Pre-transplantation iron chelation in patients with MDS or acute leukemia and iron overload undergoing myeloablative allo-SCT.
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ABSTRACT:
SUBMITTER: Armand P
PROVIDER: S-EPMC3954511 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
Publications
Pre-transplantation iron chelation in patients with MDS or acute leukemia and iron overload undergoing myeloablative allo-SCT.
Armand P P Sainvil M-M MM Kim H T HT Rhodes J J Cutler C C Ho V T VT Koreth J J Alyea E P EP Neufeld E J EJ Kwong R Y RY Soiffer R J RJ Antin J H JH
Bone marrow transplantation 20120521 1
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Project description:Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly anemia. Red cell transfusion therapy for anemia in MDS results in iron overload, correlating with reduced overall survival. Whether the treatment of iron overload benefits MDS patients remains controversial. We evaluate underlying iron-related pathophysiology and the effect of iron chelation using deferiprone on erythropoiesis in NUP98-HOXD13 transgenic mice, a highly penetrant well-established MDS mouse model. Our results characterize an iron overload phenotype with aberrant erythropoiesis in these mice which was reversed by deferiprone-treatment. Serum erythropoietin levels decreased while erythroblast erythropoietin receptor expression increased in deferiprone-treated MDS mice. We demonstrate, for the first time, normalized expression of the iron chaperones Pcbp1 and Ncoa4 and increased ferritin stores in late-stage erythroblasts from deferiprone-treated MDS mice, evidence of aberrant iron trafficking in MDS erythroblasts. Importantly, erythroblast ferritin is increased in response to deferiprone, correlating with decreased erythroblast ROS. Finally, we confirmed increased expression of genes involved in iron uptake, sensing, and trafficking in stem and progenitor cells from MDS patients. Taken together, our findings provide evidence that erythroblast-specific iron metabolism is a novel potential therapeutic target to reverse ineffective erythropoiesis in MDS.
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Project description:Relapse after allogeneic stem cell transplantation (allo-SCT) remains the primary cause of treatment failure. A second SCT can result in long-term survival in a subset of patients, but the relapse rate remains high. We conducted a single-center, phase 1, modified 3 + 3 dose-escalation study of the feasibility of combining intensity-modulated total marrow irradiation (IM-TMI) with fludarabine and melphalan for conditioning. Between December 2015 and May 2020, 21 patients with relapsed hematologic disease undergoing second or greater allo-SCT were treated with IM-TMI doses of 6 Gy, 9 Gy, or 12 Gy. Dose-limiting toxicity was defined as a grade 3 or higher treatment-related adverse event; mucositis was the primary dose-limiting toxicity. The median times to neutrophil and platelet engraftment were 10 and 18 days, respectively. The 1-year cumulative incidence of graft-versus-host disease was 65% (95% confidence interval CI, 38-83). The nonrelapse mortality at 2 years was 17% (95% CI, 4-39). Cumulative incidence of relapse at 2 years was 35% (95% CI, 13-58). Two-year progression-free survival and overall survival were 48% and 50%. We conclude that combining IM-TMI with fludarabine-melphalan is feasible. We recommend 12 Gy of IM-TMI with fludarabine-melphalan for second SCT, although 9 Gy may be used for older or underweight patients.
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Project description:Iron overload, notably caused by hereditary hemochromatosis, is an excess storage of iron in various organs that causes tissue damage and may promote tumorigenesis. To manage that disorder, free iron depletion can be induced by iron chelators like deferoxamine that are of increasing interest also in the cancer field since iron stock could be a potent target for managing tumorigenesis. Curcumin, a well-known active substance extracted from the turmeric rhizome, destabilizes endoplasmic reticulum, and secondarily lysosomes, thereby increasing mitophagy/autophagy and subsequent apoptosis. Recent findings show that cells treated with curcumin also exhibit a decrease in ferritin, which is consistent with its chemical structure and iron chelating activity. Here we investigated how curcumin influences the intracellular effects of iron overload via Fe-nitriloacetic acid or ferric ammonium citrate loading in Huh-7 cells and explored the consequences in terms of antioxidant activity, autophagy, and apoptotic signal transduction. In experiments with T51B and RL-34 epithelial cells, we have found evidence that curcumin-iron complexation abolishes both curcumin-induced autophagy and apoptosis, together with the tumorigenic action of iron overload.
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Project description:BackgroundPatients with myelodysplastic syndrome (MDS) require chronic red blood cell (RBC) transfusion due to anemia. Multiple RBC transfusions cause secondary iron overload and subsequent excessive generation of reactive oxygen species (ROS), which leads to mutations, cell death, organ failure, and inferior disease outcomes. We hypothesize that iron loading promotes AML development by increasing oxidative stress and disrupting important signaling pathways in the bone marrow cells (BMCs). Conversely, iron chelation therapy (ICT) may reduce AML risk by lowering iron burden in the iron-loaded animals.MethodsWe utilized a radiation-induced acute myeloid leukemia (RI-AML) animal model. Iron overload was introduced via intraperitoneal injection of iron dextran, and iron chelation via oral gavage of deferasirox. A total of 86 irradiated B6D2F1 mice with various levels of iron burden were monitored for leukemia development over a period of 70 weeks. The Kaplan-Meier estimator was utilized to assess AML free survival. In addition, a second cohort of 30 mice was assigned for early analysis at 5 and 7 months post-irradiation. The BMCs of the early cohort were assessed for alterations of signaling pathways, DNA damage response and gene expression. Statistical significance was established using Student's t-test or ANOVA.ResultsIron loading in irradiated B6D2F1 mice accelerated RI-AML development. However, there was a progressive decrease in AML risk for irradiated mice with increase in iron burden from 7.5 to 15 to 30 mg. In addition, ICT decreased AML incidence in the 7.5 mg iron-loaded irradiated mice, while AML onset was earlier for the 30 mg iron-loaded irradiated mice that received ICT. Furthermore, analysis of BMCs from irradiated mice at earlier intervals revealed accelerated dysregulation of signaling pathways upon iron loading, while ICT partially mitigated the effects.ConclusionsWe concluded that iron is a promoter of leukemogenesis in vivo up to a peak iron dose, but further iron loading decreases AML risk by increasing cell death. ICT can partially mitigate the adverse effects of iron overload, and to maximize its benefit this intervention should be undertaken prior to the development of extreme iron overload.
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