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 ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 611-611 ◽  
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.

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

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
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.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3656-3656
Author(s):  
Anushka Jaffer ◽  
Rebecca Barty ◽  
Erin Jamula ◽  
Grace Wang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Iron Overload ◽  
Cancer Patients ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Adult Patients ◽  
Iron Chelation Therapy ◽  
Not Given ◽  
Screening Practices ◽  
Rbc Transfusion

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.

Iron Overload and Haematopoiesis in MDS: Does Blood Transfusion Promote Progression to AML?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2685-2685 ◽  
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-&gt;300 units PRBC) and serum ferritin levels (11-&gt;10000 μg/L). ROS was strongly correlated with serum ferritin concentration for patients with iron overload (serum ferritin &gt;1000 μg/L; n=14, R=0.733, p&lt;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&lt;0.005). In contrast, no correlation between ROS and ferritin level was demonstrated for patients with serum ferritin &lt;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&lt;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.

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

Blood ◽  
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.

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

Blood ◽  
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.

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 ◽  
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.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4558-4558
Author(s):  
Lisette Del Corso ◽  
Elisa Molinari ◽  
Andrea Bellodi ◽  
Riccardo Ghio ◽  
Andrea Bacigalupo ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Chelation Therapy ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Group A ◽  
Group B

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

Clinical Parameters in 391 Iron-Overloaded Patients with Lower-Risk MDS Enrolled in a Prospective, Non-Interventional Multicenter Registry.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4834-4834
Author(s):  
Guillermo Garcia-Manero ◽  
Billie J. Marek ◽  
Roger M. Lyons ◽  
Noelia Martinez-Lopez ◽  
Carole Paley ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Lower Risk ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Advisory Committees ◽  
The Impact

Abstract Abstract 4834 Introduction Despite recent improvements in therapies for patients with myelodysplastic syndromes (MDS), 60–80% will require continuing packed red cell blood (pRBC) transfusions for prolonged periods. Complications resulting from the iron burden may, therefore, become clinically significant for many patients during the course of their disease. Patients with lower-risk MDS have a greater chance of developing the long-term toxicity of iron overload because of their prolonged survival, and are more likely to benefit from effective iron chelation therapy. This report describes data from a registry designed to study the impact of iron overload and iron chelation therapy on organ function and survival in patients with lower-risk MDS. Methods This is an ongoing, prospective, non-interventional, multicenter 5-year registry in 107 US centers, enrolling 600 patients (aged ≥18 years) with lower-risk MDS (by WHO, FAB and/or IPSS criteria) and transfusional iron overload (defined as serum ferritin ≥1000 μg/L and/or having received ≤20 cumulative pRBC units and/or an ongoing transfusion requirement ≥6 units every 12 weeks). Follow-up will be performed at least every 6 months for a maximum of 60 months or until death. Recommended assessments include serum ferritin, creatinine, calculated creatinine clearance, echocardiograms, and endocrine and hematological status. Results As of May 31 2009, 391 patients have enrolled in the registry. Demographic data are available from 389 patients. Median age: 74.4 years (range 21–99); male: 218, female: 171; ethnicity: 331 Caucasian (85%), 25 African-American (6%), 24 Hispanic (6%), five Asian (1%), two Native American (0.5%), and two other (0.5%). The median time since diagnosis (n=385) was <3 years in 217 patients (56%); ≥3–<5 years in 72 (19%); ≥5–<7 years in 48 (12%); and ≥7 years in 48 (12%). The MDS classification of the patients by WHO, FAB and IPSS, as well as patients' serum ferritin and transfusion burden, are summarized in the table. The most frequent concomitant conditions classified by organ (n=384 patients) were: 205 (53%) patients with vascular, 160 (42%) endocrine, and 171 (45%) cardiac dysfunction. At registry entry, 249 patients were receiving erythropoietin; 61 granulocyte colony stimulating factor; seven hydroxyurea; 25 thalidomide (Thalomid); 147 5-azacytidine (Vidaza); 95 lenalidomide (Revlimid) and 90 decitabine (Dacogen). 137 of 391 (35%) patients were on iron chelation therapy at study entry: 34 (9%) received deferoxamine for mean and median treatment durations of 803 and 383 (range 1–4386) days, respectively, while 117 (30%) received deferasirox for mean and median durations of 488 and 396 (9–1269) days, respectively. Calculated creatinine clearance was normal (>80 mL/min) in 37 (9%) patients; mildly abnormal (51–80 mL/min) in 30 (8%); and moderately abnormal (30–50 mL/min) in nine (2%) patients. Conclusions These baseline data indicate the demographic distribution as well as the co-morbidities associated with lower-risk MDS patients. In spite of recent guidelines, fewer than 50% of iron-overloaded patients are receiving any iron chelation treatment, despite the presence of cardiac, vascular and endocrine concomitant conditions in 40-54% of patients. Recent retrospective data highlights the impact of chelation on mortality in lower-risk MDS patients. This ongoing registry will prospectively assess the impact of iron chelation on survival and organ function in iron-overloaded patients with lower-risk MDS. Disclosures Lyons: Novartis: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Research Funding. Martinez-Lopez:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Greenberg:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Serum Ferritin Elevation and Use of Iron Chelation In Chronically Versus Sporadically Transfused Sickle Cell Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2671-2671
Author(s):  
Ismael Shaukat ◽  
Faraz Khan ◽  
Andrew Eisenberger ◽  
Marcus Stevenson ◽  
Alice J. Cohen
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Renal Dysfunction ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Cell Disease ◽  
The Mean

Abstract Abstract 2671 Background: Red cell transfusions play an integral role in the treatment and prevention of serious complications related to sickle cell disease. It has been shown that in other hemoglobinopathies, such as β-Thalassemia, patients (pts) suffer from iron overload which can result in end organ damage. There is concern that heavily transfused sickle cell pts may also develop iron overload with consequent morbidity and mortality. While pediatric pts routinely receive blood transfusions and iron chelation therapy, adult pts often discontinue chronic transfusion programs and are transfused sporadically. These pts may not receive routine iron chelation therapy. Methods: A retrospective review of our sickle cell database from 1988–2010 which also included those pts who were not routinely followed at the comprehensive sickle cell clinic. Adult pts (>18 yrs of age) with serum ferritin (SF) levels >1000 ng/ml (criteria for iron overload in our institution) were identified and use of iron chelation was reviewed in this population. Clinical characteristics evaluated were age, type of sickle cell disease, frequency of transfusions (chronic vs. sporadic), total units transfused, use and type of chelation, as well as reasons for non-use of chelation therapy. Results: 65/170(38%) pts were identified with SF >1000. The mean age is 33 years (range 19–70). 38/65 (59%) have the SS phenotype, 25/65 (38%) have the Sβ phenotype and 2/65 (3%) have the SC phenotype. The mean SF is 3697 ng/ml (range 1012–14312). Of those pts considered to have iron overload, 28/65 (43%) were treated with iron chelation: 27/65 (42%) received deferasirox and 1/65 (2%) received deferoxamine. Of the untreated pts, 24/37 (65%) had no identifiable reason for lack of chelation therapy, 10/37 (27%) had renal dysfunction, 1/37(3%) had hepatic impairment. 16/65 (25%) were transfused chronically, while 49/65 (75 %) were transfused sporadically. Chronically transfused pts received a mean of 81 units throughout their lifetime, while sporadically transfused pts received 30 units (p=0.01). The mean SF for chronically transfused pts was 5891, while the mean SF for pts transfused sporadically was 2981 (p=0.01). Of pts transfused chronically, 11/16 (69%) were on chelation therapy. Of the pts receiving sporadic transfusions, only 16/49 (33%) were on iron chelation (p= 0.01). In all pts chronically transfused, the reason for non-use of chelation therapy was renal dysfunction. In sporadically transfused pts, 33/49 (51%) had no identifiable reason for lack of chelation therapy. Conclusion: SF levels are significantly lower in pts who are sporadically transfused, though levels are high. Adult pts receiving sporadic transfusions are not routinely receiving iron chelation therapy despite elevated SF. The need for chelation therapy in both sporadically and chronically transfused pts remains to be determined. Disclosures: No relevant conflicts of interest to declare.

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