the Effects of Deferasirox on Iron in Pituitary, Pancreas and Thyroid Glands: An Observational Case-Control Study

Abstract In the absence of adequate chelation therapy, cardiomyopathy caused by iron overload is the leading cause of death in patients with β-thalassemia major (BTM). Additionally, more than half of the adult patients with BTM suffer from hypogonadism (HG), osteoporosis, diabetes mellitus (DM) or hypothyroidism. The use of iron chelators is the mainstay of treatment in patients with BTM to ameliorate these complications. In this study, we aimed to compare the chelation effects of deferasirox (DFX) and other iron chelators on iron in heart, liver, in addition to pituitary, pancreas and thyroid glands. The study included a total of 37 patients with BTM, who were on the same iron chelator for at least 1 year of duration and above 7 years of age. All of the patients were on iron chelation therapies with either monotherapy with DFX (n=29), desferrioxamine (n=4), deferiprone (n=1) or combination therapy of desferrioxamine and deferiprone (n=3). The mean dose of DFX was 30.8 ± 6.3 mg/kg/day (20-40), the mean dose of desferrioxamine 43.1 ± 5.3 mg/kg/day (39-50) and mean dose of deferiprone was 73.26 ± 9.45 mg/kg/day (70-90). All of the patients were compliant to chelation treatment. Cardiac T2*, hepatic T2*, thyroid T2 and R2, pituitary T2 and R2, pancreas T2* and R2* MRI were ordered twice to the patients in order to measure the accumulation of iron. The median time interval between the two MRI was 6 months (range 6-11 months). The effect of DFX (n=29) on iron measurements in different organs were compared to the effects of other chelators group (OCG) (n=8). The mean age of patients participating in the study was 20.8 ± 6.3 years (7.1-36.8). Of the study group, 7.1% of the patients had DM, 8.1% had hypothyroidism and 13.5% had HG at enrollment. According to our previous study for the cut-off value determinations for iron accumulation in BTM with comparison to healthy controls (data unpublished), all of the patients in both groups were found to have pituitary iron accumulation at initial MRI. The changes in iron measures in various organs were summarized in Table 1, indicating a decrease in cardiac, pituitary and pancreas iron loading in both drug groups in follow-up MRI’s (p>0.05). On the other hand δ Liver T2* was negative direction indicating a decrease in hepatic iron loading in DFX group, wheras positive in OCG indicating an increase in follow-up, although insignificant (Table 1, p=0.9). In both groups iron loading in thyroid was found to increase in follow-up and there was no difference between drug groups (Table 1). In conclusion, DFX is as effective as other drugs in chelation of iron from cardiac, hepatic, pituitary, pancreas and thyroid. The increase in iron in thyroid gland during follow-up in both groups may indicate that iron chelation may not be as efficient in thyroid as it is in other organs. Although, all patients had pituitary iron accumulation, only 13.5% were found to have HG, indicating that patients become symptomatic only occur after a threshold of accumulation was achieved. Our study is initiative for the measurements of iron accumulation with MRI in thyroid. Table 1. δT2* and δR2 change values between first and second MRI assessments Chelation type Mean±SD Median Range p δ Liver T2 * a (ms) Deferasirox -0.06 -8.5-7.20 0.90 Other chelators 0.79 -0.98-4.40 δ Cardiac T2 * b (ms) Deferasirox -3.83±9.5 0.88 Other chelators -3.2±8.82 δ Pituitary T2 b (ms) Deferasirox -0.7±11.3 0.09 Other chelators -1.4±6.4 δ Pituitary R2 a (Hz) Deferasirox 0.10 -6,20-3,10 0.25 Other chelators 0.20 -4,60-1,30 δ Thyroid R2 a (Hz) Deferasirox -1.4 -6,1-12,7 0.06 Other chelators -0.1 -3,80-8,1 δ Thyroid T2 a (ms) Deferasirox 4.8 -59,8-14,6 0.08 Other chelators 0.4 -20,6-20,1 δ Pancreas T2* b (ms) Deferasirox -7.46±21.6 0.99 Other chelators -7.52±9.63 δ Pancreas R2 * b (Hz) Deferasirox 9.24±45.23 0.11 Other chelators 56.4±73.3 SD: Standard Deviation; aNon-parametric variable, median values were provided; bParametric variables, mean±SD were provided. Disclosures No relevant conflicts of interest to declare.

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Twice Daily Use of Deferasirox Is More Effective in Decreasing Serum Ferritin

Blood ◽

10.1182/blood.v124.21.2675.2675 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2675-2675 ◽

Cited By ~ 1

Author(s):

Fatma Gumruk ◽

Sule Unal ◽

Turan Bayhan ◽

Tuncay Hazirolan ◽

A. Murat Tuncer ◽

...

Keyword(s):

Serum Ferritin ◽

Half Life ◽

Conflicts Of Interest ◽

Maximum Dose ◽

Iron Chelation ◽

Beta Thalassemia ◽

Iron Loading ◽

Once Daily ◽

T2 Mri

Abstract Patients with beta-thalassemia major (BTM) are prone to tissue iron overloading in case that not adequately chelated. Among the iron chelators, development of oral chelators have improved patients’adherence to treatment. Deferasirox is a tridentate iron chelator, used once daily with a half life of 8-16 hours. The negative chelation effect is achieved at doses above 30 mg/kg/day and the currently FDA-approved maximum dose for use in patients is 40 mg/kg/day. However, some of the deferasirox side effects are dose-dependent increasing the occurences of adverse events at high doses. Additionally, although there is data that non-transferrin bound iron is effectively decreased by once daily dosing, the iron chelation effects of the drug may increase since in some of the patients half-life of the drug has been reported to be even less than 7 hours. Herein, we compared the iron chelation effect and tolerability of deferasirox in the same patients who were using deferasirox at a dose of 40 mg/kg/day. The patients with BTM who were under iron chelation with deferasirox at a dose of median 40 mg/kg/day (38-41) once daily for at least 6 months were included (n=10). These patients were receiving deferasirox at a maximum dose in the enrollment to the study related to either serum ferritin levels above 1500 ng/ml or moderate to severe iron loading in cardiac or liver tissues. These patients were put on a twice daily regimen of the same dose and followed up at a median time period of 7 months (4-17). The serum ferritin, ALT, creatinine levels and T2* MRI of heart and liver were obtained at the beginning of the twice daily dosing and by the end of the follow-up time. Patients were given a questionairre to investigate the tolerability and satisfaction of once daily and twice daily use. The median age of the study group was 21 years (3-34), hal were males. The patients’ serum ferritin, cardiac and hepatic iron loading levels were summarized in Table 1. There was a statistically significant decrease in serum ferritin levels with twice daily use of deferasirox compared to once daily use of the same dose. The initial and follow-up ALT and serum creatinine levels did not differ significantly (p>0.05). None of the patient required a dose reduction or cessation of the drug related to a toxicity. The major tolerability concern of the patients in once daily dosing was nausea in 2 of the patients (20%). After twice daily dosing the major concern of the patients was twice daily use of the drug itself in 2 patients (20%). None of the patients reported nausea in twice-dosing. The patients’ satisfaction survey in the end of the study for once or twice daily use was for once daily use revealed preference for twice-use in 5 (50%) of the patients for either no nausea (n=2) with twice-use or better decrease in serum ferritin levels (n=3). Three (30%) preferred once daily use as a better way, related to lesser drug use. Two patients reported that there were no difference in terms of satisfaction. In conclusion, twice daily use of deferasirox at higher doses is much better tolerated and causes a better decline in serum ferritin levels of already high iron burden. Further studies in larger sample groups may be more definitive. Table 1. The initial and follow-up iron overloading evaluations Mean ± SD (Range) p Initial SF (ng/ml) Follow-up SF 2020±983 (1016-4128) 1533±1026 (521-4003) 0.047 Initial cardiac T2* MRI (ms) Follow-up cardiac T2* MRI 25.4±8.6 (14.6-38) 21.5±7.8 (13.8-30) 0.068 Initial liver T2* MRI (ms) Follow-up liver T2* MRI 3.6±1.9 (1.3-8) 6.7±5.1 (2.1-13.6) 0.465 SF: serum ferritin; SD: standard deviation Disclosures No relevant conflicts of interest to declare.

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Longitudinal Changes in Endocrine Disease in Thalassemia Major Patients on Different Iron Chelators

Blood ◽

10.1182/blood.v126.23.4565.4565 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4565-4565

Author(s):

Maurizio Poggi ◽

Francesco Sorrentino ◽

Maria Rondinelli ◽

Pellegrina Pugliese ◽

maria Paola Smacchia ◽

...

Keyword(s):

Chelation Therapy ◽

Conflicts Of Interest ◽

Demographic Data ◽

Characteristic Curve ◽

Iron Chelation ◽

Thalassemia Major ◽

Iron Chelators ◽

Iron Chelation Therapy ◽

Endocrine Disease ◽

High Prevalence

Abstract Introduction: Endocrinopathies are common in regularly transfused patients with β-thalassemia major (TM). Damage may start in childhood with the incidence of overt endocrine complications increasing with advancing age, making it essential to introduce appropriate intervention promptly to prevent the development of later morbidity. Iron overload has been consistently linked with the development of endocrine disease in TM. However, data on the role of iron chelation therapy for the prevention or management of endocrine disease, especially in the long-term, remain limited. Methods: We conducted a retrospective cohort study of all TM patients attending our center that have remained on the same chelation therapy for a minimum of 5 years. For all patients demographic data at the start of observation, type of chelator, and mean serum ferritin (SF) across the 5 year period were collected. A single endocrinologist evaluated the patients at the start and end of observation after 5 years to assess for the presence and absence of endocrinopathies as locally defined through clinical and laboratory values including: diabetes mellitus (DM), hypothyroidism, and hypogonadism. Results: A total of 165 patients were included in the analysis. Their mean age was 39.9 ± 8.3 years (range: 20-68), including 71 (43%) men. The mean SF value was 555 ng/mL (range: 63-6140).Deferoxmiane (DFO) was used in 40 (24.2%) patients, deferiprone (DFP) in 18 (10.9%), DFO+DFP in 50 (30.3%) and deferasirox (DFX) in 57 (34.5%). At the start of observation, 121 (73.3%) of patients had at least one of the three endocrinopathies (51 [31.5%] had two endocrinpathies and 8 [4.8%] had all three). After 5 years of chelation therapy, 6 patients (3.6%) had reversal of at least one existing endocrinopathy, 11 (6.7%) had the development of at least one additional endocrinopathy, and 148 (89.7%) had no change in the number of their endocrinopathies. Figure 1 illustrates the reversal of existing or development of new endocirnopathy between iron chelators. Patients on DFX had the lowest proportion of patients with the development of a new endocrinopathy and the highest proportion of patients with reversal of existing endocrinopathy. On a receiver operating characteristic curve analysis a SF level of <600 ng/mL was the best predictor for patients not developing new endocrinopathy (p=0.018). Conclusions: Our data confirmed that patients with TM experience a high prevalence of endocrine disease. Iron chelation therapy, however, has a role in preventing the development of new endocrine disease and in a minority of patients, reversal of existing endocrinopathy. These effects may be dependent on the chelator type although achieving levels <600 ng/mL should prevent newly incident disease. Disclosures No relevant conflicts of interest to declare.

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Outcome of Early Introduction of Hypertransfusion/Chelation Program in Children with Thalassemia Intermedia

Blood ◽

10.1182/blood.v120.21.3260.3260 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3260-3260

Author(s):

Yasser Wali ◽

A. Hakim Al-Rawas ◽

Shoaib Al Zadjali ◽

Murtadha K. Al-Khabori ◽

Wafa Bashir ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Conflicts Of Interest ◽

Iron Chelation ◽

Self Esteem ◽

Thalassemia Intermedia ◽

Transfusion Therapy ◽

Early Introduction ◽

The Mean ◽

The Impact

Abstract Abstract 3260 Background: The standard of care for patients with thalassemia intermedia (TI) is regular follow up and iron chelation therapy. Patients with TI are usually transfusion independent and receive irregular transfusion when they develop low hemoglobin levels as in case of infection. However, with the current policy, these patients are liable to many complications; thalassemic facies, growth retardation, splenomegaly, hypersplenism, hypercoagulability, pulmonary hypertension, heart failure, cholelithiasis, diabetes mellitus, hypothyroidism, osteoporosis, and hypogonadism. We planned to investigate the impact of early introduction of hypertransfusion on delaying these complications. Material and Methods: All newly diagnosed children with TI at the Pediatric Thalassemia Day Care Centre, Sultan Qaboos University Hospital, Oman, starting from August 2006 were included in the study. They were diagnosed as intermedia based on clinical grounds of late age presentation (>5 years), maintaining mean baseline hemoglobin of 7 g/dL (range 6.1–7.9 g/dL), and transfusion independence. In addition, eight patients had a definitive TI mutation Hb Dhofar [β29(GGC–GGT)gly-gly, β58(CCT–CGT)pro-arg]. They were 10 females and 10 males included in the study. The mean age at presentation was 7.17 ± 3.9 years. At diagnosis, they were started on monthly hypertransfusion program to maintain a pretransfusion hemoglobin level above 9.5 g/dl and a post transfusion level of 14 g/dl. The mean duration of transfusion therapy was 6.2 ± 3.7 years and the mean follow up duration was 7.1 ± 3.2 years. Results: None of the 20 patients developed thalassemic facies, splenomegaly or hypersplenism. Sixteen patients maintained a normal weight (above 5th centile) and height (above 10thcentile), while 4 patients were at or below the 3rd centile. Of the 10 children above eleven years of age, 7 children reached normal puberty at their expected age. All 10 patients above eleven years of age, had a normal thyroid function test (TSH 2.27 ± 1.07 mIU/L, T4 11.04 ± 2.65 pmol/L) with no clinical or laboratory evidence of diabetes. Eight of the elder patients who had echocardiography had no evidence of pulmonary hypertension. Baseline bone densitometry done in 2 patients revealed a low Z-Score (below −2.5), with no improvement on follow-up. The mean total transfusion requirement was 162 ± 23 ml/kg/year. Patients were maintained on either deferiprone (n=14, dose 87 ± 12 mg/kg/day) or deferasirox chelation (n=6, dose 32 ± 4 mg/kg/day). Preliminary results of a self esteem questionnaire of these patients were better than our older patients who had not received hypertransfusion/chelation. Conclusion: TI children who were started at presentation on hypertansfusion/chelation regimen, have improved growth, better self esteem and they did not develop many of the complications known to occur in the non-transfused ones. However, this regimen needs to be evaluated in a larger prospective cohort study and to confirm the cost-effectiveness given the regular blood transfusion and continuous iron chelation. Disclosures: No relevant conflicts of interest to declare.

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Complexities in the Rat Iron Loading Model for Pre-Clinical Testing of Iron Chelators.

Blood ◽

10.1182/blood.v104.11.3699.3699 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3699-3699

Author(s):

Jasmina Novakovic ◽

Angelo Tesoro ◽

Jake J. Thiessen ◽

Fernando Tricta ◽

John Connelly ◽

...

Keyword(s):

Iron Overload ◽

Lymph Nodes ◽

Iron Chelation ◽

Iron Sucrose ◽

Iron Accumulation ◽

Iron Chelators ◽

Iron Dextran ◽

Iron Loading ◽

Iron Distribution ◽

One Year

Abstract Transfusion-dependent iron overload, such as occurs in beta-thalassaemia (Cooley’s Anaemia), leads to lethal cardiac toxicity in the second decade of life if not treated by iron chelation, but even with subcutaneous desferrioxamine (DFO) cardiac disease remains a problem, although delayed by 1–2 decades. As we design novel iron chelators, we are testing them in various animal models of iron overload. While assessing outcomes we have observed relatively sparse reports of systematic studies on organs, tissues, cellular, or subcellular iron distribution. Therefore we initiated a series of studies to characterize iron distribution using various approaches. Multiple intraperitoneal injections of iron dextran, 200 mg/kg/week X 4 − 16 weeks, followed by an equilibration period of minimum 1–2 weeks was studied as a means of increasing total body iron load in hundreds of rats under various conditions. Sacrifice varied from 6 weeks to 1 year post iron loading and the concentration of iron in liver, heart, and other tissues, organs, cells and subcellular organelles was examined. Quantitatively, in untreated rats (no chelators), the liver/heart iron ratio was about 10:1, consistent with the accumulation observed in post-mortem studies in humans prior to extensive use of iron chelation. Much less-well described has been the distribution of iron in lymphatic tissues. Our studies revealed that lymph nodes become visibly enlarged. In addition, randomly distributed brown spots appeared in the omentum. Such changes persisted up to one year after iron loading, regardless whether they were treated daily with chelators (DFO or deferiprone) in standard doses for four months. Even after a single intraperitoneal iron-dextran injection of 200 mg/kg, changes were visible. Histopathological analysis (hematoxilin-eosin for general histology and Perl’s Prussian Blue for iron) showed extensive iron accumulation in the omentum, and in the cortical and subcortical regions of the enlarged lymph nodes. Electron microscopy revealed cellular (macrophages) and subcellular (mitochondria) iron localization in the lymph nodes. When iron was administered as iron sucrose (single ip dose), iron accumulation was more extensive in the omentum and in the peritoneal fat in comparison to iron dextran, but the enlargement of the lymph nodes was not observed. Quantitative iron measurement (via validated HPLC method) in the liver and heart after a single iron dextran (N=30, up to 29th day) and iron sucrose dose (N=6 up to 50th day) was in agreement with the histological observations. Iron accumulation in the omentum and lymph nodes after four months of chelation treatment and one year after iron loading indicated the resistance of these unusual iron “pools” to chelation therapy. These studies confirm that different iron formulations may result in different patterns of iron distribution and they also raise questions about the suitability of rats as an animal model for transfusional iron overload in humans.

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Outcomes of Combined Transplants of Cord Blood Plus Peripheral Blood from an HLA Matched Sibling in Thalassemia Patients

Blood ◽

10.1182/blood.v124.21.3896.3896 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3896-3896

Author(s):

Yuelin He ◽

Changgang Li ◽

Xuedong Wu ◽

Sixi Liu ◽

Xiaoqin Feng ◽

...

Keyword(s):

Cord Blood ◽

Peripheral Blood ◽

Conflicts Of Interest ◽

Thalassemia Major ◽

Antigen Level ◽

Free Survival ◽

Matched Sibling ◽

The Mean ◽

Male To Female

Abstract Background Cord blood from HLA matched sibling was widely used as stem source in transplants in patients with thalassemia major (TM), but failure of engraftment is frequent. Aim To improve engraftment of CB transplant in patients TM Patients and method A combined transplants of CB and peripheral blood (PB) from same HLA matched sibling was conducted (i.e. CB and PB were harvested and infused on day 0) from June, 2010 to February, 2014. Total 24 patients were involved in the study. Donor-recipient pairs were matched at HLA-A, B and DRB1 (antigen level) in 23 but one with HLA mismatched at one loci (DRB1). The conditioning protocol included intravenous busulfan, cyclophosphamide, fludarabine, and thiotepa. Prophylaxis of GVHD included Cyclosporine and short MTX. All donors (newborn) were sent into NICU for monitoring, and then, discharged after 3 days. Results The median age at transplant was 4 years (range, 1.5-7 years), and the ratio of male-to-female patients was 16:8. The median follow-up time was 17 months (range, 5-49 months). The mean mononuclear cell (MNC) dose of CB was 5.67×107/kg body weight of the recipient (BWR; range, 2.1-8.75×107/kg BWR) while that of PB was 3.21×107/kg BWR (range, 0.47-7.31×107/kg BWR). The mean volume of infused CB was 91ml (range, 31-131ml) while that of PB was35ml (range, 10-71ml). The median ANC engraftment time was 28 days (range, 15-47days), while the median platelet engraftment time was 34.0 days (range, 0-128days). The estimated 4-year overall survival (OS) and TM-free survival (TFS) were both 100%. The cumulative incidences of graft rejection and grades II-IV acut egraft-versus-host disease (aGVHD) were both 0%. All donors are normal as peers with following up to date. Conclusion These results suggest that patients with TM have excellent outcomes after CB plus PB combined transplant from an HLA matched sibling. Disclosures No relevant conflicts of interest to declare.

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Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up

Blood ◽

10.1182/blood-2010-11-316646 ◽

2011 ◽

Vol 118 (4) ◽

pp. 884-893 ◽

Cited By ~ 117

Author(s):

M. Domenica Cappellini ◽

Mohamed Bejaoui ◽

Leyla Agaoglu ◽

Duran Canatan ◽

Marcello Capra ◽

...

Keyword(s):

Adverse Events ◽

Iron Concentration ◽

Iron Chelation ◽

Dry Weight ◽

Thalassemia Major ◽

Efficacy And Safety ◽

Liver Iron ◽

Median Serum

Abstract Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

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Hodgkin Lymphoma Outcomes: Can We Expect Ethnic Parity in a Hispanic Prevalent Population?

Blood ◽

10.1182/blood-2019-129058 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4056-4056

Author(s):

Michelle Janania Martinez ◽

Prathibha Surapaneni ◽

Juan F Garza ◽

Tyler W Snedden ◽

Snegha Ananth ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Conflicts Of Interest ◽

Relative Survival ◽

Complete Response ◽

Statistical Testing ◽

P Value ◽

Hispanic Population ◽

Significant Difference ◽

The Mean

BACKGROUND It is estimated that 8110 persons will be diagnosed with Hodgkin Lymphoma (HL) in the US during 2019, but the advent of new treatment options has increased the cure rate to at least 80%. It has been reported that the rates of HL are lower in the adolescent and young adult (AYA) Hispanic population but significantly higher in the Hispanic population older than 65. The relative survival estimates are stated to be similar between AYA Hispanics (HI) and non-Hispanics (NH) but for ages 65-84, HI have a significantly higher mortality rate. Pediatric studies have suggested that ethnicity plays a role in outcomes in patients with HL but there is limited data in the adult population. There is an unmet need in the field, where dossiers on underrepresented ethnic minorities need to be carefully considered and compared to existing data. Therefore, our study aims to compare survival outcomes in Hispanics vs Non-Hispanics with HL, who were treated at the only NCI designated cancer center of South Texas. To our knowledge this is the largest cohort of HL patients from a single academic institution that serves primarily Hispanics. METHODS We located and retrospectively analyzed a total of 616 patients with diagnosis of Lymphoma (HL and NHL) by International Classification of Diseases (ICD) codes and identified 116 cases of HL; all the patients received care at UT Health San Antonio, between 2008-2018. Key variables for each patient included age, gender, race/ethnicity, comorbidities, insurance status, stage, BM and extranodal involvement, treatment received, outcome at 3 and 5 years and vitality status in 2018. Continuously distributed outcomes were summarized with the mean and standard deviation and categorical outcomes were summarized with frequencies and percentages. The significance of variation in the mean with disease category was assessed with one way ANOVA and the significance of associations between categorical outcomes was assessed with Pearson's Chi Square or Fisher's Exact test as appropriate. Multivariate logistic regression was used to model binary outcomes in terms of covariates and indicators of disease. All statistical testing was two-sided with a significance level of 5%. R1 was used throughout. The study was approved by the local Institutional Review Board. The findings will be available to patients, funders and medical community through traditional publishing and social media. RESULTS We identified 116 patients with HL, of which 73 were HI (63%), 43 NH (36%) and 1 not specified (1%). In regard to race, 92% identified as Caucasian, 4% as African American, 3% other and 1% Asian. The median age at diagnosis was 37.4, (SD 15.13). There were 49 females (42%) and 67 males (58%). The most common funding source was commercial insurance N=54 (47%), followed by a hospital payment plan N=30 (26%), Medicare N=16 (14%), unfunded N=13 (11%) and Medicaid N=3 (2%). Most prevalent co-morbidities were HTN N=28 (24%) and diabetes mellitus N= 23(20%); 50% of patients had no co-morbidities (N=63).At diagnosis ECOG of 0-1 was seen in 108 patients (93%); 8 were Stage I (7%), 39 stage II (33%), 32 stage III (28%), and 37 stage IV (32%). EBV was positive in 26 patients (22%). There were 15 patients that were HIV positive (13%), 54% with CD4 count <200, and 12 (75%) on antiretroviral therapy at diagnosis. Median PFS was 853.85 days (SD 912.92). We excluded patients who were lost to follow up or had not reached 3/5 years. At 3 year follow up there was: complete response in 37 HI (74%) vs 22 NH (92%); disease progression in 8 (16%) vs 0 (0%); death in 5 (10%) vs 2 (8%), respectively (p-value= 0.094). At 5 year follow up there was: complete response in 30 HI (77%) vs 17 NH (90%); progressive disease in 2 (5%) vs 0 (0); death 7 (18%) vs 2 (11%), respectively (p-value = 0.619). At the end of 2018, 41 HI (84%) were alive compared to 22 NH (88%) [p-value 0.74]. CONCLUSION Within the limitations of sample size, our study demonstrates that in the prevalently Hispanic population of our institution, HI patients with HL have no statistically significant difference in outcome when compared to NH patients. Disclosures No relevant conflicts of interest to declare.

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Influence of Iron Chelation Therapy on R1 and R2 Calibration Curves in Gerbil Liver and Heart.

Blood ◽

10.1182/blood.v108.11.1775.1775 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1775-1775

Author(s):

John C. Wood ◽

Michelle I. Aguilar ◽

Maya Otto-Duessel ◽

Hanspeter Nick ◽

Marvin D. Nelson ◽

...

Keyword(s):

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Iron Chelators ◽

Mongolian Gerbils ◽

Iron Loading ◽

Longitudinal Assessment ◽

Relaxation Rates ◽

Iron Distribution ◽

Calibration Curves

Abstract Introduction: MRI is gaining increasing importance for the noninvasive quantification of organ iron burden. To date, MRI validation studies have not systematically examined the effects of different iron chelators. Since transverse relaxation rates depend on iron distribution as well as iron concentration, physiologic and pharmacologic processes that alter iron distribution could change MRI calibration curves. This paper compares the effect of three iron chelators, deferoxamine, deferiprone, and deferasirox on R1 and R2 calibration curves according to two loading and chelation strategies. Methods: 33 Mongolian gerbils underwent iron dextran 500 mg/kg/wk for 4 weeks followed by 4 weeks of chelation therapy using deferoxamine, deferiprone and defersirox. An additional 32 animals received less aggressive iron loading (200 mg/kg/week) for 10 weeks, followed by 12 weeks of chelation therapy. R1 and R2 measurements were obtained immediately post euthanasia using an NMR relaxometer. Calibration curves from 28 unchelated animals loaded with 200 mg/kg/week from 2 to 48 weeks were used as the reference standard for both chelated groups, using Bland-Altman analysis. Results: In the liver, R2-iron calibration became more variable over time regardless of whether chelation was performed or not (mean COV 28% versus 12%); no significant changes were observed in the heart R2-iron relationship. Variability in R1 measurements did not change for either heart or liver. Two systematic chelator-specific changes in liver iron calibration curves were noted:deferiprone treated animals exhibited signficantly higher R1 values (Figure 1) anddeferasirox treated animals demonstrated lower R2 values for given iron concentration (Figure 2). Both changes were associated with obvious changes in water content or iron distribution. Discussion: The acuity of the iron loading process affects the variability but not the bias of MRI-iron calibration curves. In contrast, iron chelation can produce systematic shifts in MRI calibration curves compared with the unchelated state, reflecting gross changes in tissue hydration and iron distribution. Since the rate of iron-loading and extraction performed in animals is more extreme than occurs in humans, limiting tissue requilibration, it is possible that the present studies overestimate the potential for chelator-specific calibration bias. Nonetheless, caution should be used in extrapolating calibration curves derived from patients using deferoxamine therapy to others being treated with deferiprone and deferasirox. Careful, longitudinal assessment of MRI calibration curves of patients receiving oral chelation therapies is warranted. Figure Figure Figure Figure

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

Blood ◽

10.1182/blood.v112.11.1881.1881 ◽

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<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<0,05 for actual Hb and pre-transfusional Hb; p<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.

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Safe and Efficient Chelation by Deferasirox In Thalassemia Major Patients with Low Liver and Cardiac Iron Concentrations

Blood ◽

10.1182/blood.v116.21.5168.5168 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5168-5168

Author(s):

Regine Grosse ◽

Gritta Janka ◽

Andrea Jarisch ◽

Peter Nielsen ◽

Jin Yamamura ◽

...

Keyword(s):

Side Effects ◽

Conflicts Of Interest ◽

Iron Concentration ◽

Iron Chelation ◽

Thalassemia Major ◽

Transfusion Rate ◽

Liver Iron Concentration ◽

Measurement Interval ◽

Liver Iron ◽

Rbc Transfusion

Abstract Abstract 5168 Chelation treatment of iron overload from chronic blood (RBC) transfusion is still a challenge to both, patients and medical caretakers. Different treatment regimes have been recommended so far, especially for chronically transfused patients with low or even normal liver iron concentration. We report the results from 16 regularly transfused patients with thalassemia major (TM) who were on iron chelation treatment under normal to mild liver iron concentration (LIC). All patients received deferoxamine (DFO) treatment before they changed to deferasirox (DSX) treatment. 16 TM patients (mean age 13.6 y) were treated with DSX (median dose 18 mg/kg/d, range: 7 – 33 mg/kg/d) for 6 to 71 months. Liver iron measurements by biomagnetic susceptometry (BLS) and/or MRI-R2 as well as cardiac MRI-R2* were performed in intervals of 6 to 12 months. The median LIC was 782 μ g/g-liver wet weight (range: 460 μ g – 1122 μ g). Median RBC transfusion rate was 8500 ml/y, equivalent to about 2 erythrocyte concentrates per 3 weeks or a daily iron influx of 16.2 mg/d. For each measurement interval, the ratio of daily iron influx and DSX dose rate was calculated. This represents the equilibrium molar efficacy for iron balance. In all 16 TM patients no severe side effects were observed and creatinine was in the normal range of < 0.9 mg/d throughout the treatment with DSX. From baseline DFO treatment interval to the endpoint of DSX treatment, liver iron decreased by 124 – 4689 μ g/g-liver (conversion factor of 6 for mg/g-dry-wgt), while serum ferritin decreased by -596 to 8283 μ g/l. For all measurement intervals, molar chelation efficacies between 18 % and 56 % were calculated at equilibrium with a median efficacy of 31 % (interquartile range = 16 %). This agrees with molar efficacies of DSX reported earlier, but for relatively higher LIC and chelation doses (Blood 2005; 106(11):#2690 and Blood 2007; 110(11):#2776). The cardiac R2* (median R2* = 38 s-1) was either below the normal threshold of 50 s-1 (T2* > 20 ms) or decreased by about 24 %/y under DSX treatment. In these few patients at low LIC, this was even higher than recently reported. Conclusion: Even in patients with normal to mild LIC iron chelation treatment with DSX is safe, does not result in increased creatinine levels or severe side effects and is as efficient as in patients with higher LIC. Disclosures: No relevant conflicts of interest to declare.

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