scholarly journals Three Distinct Groups of Phenotype Severity in Beta-Thalassemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Aurelio Maggio ◽  
Angela Vitrano ◽  
Antonella Meloni ◽  
Walter Addario Pollina ◽  
Mehran Karimi ◽  
...  
Keyword(s):  
Research Funding ◽  
Wide Spectrum ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Study Data ◽  
Beta Thalassemia ◽  
Classification Error ◽  
Classification Error Rate ◽  
Transfusion Therapy ◽  
Risk Of Death

Background Thalassemia Syndromes (TS) are commonly classified as transfusion-dependent-thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT) at diagnosis on the basis of requirement for lifelong regular transfusion therapy for survival. However, data from observational studies and expert opinion suggest that these categories may reflect a wide spectrum rather than a dichotomy, and may actually be interchangeable at many parts of the disease journey. Thus, an evaluation of alternate clusters to classify TS patients remains of merit. Aims The aim of this study was to cluster TS patients on the basis of possible clinical indicators of phenotype severity (IPhS) using suitable algorithms and to determine whether these are able to detect cohorts with different clinical phenotypes. Methods Representatives from thirteen international centers from seven countries agreed on 19 IPhS to be collected for a retrospective study. Data from 7910 TS patients were collected. NbClust R Packagewas performed for exploring the existence of a substructure inside the studied TS population, determining the best number of clusters. Unsupervised Random Forest (RF)clustering and the Partitioning Around Medoids (PAM)algorithms were performed to define the clusters. The most important IPhS in defining clusters were selected according to the Gini index. Kaplan-Meier (K-M) survival curves of the identified clusters, defined by the selected IPhS, were used to represent the risk of death for these clusters. Results NbClust method showed the existence of three possible clusters. The RF-PAM procedure defined three distinct clusters with a classification error rate of 4.3% (Fig 1). Moreover, the most important IPhS were patient age, mean serum ferritin level, age at diagnosis, age at first transfusion, age at first iron chelation, and number of complications. K-M curves showed statistically significant differences in survival among the three clusters (p<0.0001,Fig 2a) but not between the original classification of NTDT and TDT (p=0.0651, Fig 2b). Conclusions The observation of statistically significant differences in survival between the three newly identified clusters but not the original TDT-NTDT classification confirms that the latter classification is interchangeable, and a new triad classification system is required. These findings warrant further evaluation in prospective studies to determine specific thresholds for IPhs indicators that can aid physicians in assigning classes and tailoring care, in order to improve survival in TS patients. Disclosures Meloni: Chiesi Farmaceutici S.p.A.: Other: speakers' honoraria. Pistoia:Chiesi Farmaceutici S.p.A.: Other: speakers' honoraria. Vichinsky:Novartis: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; GBT: Consultancy, Research Funding.

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

Blood ◽  
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.

Growth Differentiation Factor 15 (GDF15) and Erythropoietin (EPO) Levels in Beta Talassemia Major Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1881-1881
Author(s):  
Ilaria Salussoglia ◽  
Gisella Volpe ◽  
Silvia Fracchia ◽  
Simona Roggero ◽  
Filomena Longo ◽  
...  
Keyword(s):  
Iron Status ◽  
Clinical Status ◽  
Transferrin Saturation ◽  
Iron Chelation ◽  
Serum Levels ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Transfusion Therapy ◽  
Beta Thalassemia Major ◽  
The Mean

Abstract Background: The serum level of GDF15 has been recently indicated as a possible marker of erythropoiesis (Tanno et al., Nature 2007) suggesting a role of its over-expression in contributing to iron overload in thalassemia syndromes by inhibiting hepcidin expression. The aim of present study has been to evaluate GDF15 serum levels in a homogeneous series of thalassemia patients and the relationship with transfusional parameters and iron status markers. Methods: A group of consecutive patients with beta thalassemia major followed at our institution were included in the study. All patients were on regular transfusion and iron chelation treatment. Quantification of GDF15 on serum samples was performed with DuoSet ELISA for human GDF15 (R&D Systems) following the manufacturer’s protocol (Tanno et al., Nature 2007). Each patient had also a blood test for haemoglobin (Hb), serum iron, ferritin, transferrin, transferrin saturation and EPO levels. Liver Iron Concentration by SQUID and cardiac iron by MRI T2* have been assessed. The mean hemoglobin levels of the previous year (pre-transfusional, post-transfusional and mean) have been calculated for each individual. The presence of mild thalassemic mutations was used to classify mild or severe genotype. Clinical status has been assessed on the presence/absence of main complications (heart disease, liver disease, diabetes, hypothyroidism). Statistical analysis was performed using the software Statistica (StatSoft). Results: One hundred-forty patients (73 male, 67 females) were studied. The mean age was 27.9 ± 9.0 years (range: 3.5–42). One hundred (71%) were splenectomised. Betathalassemia major patients had elevated GDF15 serum levels (mean 6892 ± 6894 pg/mL; range 720–52521) in comparison with healthy volunteers (273 ± 104 pg/mL; range 129–401). GDF 15 levels were strongly related to EPO levels (r=0,81; p&lt;0,001). GDF15 levels were not related with age, gender, spleen, clinical status and iron markers. Patients with a severe genotype had higher GDF15 levels than mild genotype patients. GDF15 levels had a negative correlation with Hbs (p&lt;0,05 for actual Hb and pre-transfusional Hb; p&lt;0,001 for post-transfusional Hb and mean Hb). In thalassemia major patients with a severe genotype, GDF15 levels within thrice the normal range have been observed only in patients with pre-transfusional Hb above 9,6, post-transfusional Hb above 12,5 and a mean Hb above 11,3. Conclusions: In beta thalassemia major patients on regular transfusion and iron chelation, serum GDF15 levels are high, inversely related to the haemoglobin levels maintained. Further studies of this marker may lead to a rethinking of the optimal transfusion therapy in these conditions.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3424-3424
Author(s):  
Yoo-Hong Min ◽  
Sung-Soo Yoon ◽  
Hyeoung Joon Kim ◽  
Kyoo-Hyung Lee ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Platelet Count ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Research Funding ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Hemoglobin Level ◽  
Hematopoietic Stem ◽  
Wbc Count

Abstract Abstract 3424 Patients with aplastic anemia (AA) are suffered from various complications related to bone marrow failure and peripheral cytopenia. Although immunosuppressive therapy or hematopoietic stem cell transplantation has been performed for curative purpose, the majority of patients have been treated only by supportive cares including repeated transfusion. However, because continued transfusion eventually induces iron overload in many tissues and organs, transfusional iron overload and its consequences are another life-threatening problems for AA patients. Previous reports about iron chelation therapy (ICT) have mainly shown its efficiency for decreasing tissue iron and safety. However, improvement in hematopoiesis after iron chelation therapy has been limitedly reported as case reports or trials involving small number of patients without objective tools for measuring tissue iron content. In the KAMS0112 study (a multi-center, open label, prospective study evaluating the efficacy of ICT with deferasirox in transfusional iron overload with myelodysplastic syndrome or AA using quantitative R2-MRI, Ferriscan), a total of 54 patients with AA showing serum ferritin level over 1,000 ng/ml were enrolled from 19 institutes, and further analyzed for the changes in hemogram during ICT as well as efficacy and safely of deferasirox. During the study, the specific treatments for AA, such as immunosuppressive therapy or hematopoietic stem cells transplantation, were not undertaken. During 1 year prior to study, patients received 23.7±16.9 units of red blood cell (RBC) product, and the baseline serum ferritin level and liver iron content (LIC) were 4,164±447 ng/ml and 20.1±12.0 mg Fe/g DW, respectively. Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin level falls below 500 ng/ml, treatment was withheld. In spite of continued transfusional support during the study, serum ferritin level and LIC were significantly decreased after 1 year of ICT with deferasirox (Ds-ferritin=−3,076.7±489.9 ng/ml, p=0.0003; DLIC=−7.73 mg/Fe/g DW, p=0.001). To evaluate the improvement of each parameter in hemogram by ICT, patients with baseline hemoglobin level less than 8.0 g/dl (n=28), with baseline WBC count less than 4/ml (n=43), and with baseline platelet count less than 20/ml (n=31) were selected separately. At the end of study, hemoglobin level and platelet count (8.2±3.0 g/dl and 22.2±31.4/ml, respectively) was significantly increased from the baseline value (6.1±1.1 g/dl, p=0.001; 12.5±12.4/ml, p=0.05, respectively). WBC count was also slightly increased (from 2.1±0.9/ml to 2.3±0.9/ml, p=0.457). Considering the relatively uniform criteria of transfusion, the finding that hemoglobin level and platelet count could increase above 8 g/dl and 20/ml, respectively, after 1 year of deferasirox treatment is clinically significantly. Due to gradual improvement of anemia, requirement of RBC transfusion had continuously decreased during the study period (R2=0.31). This subanalysis of KAMS0112 study demonstrates that ICT using deferasirox can be effective in improving anemia and thrombocytopenia in the transfusional iron overload patients with AA, as well as reducing serum ferritin level and LIC. Further studies might be required to elucidate the mechanism involved in the improvement of hematopoiesis associated with correction of deranged intracellular iron homeostasis. Disclosures: Min: Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Lee:Novartis: Research Funding. Won:Novartis: Research Funding. Shim:Novartis: Research Funding. Kim:Novartis: Research Funding. Seung:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Chung:Novartis: Research Funding. Hyun:Novartis: Research Funding. Jo:Novartis: Research Funding. Jung:Novartis: Research Funding. Sohn:Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Joo:Novartis: Research Funding. Cheong:Novartis: Research Funding.

Survey of Treatment of 1021 Patients with Myelodysplastic Syndromes in a Tertiary Referal Center 2007-2013

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4647-4647
Author(s):  
Jennifer Schemenau ◽  
Kathrin Nachtkamp ◽  
Blanca Xicoy ◽  
Andrea Kuendgen ◽  
Corinna Strupp ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Allogeneic Stem Cell Transplantation ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Iron Chelation ◽  
Transfusion Therapy

Abstract Introduction: Clinical course, prognosis, and therapy are heterogeneous in patients with myelodysplastic syndromes (MDS). Iron chelation, epigenetic treatment, lenalidomide, and allogeneic stem cell transplantation are the only approved therapies. As these treatments are successful only in a minority of patients, other approaches, which do not always meet the criteria of evidence-based medicine, are also used in an individualized manner. In order to get a comprehensive picture of MDS treatment we analysed 1021 patients who were treated between 2007 and 2013. We included patients with RAEB-T (5%) and CMML (10%). Treatment regimens were inititated at our department. Methods: Diagnoses were established within the Düsseldorf MDS Registry. All treatments were documented until 31 Dec 2013. Prognostic risk assessment was performed according to the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R). Results: Median age was 68 years (18-93 years), 13.5 % of patients were >80 years of age. 41% were diagnosed as RCMD, 12% as RAEB I, 15% as RAEB II, 4% as MDSdel(5q), 5% as RARS, and 9% as RCUD. Anemia was present at first diagnosis in 62.5%, hemorrhagic diathesis in 10%, and at least one comorbidity in 51%. Transfusion therapy was the only treatment in 57% of the patients. 43% (n=441) received at least one specific treatment during the course of the disease. The median number of different therapies was 2 (range 1-9). Of these, 29.9% received cytokines (Epo, G-CSF), 14.4% iron chelation, 11.0% immunomodulation (lenalidomide, thalidomide), 8.7% immuno­suppressive treatment (ATG, CSA, AntiCD52), 16.4% cytoreduction (Ara-C, hydroxyurea), and 16.4% valproic acid as a histone-deacetylating agent (HDAC), partly in combination with all-trans retinoic acid. 28.3% were treated with hypomethylating agents (5-azacytidine, decitabine), 14.6% with induction chemotherapy, and 31.1% underwent allogeneic stem cell transplantation. 5,2 % of the patients were treated within clinical trials. Treatment approaches were distributed among IPSS risk groups as follows: cytokines (low: 55.6%/ intermediate-1: 32.8% /intermediate-2: 24.1%/ high: 9.1%), chelation (18.1%/20.9%/8.9%/4.5%), epigenetic treatment (HMA) (6.9%/19.4%/48.1%/54.5%), immunmodulation (19.4%/13.4%/7.6%/2.3%), immunosuppressive treatment (5.6%/17.2%/2.5%/0.0%), HDA (26.4%/16.4% /11.4%/13.6%), induction chemotherapy (5.6%/9.7%/20.3%/34.1%), cyto-reduction (9.7%/13.4%/20.3%/13.6%), and allogeneic stem cell transplantation (13.9%/32.8%/48.1%/54.5%). Using the IPSS-R, results were similar: cytokines (very low: 62.5%/low: 38.0%/intermediate:25.3%/high: 29.6%/very high:11.5%), chelation (15.6%/26.0%/10.1%/14.8%/5.8%), epigenetic treatment (HMA)(6.3%/8.0%/ 30.4%/40.7%/44.2%), immunmodulation (9.4%/18.0%/7.6%/7.4%/5.8%), immunosuppression (9.4%/11.0%/16.5%/3.7%/3.8%), HDA (21.9%/26.0% /13.9 %/11.1%/15.4%), induction chemotherapy (6.3%/7.0%/17.7%/20.4%/26.9%), cytoreduction (12.5%/11.0%/20.3%/14.8%/15.4%) and allogeneic transplan-tation (15.6%/22.0%/36.7%/48.1%/50.0%). More than 96% of the patients who were treated with HMA, induction chemotherapy or allogeneic transplantation had high-risk MDS (at least IPSS intermediate II) either at diagnosis or during the course of the disease. Conclusions: Our survey shows that off-label treatment is frequent in MDS because there is still a lack of efficient therapies for many patients. During the observation period several treatment modalities were employed, varying in number and type according to IPSS and IPSS-R risk groups.Although numerous clinical trials with new compounds were initiated over the last few years, only a minority of MDS patients were eligible to participate. In the future, a further increase in clinical trial activity will hopefully allow a greater proportion of MDS patients to get access to effective treatment. Disclosures Xicoy: Celgene: Honoraria. Kuendgen:Celgene: Honoraria, Research Funding. Kobbe:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Gattermann:Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Germing:Novartis: Research Funding; Celgene: Honoraria, Research Funding; AMGEN: Research Funding; Janssen-Cilag: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria.

Deferasirox Is Associated with Reduced Mortality Risk in a Medicare Population with Myelodysplastic Syndromes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 426-426 ◽  
Author(s):  
Amer M. Zeidan ◽  
Franklin Hendrick ◽  
Erika Friedmann ◽  
Steven D. Gore ◽  
Maria R. Baer ◽  
...  
Keyword(s):  
Renal Disease ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Time Varying ◽  
Iron Chelation Therapy ◽  
Transfusion Threshold ◽  
Endocrine Disease ◽  
Risk Of Death ◽  
Observation Period

Abstract Abstract 426 Background: While there is extensive evidence of the impact of iron chelation therapy (ICT) on clinical outcomes in thalassemia patients (pts), there is a paucity of data relevant to myelodysplastic syndromes (MDS). In this study, we examined the association between oral deferasirox (DFX) therapy and conditions potentially associated with iron overload [congestive heart failure (CHF) and endocrine disease (diabetes or thyroid)], drug side effects (renal disease), and overall mortality, among MDS pts in a U.S. Medicare cohort. Methods: MDS pts from 2005–2008 were identified using ICD-9 CM codes (1 inpatient or 2 outpatient) from the 100% Medicare claims database. Pts meeting a minimum transfusion threshold of 20 units packed RBC were considered “eligible” for ICT. The study cohort consisted of ICT-eligible pts enrolled in Medicare Part D, under which oral drug prescriptions are reimbursed. The observation period began the week (wk) after the RBC threshold was met and ended at incident diagnosis of a condition of interest, death, or end of study. Patients receiving parenteral ICT (deferoxamine) during the observation period were excluded. Patients with a history of the specific condition (CHF, endocrine disease, renal disease) were excluded from the outcome-specific sample, but were included in overall survival analysis. Onset of CHF or renal disease was based on the presence of 1 inpatient or 2 outpatient Medicare claims with ICD-9-CM diagnoses of each condition. Onset of diabetes or thyroid disease was measured based on new use of oral anti-diabetic or thyroid medications, respectively. Covariates in the outcome models included demographics (age, sex, race), ICD-9 coded MDS risk category at diagnosis, baseline indicators for co-morbid conditions, and time-varying exposure to RBC, erythropoiesis-stimulating agents (ESA), lenalidomide and hypomethylating agents (HMA). Marginal structural models (MSM) estimated the effects of cumulative DFX, controlling for anemia management and patient characteristics. The analysis adjusted for effects of time-varying health status on the probability of receiving DFX. Results: The cohort of 4,226 beneficiaries with MDS was 54% female, 90% white, with mean age of 77.7 years. MDS risk status was 16% lower/del5q, 5% higher, & 79% not otherwise specified. Common baseline comorbidities included CHF (46%), diabetes (18%), thyroid disease (21%), and renal disease (29%). Drug exposures prior to cohort entry included ESA (84%), HMA (19%) and lenalidomide (7%). Prior ICT was noted for 4.5% of patients. Patients were observed for a median of 35 weeks. Death occurred in 2496 (59%) of the cohort. DFX was used during the observation period by 544 (12%) patients, with mean duration of 29.2 weeks (median 20.5). Estimates from MSM indicate that each incremental week of DFX was associated with a decreased risk of death [hazard ratio (HR) 0.987; 95%CI 0.981–0.993]. The magnitude of risk reduction increased from HR 0.77 (95%CI 0.536–1.02) for patients receiving 14–26 weeks of DFX to HR 0.342 (95%CI 0.179–0.651) for patients with 53 or more weeks. Cumulative RBC units were associated with increased risk of death (HR 1.01, 95%CI 1.007–1.013 per unit), as were a baseline solid tumor diagnosis, renal and cardiac disease, and poor predicted performance status. After controlling for time-varying incidence of sepsis, bleeds, and cytopenias in MSM treatment propensity model, DFX use was not found to be associated with altered risk of CHF, endocrine or renal disease. Conclusions: This is the first large population-based Medicare study evaluating the association between DFX use in older MDS patients and sequelae of iron overload and mortality. The decrease in risk of death was proportional to the duration of therapy. Application of MSM addresses the role of observed time-varying confounders between treatment and outcomes, while permitting us to assess the duration-outcome relationships. The MSM analysis cannot address potential confounding by unobserved factors that may influence physician selection of patients for ICT. Nonetheless, this retrospective analysis controls for bias associated with observed patient health status, and lends significant support to a positive association of oral iron chelation therapy with decreased mortality in MDS patients with a minimum transfusion threshold, and ongoing transfusion needs. Disclosures: Gore: Celgene Corporation: Consultancy, Research Funding. Baer:Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding. Sasane:Novartis Pharmaceuticals: Employment. Paley:Novartis: Employment. Davidoff:GlaskoSmithKline: Research Funding; National Institutes of Health: Research Funding; Celgene: Research Funding; Novartis: Research Funding.

Changes in Extrahepatic Iron Load in Response to Iron Chelation Versus Phlebotomy: Observations from the Twitch Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 202-202 ◽  
Author(s):  
John C Wood ◽  
Alvarez Ofelia ◽  
Matthew M Heeney ◽  
Alex George ◽  
Cynthia Gauger ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Research Funding ◽  
Total Bilirubin ◽  
Binding Capacity ◽  
Iron Chelation ◽  
Iron Deposition ◽  
Liver Iron ◽  
Transfusion Therapy ◽  
Iron Storage ◽  
Urine Albumin

Abstract Introduction: The TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial was an NHLBI-funded multicenter phase 3 randomized trial that demonstrated non-inferiority of hydroxyurea versus continued transfusion therapy in children with sickle cell anemia and abnormal TCD velocities but no severe vasculopathy. Children who were randomized to continue transfusions (Standard Arm) received conventional iron chelation therapy with deferasirox, while children receiving hydroxyurea (Alternative Arm) received serial phlebotomy (10 mL/kg, maximum 500 mL) every 4 weeks. Extrahepatic iron burden was monitored by R2* MRI in the kidney, pancreas, and spleen to monitor the changes in iron overload phenotype between the two groups. Methods: R2* MRI of the abdomen was performed at baseline, 1 year, and 2 years following enrollment. Liver, spleen, pancreas, and kidney R2* were measured from axial and coronal multiecho, gradient echo images. Images were analyzed centrally at an experienced core laboratory using an exponential plus constant model for signal decay. Iron burden in the different organs was assessed using repeated measures analysis of variance (ANOVA) using JMP 11.0. Results: 120 patients underwent baseline R2* assessment, 83 completed the midpoint, and 89 patients completed the endpoint examination. Figure 1 (left) summarizes the changes in kidney R2* across the three time points. Kidney R2* was elevated at baseline in both treatment arms and correlated with LDH (r2 =0.28, p<0.0001) and total iron binding capacity, but not with age, sex, LIC, serum ferritin, years of transfusion and years of chelation. Kidney R2* and markers of hemolysis (LDH, total bilirubin), remained stable in the transfusion arm. In contrast, kidney R2* declined monotonically in the patients on hydroxyurea (F value 6.9, p=0.0021 for time-treatment interaction). These changes paralleled reductions in LDH (F value 8.1, p=0.0007) and total bilirubin (F value 28, p<0.0001) in the hydroxyurea group compared to the transfusion group. There were no group differences in mean serum creatinine or urine albumin to creatinine ratio (ACR). However, the frequency and severity of albuminuria (ACR > 30 mg albumin per g creatinine) trended lower in patients on hydroxyurea, (5/45 at baseline (p=1), 1/44 at midpoint (p=0.03), and 4/52 at endpoint (p=0.33). Figure 1 (right) demonstrates the temporal evolution of ACR in 11 study participants with baseline albuminuria; 4/6 patients on standard arm continued to have significant proteinuria on their terminal examination compared with only 1/5 patients on hydroxyurea (p=0.24). There were no groupwise differences in mean pancreas R2* at any time point and clinically significant pancreas iron deposition (R2* > 100 Hz) was only observed in two patients at the mid timepoint. Spleen R2* was markedly elevated at baseline (503 ± 396 Hz), but did not change systematically over time in either group. The change in spleen R2* was correlated with the change in liver iron (r2=0.21, p=0.003), regardless of the treatment group, suggesting that the spleen iron stores are part of the dynamic iron storage pool. 37% of the patients had no MRI-detectable spleen (surgical + autosplenectomy). The change of liver iron was not different in patients with or without a spleen. Conclusion: Hydroxyurea therapy was associated with lower intravascular hemolysis and kidney iron deposition. Further studies are necessary to determine whether these changes are associated with decreased proteinuria or improved renal function. Splenic iron burden remained high but stable in all patients, and its role in iron unloading needs further investigation. Pancreas iron loading remained rare, consistent with the low prevalence of endocrinopathies in SCD. Figure 1 Figure 1. Disclosures Wood: Apopharma: Consultancy; Ionis Pharmaceuticals: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Biomed Informatics: Consultancy; AMAG: Consultancy; Biomed Informatics: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; World Care Clinical: Consultancy; Celgene: Consultancy; Apopharma: Consultancy; Celgene: Consultancy; AMAG: Consultancy. Heeney:Sancilio and Company: Consultancy, Research Funding; Eli Lilly and Company: Research Funding; Pfizer: Research Funding. Ware:Global Blood Therapeutics: Consultancy; Nova Laboratories: Consultancy; Biomedomics: Research Funding; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Bayer Pharmaceuticals: Consultancy.

scholarly journals Clinical Profile of Thalassemia Syndrome in Children of Northern Bangladesh

2019 ◽  
Vol 31 (2) ◽  
pp. 6-11
Author(s):  
Md Rustam Ali ◽  
Md Iqbal Bari ◽  
Md Sanaul Haque Mia ◽  
Md Khalilur Rahman ◽  
Md Farid Hossain ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Standard Procedure ◽  
Iron Chelation ◽  
Hemoglobin Concentration ◽  
Folic Acid Supplementation ◽  
Beta Thalassemia ◽  
Low Grade ◽  
Thalassemia Patient ◽  
Racial Background ◽  
Hb E

Background: Thalassemia is a common hematological disorder in our country having wide spectrum of clinical presentation. The frequency and severity of the several types of thalassemia depend on the racial background of the population. Hb-E Beta thalassemia is prevalent in our country. Objective: To see the clinical features of different types of Thalassemia in northern area of Bangladesh. Methods: Hundred cases were selected from Thalassemia patient admitted in department of pediatrics, on May 2012 to October 2012. A prescribed questionnaire was used to record the information. The methods were explained to the patients and consent was taken. Necessary physical examination was performed and investigations were done. The data was analyzed by standard procedure. Results: Out of hundred (100) cases, most (61%) were Hb-E beta Thalassemia, less common (1%) was Hb-E disease, and 1 % case was Hb-E trait. Majority (64%) manifested clinically under one year of age. 54% were male and 46% were female. The major presenting symptom was progressive pallor in 70% cases. Others presenting complaints were low grade fever (40%). Hemoglobin concentration at the time of diagnosis was below 5 gm/dl in 53.33% patients. In hemoglobin electrophoresis it was Hb-E ranged from 54.64 ± 13.02%, Hb-F 34.84±13.73%, Hb-A 23.32± 18.15% and Hb-A2 3.5± 70%. Radiological findings revealed gross bony changes occur in long standing cases. Enlarged cardiac shadow was found in those cases having severe anemia with heart failure. Conclusion: In countries with a high incidence of thalassemia, it is vitally important to offer prospective genetic counseling and to warn carriers about the risks of intramarriage. Nutritional and folic acid supplementation with regular blood transfusion along with iron chelation therapy is essential to improve the prognosis. TAJ 2018; 31(2): 6-11

Serum Uric Acid As a Predictor Factor of the Response to Deferasirox Therapy for Patients with b-Thalassemia Major

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5306-5306
Author(s):  
Efthimia Vlachaki ◽  
Vasileios Perifanis ◽  
Antonia Kondou ◽  
Nikolaos Neokleous ◽  
Aikaterini Teli ◽  
...  
Keyword(s):  
Uric Acid ◽  
Serum Uric Acid ◽  
Research Funding ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Iron Chelator ◽  
Beta Thalassemia ◽  
Positive Correlation ◽  
Significant Difference ◽  
Predictor Factor

Abstract Abstract 5306 Serum uric acid of patients with beta-thalassemia major (b-MA), despite the hyperuricosuria observed in these patients, is usually in the upper normal levels or increased due to excessive catabolism of the red blood cells (ineffective erythropoiesis). Deferasirox a new oral iron chelator with potential nephrotoxicity is recently used as iron overload treatment in patients with b-MA. Aim: Aim of the study is to investigate the effect of deferasirox on uric acid levels of patients with homozygous b-MA. Material-Method: 53 patients were enrolled to the present study with b-MA major, (aged 22.4 ± 14.7 years, range 4–12 years) 36 adults and 17 children, 32 females and 21 male. All the patients were transfusion-dependent with pretransfusional haemoglobin 9gr/dl and treated with iron chelation. The comparison was made between two different time points' measurements of uric acid and ferritin, at the beginning before Deferasirox, and one year later. The blood was taken from the patients early at mornings before the transfusion. Also uric acid was measured in 24 hour urine of patients under deferasirox, or other iron chelation therapy or after weekly discontinuation of deferasirox. Patients taken allopurinol or thiazide or with abnormal kidney function were excluded. Results: There is statistically significant difference (p< 0.001) between the mean annual value of serum uric acid (before 5.2 ± 1.3mg/dl) and ferritin (before 1653,4 ± 1026,3 ng/dl) before and after the start of deferasirox (uric acid after 4.2 ± 1.3 mg/dl and ferritin after 1529,07 ± 1137,44 ng/dl). Also, statistically significant positive correlation between the levels of serum uric acid and ferritin was found during the treatment with deferasirox. However, comparing the uric acid in urine of patients, it was not reported any statistically significant difference between treatment with deferasirox (859,75 ± 122), other iron chelators or without iron chelation for one week (844,32 ± 146). Conclusion: The mechanism of uric acid reduction in patients with b-MA major treated with deferasirox is not clear. However, it does not seem to be associated with excess of excretion by urine. The positive correlation between uric acid level and ferritin, allow us to consider uric acid as a predictor factor of the response to deferasirox therapy. Disclosures: Vlachaki: Novartis Hellas S.A.C.I.: Research Funding. Oikonomou:Novartis Hellas S.A.C.I.: Research Funding.

scholarly journals Iron chelation therapy needed for serum ferritin overloaded patients of beta thalassemia major

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wasim Muhammad ◽  
Muhammad Ishaq ◽  
Muhammad J. Khan ◽  
Umair Ahmad ◽  
Muhammad Waseem
Keyword(s):  
Serum Ferritin ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Care Facility ◽  
Health Care Facility ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Cross Sectional ◽  
Beta Thalassemia Major ◽  
Khyber Pakhtunkhwa Province

The main objective of the current study is to evaluate the level and overload of serum ferritin in multi-transfused beta Thalassemia major patients. There is an earnest need to defend the chelation treatment and to make mindfulness about the results of serum ferritin in the patients beta Thalassemia major. This is a Cross sectional analytical study performed in Fatimid foundation Hayatabad, Peshawar, Khyber Pakhtunkhwa province of Pakistan. Those patients who has beta thalassemia major are included in this study. In this study there are total 108 patients in which 54 males and 54 females. The highest mean of serum ferritin level in the category of male was in the age of 12 years were finds 8160.5 ng/mL. Among the female the highest mean of ferritin level was in the age of 17 years were finds 13,349.5 ng/mL. In this study majority of patient’s revealed much high levels of serum ferritin. These levels reveal insufficient chelation. Appropriate chelation of iron load can improve the quality of the life of these patients. The low level of education, Poverty problems, and insufficient health care facility of are the main obstacle in the effective management of ferritin overload in thalassemia patients.

scholarly journals Elevated Ferritin Predicts for Inferior Survival in Patients with Acute Leukemia and May be an Early Marker of a Underlying Systemic Pathologic Inflammation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2791-2791 ◽  
Author(s):  
Preetesh Jain ◽  
Kelly Casteel ◽  
Carl E. Allen ◽  
Kenneth L. McClain ◽  
Sa Wang ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Serum Ferritin ◽  
Research Funding ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Elevated Serum ◽  
Prior Treatment ◽  
Complex Karyotype ◽  
Risk Of Death ◽  
Increased Risk

Abstract Introduction: The prognostic role of serum ferritin in adult patients (pts) with newly diagnosed and/or relapsed acute leukemia remains undefined. Significantly elevated serum ferritin level (>5,000 or >10,000) was a sensitive and specific for hemophagocytic lymphohistiocytosis (HLH). The outcome of adults with malignancy-associated HLH (M-HLH) is dismal (Tamamyam et al., Cancer 2016). Early diagnosis and timely therapy in these critically ill pts may be delayed while waiting for specialized labs such as IL-2Rα. We hypothesized that elevated serum ferritin might be prognostic in adult pts with acute leukemia and may serve as a rapid marker for a systemic cytokine process. Methods: 1819 pts with AML and 260 pts with ALL evaluated at our institution between Jan 2010 to Jan 2016 with a serum ferritin level within 30-days of initial presentation were reviewed. Survival was calculated from the date of ferritin testing. Kaplan-Meier product limit method was used to estimate the median overall survival (OS) and Cox proportional hazard models were used to model the association between survival and risks factors. Recursive partitioning (RP) was used to identify optimal cut-off of ferritin levels. Results: In the 1819 pts with AML, median (med) age was 63 years, 57% males, the med ferritin value was 1,276 ng/ml (range, 4 - 68,262). Fifty% (n=904) pts were previously untreated. AML pts with high ferritin had significantly higher WBC count, lower platelet count, lower albumin, and high LDH (P<0.05 in each) and these remained significant when only previously untreated pts were analysed. Higher prevalence of complex karyotype, prior treatment, FLT3 and NPM1 mutations were seen in pts with high ferritin and only NPM1 remained significant when previously untreated pts were analyzed. Overall pts with AML with ferritin ≥5,000 had a significantly inferior med OS (5.1 vs 11.6 months; P<0.001) (Figure 1A). The med OS remained inferior in previously untreated pts with AML with ferritin ≥5,000 (6.6 vs 16.3 months, P=0.002) (Figure 1B). By RP analysis we found an optimal cut-off of < or ≥ 1827 ng/ml which discriminated survival in all pts with AML (Figure 1C) and < or ≥ 903 when only previously untreated pts with AML were considered. Ferritin ≥ 1827 significantly predicted for increased risk of death in MVA [HR 95% CI 1.29 (1.03-1.62) (p=0.03)] along with complex karyotype, lower hemoglobin, prior treatment, and low prevalence of CBF-AML when all AML pts were analysed. In untreated AML pts, a level of ≥ 903 predicted for increased risk of death in univariate but not in MVA. In ALL pts (n=260), the med ferritin was 1081 ng/ml (range 20-72,060). Overall ALL pts with ferritin ≥5,000 (n=28) vs with <5000 (n=232) had significantly higher prevalence of elevated LDH, complex karyotype, and prior therapy, while in previously untreated pts with ferritin ≥5,000 (n=8 vs n=177) only elevated LDH was significant. Pts with ferritin ≥5,000 had significantly inferior med OS when all pts were included (Figure 1D), however in previously untreated pts, the difference was not significant (Figure 1E). By RP analysis, ferritin levels ≥ 3015 significantly predicted for increased risk of death in MVA [HR 95% CI 2.51 (1.57-4.02) (p<0.001)] (Figure 1F) along with prior treatment, high % of BM blasts and low albumin levels in all pts. No cut off could be identified in untreated ALL pts. Finally we compared the outcomes of untreated AML pts with ferritin ≥5,000 (n=25) to pts with definitive M-HLH (n=15) from our institution (Tamamyam et al., Cancer 2016) and noted a similar median OS (6 and 4 months, P=0.79). Conclusions: In this analysis, we have shown that adult pts with untreated and previously treated AML and ALL pts with ferritin ≥5,000 have an inferior survival. The optimal cut-off levels that discriminated survival were: 1807 (all AML), 903 (untreated AML), 3015 (all ALL). Untreated AML pts with ferritin ≥5,000 had a med OS of 6 months similar to pts with M-HLH. Significantly elevated ferritin in acute leukemia pts with febrile illness may be a marker to prompt a diagnostic work up for an underlying pathologic inflammation and potential benefit of augmented or targeted immune suppression. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Daver:Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding.

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