Potential anti-leukemic activity of iron chelation after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia

Michallet, Mauricette; Sobh, Mohamad; Labussière, Hélène; Lombard, Christine; Barraco, Fiorenza; Elhamri, Mohamed; Thomas, Xavier; Chapuis‐Cellier, Colette; Nicolini, Franck E.

doi:10.1080/10428194.2016.1185787

Cited by 8 publications

(4 citation statements)

References 15 publications

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“…Ferritin is a growth factor for AML cells, and it is also possible that its antioxidant activity may decrease the efficacy of cytotoxic agents such as anthracyclines . We have also shown a significant impact of ferritin level on OS and a lower relapse risk after transplantation in patients who have received iron chelators after allogeneic hematopoietic stem cell (HSC) transplantation …”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10] We have also shown a significant impact of ferritin level on OS and a lower relapse risk after transplantation in patients who have received iron chelators after allogeneic hematopoietic stem cell (HSC) transplantation. 11 The primary objective of this study was to assess the impact of hyperferritinemia regardless of age and prognostic subgroups in a larger cohort of AML patients treated by intensive chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

Bertoli

Paubelle²,

Bérard

et al. 2018

European J of Haematology

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Objectives We previously reported the prognostic value of serum ferritin in younger patients with intermediate‐risk acute myeloid leukemia (AML). The aims of this study were to confirm this finding in a larger cohort regardless of age and prognostic subgroups, to explore the expression and functional role of ferritin in AML cells as well as the regulation of serum ferritin levels in AML patients. Patients/Materials/Methods Serum ferritin levels at diagnosis were collected in a cohort of 525 patients treated by intensive chemotherapy. In silico, in vitro, and in vivo analyses were conducted to assess the pattern of expression and functional role of FTH1 and FTL in AML. Results We confirmed the independent prognostic value of serum ferritin. In transcriptomic databases, FTH1 and FTL were overexpressed in AML and leukemic stem cells compared to normal hematopoietic stem cells. The gene signature designed from AML patients overexpressing FTH1 revealed a significant enrichment in genes of the immune and inflammatory response including Nf‐KB pathway, oxidative stress, or iron pathways. This gene signature was enriched in cytarabine‐resistant AML cells in a patient‐derived xenograft model. FTH1 protein was also overexpressed in patient's samples and correlated with the in vitro cytotoxic activity of cytarabine. Lastly, we demonstrated that chemotherapy induced an inflammatory response including a significant increase in serum ferritin levels between day 1 and 8 of induction chemotherapy that was blocked by dexamethasone. Conclusion Ferritin is deregulated in most AML patients likely through inflammation, associated with chemoresistance, and could represent a new therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

Bertoli

Paubelle²,

Bérard

et al. 2018

European J of Haematology

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“…According to the guidelines, patients who have received 20–30 red blood cell (RBC) transfusions and/or have serum ferritin (SF) levels of 1000–2500 μg/l, are candidates for ICT (Santini et al , ; Malcovati et al , ; NCCN, ). Conversely, with the important exception of patients eligible for allogeneic stem cell transplantation (AlloSCT) and who have been shown to benefit from pre‐ and post‐transplant ICT (Armand et al , , ; Alessandrino et al , , ; Sivgin et al , ; Michallet et al , ; Jaekel et al , ), this treatment, although not formally contraindicated, is not generally recommended in higher‐risk MDS (HR‐MDS). Main limiting factors are the expected shorter overall survival (OS) of these patients, and the potential increased risk of renal or hepatic impairment/failure and gastro‐intestinal bleeding (NCCN, ).…”

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confidence: 99%

Iron‐chelating therapy with deferasirox in transfusion‐dependent, higher risk myelodysplastic syndromes: a retrospective, multicentre study

et al. 2017

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Iron chelation is controversial in higher risk myelodysplastic syndromes (HR-MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion-dependent, intermediate-to-very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty-six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375-2500 mg) for a median of 11 months (range 0·4-75). Eight patients (16%) showed grade 2-3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 μg/l at baseline to 1100 μg/l after 12 months of treatment (P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR-MDS are comparable, in terms of safety and efficacy, with those observed in lower-risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR-MDS patients.

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“…Therapeutic Properties of Available Iron Chelator Treatment Options75,77,176 of erythroid precursors and DNA damage associated with malignant transformation 97,98. Michallet and colleagues reviewed 23 patients with acute myeloid leukemia (AML) receiving deferasirox 20-30 mg/kg/day, starting 4 months post-allogeneic HCT for a median duration of 3 months, and demonstrated a significantly improved OS and lower relapse rate at 5 years 98. …”

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confidence: 99%

Long‐term Follow‐up of Hematopoietic Stem Cell Transplant Survivors: A Focus on Screening, Monitoring, and Therapeutics

et al. 2020

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Annually, ~50,000 patients undergo hematopoietic stem cell transplantation (HCT) worldwide with almost 22,000 of these patients receiving HCT in the United States. HCT is a curative option for a wide range of hematologic malignancies, and advances in transplantation medicine have resulted in an increase in HCT survivors. It is anticipated that the number of HCT survivors will more than double from 242,000 in 2020 to ~500,000 in 2030. Survivors of HCT are at an increased risk of developing late complications due to exposure to chemotherapy and/or radiation in the pre‐, peri‐, and post‐HCT phases and these cumulative exposures have the potential to damage normal tissue. This tissue damage leads to the early onset of chronic health conditions resulting in premature mortality in HCT survivors, who have a 15‐year cumulative incidence of severe or life‐threatening chronic health conditions exceeding 40%. Due to the significant burden of morbidity in HCT survivors and the delay in the development of long‐term complications, this delicate patient population requires life‐long monitoring due to the risk for neuropsychological, cardiac, pulmonary, renal, hepatic, ocular, skeletal, cardiac, endocrine, fertility, and sexual health complications, as well as secondary neoplasms. This review will focus on recent advances in screening, monitoring, and therapeutics for late‐occurring or long‐term complications in HCT survivors.

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Potential anti-leukemic activity of iron chelation after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia

Cited by 8 publications

References 15 publications

Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

Iron‐chelating therapy with deferasirox in transfusion‐dependent, higher risk myelodysplastic syndromes: a retrospective, multicentre study

Long‐term Follow‐up of Hematopoietic Stem Cell Transplant Survivors: A Focus on Screening, Monitoring, and Therapeutics

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