Biochemical, Radiologic, Ultrastructural, and Genetic Evaluation of Iron Overload in Acute Leukemia and Iron-chelation Therapy

Abstract

Iron overload in hereditary hemochromatosis and hematologic malignancy has unfavorable effects on morbidity. Herein, 53 children (age 108.4±58.3 mo, 25 girls and 28 boys) with acute myeloblastic and lymphoblastic leukemia, who received 4 different chemotherapy protocols, were evaluated for iron overload throughout chemotherapy. Iron overload arose: (1) before chemotherapy, which was dependent on neither chemotherapy nor packed red blood cell transfusions and (2) after chemotherapy, which was dependent on the duration and nature of chemotherapy and partially on transfusion of packed red blood cells. Iron overload was documented in 75% of patients with a ferritin level >1000 ng/mL, by liver and heart magnetic resonance imaging, and they were administered iron-chelation therapy with success. Three of 10 radiologically iron-overloaded patients were heterozygous for H63D mutation. Aminolevulinic acid and porphobilinogen levels were normal. Light microscopic examination of the bone marrow revealed increased iron granules in erythroblasts, platelets, and megakaryocytes, iron-laden macrophages, free iron in the matrix, dyshematopoiesis, and apoptotic cells. Electron microscopic examination revealed iron-laden secondary lysosomes and autolysosomes in normoblasts and iron-laden primary granules in promyelocytes, irrelevant to the ferritin level, implying autophagia due to chemotherapy as a source of the excess iron. We think that iron overload, which is an important complication of acute leukemia, should be evaluated separately from "transfusion overload," and the management principles specific to leukemia should be implemented.

Evaluation of Liver Iron Content by Magnetic Resonance Imaging in Children with Acute Lymphoblastic Leukemia after Cessation of Treatment

“…In the same study, it was concluded that the numbers of erythrocyte transusions is more reliable than serum ferritin levels in determining for screening iron accumulation. In two different studies by Olcay et al (19,20)., liver iron deposition was shown in 75% and 40% of patients with acute leukemia (AML, ALL) with serum ferritin levels above 1000 ng / mL. It has been suggested that since iron accumulation can be detected u n c o r r e c t e d p r o o f even when the erythrocyte transfusions are not intense, this accumulation may be related to the intensity of chemotherapy treatment (19).…”

“…In two different studies by Olcay et al (19,20)., liver iron deposition was shown in 75% and 40% of patients with acute leukemia (AML, ALL) with serum ferritin levels above 1000 ng / mL. It has been suggested that since iron accumulation can be detected u n c o r r e c t e d p r o o f even when the erythrocyte transfusions are not intense, this accumulation may be related to the intensity of chemotherapy treatment (19). Moreover, they reported that no association was found between serum levels of NTBI, which is thought to cause tissue damage, and oxidative stress markers (lipid hydroxyperoxide products and protein carboxyl groups) and liver iron deposition (20).…”

“…In the literature, there are many studies using different MRI methods for demonstrating liver iron deposition in thalassemia, sickle cell anemia, and myelodysplastic syndrome in children and adults, and in acute leukemia in adults (10-15). There are some studies evaluating iron overload by MRI in children with hematologic malignancy, solid tumors and hematopoietic stem cell transplantation (HSCT) (16)(17)(18)(19)(20)(21)(22). In one these studies, liver iron accumulation was determined by the liver / muscle ratio signal intensity (L / M SI) method with lower sensitivity (17), while in the other studies, acute leukemias (ALL, AML) and solid tumor cases were evaluated together (16,21).…”

“…In a study in which only ALL cases were evaluated, the patients were selected for determination of iron deposition by MRI according to transfusion frequency and / or ferritin level, causing to decrease the number of cases that was evaluated (22 of 79 patients included in the study) (18). Moreover, in some studies, subjects with serum ferritin levels above 1000 ng / mL were included in the evaluation of iron overload by MRI (19,20). The aim of this study was to determine the LIC in children with ALL, who had been completed the treatment, by R2 MRI method and to compare with serum iron parameters.…”

Inhibitory effect of iron withdrawal by chelation on the growth of human and murine mammary carcinoma and fibrosarcoma cells

“…Clinical trials suggest that iron chelation is effective in the treatment of certain hematopoietic cancers (Lyons et al, 2014;Olcay et al, 2014;Yee et al, 2006); however, iron withdrawal has yet to undergo clinical trials as a treatment option for solid tumors. In this study, we show that the novel hydroxypyridinone-class iron chelator DIBI inhibited the growth of MDA-MB-468 human mammary carcinoma, 4T1 mouse mammary carcinoma, HT1080 human fibrosarcoma, and L929 mouse fibrosarcoma cells in a time-and dose-dependent manner.…”