Natural Course Of Serum Ferritin In Childhood Cancer Survivors: Need For Iron Removal 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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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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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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Iron Overload and Haematopoiesis in MDS: Does Blood Transfusion Promote Progression to AML?

Blood ◽

10.1182/blood.v112.11.2685.2685 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2685-2685 ◽

Cited By ~ 7

Author(s):

Lap Shu Alan Chan ◽

Rena Buckstein ◽

Marciano D. Reis ◽

Alden Chesney ◽

Adam Lam ◽

...

Keyword(s):

Bone Marrow ◽

Dna Damage ◽

Iron Overload ◽

Serum Ferritin ◽

Chelation Therapy ◽

Bone Marrow Cells ◽

Ferritin Level ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Ferritin Concentration

Abstract Introduction: The biology of myelodysplastic syndrome (MDS) is poorly understood, and treatment options are limited. Thus, most MDS patients require chronic red blood cell transfusion, and many develop secondary iron overload. Although the pathophysiological consequences of iron overload to the heart, liver, and endocrine organs have been well characterized, its effects on haematopoiesis have not been studied. However, it has been observed that chelation therapy in iron-overloaded MDS patients may result in reduction of transfusion requirements, and recent studies have suggested a correlation between the use of iron chelation therapy and improvement in leukaemia-free survival in MDS. At the cellular level, iron toxicity is mediated in large part via the generation of reactive oxygen species (ROS). It has been shown in animal models that accumulation of ROS leads to senescence of haematopoietic stem cells, and that ROS cause DNA damage and promote the development of malignancy. These effects of ROS may be particularly important in MDS, in which haematopoiesis is already severely compromised and genetic instability is a striking feature. Hypothesis: We hypothesize that iron overload secondary to transfusion leads to increased levels of intracellular ROS in early haematopoeitic cells in MDS. The increase in intracellular ROS in MDS would be predicted to lead further impairment of haematopoiesis via stem cell exhaustion and while promoting accumulation of DNA damage by myelodysplastic stem cells and early progenitors, thus accelerating progression of MDS to acute leukaemia. Results: To test this hypothesis, we examined the relationship between transfusion-related iron overload and ROS content of CD34+ bone marrow cells in MDS. ROS content was measured in CD34+ cells by flow cytometry in bone marrow aspirates from 34 consecutive MDS patients (CMML=4, MDS/MPD=2, RA=4, RARS=3, RCMD=2, RAEB 1=6, RAEB 2=12, RAEB-t/AML=1). The patients represented a wide range of prior transfusion burden (0->300 units PRBC) and serum ferritin levels (11->10000 μg/L). ROS was strongly correlated with serum ferritin concentration for patients with iron overload (serum ferritin >1000 μg/L; n=14, R=0.733, p<0.005). The correlation between ROS and ferritin level was even stronger in the subset of patients with RAEB 1 or RAEB 2 and iron overload (n=11, R=0.838, p<0.005). In contrast, no correlation between ROS and ferritin level was demonstrated for patients with serum ferritin <1000 μg/L (n=20). Importantly, iron chelation therapy was associated with a reduction in CD34+ cell ROS content in one patient. To assess the effect of iron overload on normal stem cell and progenitor function, we established a mouse model of subacute bone marrow iron overload. B6D2F1 mice were loaded with iron dextran by intraperitoneal injection (150mg total iron load over 21 days), and sacrificed three days after the end of iron loading. Iron staining of tissue sections confirmed iron deposition in the bone marrow, liver, and myocardium. The development of splenomegaly was noted in iron-loaded animals. Flow cytometric analysis revealed increased apoptosis of bone marrow cells in iron loaded mice based on annexin V+/7 AAD-staining (6.26±0.96% versus 3.54±0.99% for control mice, paired student’s t-Test p<0.005). However, ROS content in CD117+ progenitors of iron loaded mice was similar to control mice. Thus, subacute iron loading in mice increases apoptosis but does not alter the ROS content of HSCs; we postulate that chronic iron overload is required to achieve this effect. Conclusions: These results establish a relationship between CD34+ cell ROS content and serum ferritin concentration in MDS patients with iron overload, and indicate that iron chelation therapy in this patient population reverses this ROS accumulation. The physiological consequences of this relationship are currently being investigated in this patient set by haematopoietic colony assays and assessment of DNA damage in CD34+ cells. Nonethelesss, these data may have key implications for the deployment of iron chelation therapy in MDS patients, and may explain the association between the use of iron chelation and improved leukaemia-free survival in MDS.

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Comparative study of Deferiprone versus Deferiprone with Deferasirox as iron chelation therapy in Thalassemic children

Bangladesh Journal of Child Health ◽

10.3329/bjch.v43i3.49571 ◽

2020 ◽

Vol 43 (3) ◽

pp. 152-156

Author(s):

Syeda Jarka Jahir ◽

Sayeeda Anwar ◽

AKM Amirul Morshed ◽

Afiqul Islam ◽

Kabirul Islam

Keyword(s):

Combination Therapy ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Combination Group ◽

Iron Chelation Therapy ◽

Monotherapy Group ◽

Thalassemia Minor

Background: Combination therapy of Deferiprone (DFP) with Deferasirox (DFX) is an efficacious and safe modality to reduce serum ferritin in multi-transfused children with thalassemia. Objectives: To compare the efficacy of Deferiprone versus Deferiprone with Deferasirox as iron chelation therapy of transfusion dependent thalassemia children. Materials and Methods: A non-randomized control clinical trial was done in department of Pediatric Hematology and Oncology, Dhaka Medical College Hospital and Bangladesh Thalassemia Hospital in Dhaka during the period of October 2016 to September 2017. Thirty children with transfusion dependent thalassemia major between 3 to 12 years of age were included in each group in this study. Children with thalassemia minor, after splenectomy, with comorbidities and on other iron chelation therapy were excluded from this study. Results: Among total enrolled 60 cases in this study, initial mean serum ferritin level was 3397.48 ± 774.48 ng/ml in DFP-monotherapy group and 3413.70 ± 1114.05ng/ ml in DFP-DFX combination group. Mean serum ferritin level at 6thmonth was found 2730.63 ± 839.91ng/ml in DFP-monotherapy group and 1654.20 ± 934.90 ng/ml in DFP-DFX-combination group which shows rapid reduction of serum ferritin level in DFP-DFX-combination group. 12 (40.0%) patients had arthralgia in DFPmonotherapy group and 5(16.7%) patients had vomiting in DFP-DFX-combination group. No abnormalities seen in liver and renal function tests. Conclusion: Combination therapy with Deferiprone and Deferasirox is more effective in reduction of iron overload and drug related complications in transfusion dependent thalassemia patients. Bangladesh J Child Health 2019; VOL 43 (3) :152-156

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

Blood ◽

10.1182/blood.v122.21.180.180 ◽

2013 ◽

Vol 122 (21) ◽

pp. 180-180 ◽

Cited By ~ 4

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.

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Correlation between serum ferritin level, cardiac and hepatic T2-star MRI in patients with β-thalassemia major in Al-Diwaniya thalassemia center

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v9ispl1.1392 ◽

2018 ◽

Vol 9 (SPL1) ◽

Author(s):

Alaa Mutter Jabur Al-Shibany ◽

AalanHadi AL-Zamili

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Chelation Therapy ◽

Ferritin Level ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Iron Level ◽

The Mean ◽

T2 Mri

Patients with transfusion dependent thalassemia major is often associated with iron overload. Proper use of iron chelators to treat iron overload requires an accurate measurement of iron levels. Magnetic resonance T2-star (T2* MRI) is the preferred method to measure iron level in the liver andthe heart. The goal of our study was to see if there is an association exists between serum ferritin level and T2* MRI results in patients with beta thalassemia major.This study was done in Al-Diwaniya Thalassemia center,Maternity and children teaching hospital,Iraq. During the period from 1st of January to 31st of October. Fifty eight patients with a diagnosis of beta thalassemia major were enrolled in the study. They were older than five years old,transfusion dependent and on chelation therapy. Hepatic and Myocardial T2*MRI and the mean serum ferritin levels were measured during the study period for all patients.There is a significant correlation was observed between serum ferritin level and cardiac T2*MRI (p=0.018 ). also a significant correlation was observed between serum ferritin and hepatic T2*MRI (p=0.02). Neither cardiac T2* MRI nor hepatic T2* MRI show any correlation with the mean age.our study also showa positive correlation between the patients withcardiac T2* MRI and the development of diabetes mellitus in contrast to hepatic T2* MRI in which there is no any correlation. Hypothyroidism was observedno correlation with either cardiac or hepatic T2* MRI.Our results showed a positiveassociation between hepatic, cardiac T2*MRI and serum ferritin levels.

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Deferasirox Safety Profile in Patients with Transfusion-Dependent Anaemias:Results From the Interim Analysis of a Hellenic Study,

Blood ◽

10.1182/blood.v118.21.3183.3183 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3183-3183

Author(s):

Vassilis Ladis ◽

Marouso Drossou ◽

Dimitria Vini ◽

Ersi Voskaridou ◽

Miranda Athanasiou-Metaxa ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Safety Profile ◽

Interim Analysis ◽

Pediatric Patients ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Liver Iron ◽

Liver Iron Overload

Abstract Abstract 3183 Background: The introduction of iron chelation treatment has led to a significant improvement in morbidity and overall survival in patients with transfusion-dependent anemias. Deferasirox is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload in both adult and pediatric patients. The efficacy and safety of deferasirox in a variety of transfusion-dependent anemias has been established in numerous Phase II/III clinical trials. Since most patients with transfusion-dependent anemias require lifelong iron chelation therapy, there is a need to assess the long-term safety of deferasirox in both adult and pediatric patients. Aim: To assess the safety profile of deferasirox in patients with transfusional iron overload in a real-world clinical setting. To further investigate the safety profile of deferasirox in patients with congenital erythrocyte disorders and transfusional iron overload, with ferritin levels <4000 ng/ml and without severe cardiac siderosis. Methods: Between July 2009 and September 2010, 85 patients with transfusion-induced iron overload treated with deferasirox as per the approved product labeling were enrolled in the study. These data represent the 24-week planned interim analysis of a 12-month observational study on deferasirox safety profile in the treatment of pediatric and adult patients with transfusion-dependent anemias who were newly-treated with deferasirox. Safety was evaluated through the monitoring and recording of all adverse events and serious adverse events, as well as routine laboratory testing, including hematology, blood chemistry and hepatic function assessments. Results: The population had a median age of 37.6 years (range: 5.3–61.4) and a female to male ratio of 1.3. Beta-thalassemia (67.1%) was the most common transfusion-dependent anemia, followed by thalassemia intermedia requiring periodic transfusions (20.0%) and sickle cell anemia (12.9%). Mean baseline ferritin levels were 1502.1±870.5 (pediatric group: 1480.2±522.8 and adult group: 1503.6±891.4), while 53 out of the 85 patients (62.4%) had serum ferritin level above 1000 ng/ml. Mean baseline liver T2* value was 10.4±9.7 ms; 44.4% of patients demonstrated minimal liver iron deposition (MRI T2* > 6.3 ms), 51.4% had mild to moderate liver iron overload (T2* ≤ 6.3 ms), and 4.2% had severe liver iron overload (T2*<1.4 ms). 54 (63.5%) of patients analysed had been pre-treated with iron chelators and 31 (36.5%) were chelation-naïve. The initial average daily dose of deferasirox was 25.9±4.8 mg/kg, and 70.6% of patients had no dose modification during the 24-week follow-up period. A statistical significant decrease in median serum ferritin levels was observed by Week 24 (mean absolute change from baseline:-214.5 ng/mL; p=0.009) [Figure 1]. No statistically significant changes were observed in creatitine levels, creatinine clearance and transaminases by Week 24 [Figure 1]. 37 ADRs were reported by 17 patients (20%) over the 24-week period. Among the most frequently observed ADRs (>5%) were epigastralgia reported by 7.1% of patients (6/85) and loose stools/diarrhoea by 5.9% of patients (5/85). The majority of ADRs reported (nevents=25; 67.6%) were graded as mild in severity, while 21.6% (nevents=8) were graded as moderate and 10.8% (nevents=4) as severe. Most ADRs (nevents=31; 83.8%) resulted in full recovery by Week 24. The overall incidence of SADRs was as low as 1.2% (in particular one patient experienced severe epigastralgia and upper extremity pain which resulted in her withdrawal from the study after four months of treatment). The all-cause discontinuation rate was 9.4% (8/85), while only two patients (2.4%) discontinued the study therapy due to ADR; 1 patient due to increased transaminase levels and 1 patient due to the aforementioned SADR. Conclusions: These data highlight the safety profile of deferasirox in both adult and pediatric patients; the regular monitoring of serum ferritin levels as well as other iron-overload parameters and transfusion requirements play a major role in determining and optimizing the outcome of iron chelation therapy. Disclosures: Ladis: Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Drossou:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Vini:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Athanasiou-Metaxa:Novartis Hellas S.A.C.I.: Research Funding. Oikonomou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Vlachaki:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Tigka:Novartis Hellas S.A.C.I.: Employment. Tzavelas:Novartis Hellas S.A.C.I.: Employment. Liakopoulou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Adamopoulos:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Kattamis:Novartis Hellas S.A.C.I.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Are Children with Cancer Receiving Myelosuppressive Therapy At Risk for Transfusion-Related Iron Overload?

Blood ◽

10.1182/blood.v120.21.1180.1180 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1180-1180

Author(s):

Anushka Jaffer ◽

Rebecca Barty ◽

Erin Jamula ◽

Grace Wang ◽

Yang Liu ◽

...

Keyword(s):

At Risk ◽

Iron Overload ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Children With Cancer ◽

Screening Practices ◽

The Impact ◽

Rbc Transfusion

Abstract Abstract 1180 Background Transfusion-related iron overload (TRIO) is associated with significant morbidity and mortality. Adequate screening for iron overload (IO) and the use of iron chelators, if needed, should be employed for chronically transfused individuals. However, with the exception of patients with hemoglobinopathies, screening for iron overload is not a consistent part of routine care for patients receiving multiple red cell transfusions, and is not identified as a treatable problem. Objective This study aimed to identify the population at risk for TRIO and to evaluate current screening practices. Methods All children (≤ 18 years) receiving at least one red blood cell (RBC) transfusion between January 1, 2008 and December 31, 2011 at our institution were identified using the TRUST (Transfusion Registry for Utilization, Surveillance and Tracking) database. Only patients receiving chronic RBC transfusion were included in this study, which was defined as receiving ≥20 units of RBC or ≥ 20 RBC transfusions dosed at 15ml/kg within 12 consecutive months where the transfusions were not administered in the setting of an operating room, trauma or surgical procedure(s), not administered 7 days prior/post-surgical procedures and not all administered within one day. Adjudication by a second reviewer resolved any ambiguity regarding study inclusion. Medical records of eligible patients were reviewed to collect patient demographics, underlying diagnosis and reason for transfusions, and to evaluate IO screening practices (e.g. ferritin level, testing for systemic IO (e.g. FerriScan) if persistently high ferritin) and frequency of iron chelation therapy. Results A total of 35 patients fulfilled the eligibility criteria, with a mean age of 8.82 years (SD 5.36). Table 1 summarizes the demographics of the population, the transfusion requirements, how often the patient subgroups were screened and the screening results. In summary, 20 patients had ferritin levels checked, where 2 (AML and hepatoblastoma) patients had values under 500 μg and no screening was required. Of the remaining 18, 10 patients were diagnosed with a hemoglobinopathy (8) and congenital anemia (2) requiring chronic transfusions and underwent regular screening for iron overload and received iron chelation therapy. The remaining 8 patients had ferritin level >500 μg but no IO screening ordered. Of these 8 patients the majority were diagnosed with a cancer (leukemia, solid tumours) (5), acquired aplastic anemia (2), and hemophagocytic syndrome (1). The total number of transfusions for these 8 patients ranged from 20 to 52 with a median of 25 transfusions. Conclusion The majority (63%) of chronically transfused patients in this cohort had underlying cancer requiring aggressive chemotherapy. Only 32% of these patients had ferritin level tested and none were evaluated for systemic IO. TRIO may represent an additional, as yet unidentified, co-morbidity of cancer therapy. Therapies such as anthracycline or radiation may potentiate the end organ effect of TRIO at levels lower than that observed in patients with a hemoglobinopathy. Hence, it is important to develop strategies to evaluate children with cancer at risk for IO and to study the impact of transfusional iron accumulation on end organ function. Disclosures: No relevant conflicts of interest to declare.

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