Cardiovascular Complications Of Thalassemia Patients In The Iron Chelation Therapy Era

Abstract Background Cardiac complications are the most common cause of death in thalassemia, accounting for up to 71% in the past. Iron chelation therapy is given to patients with iron overload to prevent these complications. The cost effectiveness of iron chelation therapy was arguable. This study aims to evaluate the prevalence of cardiac complication and the correlation between risk factors in iron chelation therapy era. Method This is a cross sectional study from June 2011- May 2012. All thalassemia aged > 15 years old were enrolled. Clinical data and hemoglobin typing were reviewed. Echocardiography and CMR T2*, a technique represent cardiac iron deposition used to evaluate cardiac function, were used to evaluate cardiac complications. Results Ninety one patients were enrolled, 63.7% were females, median age of 31 years (16-75). There was 49.5 % homozygous β thalassemia, 31.9% β thalassemia/Hb E disease, 18.7% Hb H disease. Half of patients were transfusion dependent and 63.7% underwent splenectomy. Eighty four percent of patients received iron chelation therapy but few of them got their preferable choice in adequate dosage. Patients with serum ferritin levels more than 1,000 ng/ml. received deferoxamine, deferiprone or deferasirox. Even with the iron chelation therapy, mean serum ferritin level was still high at 3,820 ng/ml for the whole group. CMR T2* was more sensitive in detecting cardiac function. The CMR T2* showed shorter signal (≤ 20 msec) in 11.1%. Only 8.2% had impaired ejection fraction <55% by echocardiography. The CMR T2* ≤ 20 msec was significant correlated with higher maximum ferritin 5,739.14 ng/ml compared to 3,614 ng/ml (p=0.001). Pulmonary hypertension was found 7 patients (12.7%) and 71.42% had underwent splenectomy. Conclusion From our study, the CMR T2* is the sensitive method for detecting cardiomyopathy and highly correlated with serum ferritin levels. Splenectomy remains the major risk factor for pulmonary hypertension. The incidence of cardiac complications has decreased with iron chelation therapy for maintaining acceptable serum ferritin levels but the problem with cardiomyopathy and pulmonary hypertension still exist. Early detection, more sensitive implementation and aggressive iron chelation therapy are necessary to prevent these complications. The majority of the patients in Thailand which are under universal health-care coverage scheme could not get access to more effective and expensive iron chelator. Regular and adequate chelation plays a major role in the prevention of cardiac complications and the achievement of better quality of life. Disclosures: No relevant conflicts of interest to declare.

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Socio-Economic Impact of Infused Iron Chelation Therapy in France: ISOSFER Study Results.

Blood ◽

10.1182/blood.v108.11.3354.3354 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3354-3354 ◽

Cited By ~ 2

Author(s):

Catherine Brun-Strang ◽

Dora Bachir ◽

Mariane De Montalembert ◽

Isabelle Thuret

Keyword(s):

Adverse Events ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Organ Damage ◽

Total Direct Cost ◽

Iron Chelation Therapy ◽

Cross Sectional ◽

Study Results ◽

The Cost

Abstract Background: Patients suffering from β-thalassemia (TM), sickle cell disease (SCD), and myelodysplastic syndromes (MDS) undergoing chronic blood transfusions are at risk for iron overload which, if not treated by iron chelation therapy (ICT), can cause serious organ damage and reduce life expectancy. Deferoxamine (DFO) is the standard of care for the depletion of excess body iron. It has to be infused for 8–10 hours, 5–7 times a week. Although the clinical need for ICT is clearly established, less is known about the economic burden of DFO treatment. Aim: To estimate the total annual costs of DFO ICT in treatment centers in France. Methods: A cross-sectional study with a prospective recruitment. Among 278 consecutive patients receiving regular transfusions for TM, SCD or MDS who consulted between October 2005 and February 2006 in 24 French centers, 161 were on ICT. 124 patients were treated with DFO alone for more than 1 year. Among them, 67 aged 14 years or more agreed to participate. Resources used were collected through patient and physician questionnaires. Unit costs (2004/2005 €) were applied according to French economic guidelines. Results: DFO was administered via subcutaneous (sc) infusion for 70% of patients, mainly nightly and with a mean duration of 10 hours. Other ways of administering DFO included intravenous (iv) infusion (15%), sc bolus (9%) and combined sc and iv treatment (5%). Patient characteristics are summarized in the table below. TM (n=24) SCD (n=17) MDS (n=26) *Cardiac, liver and endocrine diseases, lens opacities, osteoporosis Median age (min-max), years 30 (15–70) 32 (14–57) 69 (45–85) Sex, M/F 11/13 6/11 14/12 Organ dysfunction potentially related to hemosiderosis* (%) 75 47 54 Ferritin level (median), ng/mL 1049 2653 2627 DFO nb/week (mean) 3.7 4.5 4 Dose (mean) 40 17 43 For all patients, the estimated mean weighted annual cost of infusions is 16009 € (SD ± 13867). Costs are similar for the three diseases. ICT delivery equipment (infusion set and pump) and nursing administration, drug cost, DFO adverse events monitoring, periodic exams and treatment of infused ICT-related adverse events represent respectively 56.5%, 38.5%, 0.3%, 3.7% and 0.9% of total direct cost. The estimated annual mean cost of the drug alone was 6160 € (SD ± 4145). Average cost for DFO adverse events management is low at 151.5€ (SD ± 1224), essentially due to one patient complication. Costs of periodic exams are also low due to the fact that exams are not strictly performed annually as recommended. These estimates of the total annual costs of DFO ICT are likely to be underestimating the overall cost of DFO therapy because treatment costs of the clinical consequences of poor adherence to DFO and lost productivity were not collected in the study. Conclusions: ISOSFER demonstrated that total direct costs of ICT are substantial and well exceed the cost of DFO alone. The cost of DFO administration constitutes a significant portion of the total cost of iron chelation (54%). These data are comparable to other analyses published from US (43% of the total costs, n=155) and Swiss (45%, n=17) databases.

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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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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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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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Analysis Of Hematological Improvement With Iron Chelation Therapy Using Deferasirox In Subject Ts With Therapy-Refractory Severe Aplastic Anemia

Blood ◽

10.1182/blood.v122.21.4878.4878 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4878-4878

Author(s):

Wataru Jomen ◽

Hiroyuki Kuroda ◽

Masahiro Yoshida ◽

Michiko Yamada ◽

Tomoyuki Abe ◽

...

Keyword(s):

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Serum Ferritin ◽

Chelation Therapy ◽

Conflicts Of Interest ◽

Iron Chelation ◽

Iron Chelator ◽

Iron Chelation Therapy ◽

Transfusion Independence ◽

Quality Life

Abstract Introduction It has been shown that iron chelation therapy (ICT) improves survival and quality life in subjects with transfusion-dependent hematological disorder including aplastic anemia (AA). In most cases of aplastic anemia, hematopoiesis is impaired by immunological disturbance, so the number of CD34+ stem/progenitor cells decreases drastically in severe AA. Little is known, however, about the hematological response to deferasirox therapy in those with severe AA, especially refractory cases with immunosuppressive therapy (IST). Methods Nine subject 5 men and 4 women aged 20 to 83 (median age: 59.4 years) with transfusional iron overload who were administered the oral iron chelator, deferasirox (DFX) were evaluated from April 2010 to March 2013.at our hospital. Of these, one had non-severe AA, and 8 severe AA classified by severity criteria (Hematology 2011). These 8 were administered immunosuppressive therapy (IST) with rabbit antithymocyte globulin (rATG) in combined with cyclosporine A (CsA), but no hematological improvement was seen.After informed consent was obtained, all 9 were administered iron chelation therapy when serum ferritin (SF) exceeded 1,000 ng/mL or they required over 20 RBC in transfusions (or 100 mL/kg of RBC). Hematological improvements was assessed using International Working Group 2006 criteria. Results The initial median DFX dose was 12.0 mg/kg per day and median treatment duration was 13.4 months. Two discontinued treatment. Hematologic improvements was observed in 50% (4/8) of those with severe AA and all 4 no longer required blood transfusions, and while 3 of the remaining 4 no longer required platelet transfusion. Median time to transfusion independence was 4.3 months while that to transfusion independence was 7.2 months In these 4 subject ts, median serum ferritin was 1,708 ng/ml immediately before ICT and decreased to less than 500 ng/ml after ICT. Bone marrow (BM) biopsied was in subjects with hematological improvement, showed that BM cellularity had slightly but significantly recovered in all cases. Conclusions ICT using DFX improved hematopoiesis in subjects with severe AA even after IST. This finding suggested that DFX induction should be considered as a potential treatment in IST-refractory severe AA. Thus, DFX appears to support the efficacy of IST due to the chelation of cellular excess iron in BM cells. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.2394.2394 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2394-2394 ◽

Cited By ~ 1

Author(s):

Hideaki Maeba ◽

Rie Kuroda ◽

Toshihiro Fujiki ◽

Shintaro Mase ◽

Raita Araki ◽

...

Keyword(s):

Iron Overload ◽

Cancer Survivors ◽

Childhood Cancer ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Childhood Cancer Survivors ◽

Iron Chelation Therapy

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

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MRI evaluation of hepatic and cardiac iron burden in pediatric thalassemia major patients: spectrum of findings by T2*

Egyptian Journal of Radiology and Nuclear Medicine ◽

10.1186/s43055-019-0044-5 ◽

2019 ◽

Vol 50 (1) ◽

Cited By ~ 1

Author(s):

Samar M. Shehata ◽

Mohamed I. Amin ◽

El Sayed H. Zidan

Keyword(s):

Chelation Therapy ◽

Statistical Significance ◽

Iron Chelation ◽

Good Method ◽

Thalassemia Major ◽

Local Magnetic Field ◽

Cardiac Complications ◽

Liver Iron ◽

Cross Sectional ◽

Signal Decay

Abstract Background Iron deposition distorts the local magnetic field exerting T2* signal decay. Biopsy, serum ferritin, echocardiography are not reliable to adjust iron chelation therapy. Quantified MRI signal decay can replace biopsy to diagnose iron burden, guide treatment, and follow up. The objective of this study is to evaluate the role of T2* in quantification of the liver and heart iron burden in thalassemia major patients. This cross-sectional study included 44 thalassemia patients who were referred to MRI unit, underwent T2* MRI. Results Twenty-one male (47.7%) and 23 female (52.3%) were included (age range 6–15 years, mean age 10.9 ± 2.9 years). Patients with excess hepatic iron show the following: 11/40 (27.5%) mild, (13/40) 32.5% moderate, and (14/40) 35% severe liver iron overload. High statistical significance regarding association between LIC and liver T2* (p = 0.000) encountered. Cardiac T2* values showed no relationship with age (p = 0.6). Conclusion T2* is a good method to quantify, monitor hepatic and myocardial iron burden, guiding chelation therapy and prevent iron-induced cardiac complications.

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Red Blood Cell Transfusion Independence Following the Initiation of Iron Chelation Therapy in Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v114.22.4844.4844 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4844-4844

Author(s):

Maha A Badawi ◽

Linda M Vickars ◽

Jocelyn M Chase ◽

Heather A Leitch

Keyword(s):

Platelet Count ◽

Myelodysplastic Syndrome ◽

Research Funding ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Transfusion Independence ◽

Transfusion Requirements ◽

Rbc Transfusion

Abstract Abstract 4844 Background Iron chelation therapy (ICT) is often used to treat iron overload (IOL) in patients (pts) requiring transfusion of red blood cells (RBC) for chronic anemia. In myelodysplastic syndrome (MDS), guidelines recommend consideration of ICT in pts with lower risk International Prognostic Scoring System (IPSS) and IOL as defined by a ferritin level >1000 ug/l; IOL related organ dysfunction; or receipt of ≥20 RBC units. During treatment of a pt with MDS and IOL with ICT, RBC transfusion requirement (TR) ceased. Here we report his course and review reported cases of RBC transfusion independence (TI) or decreased RBC TR in MDS pts receiving ICT. Methods The pt chart was reviewed and reported cases identified by PubMed search using the terms ‘MDS’ and ‘iron chelation’. The clinical characteristics and course of published cases were summarized. Case A 76 year (y) old man was referred in May 2004 for management of MDS diagnosed in 1997, when the white blood cell (WBC) count was 2.4 ×109/l; neutrophils, 0.7 ×109/l; hemoglobin (Hb), 133 g/l; platelets, 108 ×109/l. Bone marrow aspiration and biopsy showed refractory anemia (RA), karyotype analysis 46,X,-Y,+8, and the IPSS score was intermediate-1. The erythropoitin (epo) level was 148.3 mIU/ml and the stem cell assay showed no epo-independent colony growth. In 2004 the Hb dropped to 60 g/l prompting the initiation of RBC transfusion support. He required 3 RBC units every 4 weeks to maintain a Hb >90 g/l and complained of fatigue and functional limitation. Creatinine, bilirubin, TSH, reticulocyte count, B12 and folate levels were all normal. The ferritin level in 2004 was 1293 ug/l and 2197 ug/l in 2006. He declined ICT with deferoxamine (DFO) but in 2006 accepted deferasirox (DFX). He required several dose interruptions and adjustments for renal insufficiency; the current dose is 5mg/kg/d with a normal creatinine. Two months (mo) after starting ICT, the Hb increased spontaneously to 109 g/l and he has not required RBC transfusion since. The mean Hb since starting ICT was 122 g/l and the ferritin decreased to 1082 ug/l in 2009. The most recent neutrophil count was 3.5 ×109/l, platelets consistently clump and the MCV is unchanged at 120 fl. He reports excellent energy and an improved quality of life, and has remained clinically well and RBC transfusion independent to the present, 36 mo from the initiation of ICT. Literature review There are 18 published cases of MDS showing improvement in Hb with ICT; 9 became RBC transfusion independent. Characteristics of the 10 TI pts were: median age at MDS diagnosis 58 (range 18-74) y; male, n=5. MDS subtype: RA, n=5; RARS, n=2, RCMD, n=1; RAEB, n=2. IPSS (reported in 8): low, n=1; int-1, n=5; int-1 or 2, n=1; high, n=1. ICT was: DFO, n=7; DFX, n=3. Median time to RBC TI was 17.5 (1-24) mo and TI duration 13 (3-28) mo to date. Of pts who had decreased RBC transfusion requirements with ICT but did not achieve transfusion independence: median age (reported in 3) was 67 (45-78) y; gender (reported in 3) female, n=3; MDS subtype: RA, n=8; RAEB-t, n=1; IPSS: int-1, n=3; ICT: DFO, n=8; DFX, n=1. Median time to decreased TR was 14.4 (3-24) mo; median duration of decreased TR (reported in 3) 9 (6-32) mo; initial TR 50.9 (19.7-447) g Hb/mo; median decrease in TR 12.7 (0.1-88) g Hb/mo. In one report of 6 pts, 2 with pancytopenia showed improvement with ICT in WBC from 1.4 to 1.9 ×109/l (p<0.0001) and neutrophils from 0.51 to 0.94 ×109/l (p<0.001). The platelet count increased from 16.6 to 22.5 ×109/l (p<0.001) and 14.6 to 29.6 ×109/l (p<0.00001) within 3 mo and the MCV decreased significantly in 5 by a mean of 5.1 (2.1-11.7) fl, normalizing in 2. In a second report, neutrophils increased in 8 of 9 pts; in 4 the initial neutrophil count was <1 ×109/l, and platelet counts increased in 7 of 11 pts, in 4 the initial platelet count was <20 ×109/l. Conclusions In summary, our pt is the 19th patient with MDS reported to date in whom improved Hb followed the initiation of ICT; 9 had a decrease in RBC transfusion requirements, and RBC transfusion independence occurred in 10. The remarkable course of these pts adds to evidence that ICT may be of clinical benefit for selected patients with MDS and IOL. Although the improvement in WBC and platelet counts with ICT in some pts implies a suppressive effect of IOL on hematopoiesis that may be abrogated by ICT, the mechanism by which the effects of ICT on transfusion requirements occur, and the frequency with which they occur, remains an area for future investigation. Disclosures Off Label Use: This presentation discusses the use of iron chelation therapy deferoxamine and deferasirox in patients with myelodysplastic syndrome.. Vickars:Novartis Canada: Honoraria, Research Funding. Leitch:Novartis Canada: Honoraria, Research Funding, Speakers Bureau.

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Effects of Leucine Administration in Diamond-Blackfan Anemia Patients.

Blood ◽

10.1182/blood.v110.11.1686.1686 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1686-1686

Author(s):

Dagmar Pospisilova ◽

Jana Cmejlova ◽

Tomas Adam ◽

Radek Cmejla

Keyword(s):

Dose Reduction ◽

Serum Ferritin ◽

Chelation Therapy ◽

Iron Chelation ◽

Steroid Treatment ◽

Translational Efficiency ◽

Iron Chelation Therapy ◽

Gradual Improvement ◽

Diamond Blackfan Anemia ◽

Steroid Dose

Abstract Diamond-Blackfan anemia (DBA) attracts much attention, since the symptoms of the disease are associated with mutations in ribosomal protein (RP) S19 in 25% of patients and in RPS17 and RPS24 in other DBA patients, indicating a possible relationship between ribosomal function, translation level and erythropoiesis. Indeed, translational efficiency has been found to be lowered in most DBA patients, and the amino acid leucine was tested in vitro as a potential modulator of protein synthesis with promising results. We therefore decided to evaluate the effects of leucine administration in several DBA patients. For leucine therapy, 4 patients with the lowest levels of translation (patients 1, 2, 4 and 6; see Table) and 2 others were selected from the Czech DBA registry. Due to iron overload, all patients were receiving iron chelation therapy at the start of the leucine therapy. A total dose of 2000 mg/m2/day of L-leucine was administered orally in three subdoses in the form of a capsule prepared by the hospital pharmacy. The doses were based on the leucine content in sports dietary protein supplements, and reduced according to each patient’s body surface area. Two and 4 hours after administration, serum leucine levels doubled, but did not exceed normal values. Changes in other amino acids serum levels were not observed. After 8 weeks of leucine supplementation, all patients reported a noticeable increase in appetite and weight gain. Over a period of 6 months of follow-up, a gradual improvement in reticulocyte counts, hemoglobin levels and a reduction of serum ferritin levels were observed in all patients (see Table). One patient became transfusion independent, and is currently still in remission (>5 months); in two other transfusion dependent patients, the inter-transfusion period doubled; in steroid-dependent patients, the steroid dose could be reduced. The patient with the RPS17 mutation significantly improved in weight and well-being, and the iron chelation therapy was stopped. Our results thus show for the first time that leucine administration can greatly improve the quality of life of DBA patients in at least two ways - it can reduce the need for iron chelation; and it can gradually enhance erythropoiesis, reducing the steroid dose or the frequency of transfusions. Patients’ characteristics Patient No. Age (y) / Sex Status before Leu Level of translation (% of controls)* Duration of Leu administration (mo) Serum ferritin level before Leu/current (μg/l) Reticulocyte count before Leu/current (%) Effect of Leu administration MUT: mutation in RPS17; NM: no mutation in RPS17, RPS19 or RPS24; TD: transfusion dependent; HDS: high dose steroid treatment; LDS: low dose steroid treatment; ND: not done; PTP: prolongation of the transfusion period (before Leu/ current); *: Haematologica91:1456(2006) 1 NM 7 / F TD 21 12 1220 / 381 0.1 / 3.3 Remission 2 NM 8 / M TD 47 9 1311 / 492 0.1 / 0.4 PTP (3 / 6 weeks) 3 NM 11 / F TD ND 2 1950 / ND 0.1 / ND Increased appetite 4 MUT 31 / M LDS 39 8 860 / 496 1.1 / 1.5 Steroid dose reduction 5 NM 13 / M TD 77 6 1427 / 1110 0.6 / 1.4 PTP (4 / 8 weeks) 6 NM 18 / M HDS 42 12 1605 / 862 0.4 / 0.8 Steroid dose reduction

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The Palatability and Tolerability of Deferasirox (Exjade®) Taken with Meals, Different Liquids, or Crushed and Added to Food

Blood ◽

10.1182/blood.v116.21.5155.5155 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5155-5155

Author(s):

Stuart L Goldberg ◽

Patricia Giardina ◽

Joan Parkhurst Cain ◽

Deborah Chirnomas ◽

Jason Esposito ◽

...

Keyword(s):

Adverse Events ◽

Serum Ferritin ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Thalassemia Major ◽

Iron Chelation Therapy ◽

Age Group ◽

Baseline Serum ◽

Off Label

Abstract Abstract 5155 Introduction: Deferasirox (Exjade®, Novartis Pharmaceuticals) is an oral iron chelator indicated for the treatment of transfusional iron overload. The recommended mode of administration is to be taken on an empty stomach in water, apple juice or orange juice ≥30 minutes before food. However, there have been post-marketing reports of discontinuation or reduced compliance of deferasirox secondary to palatability and gastrointestinal adverse events. Registration trials with deferasirox did not evaluate different food combinations in an attempt to maintain predictable plasma levels. Early single dose studies suggested that the bioavailability of deferasirox is increased when administered with or before meals, and is positively influenced by fat content, but is not affected by degree of dispersion nor type of liquid. Long-term pharmacokinetic and tolerability studies involving a food effect have not been conducted to date, and the ability of alternate methods of administration to improve patient compliance with iron chelation therapy is unknown. Method: This is an ongoing single-arm, open-label, multi-center study designed to evaluate the palatability, safety, tolerability and pharmacokinetics of deferasirox when administered with food, dispersed in any liquid of choice, or crushed and added to food. The patient population includes patients with transfusional hemosiderosis (minimum entry serum ferritin ≥500 μ g/L) aged >2 years with thalassemia major, sickle cell disease (SCD), low or intermediate (INT-1) risk MDS or other anemias, who are on, starting, or resuming treatment with deferasirox. The study began with a 1-month run-in phase with deferasirox dosed according to prescribing information, then a 3-month assessment phase where subjects could choose each week from 5 general administration options including with or without meals, in the morning or evening, crushed and added to a soft food, or mixed in a liquid of choice. Subject diaries are used to record the meal and method of administration at the end of each week. Palatability is assessed with a modified facial hedonic scale, with additional directed questions capturing gastrointestinal side effects. This is a data analysis of the run-in phase. Result: Target enrollment has been met with 65 patients. Baseline data on the first 58 subjects include 8 in the 2 to <10 years of age group (median 7.5 years; range 3–9); 42 in the 10 to <60 years of age group (median 18.5 years; range 10–48); and 8 in the ≥60 years of age group (median 74 years; range71-83). Underlying hematologic diagnoses included SCD (41%), thalassemia major (29%), MDS (12%) and other anemias (17%). Sixty-nine percent of subjects were receiving deferasirox prior to entering the study. The median baseline serum ferritin level was 2405 μ g/L (range 560–8660) and was distributed as shown in Table 1. The most frequent adverse events were diarrhea (19%) and nausea (9%) (Table 2), which were more common in MDS (P=0.23 and P<0.01, respectively). Conclusion: This ongoing trial (NCT00845871) is evaluating whether alternative modes of administration improve palatability and tolerability while maintaining safety. Preliminary data from the assessment phase (deferasirox taken with meals, different liquids, or crushed and added to food) will be presented at the meeting. Disclosures: Goldberg: Novartis Oncology: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Exjade, iron chelation therapy, off-label method of administration. Giardina:Novartis: Research Funding. Parkhurst Cain:Novartis: Research Funding. Chirnomas:Novartis: Research Funding. Esposito:Novartis: Employment. Paley:Novartis: Employment. Vichinsky:Novartis: Consultancy, Research Funding, Speakers Bureau; Hemaquest: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apotex: Consultancy, Research Funding.

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