Significant Impact Of Iron Chelation After Allogeneic Hematopoetic Stem Cell Transplantation On Disease Recurrence: Potential Anti-Leukemic Activity

Abstract Iron overload (IO), primarily related to multiple red blood cell transfusions, is a relatively common complication in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Elevated pre-transplant ferritin level, a surrogate marker of iron overload, was demonstrated to be an important cause of mortality and morbidity in patients who have undergone allo-HSCT. Excessive iron accumulation results in tissue damage and organ failure, mainly as a result of the generation of free radicals that cause oxidative damage and organ dysfunction. Iron chelators have been widely used leading to normalisation for ferritine level and lower IO-related complications. As iron has a fundamental role in cell survival affecting pathways involved in DNA synthesis, cell differentiation, and apoptosis, some studies evaluated the anti-proliferative activity of iron chelators in cancer and leukemia patients on disease recurrence. The objective of this study was to determine at a first time the impact of serum ferritin level measured at time of allogeneic HSCT in adult patients with hematological disorders on the different outcomes and to investigate at a second time the role of iron chelation on relapse incidence. We included 158 patients, 100 males and 58 females with a median age of 45 years (18-67) who underwent allo-HSCT between 2002 and 2010. There were 83 acute myeloid leukemias, 10 chronic myeloid leukemias, 11 myelodysplastic syndromes, 7 myeloproliferative disorders, 19 myelomas, 9 non-Hodgkin lymphomas, 6 Hodgkin diseases, 5 aplastic anemias and 3 hemoglobinopathies. Sixty-seven (42%) patients were sex mismatched (F→M:37; M→F:30); for ABO compatibility, 61% were compatible, 18% had minor incompatibility and 21% had major incompatibility. Concerning the HSCT procedures, 60 patients (38%) received peripheral blood stem cell and 98 (62%) received bone marrow from 97 (61%) HLA related donors [matched, n=76; mismatched, n=21], and 61 (39%) HLA unrelated donors [matched, n=36; mismatched, n=25] after myeloablative [n=64, (41%)] or reduced intensity conditioning [n=94, (59%)]. At transplantation, 91 (58%) were in complete remission (CR) or chronic phase [CR1: n=61 (67%); ≥CR2: n=30 (33%)]. The median serum ferritin level at HSCT was 1327 microg./l (26-14136); 31(20%) patients had a level 26-500, 33 (21%) had a level 500-2500, and 94 (59%) >2500. There was no significant correlation between the different ferritin levels, disease kind and status at HSCT. After transplantation, 23 patients received iron chelating agents after a serum ferritin level of 1000 microg/l and stopped when the level decreased below 1000. The cumulative incidence of acute GVHD ≥ II at 3 months was 14% (11-16.5) with 10.5% (8-13) for grade III and 7% (5-9) for grade IV; the 1 year cumulative incidence of limited and extensive chronic GVHD were 4% (2-6) and 12.4% (9-16) respectively. After a median follow-up of 18 months (1-106), the 5 years OS probability was 65% for patients with ferritin level below 500 microg./l, 39% for level between 500 and 2500 microg./l and 28% for level > 2500 micog./l, [Hazard ratio= 3.5 (1.5-8.1), p=0.002]; this was explained by a significant higher TRM in patients with level >2500 [Hazard ratio= 4.3 (1.02-18), p=0.04]. Interestingly, we found in multivariate analysis that patients receiving iron chelators had significantly better OS [5 years OS= 59% vs. 34% for non-chelated patients, Hazard ratio= 0.34 (0.15-0.76), p=0.008], (Figure 1a), and experienced less disease relapse [5 years relapse incidence= 18% vs. 41% for non-chelated patients, Hazard ratio= 0.22 (0.07-0.73), p=0.012], (Figure 1b). In conclusion, we confirmed the negative impact of iron overload on the outcomes allo-HSCT recipients. More importantly, we demonstrated that iron chelators have a positive impact in reducing disease relapse by the possible mechanism of iron deprivation in leukemic cells. This clinical observation needs to be confirmed by prospective randomized trials.Figure 1a: Overall survival probability and b: relapse incidence in patients with or without iron chelationFigure 1. a: Overall survival probability and b: relapse incidence in patients with or without iron chelation Disclosures: Michallet: Novartis: Honoraria, Research Funding. Nicolini:Novartis: Consultancy, Honoraria, Research Funding.

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Hematologic Improvement with Iron Chelation using therapy Deferasirox in Patients with Aplastic Anemia: A Subgroup Analysis of KAMS0112 Prospective Study,

Blood ◽

10.1182/blood.v118.21.3424.3424 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3424-3424

Author(s):

Yoo-Hong Min ◽

Sung-Soo Yoon ◽

Hyeoung Joon Kim ◽

Kyoo-Hyung Lee ◽

Jae Hoon Lee ◽

...

Keyword(s):

Platelet Count ◽

Iron Overload ◽

Serum Ferritin ◽

Research Funding ◽

Serum Ferritin Level ◽

Ferritin Level ◽

Iron Chelation ◽

Hemoglobin Level ◽

Hematopoietic Stem ◽

Wbc Count

Abstract Abstract 3424 Patients with aplastic anemia (AA) are suffered from various complications related to bone marrow failure and peripheral cytopenia. Although immunosuppressive therapy or hematopoietic stem cell transplantation has been performed for curative purpose, the majority of patients have been treated only by supportive cares including repeated transfusion. However, because continued transfusion eventually induces iron overload in many tissues and organs, transfusional iron overload and its consequences are another life-threatening problems for AA patients. Previous reports about iron chelation therapy (ICT) have mainly shown its efficiency for decreasing tissue iron and safety. However, improvement in hematopoiesis after iron chelation therapy has been limitedly reported as case reports or trials involving small number of patients without objective tools for measuring tissue iron content. In the KAMS0112 study (a multi-center, open label, prospective study evaluating the efficacy of ICT with deferasirox in transfusional iron overload with myelodysplastic syndrome or AA using quantitative R2-MRI, Ferriscan), a total of 54 patients with AA showing serum ferritin level over 1,000 ng/ml were enrolled from 19 institutes, and further analyzed for the changes in hemogram during ICT as well as efficacy and safely of deferasirox. During the study, the specific treatments for AA, such as immunosuppressive therapy or hematopoietic stem cells transplantation, were not undertaken. During 1 year prior to study, patients received 23.7±16.9 units of red blood cell (RBC) product, and the baseline serum ferritin level and liver iron content (LIC) were 4,164±447 ng/ml and 20.1±12.0 mg Fe/g DW, respectively. Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin level falls below 500 ng/ml, treatment was withheld. In spite of continued transfusional support during the study, serum ferritin level and LIC were significantly decreased after 1 year of ICT with deferasirox (Ds-ferritin=−3,076.7±489.9 ng/ml, p=0.0003; DLIC=−7.73 mg/Fe/g DW, p=0.001). To evaluate the improvement of each parameter in hemogram by ICT, patients with baseline hemoglobin level less than 8.0 g/dl (n=28), with baseline WBC count less than 4/ml (n=43), and with baseline platelet count less than 20/ml (n=31) were selected separately. At the end of study, hemoglobin level and platelet count (8.2±3.0 g/dl and 22.2±31.4/ml, respectively) was significantly increased from the baseline value (6.1±1.1 g/dl, p=0.001; 12.5±12.4/ml, p=0.05, respectively). WBC count was also slightly increased (from 2.1±0.9/ml to 2.3±0.9/ml, p=0.457). Considering the relatively uniform criteria of transfusion, the finding that hemoglobin level and platelet count could increase above 8 g/dl and 20/ml, respectively, after 1 year of deferasirox treatment is clinically significantly. Due to gradual improvement of anemia, requirement of RBC transfusion had continuously decreased during the study period (R2=0.31). This subanalysis of KAMS0112 study demonstrates that ICT using deferasirox can be effective in improving anemia and thrombocytopenia in the transfusional iron overload patients with AA, as well as reducing serum ferritin level and LIC. Further studies might be required to elucidate the mechanism involved in the improvement of hematopoiesis associated with correction of deranged intracellular iron homeostasis. Disclosures: Min: Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Lee:Novartis: Research Funding. Won:Novartis: Research Funding. Shim:Novartis: Research Funding. Kim:Novartis: Research Funding. Seung:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Chung:Novartis: Research Funding. Hyun:Novartis: Research Funding. Jo:Novartis: Research Funding. Jung:Novartis: Research Funding. Sohn:Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Joo:Novartis: Research Funding. Cheong:Novartis: Research Funding.

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A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox in Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 MRI

Blood ◽

10.1182/blood.v112.11.3649.3649 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3649-3649 ◽

Cited By ~ 1

Author(s):

Yoo-Hong Min ◽

Hyeoung Joon Kim ◽

Kyoo Hyung Lee ◽

Sung-Soo Yoon ◽

Jae Hoon Lee ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Chelation Therapy ◽

Transfusion Requirement ◽

Ferritin Level ◽

Iron Chelation ◽

Dry Weight ◽

Mean Value ◽

One Year

Abstract Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data. A total of 79 patients with de novo MDS (n = 29) or idiopathic AA (n = 50) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a median of 30 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (10.3%), 20 (69.0%), and 4 cases (13.8%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64%) were severe form. Mean value of serum ferritin level in enrolled patients was 4,417 ± 3,378 (4,788 ± 3,996 in MDS, 4,185 ± 2,962 in AA) ng/ml at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 23.9 ± 13.8 (26.1 ± 15.0 in MDS, 22.8 ± 13.2 in AA) mg Fe/g dry weight. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p<0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. A consistent decrease in the serum ferritin level was demonstrated during the first 6 months in vast majority of patients despite of continued transfusion (209.7 ± 159.9 ng/ml and 324.0 ± 289.4 ng/ml per month in MDS and AA, respectively). Over the study period, patients with MDS or AA received a mean of 3.7 and 2.7 units RBC per month, respectively. After 6 months of medication, a slower decrease in the serum ferritin level was observed in MDS patients. In 30 cases, one-year medication of deferasirox was completed. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,085 ± 2,150 ng/ml (64.4% of baseline level) and 2,913 ± 2,232 ng/ml (69.6% of baseline level, p<0.01) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 24 cases, and LIC was significantly decreased to the level of 19.3 ± 13.6 mg Fe/g dry weight (67.4% of baseline value, p=0.01). Decrease in the level of LIC at EOS in MDS (64.3% of baseline) was comparable to that in AA cases (68.5% of baseline). The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 28 (35.4%) cases because of death (7 in MDS and 6 in AA), patient refusal (11 cases), and decrease in the serum ferritin level below 500ng/ml (4 cases). All death was ascribed to disease-related causes including cytopenia in nine (11.4%) and disease progression in one (1.3%). This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient’s transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients.

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Multidisciplinary Evaluation Improves Efficacy and Safety of Iron Chelation Therapy with Deferasirox in MDS Elderly Patients

Blood ◽

10.1182/blood.v126.23.4558.4558 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4558-4558

Author(s):

Lisette Del Corso ◽

Elisa Molinari ◽

Andrea Bellodi ◽

Riccardo Ghio ◽

Andrea Bacigalupo ◽

...

Keyword(s):

Serum Creatinine ◽

Iron Overload ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Group A ◽

Group B

Abstract BACKGROUND: Iron overload from chronic transfusion therapy can be extremely toxic and most patients (pts) do not receive adequate iron chelation therapy (ICT) despite evidence of transfusional iron overload (IOL). Deferasirox (DFX) is the principal option currently available for ICT in the management of IOL due to transfusion dependent anemia, such as in MDS pts. The most common adverse events (AEs) are gastrointestinal disorders, skin rash, elevations in liver enzymes levels and non-progressive transient increases in serum creatinine also in MDS pts, most of whom are elderly with significant comorbidities and side effects of other concomitant therapies. In order to achieve effective ICT with minimal toxicity in individual pts, regular monitoring to assess IOL and adverse effects of DFX treatment is essential. METHODS: The safety and efficacy of DFX were examined in a retrospective multicenter observational study of transfusion-dependent (TD) MDS pts with International Prognostic Scoring System (IPSS) low-or Int-1-risk. We included all pts treated with DFX up to 12 months, divided into two groups; the first one (group A) not under a multidisciplinary assessment, including pts not adequately treated, in terms of dosing and discontinuation of ICT and the second one (group B) with pts under multidisciplinary control. The DFX starting dosing was 10 mg/kg/die in all pts. The aim of our retrospective analysis was to assess the effectiveness of ICT in relation of dosing and right management of AEs. RESULT: We evaluated 45 MDS pts (12F/33M); 27 belonging to the group A and 18 to group B. The age was 74.2±8.8 and 77.3±4.8 respectively. The ECOG 0-1 was 85,1% in group A and 88,9% in group B. The transfusion episodes prior starting DFX were22.1±12.1 and 24.5±35.4 in the first and in the second group, respectively. The serum ferritin level at baseline was respectively 1285.1±489.6 ng/mL and 1452.6±748.1 ng/mL. The mean serum ferritin level increased from 1285.1+489.6 ng/mL to 1412.1+842.8 ng/mL in group A while decreased from 1452.6+748.1 ng/mL to 1166.1+ 723.4 ng/mL in group B. The rate of inadequate therapy, in terms of dosing and/or discontinuation ICT, was 85% in group A compared to 60% in group B (p= 0.086).The rate of severe SAE observed in all pts was 10%.The most common AEs were diarrhea, nausea, upper abdominal pain, serum creatinine increase. The positive hematological response rate was observed in 15% of all pts. CONCLUSIONS: The study showed that group B obtained advantage in terms of efficacy and toxicity. The difference between the two groups derived from the ability to manage comorbidities, concomitant therapies and AEs, in particular the rise in serum creatinine, the most common cause DFX discontinuation or dosing reduction. In this setting, the most important specialist was the nephrologist. In our multidisciplinary group experts in management of ICT were hematologist, internist, immune-hematologist and nephrologist. We shared how we monitored kidney function and managed a possible nephrotoxicity (table.2), in order to ensure DFX efficacy. Positive hematological responses were observed, and a subset of pts achieved transfusion independence. The timing of future multidisciplinary evaluation is set on 24 and 36 months, time in which we expect the best response to DFX therapy. Table 1. Ferritin trend group A (n27) group B (n18) Ferritin N mean±SD Median (range) N mean±SD Median (range) Baseline 27 1285.1±489.6 1134 (388-2099) 18 1452.6±748.1 1515 (160-3018) 3 months 22 1451.5±720.5 1247.5 (529-2791) 13 1312.7±909.8 1064 (521-3859) 6 months 23 1850.5±1079.1 1419 (374-4185) 11 1168.4±648.4 1300 (160-2409) 12 months 17 1412.1±842.8 1372 (111-3127) 9 1166.1±723.4 930 (277-2536) Table 2. Management of renal changes during therapy with DFX Creatinine and urine examination:1) in two successive determinations prior to initiation of therapy, then every month 2) in pts with other risk factors for kidney disease, every week for 1 month after start of DFX or dose increase and, subsequently, every month Changes in creatinine:1) increased by 33% in two successive determinations: reduce DFX dose of 5 mg/kg 2) progressive increase of creatinine: interrupt DFX and then re-challenge it at a lower dose with gradual increase if the clinical benefits outweigh the risks Disclosures No relevant conflicts of interest to declare.

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Prognostic Impact of Posttransplantation Serum Ferritin In Allogeneic Stem Cell Transplantation for Leukemia or Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v116.21.3444.3444 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3444-3444

Author(s):

Heiwa Kanamori ◽

Takayoshi Tachibana ◽

Ayumi Numata ◽

Masatsugu Tanaka ◽

Yoshiaki Ishigatsubo ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Iron Overload ◽

Cell Transplantation ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Disease Risk ◽

Ferritin Level ◽

Standard Risk

Abstract Abstract 3444 Background: Although pretransplantation iron overload is an adverse prognostic factor in patients undergoing allogeneic stem cell transplantation (SCT), the impact of posttransplantation iron overload on the outcome is not clear. In this study, we retrospectively assessed the association of the posttransplantation serum ferritin level with the result of transplantation in patients surviving for 1 year or more after SCT. Patients and Methods: The serum level of ferritin, a marker of iron overload, was measured at the time of preconditioning and then annually in adult patients who underwent SCT between January 2000 and December 2008. Patients who received repeat transplantation or died within 1 year after the first SCT were excluded. There were 107 patients (pts), including 51 pts with acute myeloid leukemia, 30 pts with acute lymphoblastic leukemia, 14 pts with myelodysplastic syndrome, and 12 pts with chronic myelogenous leukemia. Their median age was 41 years (range: 16–60 years), with 52 males and 55 females. The disease risk at transplantation was standard risk in 82 pts and high risk in 25 pts. Myeloablative preconditioning was employed for 87 pts and reduced-intensity preconditioning was done for 20 pts. Bone marrow transplantation, peripheral blood stem cell transplantation, and cord blood transplantation were performed in 74, 25, and 8 pts, respectively. The serum ferritin level was categorized as low (< 1000 ng/ml) or high (≥ 1000 ng/ml). Patients who had one or more high ferritin levels after SCT were classified into the high ferritin group. Results: The median serum ferritin level before transplantation and 1, 2, 3, 4 and 5 years after SCT was 770 (n=107), 695 (n=75), 590 (n=65), 552 (n=61), 476 (n=51), and 430 (n=44) ng/ml, respectively. The median amount of red blood cells (RBC) transfused within 1 year after SCT was 6 units (range: 0–128). Patients receiving more than 6 units of RBC had significantly higher serum ferritin levels from 1 to 3 years after SCT. Patients with chronic graft-versus-host disease (cGVHD) showed significantly higher serum ferritin levels from 2 to 4 years after SCT compared to patients without chronic GVHD. There was no significant difference between the low and high pretransplantation ferritin groups with respect to 5-year overall survival (OS) (78% vs 82%, p=0.329). On univariate analysis, factors associated with worse 5-year OS included a high disease risk at transplantation (vs standard risk: 60 vs 87%, p=0.009), higher amount of RBC transfusion after SCT (vs lower: 73 vs 87%, p=0.015), the presence of cGVHD (vs absence: 73 vs 90%, p=0.023) and a high ferritin level after SCT (vs low ferritin: 64 vs 91%, p<0.001). A high ferritin after SCT was independently associated with worse 5-year OS according to multivariate analysis (relative to low ferritin; hazard ratio (HR), 3.42; 95% confidence interval (CI), 1.21–9.71; p=0.021). In addition multivariate analysis showed that a high disease risk (HR, 2.64; CI, 1.05–6.58; p=0.037) and a high ferritin level after SCT (HR, 5.24; CI, 1.94–14.27; p=0.001) were independent determinants of 5-year disease-free survival. Furthermore, the cumulative incidence of relapse was significantly higher in patients without cGVHD (HR, 3.44; CI, 1.19–9.92; p=0.023) and those with high ferritin levels after SCT (HR, 5.53; CI, 1.86–16.45, p=0.002). The cumulative non-relapse mortality rate was significantly higher in patients with cGVHD and high ferritin levels after SCT according to univariate, but not multivariate, analysis. Conclusions: Elevation of the serum ferritin level after SCT was significantly associated with a worse outcome for patients surviving more than 1 year, although various factors including RBC transfusion and/or cGVHD might have a role in the increase of posttransplantation serum ferritin. These results might help to decide which patients should be treated with iron chelating therapy after SCT. Disclosures: No relevant conflicts of interest to declare.

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A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox In Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 mri.

Blood ◽

10.1182/blood.v116.21.1125.1125 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1125-1125

Author(s):

Yoo-Hong Min ◽

Hyeoung Joon Kim ◽

Kyoo-Hyung Lee ◽

Jae Hoon Lee ◽

Hee-Sook Park ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Myelodysplastic Syndromes ◽

Serum Ferritin Level ◽

Chelation Therapy ◽

Transfusion Requirement ◽

Ferritin Level ◽

Iron Chelation ◽

Dry Weight ◽

Mean Value

Abstract Abstract 1125 Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data. A total of 97 patients with de novo MDS (n = 44) or idiopathic AA (n = 53) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a mean of 28.6 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (8.3%), 25 (69.4%), and 4 cases (11.1%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64.2%) were severe form. Mean value of serum ferritin level in enrolled patients was 3,482.6±436.7 ng/ml in MDS, and 3,904.4±399.2 ng/ml in AA at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 20.8 ± 3.5 mg Fe/g dry weight in MDS and 22.6 ± 2.2 mg Fe/g dry weight in AA. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p<0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. Over the study period, patients with MDS and AA received a mean of 24.2 and 22.0 units RBC per year, respectively. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,045.1±446.5 ng/ml and 2,614.7±311.9 ng/ml (p=0.005) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 55 cases, and at the end of study (EOS), the LIC were significantly decreased to 14.3±2.9 mg Fe/g dry weight (p=0.05) and 15.3±2.3 mg Fe/g dry weight (p=0.001) in MDS and AA, respectively. The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 30.9% cases because of death, patient refusal, and decrease in the serum ferritin level below 500ng/ml. All death was ascribed to disease-related causes. This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient's transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients. Disclosures: No relevant conflicts of interest to declare.

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Variables associated with malondialdehyde level in thalassemia major patients

Paediatrica Indonesiana ◽

10.14238/pi52.3.2012.125-31 ◽

2012 ◽

Vol 52 (3) ◽

pp. 125

Author(s):

Arum Gunarsih ◽

Pustika Amalia ◽

Imam Boediman

Keyword(s):

Oxidative Stress ◽

Vitamin E ◽

Iron Overload ◽

Serum Ferritin ◽

Medical Records ◽

Serum Ferritin Level ◽

Ferritin Level ◽

Iron Chelation ◽

Thalassemia Major ◽

Indirect Measurement

BackgmundThalassemia is the most cormnon hereditary haemolyticanaemia in the world, including in Indonesia. The main treatmentfor thalassemia is regular transfusions, but these are knO\vn to causeiron overload. Moreover, iron overload in jJ􀁮thalassemia patientsgenerates oxygen free radicals and peroxidative lipid injury. Ferritinserum concentration is used as indirect measurement of iron overload.Malondialdehyde (MDA), a terminal compound oflipid peroxidation,is used as an index of oxidative stress status.Objective To assess the correlation between iron overload (serumferritin level) and MDA as a marker of oxidative stress in thalassemiamajor patients.Methods This c ross􀁮sectional study was conducted at CiptoMangunkusumo Hospital, Jakarta, from May􀁮June 2009. Subjectswere thalassemia major patients (homozygous jJ􀁮thalassemia orjJ􀁮thalassemia;HbE) who received regular blood transfusions, iron􀁮chelation, and vitamin E as an antioxidant. Data was collected by his􀁮tory􀁮taking, physical examination, medical records, and questionnaires.Blocd specimens were dra\Vll from the thalassemia major subjects beforetransfusion and examined for serum ferritin and MDA levels.Results Fifty􀁮five subjects Mth thalassemia major (34 homozygousjJ􀁮thalassemia and 21 jJ􀁮thalassemia;HbE) were included in ourstudy. Mean serum ferritin level was 3693.2 (SD 21423),ug/L andme811 MDA level was 0.641 (SD 0.283) nmolimL. No cor relationwas found between serum ferritin and MDA levels in thalassemiamajor subjects (r=0.147, P=0.285). As additional results, this studyalso showed no correlation between MDA to reguler vitamin Econsumption (r=0.277, P=0.028) as well as MDA and nutritionalstatus (F0371, P􀁯0.()J4).Conclusion There was no cor relation between serum ferritin leveland plasma MDA level in thalassemia major subjects, no cor relationsbetween MDA and regular vitamin E consumption, as well as MDAand nutritional status. [paediatr Indones. 2012;52:125,31].

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Natural Course Of Serum Ferritin In Childhood Cancer Survivors: Need For Iron Removal Therapy?

Blood ◽

10.1182/blood.v122.21.2394.2394 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2394-2394 ◽

Cited By ~ 1

Author(s):

Hideaki Maeba ◽

Rie Kuroda ◽

Toshihiro Fujiki ◽

Shintaro Mase ◽

Raita Araki ◽

...

Keyword(s):

Iron Overload ◽

Cancer Survivors ◽

Childhood Cancer ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Childhood Cancer Survivors ◽

Iron Chelation Therapy

Abstract Background Iron overload has been reported in adult survivors of leukemia after chemotherapy with or without allogeneic hematopoietic stem cell transplantation (allo-HSCT). Approximately 10-15% of adult survivors suffer from liver dysfunction, endocrine disorders, and/or cardiac dysfunction due to iron overload, in which free radicals produced by iron could damage tissues. Therefore phlebotomy and iron chelation therapy in adult survivors have been used prophylactically, however iron overload has not been studied extensively in childhood survivors, so that it would be a problem how to manage the childhood patients in whom serum ferritin level was high at the completion of chemotherapy. In this study, we retrospectively analyzed the serum ferritin level over time after the completion of therapy and also referred to whether iron chelation therapy and/or phlebotomy would be needed or not in childhood survivors. Patients and methods We retrospectively analyzed the level of serum ferritin overtime in 48 childhood cancer survivors (ALL 19, AML 13, Lymphoma 5, Pediatric solid tumor 11) except allo-HSCT, who were transfused concentrated red cells in our hospital. All the patients did not receive any phlebotomy and iron chelation therapy throughout the course. Results The total mean concentrated blood transfusion volume was 114 ml/kg (114±16, ranges 7-672). At the completion of chemotherapy, the median serum ferritin level was 867 ng/ml (867±216, ranges 7-6558). Three years after chemotherapy, the median serum ferritin levels decreased to 281 ng/ml (281±77, ranges 7-1285). All patients did not show any symptoms related to iron overload such as liver dysfunction and glucose intolerance. Twelve out of 48 patients (25%) exceeded 1000 ng/ml of the serum ferritin at the time of completion of chemotherapy, which has been considered as the initiation of iron chelation therapy in adult patients. However all patients except one decreased the serum ferritin level below 1000 ng/ml in 3 years after chemotherapy without any iron removal therapy. Although serum ferritin level in the exceptional case was extraordinary high (6558 ng/ml) compared to other cases at the completion of chemotherapy, it declined to 1285 ng/ml spontaneously in 3 years, which was much better than expected. Conclusions Although 25 percent of our childhood cancer survivors showed high level of serum ferritin more than 1000 ng/ml at the time of completion of chemotherapy, almost all the cases eventually declined thereafter without any iron removal therapy probably due to the iron consumption with growth. Further study would be needed to make specialized criteria for initiating iron removal therapy for childhood cancer survivors. Disclosures: No relevant conflicts of interest to declare.

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Noninvasive assessment of iron overload by magnetic resonance imaging

Pediatric Hematology/Oncology and Immunopathology ◽

10.24287/1726-1708-2020-19-3-158-163 ◽

2020 ◽

Vol 19 (3) ◽

pp. 158-163

Author(s):

E. E. Nazarova ◽

D. A. Kupriyanov ◽

G. A. Novichkova ◽

G. V. Tereshchenko

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Iron Overload ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Ferritin Level ◽

Iron Concentration ◽

The Body ◽

Iron Accumulation ◽

Resonance Imaging

The assessment of iron accumulation in the body is important for the diagnosis of iron overload syndrome or planning and monitoring of the chelation therapy. Excessive iron accumulation in the organs leads to their toxic damage and dysfunction. Until recently iron estimation was performed either directly by liver iron concentration and/or indirectly by measuring of serum ferritin level. However, noninvasive iron assessment by Magnetic resonance imaging (MRI) is more accurate method unlike liver biopsy or serum ferritin level test. In this article, we demonstrate the outlines of non-invasive diagnostics of iron accumulation by MRI and its specifications.

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Tissue doppler imaging in thalassemia major patients: correlation between systolic and diastolic function with serum ferritin level

Paediatrica Indonesiana ◽

10.14238/pi52.4.2012.187-93 ◽

2012 ◽

Vol 52 (4) ◽

pp. 187 ◽

Cited By ~ 1

Author(s):

Syarif Rohimi ◽

Najib Advani ◽

Sudigdo Sastroasmoro ◽

Bambang Mardiyono ◽

Sukman Tulus Putra ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Tissue Doppler Imaging ◽

Negative Correlation ◽

Serum Ferritin Level ◽

Systolic Function ◽

Ferritin Level ◽

Tissue Doppler ◽

Doppler Imaging ◽

Number Of Patients

Background Thalassemia is a major public health problem inIndonesia. Cardiac diseases remain as the main cause of death inthese patients due to iron overload. Although the T2* magneticresonance imaging has been considered as the gold standard forassessing cardiac iron overload but it has limited availability.The tissue doppler imaging (TDI) echocardiography, a fairly newand easy method that is suggested, can detect early abnormalmyocardial iron overload.Objective To assess myocardial systolic and diastolic functionof thalassemic patients using TDI and examine their correlationwith serum ferritin level.Methods A cross􀁌sectional study was conducted from January toMarch 2011 at the Harapan Kita Women and Children Hospital.We performed clinical examination, serum ferritin level, as wellas conventional and tissue doppler echocardiography on allsubjects.Results We included 34 regularly􀁌tranfused patients, of which17 were boys. The mean age of the subjects was 11.6 (SD 4.7years, range 2.6 􀁌 20 years). Mean pulse rate and blood pressurewere within normal range. Hemoglobin level at inclusion rangedfrom 5.8 to 6 g/dL. Almost all patients did not receive regularchelation therapy. Median serum ferritin level was 6275 ng/mL(range 2151 - 17,646 ng/mL). Conventional echocardiographyshowed normal systolic function, but some diastolic dysfunctionswere found including E wave abnormalites in 4 patients, A waveabnormalites in 3, and E/A ratio abnormalites found in 3. TheTDI showed decreased systolic function (Sa wave abnormality) in9 patients and diastolic dysfunctions (Ea wave abnormality in 11patients and Aa wave abnormaly in 2). No abnormality was foundin Ea/Aa and ElEa ratios. There was a weak negative correlationbetween ferritin level and Sa wave and Ea wave respectively anda moderately negative correlation between ferritin level and Ea/Aa ratio. There was no correlation between serum ferritin andAa wave or ElEa ratio.Conclusion TDI identifies a greater number of patients Mthsystolic and diastolic myocardial dysfunction than was revealedby conventional echocardiography. There was a weak negativecorrelation between serum ferritin to Sa wave and Ea wave, and amoderately negative correlation between ferritin and Ea/Aa ratio.There was no correlation between serum ferritin and Aa wave orElEa ratio. [paediatr Indones. 2012;52:187,93].

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LONGITUDINAL STUDY ON LIVER FUNCTIONS IN PATIENTS WITH THALASSEMIA MAJOR BEFORE AND AFTER DEFERASIROX (DFX) THERAPY

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2014.025 ◽

2014 ◽

Vol 6 (1) ◽

pp. e2014025 ◽

Cited By ~ 5

Author(s):

Ashraf Tawfik Soliman ◽

Mohamed Yassin ◽

Fawzia AlYafei ◽

Lolwa Al-Naimi ◽

Noora Almarri ◽

...

Keyword(s):

Liver Function ◽

Iron Overload ◽

Serum Ferritin ◽

Negative Correlation ◽

Ferritin Level ◽

Iron Chelation ◽

Thalassemia Major ◽

Growth Potential ◽

Igf I ◽

Liver Functions

With regular blood transfusion and iron chelation therapy, most patients with thalassemia major (BTM) now survive beyond the third decade of life . Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are important causes of liver pathology. Iron chelation with desferrioxamine (Desferal) reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox (Exjade- DFX ), an oral single dose therapy has improved the compliance to chelation therapy.Aims: To study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX therapy in relation to ferritin level and IGF-I level.Methods: Liver function tests including: serum bilirubin, alanine transferase (ALT), aspartate transferase (AST) , albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every 6 months in 40 patients with BTM, with hepatitis negative screening (checked every year), for at least five years of DFO therapy and 4-5 years of DFX therapy .Results: DFX therapy (20 mg/kg/day) significantly decreased serum ferritin level in patients with BTM, this was associated with significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum ferritin concentrations ( r = 0.45 and 0.33 respectively , p < 0.05) . IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels.The negative correlation between serum ferritin concentrations and ALT suggests that impairment of hepatic function negatively affects IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis.Conclusions: Some impairment of liver function can occur in hepatitis negative BMT patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients.

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