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1.
Iron overload following hematopoietic stem cell transplantation: Prevalence, severity and management in children and adolescents with malignant and non-malignant diseases
Cattoni, A., Capitoli, G., Casagranda, S., Corti, P., Adavastro, M., Molinaro, A., Gennaro, F. D., Bonanomi, S., Biondi, A., Galimberti, S., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Iron overload (IOL) is a frequently reported complication following hematopoietic stem cell transplantation (HSCT) which has been extensively assessed in the field of hemoglobinopathies, but has not been thoroughly characterized after HSCT in pediatric malignancies. OBJECTIVES Our aim was to assess prevalence, severity, risk factors and management of IOL, as defined by means of biochemical (serum ferritin) and radiological tools (T2*-MRI), in a cohort of pediatric patients transplanted for either malignant or benign diseases. STUDY DESIGN Monocentric, retrospective, observational study. All the 163 patients alive and in continuous remission 24 months after HSCT, out of the 219 consecutive children and adolescents transplanted at our Institution between 2012 and 2018, were included in the study. IOL was classified into four categories, i.e. absent, mild, moderate and severe. RESULTS Of the 163 patients, 73% had some degree of IOL, which was mild, moderate and severe in 37%, 29% and 7%, respectively. Moderate/severe IOL was more frequent among patients diagnosed with a malignant versus benign disease (43% vs 19%; p 0.0065). Ferritin trend lines showed a "bell-shaped" distribution, with the highest levels being recorded during the first 6 months after HSCT, followed by a spontaneous reduction. Both pre-HSCT (1659 versus 617 ng/mL, p<0.001) and maximum post-HSCT (2473 ng/mL versus 1591 ng/mL, p<0.001) median ferritin levels were statistically higher among patients with malignancies. Radiological assessment of IOL confirmed a more severe degree in malignant compared to benign disorders (median T2*-MRI 4.20 msec, IQ: 3.0-6.40 versus 7.40, IQ: 4.90-11.00, respectively - p 0.008). T2* levels were associated with the number of transfusions performed (p 0.0006), with a steeper drop in T2* values for the first 20 transfusions and a milder slope subsequently. T2* and ferritin values showed a statistically significant negative exponential relationship (p<0.0001), though ferritin levels ≥1000 ng/mL showed a poor specificity (48%) and positive predictive value (53%) in discriminating moderate-to-severe from absent-mild IOL as assessed by T2*-MRI, but high sensitivity (92%) and negative predictive value (91%). In a multivariable model, >20 transfusions (OR 4.07, 95% CI 1.61-10.68, p 0.003) and higher pre-HSCT ferritin levels (p<0.001) were associated with the risk of developing moderate-to-severe IOL. A sibling donor (OR 0.29, 95% CI 0.10-0.77, p 0.015) and a non-malignancy (OR 0.27, 95% CI 0.08-0.82, p 0.026) were protective factors. Phlebotomies (66%), low-dose oral chelators (9%) or a combined approach (25%) were started at a median of 12 months after HSCT in 78% of the patients with IOL. Six% of the patients treated exclusively with phlebotomies (median 14, significantly higher in patients >40 kg) discontinued them due to poor venous accesses, lack of compliance or hypotension, whereas 39% of patients treated with chelators developed mild renal or hepatic side effects which resolved upon tapering or discontinuation. CONCLUSIONS Patients with malignancies showed statistically higher pre- and post-HSCT ferritin levels and lower T2*. High ferritin recorded upon T2*-MRI showed unsatisfactory diagnostic accuracy in predicting IOL, thus, T2*-MRI should be regarded as a key element to confirm IOL after HSCT in patients with elevated ferritin levels. IOL treatment is feasible after HSCT.
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2.
Efficacy and Safety of Iron Chelation Therapy After Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Thalassemia Patients: A Retrospective Observational Study
Kupesiz, F. T., Sivrice, C., Akinel, A., Kintrup, G. T., Guler, E., Kupesiz, A.
Journal of pediatric hematology/oncology. 2022;44(1):e26-e34
Abstract
BACKGROUND Studies on the increased body iron load in patients with thalassemia major have thoroughly demonstrated the problems caused by iron overload. In patients who undergo hematopoietic stem cell transplantation (HSCT) as curative therapy, iron overload continues long after transplantation. There are few pediatric studies on chelation therapy in the posttransplant period. In this study, we present the outcomes of our patients who received posttransplant oral chelation therapy. PATIENTS AND METHODS This retrospective observational study evaluated the outcomes of pediatric patients with thalassemia major who used oral chelation therapy after allogeneic HSCT at the Akdeniz University Pediatric Bone Marrow Unit between January 2008 and October 2019. RESULTS Deferasirox therapy was initiated in 58 pediatric patients who underwent HSCT for thalassemia. Pretreatment mean serum ferritin was 2166±1038 ng/mL. Treatment was initiated at a mean of 12±6.7 months after transplantation and continued for a mean of 15.7±11.5 months. At treatment discontinuation, the mean serum ferritin was 693±405 ng/mL and the mean reduction was -1472.75±1121.09 ng/mL (P<0.001 vs. posttreatment). Serum ferritin was below 500 ng/mL in 52% of the patients at treatment discontinuation. Manageable side effects such as nausea, vomiting, liver enzyme elevation, and proteinuria were observed in 17% of the patients, while one patient developed ototoxicity. CONCLUSIONS Deferasirox therapy effectively reduces iron overload in the posttransplant period. Studies evaluating the effects of early treatment on the graft may help to establish guidelines for posttransplant chelation therapy. Clear guidelines are needed regarding when to initiate and discontinue treatment.
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3.
Outcome of iron reduction therapy in ex-thalassemics
Aboobacker, F. N., Dixit, G., Lakshmi, K. M., Korula, A., Abraham, A., George, B., Mathews, V., Srivastava, A.
PloS one. 2021;16(1):e0238793
Abstract
There is limited data on iron reduction therapy (IRT) after successful allogeneic haematopoietic stem cell transplantation (aHSCT) for patients with thalassemia major (TM). We present the long term outcome of IRT in 149 patients with TM who underwent aHSCT during January, 2001-December, 2012. The median age was 7 years (range:1-18) and 92 (61.7%) belonged to Pesaro class 3 with a median ferritin at aHSCT of 2480ng/ml (range:866-8921). IRT was reinitiated post-aHSCT at a median of 14 months (range:5-53) post aHSCT with phlebotomy alone in 10 (6.7%) patients or iron chelation alone in 60 (40.3%) patients while 79 (53%) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month) was as follows: 87 (range:33-195), 130 (range:17-1012) and 147 (range:27.7-1427) in the phlebotomy, chelation and combination therapy groups, respectively (p = 0.038). With a median follow up of 80 months (range:37-182), target ferritin level of <300ng/ml was achieved in 59(40%) while a level <500ng/ml was achieved in 88 patients (59%) in a median duration of 41 months of IRT (range: 3-136). Patients in class III risk category and higher starting serum ferritin levels (>2500ng/ml) were associated with delayed responses to IRT. Our data shows that IRT may be needed for very long periods in ex-thalassaemics to achieve target ferritin levels and should therefore be carefully planned and initiated as soon as possible after aHSCT. A combination of phlebotomy and iron chelators is more effective in reducing iron overload.
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4.
Retrospective Evaluation of Relationship Between Iron Overload and Transplantation Complications in Pediatric Patient Who Underwent Allogeneic Stem Cell Transplantation Due to Acute Leukemia and Myelodysplastic Syndrome
Kupesiz, F. T., Hazar, V., Eker, N., Guler, E., Yesilipek, M. A., Tuysuz, G., Kupesiz, A.
Journal of pediatric hematology/oncology. 2020
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is a curative therapy option for hematologic malignancies. Iron overload is common in this patient group and can impact short-term and long-term nonrelapse mortality. STUDY DESIGN Retrospective observational cohort study. AIMS To evaluate the effect of iron load on early and late HSCT outcomes in patients with acute leukemia and myelodysplasia in order to assess the necessity of reducing iron load. PATIENTS AND METHODS Sixty patients who underwent HSCT in pediatric stem cell transplantation unit between 2000 and 2012 were evaluated retrospectively. The patients were divided into those with pretransplantation serum ferritin levels above and below the median value of 1299 ng/mL. RESULTS Forty-two (70%) of the patients were male, mean ages of the low and high ferritin groups were 85.43+/-9.42 and 118.56+/-10.04 months, respectively. Acute graft-versus-host disease (GVHD) within the first 100 days and acute liver GVHD were significantly more common in the high ferritin group (P<0.011 for both). Ferritin level was not associated with rates of engraftment syndrome, veno-occlusive disease, early/late infection, relapse, or overall and disease-free survival. CONCLUSIONS In our study, significant result especially in terms of acute liver GVHD, was important to emphasize the need to be more careful in terms of acute liver GVHD risk in early liver pathologies in patients with high levels of ferritin after transplantation. In future large studies may be helpful to explain the relationship between acute liver GVHD and high ferritin levels.
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5.
Quantification of Liver Iron Overload: Correlation of MRI and Liver Tissue Biopsy in Pediatric Thalassemia Major Patients Undergoing Bone Marrow Transplant
Bafna, V., Bhat, S., Raj, V., Badiger, S., Annapandian, V. M., Nataraj, K. S., Damodar, S.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2020;36(4):667-673
Abstract
Determination of the magnitude of body iron stores helps to identify individuals at risk of iron-induced organ damage in Thalassemia patients. The most direct clinical method of measuring liver iron concentration (LIC) is through chemical analysis of needle biopsy specimens. Here we present a noninvasive method for the measurement of LIC in vivo using magnetic resonance imaging (MRI). Twenty-three pediatric Thalassemia major patients undergoing bone marrow transplantation at our centre were studied. All 23 patients had MRI T2* and R2* decay time for evaluation of LIC on a 1.5 Tesla MRI system followed by liver tissue biopsy for the assessment of iron concentration using an atomic absorption spectrometry. Simultaneously, serum ferritin levels were measured by enzymatic assay. We have correlated biopsy LIC with liver T2* and serum ferritin values with liver R2*. Of the 23 patients 11 were males, the mean age was 8.3 ± 3.7 years. The study results showed a significant correlation between biopsy LIC and liver T2* MRI (r = 0.768; p < 0.001). Also, there was a significant correlation between serum ferritin levels and liver R2* MRI (r = 0.5647; p < 0.01). Two patients had high variance in serum ferritin levels (2100 and 4100 mg/g) while their LIC was around 24 mg/g, whereas the difference was not seen in T2* MRI. Hence, the liver T2* MRI is a better modality for assessing LIC. Serum ferritin is less reliable than quantitative MRI. The liver T2* MRI is a safe, reliable, feasible and cost-effective method compared to liver tissue biopsy for LIC assessment.
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6.
Evaluation of liver tissue by ultrasound elastography and clinical parameters in children with multiple blood cell transfusions
Wurschi, G. W., Kentouche, K., Herrmann, K. H., Krumbein, I., Nold, M., Beck, J. F., Reichenbach, J. R., Mentzel, H. J.
Pediatric radiology. 2019
Abstract
BACKGROUND Children receiving multiple blood cell transfusions are prone to iron overload and successive tissue damage in liver parenchyma, making noninvasive screening options desirable. Ultrasound (US) elastography using acoustic radiation force impulse (ARFI) imaging enables evaluation of liver parenchyma stiffness, and MRI allows for quantification of liver iron concentration. OBJECTIVE The objective was to correlate US elastography with MRI in children who had undergone bone marrow transplantation and to evaluate the modification of liver tissue with US in combination with clinical parameters at follow-up. MATERIALS AND METHODS ARFI, T2*-weighted MRI and a clinical score (HepScore, based on parameters of liver function) were performed in 45 patients (24 male; mean age 9.7 years) before and 100 days and 365 days after transplantation. All received multiple blood transfusions (mean number 22.2 up until 1 year after transplantation). We correlated US findings and HepScore with MRI findings. RESULTS We observed signs of iron accumulation in 29/45 (64.4%) patients on MRI (T2*<10 ms) and 15/45 (33.3%) showed increased tissue stiffness (ARFI>5.5 kPa). Correlation of elastography and MRI was not significant (P=0.57; n=51 matched measurements). Comparing US elastography with HepScore in receiver operating characteristic (ROC) curve analysis indicated a cut-off for affected parenchyma if HepScore was >5 points (sensitivity 67%, specificity 68%). Simultaneous increases of both indicated tissue alteration. CONCLUSION Combining US and HepScore enabled detection of liver tissue alteration through iron overload, but we found no direct significant effect of estimated iron from MRI on ARFI imaging.
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7.
MRI as an alternative to serum ferritin for diagnosis of iron overload in children in the context of immune response after stem cell transplantation
Wurschi, G. W., Mentzel, H. J., Herrmann, K. H., Krumbein, I., Beck, J. F., Reichenbach, J. R., Kentouche, K.
Pediatric transplantation. 2019;:e13583
Abstract
Multiple blood cell transfusions may cause iron overload or even liver fibrosis, requiring early diagnosis and intervention. SF is the standard for estimating iron levels in the body, but it also increases with inflammation. We hypothesized that T2 * magnetic resonance (MR) relaxometry is a more accurate alternative for follow-up in pediatric patients before and after allogenic SCT. Twenty-three children (mean age 10.2 years, 10 female, 13 male) were evaluated prospectively before SCT as well as at least 1 year after SCT with T2 * relaxometry on a 1.5 T MR-scanner to estimate liver iron concentrations from the T2 * values ("MR-Fe"). The results were compared with SF, while also considering CRP, and correlated with the number of transfusions. Overall, 24.3 transfusions were administered in average, mainly within 100 days of SCT (mean 10.5 units). Both MR-Fe and SF increased after SCT and decreased in the absence of new transfusions 1 year later without chelate therapy. This suggests regeneration of LP and iron loss, although the original states were not reached. Additionally, simultaneous peaks of CRP and SF were observed directly after SCT. MR-Fe did neither reveal these peaks nor was it associated with CRP (P = .39). We postulate that these early CRP and SF peaks after SCT are probably related to inflammatory reactions and not to iron overload. Thus, SF is not reliable for iron overload diagnosis after SCT in every condition. Beside this interaction, SF and MR-Fe revealed similar accuracy. MRI, however, has practical and economical disadvantages in routine estimation of iron.
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8.
Hepatic focal nodular hyperplasia after pediatric hematopoietic stem cell transplantation: The impact of hormonal replacement therapy and iron overload
Cattoni, A., Rovelli, A., Prunotto, G., Bonanomi, S., Invernizzi, P., Perego, R., Mariani, A. M., Balduzzi, A.
Pediatric blood & cancer. 2019;:e28137
Abstract
BACKGROUND The advent of techniques for the assessment of iron overload (liver T2*-MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. METHODS We performed a retrospective analysis of the liver T2*-MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. RESULTS Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 +/- 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate-to-severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI-T2* values in affected patients were statistically lower than healthy controls (P < .001). CONCLUSIONS We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.
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9.
One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation
Inati, A., Kahale, M., Sbeiti, N., Cappellini, M. D., Taher, A. T., Koussa, S., Nasr, T. A., Musallam, K. M., Abbas, H. A., Porter, J. B.
Pediatric Blood & Cancer. 2017;64(1):188-196
Abstract
BACKGROUND Iron overload is well documented in patients with beta-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with beta-thalassemia major following HSCT. RESULTS Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 +/- 10.1 to 8.5 +/- 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 +/- 6.8 to 8.3 +/- 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 +/- 1.5 vs. -3.5 +/- 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with beta- thalassemia major post-HSCT, with a manageable safety profile. Copyright © 2016 Wiley Periodicals, Inc.
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10.
MRI-based evaluation of multiorgan iron overload is a predictor of adverse outcomes in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation
Maximova, N., Gregori, M., Boz, G., Simeone, R., Zanon, D., Schillani, G., Zennaro, F.
Oncotarget. 2017;8(45):79650-79661
Abstract
The medical records of 44 pediatric patients who underwent allogeneic transplantation from 2011 to 2015 were retrospectively reviewed. Magnetic resonance imaging was used to measure iron concentrations in the liver, spleen, pancreas and bone. These patients were divided into two groups, 18 with non-elevated (< 100 mumol/g; Group 1) liver iron concentration before transplantation and 26 with elevated (> 100 mumol/g; Group 2) concentration . We compared transplant-related outcomes in the two groups. Iron overload was a negative prognostic risk factor for sinusoidal obstruction syndrome (OR = 17), osteoporosis (OR = 6.8), pancreatic insufficiency (OR = 17) and metabolic syndrome (OR = 15.1). No statistically significant differences in overall survival, disease-free survival, relapse incidence and incidence of acute or chronic graft-versus host disease were observed between the two groups. Mean times to engraftment of platelets (43.0 +/- 35.3 days vs. 22.1 +/- 9.5 days, p < 0.05) and neutrophils (23.1 +/- 10.4 days vs. 17.8 +/- 4.6 days, p < 0.05) appear significantly longer in Group 2 than in Group 1. Time to platelet engraftment showed statistically significant correlation with pre-transplant liver (r = 0.5775; p < 0.001) and bone iron concentration (r = 0.7305; p < 0.001). Post-transplant evaluation pointed out that iron concentration analyzed at the first follow-up peaked in all tissues. The iron accumulation was highest in bone, followed by the spleen, liver and pancreas. One year post transplant 9 of 18 (50%) patients in Group 1 and 6 of 22 (27%) in Group 2 presented with bone and/or spleen iron overload, but not with liver overload. Liver iron concentration is not always a reliable indicator of systemic siderosis or of the efficacy of chelation therapy. CONFLICTS OF INTEREST The authors declare that they have no competing interests.