Transfusion-Related Iron Overload: A Covert Risk Of Supportive Cancer Care

Abstract Background Chronic transfusion support plays a key role in survival and quality of life for patients with hematological disorders. However, transfusion-related iron overload (TRIO) is a significant cause of morbidity and mortality in these patients.Adequate iron overload (IO) screening and use of iron chelators, if necessary, is now standard practice in chronically transfused individuals such as hemoglobinopathy patients. Screening practices for IO for patients receiving multiple red blood cell (RBC) transfusions for other reasons (e.g. cancer) are unknown. Objective This two part study aimed to detect pediatric (Jaffer et al., 2012) and adult populations at risk for TRIO and to evaluate and compare current screening practices. Methods Children (≤ 18 years) and adults (> 18 years) receiving at least 1 RBC transfusion from January 1, 2008 to December 31, 2011 at a tertiary care academic institution were identified using a transfusion registry database. Only those receiving chronic RBC transfusions were included in the study. Chronic transfusion was defined as ≥20 units of RBC or ≥ 20 RBC transfusions dosed at 15ml/kg within 12 consecutive months where transfusions were not given in the setting of an operating room, trauma or surgical procedures, not given 7 days prior/post-surgical procedures and not all given in one day. An adjudicator resolved study inclusion ambiguity. The analysis excluded hemoglobinopathy patients. Medical records were reviewed to collect patient demographics, diagnosis, and to evaluate IO screening practices and frequency of iron chelation therapy. Results A total of 343 patients met the eligibility criteria: 27 pediatric and 316 adult patients, with mean ages of 8.1 years (SD 5.7) and 62 years (SD 12.6), respectively. Table 1 summarizes demographics, number of transfusions, and IO screening and results. Ferritin levels were checked for 12 (44%) pediatric and 227 (72%) adult patients: 2 (17%) pediatric and 30 (13%) adult patients had values<500 μg indicating no further TRIO screening was required. In the pediatric population, 81% had a cancer diagnosis, and just under a third were tested for ferritin, whereas 64% of the adults had cancer, with nearly two-thirds tested for ferritin. A statistically significant difference was observed in the percentage of pediatric and adult cancer patients screened for IO. Of those cancer patients screened, ferritin level > 500 occurred in 71% of pediatric and 85% of adult patients, with an iron chelator reported in 1 adult. Total RBC transfusions ranged from 20 to 44 with a median of 26.5 for pediatrics and 20 to 176 with a median of 31 for adults. Conclusion Despite high rates of RBC transfusion, screening for TRIO was inconsistent. Although information regarding reasons for not screening for TRIO or not treating with chelation therapy was not collected, the possibilities include a lack of awareness of the risk of TRIO and lack of access to ferriscan and/or to oral iron chelator in Canada for conditions other than hemoglobinopathy and a select subset of MDS cases. Considering TRIO presents an additional, yet unidentified, co-morbidity of cancer therapy and that the therapy (e.g. anthracyclines) may potentiate the end organ effect of TRIO, it is vital to develop strategies to evaluate cancer patients at risk for TRIO and ensure they have access to appropriate iron chelation therapy. Research is needed to explore the comorbidities associated with failure to treat TRIO and to identify barriers to treatment so cancer patients can receive optimal care. Disclosures: Leber: Novartis Canada: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Heddle:Canadian Blood Services and Health Canada: Research Funding.

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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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Durable Red Blood Cell Transfusion Independence in a Patient with an MDS/MPN Overlap Syndrome Following Discontinuation of Iron Chelation Therapy

Case Reports in Hematology ◽

10.1155/2015/253294 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Harpreet Kochhar ◽

Chantal S. Leger ◽

Heather A. Leitch

Keyword(s):

Blood Cell ◽

Iron Overload ◽

Red Blood Cell ◽

Chelation Therapy ◽

Iron Chelation ◽

Red Blood Cell Transfusion ◽

Favorable Effect ◽

Iron Chelation Therapy ◽

Transfusion Independence ◽

Rbc Transfusion

Background. Hematologic improvement (HI) occurs in some patients with acquired anemias and transfusional iron overload receiving iron chelation therapy (ICT) but there is little information on transfusion status after stopping chelation.Case Report. A patient with low IPSS risk RARS-T evolved to myelofibrosis developed a regular red blood cell (RBC) transfusion requirement. There was no response to a six-month course of study medication or to erythropoietin for three months. At 27 months of transfusion dependence, she started deferasirox and within 6 weeks became RBC transfusion independent, with the hemoglobin normalizing by 10 weeks of chelation. After 12 months of chelation, deferasirox was stopped; she remains RBC transfusion independent with a normal hemoglobin 17 months later. We report the patient’s course in detail and review the literature on HI with chelation.Discussion. There are reports of transfusion independence with ICT, but that transfusion independence may be sustained long term after stopping chelation deserves emphasis. This observation suggests that reduction of iron overload may have a lasting favorable effect on bone marrow failure in at least some patients with acquired anemias.

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Effective and Safe Deferasirox Treatment of Patients with Various anemia's and Transfusional Iron-Overload in the Medical Practice: Results From Two German Observational Studies

Blood ◽

10.1182/blood.v118.21.5165.5165 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5165-5165

Author(s):

Christian Junghanss ◽

Rudolf Schlag ◽

Bernd Gaede ◽

Matthias Moelle ◽

Steffen Doerfel ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Observational Studies ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelator ◽

Beta Thalassemia ◽

Final Visit ◽

Iron Chelation Therapy ◽

The Mean

Abstract Abstract 5165 Background: Progressive anaemia is highly prevalent amongst many malignant diseases leading to RBC transfusion-dependency. Therefore transfusion-related iron overload (IOL) is common in these patients (pts) and can result in multiple organ failure. Iron chelation therapy prevents organ failure, reduces the risk of infections and can improve hematopoesis in some diseases. The once-daily oral iron chelator deferasirox has been shown to reduce iron overload in pts with various transfusion-dependent anaemias assessed by serum ferritin (SF). Despite extensive knowledge of iron chelation in MDS or beta-thalassemia pts, data in pts with other anaemias is limited. Here, we present data from a subgroup of transfusion-related IOL pts that were included two non-interventional studies (EXTEND, EXJANGE) performed in Germany and who suffered from diseases other than MDS or beta thalassemia. Methods: 130 pts with various malignant diseases such as myeloproliferative disorders (43 pts, including 31 pts particular specified as myelofibrosis), acute myeloid leukaemia (14 pts), sickle cell anaemia (6 pts), aplastic anaemia (11), congenital aplastic anaemia (5) or Non-Hodgkin's lymphoma (6 pts) were treated with deferasirox in the daily-routine setting of office-based physicians and included in either the EXTEND or EXJANGE study. Patient with MDS or beta-thalassemia were also included in the studies, but are excluded from this analysis. Analysis is based on 1-year pooled data of these two, multicenter, non-interventional observational studies. Transfusion-dependent pts with IOL with or without prior chelation were enrolled and received the iron chelator deferasirox. Prescription of deferasirox, just as inclusion and exclusion criteria was in accordance with the terms of Exjade marketing authorization in the EU. Efficacy and safety parameters, including serum ferritin and adverse events (AEs), were collected in 2-monthly intervals. Results: 98 pts had no prior chelation therapy (51 M, 45 F, 2 missing; mean age 63.3, range 3.2–91.9 yrs) and a median baseline SF of 2,968 (range 561–11, 423) ng/mL. 32 pts had prior received prior chelation therapy (mainly with desferal; 17 M, 15 F; mean age 50.1, range 3.5–80.9 yrs) and a median baseline SF of 2,635 (range 539–19, 540) ng/mL. The mean number of prior red blood cell transfusions was 55. The mean prescribed daily dose of deferasirox at the first visit was 16.3 mg/kg/d rising up to 18.1 mg/kg/d after 12 months. During treatment, median SF levels clearly decreased from first to final visit [-806 ng/mL; p<0.0001 (explorative analysis)] in the chelation-naïve and also in the pre-chelated population [-300 ng/ml; p = 0.1705 (explorative analysis)]. The median observation period and days on therapy was 349 and 343 days, respectively. At final visit 74 pts (56.9%) were still on deferasirox therapy. Reasons for discontinuation by the final visit included 19 AEs (35.2%). 45 pts (34.6%) experienced an investigator assessed drug-related AE. The most common drug-related AEs were diarrhea (n=17; 37.8%), nausea (n=11; 24.4%) and blood creatinine increased (n=6; 13.3%). As in previous clinical trials, serum creatinine clearances showed a minor decrease over the study period (median decrease until final visit: 4 ml/min). Conclusion: Our analysis confirmed that deferasirox is effective and well tolerated in chelation-naïve as well as in previously chelated pts with transfusion-related IOL and diseases other than MDS or beta thalassemia. As baseline serum ferritin values were >2,500 ng/mL even in pts with prior chelation therapy, adequate chelation treatment should be considered earlier at a serum ferritin >1,000 ng/mL in pts with transfusion-dependent IOL for adequate iron chelation therapy. Disclosures: Junghanss: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Haus:Novartis Pharma: Employment. Junkes:Novartis: Employment. Leismann:Novartis: Employment.

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Consequent Iron Chelation Therapy in Patients with Low Risk Myelodysplastic Syndrome Leads to up-Regulation of .CXCL12, JAK2 and HSF2: Possible Link Between Iron Chelation and Improvement of Erythropoiesis.

Blood ◽

10.1182/blood.v114.22.2787.2787 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2787-2787

Author(s):

Florian Nolte ◽

Martin Neumann ◽

Ouidad Benlasfer ◽

Sandra Heesch ◽

Eckhard Thiel ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Iron Overload ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelator ◽

Janus Kinase ◽

Refractory Anemia ◽

Iron Chelation Therapy ◽

Oral Iron Chelator

Abstract Abstract 2787 Poster Board II-763 Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and an increased risk of evolution to acute myeloid leukemia. The majority of MDS patients will depend on regular transfusions of packed red blood cells (PRBC) during their course of disease due to symptomatic anemia. Since recurrent transfusions of PRBC will result in iron overload with the risk of damage of organs such as heart, endocrine glands and the liver, consequent iron chelation therapy (IC) became an important element of supportive care in MDS patients. Recently, the availability of the oral iron chelator deferasirox provides a convenient management of iron overload in MDS. Since intensive IC has been shown to improve hematopoiesis in iron overloaded patients we performed gene expression profiling on patients with low or intermediate MDS prior and after IC, to elucidate wheter IC leads to alteration of genes involved in hematopiesis, in particular in erythropoiesis. Heparinized bone marrow samples were obtained after informed consent from 6 MDS patients (2 refractory anemia, 4 refractory anemia with ringed sideroblasts) upon initial diagnosis of iron overload (prior IC) and after a period of 1 year of iron chelation (after IC) with the oral iron chelator deferasirox. CD34+ hematopoietic progenitor as well as CD71+ erythroid progenitor cells were isolated by high gradient magnetic cell separation (Miltenyi Biotech, Bergisch Gladbach, Germany). RNA was extracted from CD34+ cells and CD71+ cells using TRIzol reagent (Invitrogen, Life Technologies, Grand Island, NY) according to the manufacturer's protocol. Quality controlled RNA was hybridized according to the standard Affymetrix protocol to HG-U133 Plus 2.0 microarrays. Data analysis was performed using the Gene Spring Software version 4.0 (Silicon genetics, San Carlos, CA). Restrictions were set as follows: only genes that were ‘present' in at least 75% of samples were used for further analyses, genes were considered as ‘differentially expressed' when they showed at least 3 fold change between the different groups. Statistical significance was calculated by non-parametric t-test, with P < 0.05. In a first step we compared gene expression patterns of CD71+ cells in MDS patients prior and after IC. In total 106 probe sets representing unique genes, hypthetical proteins and open reading frames matched the restriction settings. In an intensive survey on these genes we identified several genes that have been associated with erythropoiesis including Stromal derived factor-1 (CXCL12), Janus kinase 2 (JAK2), and Heat shock transcription factor 2 (HSF2). To exclude that these changes in gene expression where due to the natural course of the disease in specific patients, we compared gene expression of CD71+ cells from patients after IC to an independent test set of CD71+ MDS samples (n=12). Interestingly, we still found an aberrant expression of these genes, indicating that the observed gene expression changes were related to the IC in these patients rather than to the natural course of diesease. However, we were not able to find an altered expression of these genes in CD34+ progenitor cells prior and after IC, suggesting that the effect on gene expression is restricted to CD71+ cells. Iron overload is an inevitable side effect of regular blood transfusions in MDS patients. Intensive IC has been shown to improve erythropoiesis in iron overloaded patients. We found, that IC results in upregulation of Stromal derived factor-1, Janus kinase 2 and Heat shock transcription factor 2 all of them known to regulate hematopoiesis. Moreover, HSF2 and JAK2 have been closely involved in regulation of erythropoiesis. JAK2 deficiency has been shown to result in abrogated erythropoiesis and therefore increase of JAK2 expression after iron chelation might link IC to improvement of erythropoiesis and subsequently decrease of transfusion requirement in some patients receiving IC. Disclosures: Hofmann: Novartis Oncology, Nürnberg, Germany: Research Funding.

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Iron Chelation Therapy with Deferasirox Results in Improvement of Liver Enzyme Level in Patients with Iron Overload-Associated Liver Dysfunction

Case Reports in Medicine ◽

10.1155/2010/675060 ◽

2010 ◽

Vol 2010 ◽

pp. 1-3 ◽

Cited By ~ 2

Author(s):

Yasuo Miura ◽

Yusuke Matsui ◽

Hitomi Kaneko ◽

Mitsumasa Watanabe ◽

Mitsuru Tsudo

Keyword(s):

Iron Overload ◽

Liver Dysfunction ◽

Chelation Therapy ◽

Enzyme Level ◽

Elevated Serum ◽

Iron Chelation ◽

Iron Chelator ◽

Similar Efficacy ◽

Iron Chelation Therapy ◽

Red Blood Cell Transfusions

Iron chelation therapy (ICT) has been applied for the patients with iron overload-associated liver dysfunction since it is one of the causes of death in patients with intractable hematological diseases requiring multiple red blood cell transfusions. Recently, deferasirox (DSX), a novel, once-daily oral iron chelator, was demonstrated to have similar efficacy to the conventional continuous infusion of deferoxamine on a decrease in serum ferritin (SF) level in heavily transfused patients. We show three cases of transfusion-mediated iron-overloaded patients with an elevated serum alanine aminotransaminase (ALT). All three patients who received the ICT with DSX showed a decrease in ALT level in association with a decrease in SF level. It is suggested that DSX therapy could be considered to expect the improvement of liver damage for iron-overloaded patients with an abnormal ALT level.

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High Rate of Erythroid Response During Iron Chelation Therapy in a Cohort of 105 Patients Affected by Hematologic Malignancies with Transfusional Iron Overload: An Italian Multicenter Retrospective Study

Blood ◽

10.1182/blood.v118.21.611.611 ◽

2011 ◽

Vol 118 (21) ◽

pp. 611-611 ◽

Cited By ~ 8

Author(s):

Daniela Cilloni ◽

Emanuela Messa ◽

Lucia Biale ◽

Margherita Bonferroni ◽

Flavia Salvi ◽

...

Keyword(s):

High Risk ◽

Iron Overload ◽

Serum Ferritin ◽

Chelation Therapy ◽

Iron Chelation ◽

Hematologic Malignancies ◽

High Rate ◽

Iron Chelation Therapy ◽

Erythroid Response ◽

Rbc Transfusion

Abstract Abstract 611 Background: Improvements in hematologic parameters have been associated with iron chelation therapy (ICT) in transfusion-dependent patients with chronic anemia associated with hematologic malignancies. Data from a significant cohort of myelodysplastic syndromes (MDS) patients enrolled in the EPIC study and treated with deferasirox reported a percentage of 22.6% of erythroid responses. Several sporadic reports showed hematologic improvement in patients treated with deferoxamine or deferasirox in patients affected by myelofibrosis (PMF) and Aplastic Anemia (AA). The aim of this study was to retrospectively evaluate the hematologic response in the entire cohort of chronic anemias with iron overload receiving ICT with both deferasirox (DFX) or deferoxamine (DFO) in 6 hematological Italian centers from 1993 to 2011. Methods: 105 patients received ICT for at least 3 months. Sixteen were PMF, 8 AA, 75 MDS, 4 Chronic Myelomonocytic Leukemia (CMML), 2 Acute Myeloid Leukemia (AML). 30 patients received deferoxamine (6 PMF, 3 AA, 1 CMML, 2 AML, 18 MDS), and 68 deferasirox (9 PMF,5 AA, 3 CMML, 51 MDS), and 7 received deferasirox after a prior treatment with deferoxamine (1 PMF, 6 MDS). The median serum ferritin levels at the time of ICT was 1983 ng/ml and it was not significantly different between the two cohorts (p=0,8). Patients, at the time of ICT, had transfused a median of 30 Units of RBC (40 in the DFO cohort and 24.5 in DFX cohort, p=0.001). 25 out of 105 were receiving EPO therapy at the time of chelation, started at least 6 months before ICT, without a significant clinical improvement and three were receiving a JAK2 inhibitor started at least 1 year before ICT. Patients receiving any kind of therapy able to modify the erythroid response including azacitidine were excluded as well as patients receiving EPO started less than 6 months before ICT or JAK2 inhibitors or immunosuppressive therapy less than 12 months before. Hematological response (HR) was evaluated as follow: Achieving a RBC transfusion independency (complete HR) or Hematological improvement (HI-e) for patients showing a Hb increase of 1.5 g/dL or a reduction of 4 RBC transfusions/8 weeks (IWG 2006). Results: We retrospectively analyzed an unselected cohort of patients with transfusion dependent iron overload affected by different hematologic malignancies who received ICT outside clinical trials thus allowing the inclusion of high risk MDS/AML. 13 patients were not evaluable because they were receiving ICT for less than 3 months. 41 patients out of 92 (42.7%) evaluable patients achieved a hematologic response. In details: 18 (19,5%) became completely RBC transfusion independent. Six (1 AA, 3 RARS, 1 RCMD, 1 AML) were under DFO treatment and 12 (3 AA, 2 RA, 3 RARS, 1 RAEBII, 1 CMML, 2 PMF) under DFX. In addition, all 4 AA patients who achieved transfusion independency significantly increased the number of platelets ( median 17.000/mm3 before ICT and 35.000 and 55.000 after 6 and 12 months of ICT). Median time to response was 15 months for DFO and 3 months for DFX. 16 patients (17.3%) (6 RA, 4 RARS,1 RCMD, 1 RAEB, 4 PMF) obtained HI-e defined as a reduction of 4 U/8 weeks (5 in DFO and 11 in DFX cohorts) after a median of 6 months for both DFO and DFX. HI-e defined as an increased of 1.5 g/dL was observed in 7 patients (7.6%) ( 4 RA, 1 RARS, 1 RCMD, 1 PMF) after a median of 6 months for DFO and 3 for DFX. The hematologic improvement is not strictly related to an effective reduction of serum ferritin (p=0,4). Conclusions: Our data show a high rate of complete responses, mainly in AA and RARS but also in high risk MDS/AML representing 11% of those achieving complete transfusion independency. Notably 50% of AA achieved RBC and platelet transfusion independency. Despite the limitation due to the retrospective collection of data we suggest the ICT could result in hematologic improvement in a wide population including patients who are, at present, outside the published ICT guidelines. This study warrants further investigation on the mechanism of action of ICT in inducing erythroid response. Disclosures: Saglio: Novartis, Brystol Myers: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Iron Chelation Therapy in CAPD: A New and Effective Treatment of Iron Overload Disease in Esrd Patients

Peritoneal Dialysis International ◽

10.1177/089686088300300214 ◽

1983 ◽

Vol 3 (2) ◽

pp. 99-101 ◽

Cited By ~ 13

Author(s):

Glen H Stanbaugh ◽

A. W, Holmes Diane Gillit ◽

George W. Reichel ◽

Mark Stranz

Keyword(s):

Peritoneal Dialysis ◽

Iron Overload ◽

End Stage Renal Disease ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Peritoneal Dialysate ◽

Stage Renal Disease ◽

End Stage ◽

Esrd Patients

A patient with end-stage renal disease on CAPD, and with massive iron overload is reported. This patient had evidence of myocardial and hepatic damage probably as a result of iron overload. Treatment with desferoxamine resulted in removal of iron in the peritoneal dialysate. On the basis of preliminary studies in this patient it would appear that removal of iron by peritoneal dialysis in conjunction with chelation therapy is safe and effective. This finding should have wide-ranging signficance for patients with ESRD.

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Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials

Blood ◽

10.1182/blood-2019-130237 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3542-3542 ◽

Cited By ~ 1

Author(s):

Natalia Scaramellini ◽

Carola Arighi ◽

Alessia Marcon ◽

Dario Consonni ◽

Elena Cassinerio ◽

...

Keyword(s):

Clinical Practice ◽

Liver Function ◽

Iron Overload ◽

Board Of Directors ◽

Chelation Therapy ◽

Iron Chelation ◽

Published Data ◽

Iron Chelation Therapy ◽

Iron Intake ◽

Advisory Committees

Introduction The current therapeutic management of transfusion dependent thalassemia (TDT) is based on regular blood transfusion and iron chelation therapy. Transfusion iron overload remains one of the major causes of morbidity and mortality in these patients because of the accumulation in heart, liver and endocrine glands. Three iron chelators are available in clinical practice: deferoxamine (DFO), deferiprone(DFP) and deferasirox (DFX). Guidelines clearly recommend when to start iron chelation, while discontinuation criteria are not well defined. Authorised product information state that we should consider interrupting DFX if serum ferritin (SF) falls consistently below 500mcg/L. This cut off was arbitrarily determined and there are no studies evaluating the effects of chelators in presence of SF below 500 mcg/L. In our clinical practice at Rare Diseases center of Fondazione IRCCS Ca' Granda Policlinico in Milan we do not completely interrupt iron chelation in TDT patients for SF levels below 500 mcg/L. Aims and methods Aim of our study was to evaluate the appearance of adverse events due to the assumption of iron chelation therapy in those TDT patients who had SF below 500 mcg/L. In this study we retrospectively evaluated renal and liver function from 2008 throughout December 2018 in TDT patients on DFX who presented SF below 500 mcg/L for 24 consecutive months. DFX dose are all expressed with the new tablets formulation dose. We evaluated SF, iron intake, LIC and MIC, renal and hepatic function. .A total of 5076 observations were collected, with 99.5 average per patient. We evaluated the relationships among variables with correlation models with random intercept Results One hundred ninety-two TDT patients are regularly followed at our center. They receive regular transfusion treatment and iron chelation therapy to prevent secondary iron overload. 51 out of 192 patients (32 F, 19 M, aged 44 ± 7 years) treated with DFX presented mean SF below 500 mcg/L for at least 24 consecutive months. Hematological and iron status parameters are described in Table 1. We found a strong correlation between SF and LIC (p<0.001) and for SF<500 mcg/L no hepatic iron overload was observed. Conversely we did not found a correlation between SF and MIC. For SF values below 500 mcg/L there was a minimal increase in creatinine levels, however the mean creatinine values remained within the normal range.Moreover, creatinine variation between two consecutive evaluation was below 0.3 mg/dl, cut off for acute kidney injury. Similar results were observed for liver function. Although a minimal increase of mean ALT value was observed for SF below 500 mcg/L, it remained within the normal range. None of our patient showed ALT level indicative of liver damage (ALT> 10 x upper limit of normal) We evaluated the relation between SF and DFX dose. Mean DFX dose decreases according to SF reduction. However, for SF value < 240 mcg/L, DFX dose remained stable at an average of 14 mg/kg per day. Conclusion According to our preliminary data, administration of DFX in TDT patients in presence of SF below 500 mcg/L is safe. Creatinine and ALT fluctuations, that usually remain within the range of normality, are mild, and transient and do not require specific treatment. Consistently with previously published data by Cohen et al, we show that a mean dosage of DFX of 14 mg/Kg die of film-coated tablet (20 mg/Kg of dispersable formulation) are necessary to balance an iron intake of 0.3 mg/kg die in absence of iron overload. Based on these results we suggest that in TDT patients with a continuous iron intake, iron chelation should be continued even when ferritin is below 500mcg/L. Monitoring of liver and kidney function tests are recommended in patient's follow up, as well as tailoring iron chelation. Disclosures Cappellini: Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Motta:Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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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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