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

Blood ◽  
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.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 180-180 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Helene Labussiere ◽  
Marie Y. Detrait ◽  
...  
Keyword(s):  
Stem Cell ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Disease Recurrence ◽  
Hazard Ratio ◽  
Iron Chelators ◽  
Myeloid Leukemias

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.

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 ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3649-3649 ◽  
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.

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

Blood ◽  
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.

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 ◽  
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.

scholarly journals High Post-Transplant Ferritin Level Associates with Adverse Survival and Higher Mortality Rate following Allogeneic Hematopoietic Stem Cell Transplant, whereas Pre-Transplant Ferritin Level Does Not

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3454-3454
Author(s):  
Warren Fingrut ◽  
Arjun Law ◽  
Wilson Lam ◽  
Fotios V. Michelis ◽  
Santhosh Thyagu ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Serum Ferritin ◽  
Research Funding ◽  
Serum Ferritin Level ◽  
Acute Gvhd ◽  
Ferritin Level ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Independent Prognostic Marker

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy for many hematologic and non-hematologic diseases; however, it is associated with significant morbidity and mortality. Many studies have shown that elevated pre-transplant ferritin levels are associated with increased risk of morbidity and mortality following HCT. Given ferritin's association with systemic inflammation, it is a plausible potential prognostic marker in the post-HCT period, including in patients with graft-versus-host disease (GVHD). The present study attempts to determine whether post-transplant serum ferritin level is an independent prognostic marker for outcomes post-HCT, especially in the subgroups of patients with acute or chronic GVHD. Methods and patients: A total of 229 patients who had serum ferritin level data available within one-year post HCT were enrolled into this retrospective study. These patients underwent HCT at Princess Margaret Cancer Centre, Toronto, Canada between 2001-2013. Patients' characteristics and transplant procedures were: median age: 51 (range:19-70); refined disease risk index: low (n=70), intermediate (n=108), high (n=51); donor type: HLA-matched related donors (n=94), HLA-matched or partially-matched unrelated donors (n=135); conditioning regimen: myeloablative (n=120), reduced intensity (n=109). Acute and chronic GVHD were respectively classified using the 1994 consensus conference and NIH consensus criteria. Primary outcomes were overall survival (OS), non-relapse mortality (NRM), and relapse. Kaplan-Meier method was used for OS; cumulative incidences were used for NRM and relapse, considering competing risks. Multivariate analysis employed Cox or Fine-Gray proportional hazard regression model. Factors evaluated included recipient age and CMV status, donor-recipient sex, comorbidity score, performance index, GVHD prophylaxis, post-transplant serum ferritin level (ferritinPost-HCT), and serum ferritin level prior to HCT (ferritinPre-HCT). Recursive partitioning was used to stratify patients into low or high risk groups based on ferritinPost-HCT (≤3,169 vs >3,169 ng/mL) and ferritinPre-HCT (≤669 vs >669 ng/mL). Results: Median follow-up duration among survivors was 46 months post-HCT (range:2.8-147.2 months). Median ferritinPost-HCT was 2,178 ng/mL (range: 45-30,647; Figure A), measured at a median of 137 days post-HCT. There was a weak correlation between ferritinPost-HCT and ferritinPre-HCT (Pearson's correlation r=0.242, p=0.002). Compared to the group with low ferritinPost-HCT, the high ferritinPost-HCT group had lower three-year OS (40.0% vs 66.7%, p<0.001; Figure B) and higher NRM (48.6% vs 17.8%, p<0.001 Figure C), but no difference in cumulative incidence of relapse (10.5% vs 19.7%, p=0.079; Figure D). A landmark analysis was performed where the day of ferritinpost-HCT measurement was considered day 0. Results of this landmark analysis showed consistent findings: high ferritinPost-HCT showed lower three-year OS (38.3% vs 65.4%; p<0.001) and higher NRM (50.6% vs 17.7%; p<0.001) compared to low ferritinPost-HCT, but no difference in relapse (10.7% vs 21.3%, p=0.077). In multivariate analysis, ferritinPost-HCT was found to be an independent prognostic factor for OS (p=0.001, HR 2.323) and NRM (p<0.001, HR 3.905). However, pre-transplant ferritin level (ferritinPre-HCT) did not stratify well for OS (57.0% vs 61.8%, p=0.636) or NRM (30.8% vs 22.7%, p=0.247). Out of 229 patients, 171 (74.6%) developed any grade of acute GVHD, and 61 (26.6%) developed chronic GVHD. Median onset of acute and chronic GVHD were, respectively, 33.5 days and 145 days. Level of ferritinPost-HCT was significantly higher in the group that developed acute GVHD than in those without acute GVHD. However, there was no difference in ferritinPost-HCT between patients with or without chronic GVHD. FerritinPost-HCT was found to be an independent prognostic marker in the subgroup with acute GVHD for OS (p=0.001, HR 2.531) and NRM (p<0.001, HR 3.584), and in the subgroup with chronic GVHD for OS (p=0.042, HR 3.226) and NRM (p=0.009, HR 14.130). Conclusions: In our cohort, high ferritinPost-HCT levels were significantly associated with decreased OS and increased NRM, independent of other prognostic factors including ferritinPre-HCT or GVHD. Further prospective study including larger number of patients is warranted. Figure. Figure. Disclosures Lipton: ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy.

scholarly journals Variables associated with malondialdehyde level in thalassemia major patients

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].

Two-Year Analysis of Efficacy and Safety of Deferasirox (Exjade®) Treatment in Myelodysplastic Syndrome Patients Enrolled in the US03 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3829-3829 ◽  
Author(s):  
Alan F. List ◽  
Maria R. Baer ◽  
David P. Steensma ◽  
Azra Raza ◽  
Jason Esposito ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Lower Risk ◽  
Research Funding ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Efficacy And Safety ◽  
The Mean ◽  
Neutrophil Response

Abstract Abstract 3829 Poster Board III-765 Introduction A large proportion of patients (pts) with myelodysplastic syndromes (MDS) become dependent on red blood cell (RBC) transfusions, escalating the risk of transfusional hemosiderosis and associated adverse effects. The US03 study was designed to evaluate the long-term efficacy and safety of the oral iron chelator, deferasirox, administered once-daily in pts with lower-risk MDS. 173 pts at 45 centers in the US and Canada enrolled in the 1-year core phase of the study and 83 pts participated in the 2-year extension phase. We now present data from pts who have completed 2 years of deferasirox treatment. Methods US03/E is an ongoing, Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS-risk MDS. Eligible pts had transfusional iron overload (serum ferritin ≥1000 μg/L and >20 units of RBC transfusions) with serum creatinine (SCr) ≤2-fold the upper limit of normal (ULN). Initial deferasirox dose was 20 mg/kg/day, which could be increased up to 40 mg/kg/day based on tolerability and response criteria. Serum ferritin and creatinine were monitored monthly. Baseline features 83 pts entered the extension study; mean age was 68 years (range 21–90) with 41 men and 42 women. IPSS risk groups were Low in 23 (28%) pts and Int-1 in 60 (72%). Mean serum ferritin level at the beginning of the extension phase was 2496 μg/L (range 546–7770); mean lifetime number of transfusions was 83.6 (range 20–364) and the mean duration of transfusion therapy was 4.6 (2–12) years. 18 (22%) pts were receiving growth factors (8 darbepoetin, 5 G-CSF, 4 epoetin alpha and 1 tranexamic acid), and 13 pts were receiving other MDS specific therapies (5 decitabine, 4 azacitidine, 3 lenalidomide, and 1 hydroxyurea). The calculated creatinine clearance at extension study entry was normal (>80 mL/min) in 20 (25%) pts and abnormal in 59 (75%), including mild renal insufficiency (51–80 mL/min) in 41 (52%) pts, moderate (30–50 mL/min) in 16 (20%) and severe in 2 (3%). Two-year efficacy results At the time of this analysis, 54 pts completed 2 years of treatment (1 year in the core and one year in the extension portion of the study). Over 24 months, the mean dose of deferasirox was 22.8 mg/kg/day and the mean transfusion rate was 4 units/month. Serum ferritin results are available from 50 pts who have received deferasirox for 100 weeks (Figure). The mean serum ferritin level decreased significantly from study baseline: 3002 to 2069 μg/L at 100 weeks (Δ=933 μg/L; P<0.001, signed rank test). Six (7%) pts experienced hematological improvement according to IWG 2000 criteria. Three patients experienced an erythroid response (major, n=2; minor n=1); only one who achieved a minor response received MDS treatment with darbepoetin. Others included major platelet response (n=1; not receiving MDS treatment), major neutrophil response (n=1; not receiving MDS treatment) and one combined major platelet and neutrophil response while receiving G-CSF and decitabine treatment. Safety Of 83 pts, 35 (42%) discontinued from the study: 8 (9.6%) due to abnormal laboratory values (increase of creatinine 6, thrombocytopenia 1, and neutropenia and thrombocytopenia 1), 8 (9.6%) due to adverse events (gastrointestinal symptoms 3, Clostridium dificile infection 1, renal dysfunction 1, cardiac symptoms 1, unknown 1), 11 (13.2%) due to serious AEs with an outcome of death (none of the deaths were related to deferasirox) and 8 (9.6%) due to MDS progression/AML. Of 67 pts with normal baseline SCr, 24 (30%) had an increase in SCr values above the ULN on at least two occasions (3.0 mg/dL max SCr). Of 16 pts with abnormal baseline SCr, one had an increase to above the ULN on at least two occasions. New onset of grades 3 and 4 thrombocytopenia and neutropenia occurred in 15 (18%) and 29 (35%) pts, respectively. Conclusions In pts with lower-risk MDS and iron overload, deferasirox significantly reduced serum ferritin over 2 years. Deferasirox was generally well tolerated over 2 years. The final year of this study will continue to assess the long-term safety and efficacy of deferasirox in these lower-risk MDS pts with iron overload. Disclosures: Raza: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Esposito:Novartis Pharmaceuticals: Employment. Martinez-Lopez:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Besa:Novartis: Research Funding, Speakers Bureau.

Assessment and Management of Iron Overload in β-Thalassemia Major Patients in Italy: A Real-Life Experience From the Webthal® Project

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1030-1030
Author(s):  
Antonio Piga ◽  
Filomena Longo ◽  
Khaled M Musallam ◽  
Maria Domenica Cappellini ◽  
Gian Luca Forni ◽  
...  
Keyword(s):  
Heart Disease ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Research Funding ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Real Life ◽  
Thalassemia Major ◽  
Iron Intake ◽  
History Of

Abstract Abstract 1030 Background: As the ideal assessment and management strategies of iron overload in patients with β-thalassemia major (TM) remain unclear, evaluation of real-life experiences is warranted. Methods: This was a cross-sectional study of 924 TM patients actively treated at nine Italian centers. Data were retrieved on 15-09-2009 through a common software (Webthal®) used by participating centers, and included: demographics; splenectomy and transfusion history; detailed iron overload assessment history; type of iron chelator used; existence of hepatitis C virus, heart disease, or diabetes mellitus; alanine aminotransferase and serum creatinine levels. Results: The mean age of patients was 30.1 ± 9.1 years (48.8% males, 42.8% splenectomized). Among the 924 patients, 83.9% had at least one previous liver iron concentration (LIC) measurement and 68.7% had it within two years prior. On step-wise multivariate logistic regression, a serum ferritin level <2500 ng/ml was a risk factor for absence of LIC measurement, while absence of heart disease and a history of normal cardiac magnetic resonance (CMR) T2* value were risk factors for a delay in LIC measurement >2 years. Moreover, 69.6% had at least one previous CMR T2* measurement and 73.4% patients had it within two years prior. Patients who never had a CMR T2* were <18 years, had iron intake ≤0.4 mg/kg/day, or a serum ferritin level <2500 ng/ml; while a history of a normal CMR T2* value was the main risk factor for a delay in CMR T2* assessment for >2 years. Using similar multivariate modeling, desferrioxamine (23.3%) was more commonly used in patients with hepatitis C virus infection or high serum creatinine level. Deferiprone (20.6%) was less commonly prescribed in patients with elevated alanine aminotransferase; while a desferrioxamine+deferiprone combination (17.9%) was more commonly used in patients with serum ferritin levels >2500 ng/ml or CMR T2* <20 ms. Deferasirox (38.3%) was more commonly prescribed in patients <18 years, but less commonly used in patients who had heart disease or those with a high iron intake. Conclusion: Assessment and management of iron overload in TM patients in Italy largely reflects findings from clinical research and recommendations from available guidelines, although some practices are expected to change in light of evolving evidence. Disclosures: Piga: Apopharma: Research Funding; Novartis Pharmaceuticals: Research Funding; Ferrokin: Research Funding. Musallam:Novartis Pharmaceuticals: Honoraria. Cappellini:Novartis Pharmaceuticals: Honoraria, Research Funding. Forni:Novartis Pharmaceuticals: Research Funding; Ferrokin: Research Funding. Quarta:Novartis Pharmaceuticals: Research Funding. Galanello:Apopharma: Honoraria, Research Funding; Novartis Pharmaceuticals: Honoraria, Research Funding; Ferrokin: Research Funding.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2394-2394 ◽  
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.

Safety and Efficacy of Iron Chelation with Deferasirox in Adult Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5539-5539
Author(s):  
Young-Woo Jeon ◽  
Byung-Sik Cho ◽  
Hee-Je Kim ◽  
Jae-Ho Yoon ◽  
Seung-Hwan Shin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Serum Ferritin ◽  
Myeloid Leukemia ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Chronic Gvhd ◽  
Iron Chelation ◽  
Hematopoietic Stem ◽  
Safety And Efficacy ◽  
Acute Myeloid

Abstract Background The prognostic impact of serum ferritin level has been well established in patients with myelodysplastic syndrome and acute myeloid leukemia (AML) in the context of allogeneic hematopoietic stem cell transplantation (Allo-HSCT). However, the clinical safety and efficacy of iron-chelation therapy (ICT) for adult AML with hyperferritinemia post-Allo-SCT has not been evaluated. Materials and methods We retrospectively evaluated 320 consecutive patients with de novo AML who received Allo-HSCT at complete remission in a single institution between January 2007 and February 2012. Serum ferritin levels were monitored from initial diagnosis to the several time points during the post-transplantation period in both the ICT group (n=113) and the non-treated group (NT, n=191). In the ICT group, ICT was started at least a month after transplantation when serum ferritin levels over 1,000 ng/mL, and continued to the ferritin level lower than 500 ng/ml unless serious adverse effects and/or relapse. Sixteen patients treated less than one month with ICT due to early complications, such as infection(n= 10, 62.5%), liver toxicity (n=4, 25%), and poor compliance (n=2, 12.5%) were excluded in the ICT group. The baseline characteristics between two groups were not significantly different. Results The median treatment duration in ICT group was 6.4 months (range, 1.0-49.2) with dosage of 20-40 mg/kg/day. Deferasirox treatment was discontinued at least one time in 43 patients (38%) in ICT group due to toxicities and/or poor compliance, but almost patients (n=40, 93%) could be treated again with deferasirox without further toxicities. High serum ferritin level of pre-Allo-HSCT over 1,000 ng/ml was significantly associated with poor overall survival (OS, 52.2% vs. 75.4%, HR 0.78, P <0.001) and lower chronic graft-versus-host disease (GVHD, 53.3% vs. 74.6%, HR 0.83, P =0.001). With a median follow up of 40.2 months, OS, disease-free survival (DFS), and cumulative incidence of relapse (CIR), non-relapse mortality, acute (over grade II) and chronic GVHD were 62.7%, 63.7%, 11.6%, 5.9%, 24.4% and 42.8%, respectively. On multivariate analyses, ICT group had significantly lower CIR (25.9% vs. 37%, HR 0.65, P=0.011) and higher cumulative incidence of chronic GVHD (46% vs. 20.1%, HR 1.88 P<0.001), with a trend of superior survival (OS, 72.0% vs 63.4%, P=0.053; DFS, 70.3% vs 61.4 %, P=0.058), whereas no association with acute GVHD (P=0.473) Conclusion Our data demonstrate that ICT with deferasirox was well tolerable in AML with hyperferritinemia after Allo-SCT, and suggest the independent association of ICT with increased incidence of chronic GVHD and decreased relapse. Iron chelation may modulate of immunobiologic properties during the period of immune reconstitution (low level of Treg cells and higher CD16+ NK cells, 2014 ASH Abstract #2543) and/or induce direct anti-leukemia effect by iron depletion, which need to be further evaluated. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document