRI, 63% of patients remained within target ranges for cT2* and LIC, and 13% improved from high values to the target range. Both the median LIC and cT2* (cR2* = 1000/cT2*) status improved over time: LIC 7.3 to 4.5 mg/g dry weight, P = 0.0004; cR2* 33.4 to 28.3 Hz, P = 0.01. Individual responses varied widely. Two patients died of heart failure during the study period. Annual MRI iron assessments and availability of oral chelators both facilitate changes in chelation dose and strategies to optimize care.
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Immunological evaluation of β-thalassemia major patients receiving oral iron chelator deferasirox.
Aleem, A, Shakoor, Z, Alsaleh, K, Algahtani, F, Iqbal, Z, Al-Momen, A
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2014;(7):467-71
Abstract
OBJECTIVE To determine the immune abnormalities and occurrence of infections in transfusion-dependent β-thalassemia major patients receiving oral iron chelator deferasirox (DFX). STUDY DESIGN An observational study. PLACE AND DURATION OF STUDY Hematology Clinics, King Khalid University Hospital, Riyadh, Saudi Arabia, from July to December 2010. METHODOLOGY Seventeen patients with β-thalassemia major (12 females, median age 26 years) receiving deferasirox (DFX) for a median duration of 27 months were observed for any infections and had their immune status determined. Immune parameters studied included serum immunoglobulins and IgG subclasses, serum complement (C3 and C4) and anti-nuclear antibody (ANA) level, total B and T-lymphocytes, CD4+ and CD8+ counts, CD4+/CD8+ ratio, and natural killer (NK) cells. Immunological parameters of the patients were compared with age, gender, serum ferritin level and splenectomy status. Lymphocyte subsets were also compared with age and gender matched normal controls. RESULTS A considerable reduction in serum ferritin was achieved by DFX from a median level of 2528 to 1875 μmol/l. Serum IgG levels were increased in 7 patients. Low C4 levels were found in 9 patients. Total B and T-lymphocytes were increased in 14 patients each, while CD4+, CD8+ and NK cells were increased in 13, 12 and 11 patients respectively. Absolute counts for all lymphocyte subsets were significantly higher compared to the normal controls (p ² 0.05 for all parameters). Raised levels of IgG were associated with older age, female gender, splenectomized status and higher serum ferritin levels but this did not reach statistical significance except for the higher ferritin levels (p=0.044). Increased tendency to infections was not observed. CONCLUSION Patients with β-thalassemia major receiving DFX exhibited significant immune abnormalities. Changes observed have been described previously, but could be related to DFX. The immune abnormalities were not associated with increased tendency to infections.