Iron Overload Following Hematopoietic Stem Cell Transplantation: Prevalence, Severity, and Management in Children and Adolescents with Malignant and Nonmalignant Diseases

Cattoni, Alessandro; Capitoli, Giulia; Casagranda, Sara; Cortí, Paola; Adavastro, Marta; Molinaro, Alessandro; Gennaro, Filiberto Di; Bonanomi, Sonia; Biondi, Andrea; Galimberti, Stefania; Balduzzi, Adriana

doi:10.1016/j.jtct.2023.01.020

Cited by 5 publications

(11 citation statements)

References 21 publications

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“…There are three iron-chelating drugs, namely, deferoxamine (DF), deferiprone (L1) and deferasirox (DFRA), which are widely used in thousands of patients worldwide mainly for the treatment of transfusional iron overload in TM and other diseases [82][83][84][85][86]. The general aim of these three iron-chelating drugs is the removal of excess iron, which is accumulated in the body as a result of chronic RBC transfusions; it is toxic and can be fatal unless removed.…”

Section: Design and Developmental Aspects Of Chelating Drugs For The ...mentioning

confidence: 99%

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Kontoghiorghes

2023

IJMS

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The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.

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Section: Design and Developmental Aspects Of Chelating Drugs For The ...mentioning

confidence: 99%

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Kontoghiorghes

2023

IJMS

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“…Many other differences in hematologic disease characteristics and therapeutic requirements, including the initiation and rate of RBC transfusions, exist between the various categories of transfusional iron-loaded patients ( Table 1 ) [ 1 , 2 , 3 , 4 ]. For example, the initiation of RBC transfusions ranges from the first few years to the rest of remaining life in TM, whereas in SCD and TI they may be intermittent at different patient ages [ 3 , 36 , 37 ].…”

Section: Major Diseases Of Transfusional Iron Overloadmentioning

confidence: 99%

“…For example, HCT is a widely used form of treatment for many hematologic malignancies and genetic disorders. The number of diseases and the number/age range of patients undergoing HCT is rapidly increasing as a result of technological and therapeutic management improvements ( Table 1 ) [ 2 , 40 , 41 , 42 , 43 ].…”

Section: Major Diseases Of Transfusional Iron Overloadmentioning

confidence: 99%

“…The level of iron overload caused from RBC transfusions is considered an independent adverse prognostic factor in all diseases associated with HCT and is one of the many complications in pre- and post-transplantation side effects, affecting the long-term survival of about 0.5 million HCT patients [ 2 , 40 , 41 , 42 , 43 ]. Iron overload mostly develops in the pre-transplantation period in many HCT patient categories, including about 4000 patients with TM and 1000 with SCD, as well as many more with myelodysplasia, leukemia, and other patients [ 2 , 40 , 41 , 42 , 43 ]. The excess iron burden in the transfusion-independent or reduced transfusion dependent post-allogeneic iron-loaded HCT patients always remains a potential source of toxicity and clinical complications unless it is removed.…”

Section: Major Diseases Of Transfusional Iron Overloadmentioning

confidence: 99%

“…Millions of patients with hemoglobinopathies and other refractory anemias worldwide, including thalassemia, sickle cell disease (SCD), myelodyspasia, and hematopoietic stem cell transplantation (HCT), receive regular red blood cell (RBC) transfusions for the treatment of their anemia [ 1 , 2 , 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

Kontoghiorghes

2023

IJMS

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Iron is essential for all organisms and cells. Diseases of iron imbalance affect billions of patients, including those with iron overload and other forms of iron toxicity. Excess iron load is an adverse prognostic factor for all diseases and can cause serious organ damage and fatalities following chronic red blood cell transfusions in patients of many conditions, including hemoglobinopathies, myelodyspasia, and hematopoietic stem cell transplantation. Similar toxicity of excess body iron load but at a slower rate of disease progression is found in idiopathic haemochromatosis patients. Excess iron deposition in different regions of the brain with suspected toxicity has been identified by MRI T2* and similar methods in many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Based on its role as the major biological catalyst of free radical reactions and the Fenton reaction, iron has also been implicated in all diseases associated with free radical pathology and tissue damage. Furthermore, the recent discovery of ferroptosis, which is a cell death program based on free radical generation by iron and cell membrane lipid oxidation, sparked thousands of investigations and the association of iron with cardiac, kidney, liver, and many other diseases, including cancer and infections. The toxicity implications of iron in a labile, non-protein bound form and its complexes with dietary molecules such as vitamin C and drugs such as doxorubicin and other xenobiotic molecules in relation to carcinogenesis and other forms of toxicity are also discussed. In each case and form of iron toxicity, the mechanistic insights, diagnostic criteria, and molecular interactions are essential for the design of new and effective therapeutic interventions and of future targeted therapeutic strategies. In particular, this approach has been successful for the treatment of most iron loading conditions and especially for the transition of thalassemia from a fatal to a chronic disease due to new therapeutic protocols resulting in the complete elimination of iron overload and of iron toxicity.

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Risk of transfusion‐related iron overload varies based on oncologic diagnosis and associated treatment: Retrospective analysis from a single pediatric cancer center

Winzent‐Oonk,

Staley,

Alami

et al. 2024

Pediatric Blood & Cancer

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BackgroundTransfusion‐related iron overload (TRIO) is a widely acknowledged late effect of antineoplastic therapy in pediatric cancer survivors, but firm guidelines as to screening protocols or at‐risk populations are lacking in the literature.ProcedureWe performed retrospective analysis of all oncology patients diagnosed at our center from 2014 to 2019, who underwent TRIO screening as part of an internal quality improvement project. Correlations of MRI‐confirmed TRIO with patient‐, disease‐, and treatment‐specific features were evaluated.ResultsWe show that a tiered screening algorithm for TRIO, when followed as intended, led to the identification of the highest proportion of patients with TRIO. We confirm that cardiac TRIO is quite rare in the oncology patient population. However, accepted surrogate markers including red blood cell transfused volume and ferritin only modestly correlated with TRIO in our patient cohort. Instead, we found that older age, leukemia diagnosis, anthracycline exposure, and receipt of stem cell transplant were most strongly associated with risk for TRIO.ConclusionsWe describe associations between TRIO and patient, disease, and treatment characteristics in a multivariate risk model that could lead to an improved risk stratification of off‐therapy patients, and which should be validated in a prospective manner.

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Iron Overload Following Hematopoietic Stem Cell Transplantation: Prevalence, Severity, and Management in Children and Adolescents with Malignant and Nonmalignant Diseases

Cited by 5 publications

References 21 publications

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

Risk of transfusion‐related iron overload varies based on oncologic diagnosis and associated treatment: Retrospective analysis from a single pediatric cancer center

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