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Tens of thousands of transfusion-dependent (eg, thalassemia) patients worldwide suffer from chronic iron overload and its potentially fatal complications. The oral iron chelator deferasirox has become commercially available in many countries since 2006. Although this alternative to parenteral deferoxamine has been a major advance for patients with transfusional hemosiderosis, a proportion of patients have suboptimal response to the maximum approved doses (30 mg/kg per day), and do not achieve negative iron balance. We performed a prospective study of oral deferasirox pharmacokinetics (PK), comparing 10 transfused patients with inadequate deferasirox response (rising ferritin trend or rising liver iron on deferasirox doses > 30 mg/kg per day) with control transfusion-dependent patients (n = 5) with adequate response. Subjects were admitted for 4 assessments: deferoxamine infusion and urinary iron measurement to assess readily chelatable iron; quantitative hepatobiliary scintigraphy to assess hepatic uptake and excretion of chelate; a 24-hour deferasirox PK study following a single 35-mg/kg dose of oral deferasirox; and pharmacogenomic analysis. Patients with inadequate response to deferasirox had significantly lower systemic drug exposure compared with control patients (P < .00001). Cmax, volume of distribution/bioavailability (Vd/F), and elimination half-life (t1/2) were not different between the groups, suggesting bioavailability as the likely discriminant. Effective dosing regimens for inadequately responding patients to deferasirox must be determined. This trial has been registered at http://www.clinicaltrials.gov under identifier NCT00749515.

This study examined the relationship between hepatic and myocardial iron concentration, assessed by T2*-MRI in 66 patients (3–82 years) with transfusion-dependent anemias and thalassemia intermedia, to determine whether hepatic iron levels alone suffice for chelation adjustments. We found a poor correlation between hepatic and myocardial iron (r = 0.10, P = 0.43) and identified a subgroup (14%) with increased myocardial iron without a matched degree of hepatic hemosiderosis. Left ventricular ejection fraction was insensitive for detecting elevated myocardial iron. These findings were present in both adult and pediatric patients. We recommend therapeutic monitoring of iron burden by evaluation of both liver and myocardial iron with T2*-MRI.

Deferasirox, the only oral iron chelator approved in the US and Canada, achieved a pediatric label indication down to 2 years of age. FDA-mandated post-marketing safety surveillance in children under age 6 is ongoing. We wish to raise a non-safety-related concern with deferasirox chelation in very young children (2–5 years old). Specifically, the circumstances required for reliable daily ingestion of deferasirox do not mesh well with the developmental characteristics common in young children, which may limit adherence and cause parental distress. We review developmental challenges associated with oral chelation in this age group and provide suggestions to improve adherence in this population. Pediatr Blood Cancer. 2010;55:603–605. © 2010 Wiley-Liss, Inc.

Abstract 256 Background: Pain is not a symptom generally associated with thalassemia. However, healthcare providers have anecdotally noted increasing patient reports of chronic pain over the last decade creating an impetus for the TCRN to conduct this prospective, observational assessment of pain in patients with thalassemia over the age of 12. Study goals include assessment of pain prevalence, severity and sites and whether these factors are impacted by age, gender or diagnosis. Methods: Pain was assessed quarterly using the Brief Pain Inventory (BPI). Two hundred fifty-one thalassemia patients ranging in age from 12 to 71 (average age of 28.75) receiving care at one of 12 thalassemia centers across the US and Canada participated in the study. Fifty-four percent of participants were female. Diagnoses included: Beta Thalassemia (80%), E Beta thalassemia (11%), Hemoglobin H and H Constant Spring (6%) and other thalassemia conditions (3%). Eighty percent of participants were chronically transfused, 6% intermittently transfused and 14% had never been transfused. This report reviews baseline findings. Results: At study entry, 64% of the 251 participants reported experiencing pain over the last four weeks, of whom 21% reported pain on a daily basis. In comparison, 26% of the American public, 20 years and older, reported pain over a one month period according to National Center for Health Statistics data, 2006. Ordinal regression analysis of participant ratings of worst, least, and average pain over the last seven days demonstrated significant (p Conclusions: These data show that pain is a significant issue for patients with thalassemia and as patient's age pain increases. Pain assessment should be conducted on a regular basis for all patients with thalassemia since neither transfusion status nor diagnosis are a reliable indicator of pain status. The study also indicates that chronic pain (pain lasting greater than one year) is an issue for thalassemia patients and underscores the need for further study of pain in this population. Analysis of pain follow up data collected at 3 month intervals post baseline is being conducted to assess whether severity levels vary over time. Disclosures: Coates: Novartis: Research Funding, Speakers Bureau. Neufeld:Novartis, Inc: Research Funding; Ferrokin, Inc: Research Funding.

BACKGROUND: MRI measures of hepatic iron content (HIC) in patients with transfusional iron overload correlate well with invasive liver biopsy- based HIC measures. HIC is the major component of, and a good surrogate for total body iron burden, and has been used worldwide as an index for chelation management [Olivieri&Brittenham, Blood 1997]. However, cardiac iron toxicity, not liver iron per se, causes the most mortality in transfusional iron overload, particularly in thalassemia major (TM). The objective of this study was to evaluate in adults and children with transfusional iron overload, for whom these measures were obtained by MRI as standard clinical care, the relationship between cardiac and liver iron assessments and how the combined information might influence clinical practice decisions. METHODS: IRB approved, single-center retrospective chart review of patients age 2–45y with transfusional iron overload who had MRI liver and heart iron assessments from Jan 02 to Mar 07. Sixty-six patients were evaluated. This was a cross-sectional analysis of one MRI per patient. Iron in myocardium and liver was measured by R2* (1/T2*), an MR relaxation parameter which varies proportionally with tissue iron concentration, using a 1.5 T scanner. Myocardial T2* was assessed from one midpapillary ventricular short-axis slice using a cardiac-gated, segmented, multiecho gradient sequence obtained in a single breath-hold, similar to the method of Westwood et al [J Magn Reson Imaging, 2003]. Left Ventricular Ejection Fraction (LVEF) was measured by standard cardiac MRI methods. We express cardiac iron status as T2* values (normal >20 msec), and liver iron values as predicted HIC (mg/g dry wt) based on standard curves from [Wood et al, Circulation 2005]. RESULTS: Among the 34 pediatric patients (65% male), diagnoses were: TM (n= 17), transfused sickle cell disease (SS) (n= 8), and marrow failure (MF) (n=9). Mean age was 14.3 ± 4.4 y (range 5–20). Adult patients (n=32, 47% male), mean age 33.5 ± 12.3 y (range 21–78) had these diagnoses: TM (n= 21), thal intermedia (n= 7), 4-gene alpha thal (n= 1), MF or MDS (n=3). Cardiac T2* and the MRI-based HIC are correlated in neither age cohort (adults: Spearman coeff. ρ 0.265, p = 0.14; children ρ-0.061, p=0.73). We identified a subset of subjects (2/34 children (6%), 7/32 adults (23%)) with severely low cardiac T2* but HIC within target range for therapy (predicted HIC 60%) but abnormal T2*, at risk for cardiac disease. We observed a significant difference in LVEF in children with TM vs. SS (59.5 ± 3.9 vs. 64.3±3.6%, p=0.008), and also a less significant difference between these groups in mean T2* measures (TM 26.11±3.55, SS 34.76±2.12 msec p = 0.1136). CONCLUSION: We demonstrate that in children and adults with transfusional iron overload (and non-transfused thal intermedia), combined T2* cardiac and R2* hepatic iron determination detects a population with severe cardiac iron deposition without matched increased HIC. As MRI assessments of cardiac and liver iron become prevalent, prospective studies will be needed to understand the best ways to use these data for management.