High hepatic iron concentration (HIC) is associated with cardiac iron overload. However, simultaneous measurements of heart and liver iron often demonstrate no significant linear association. We postulated that slower rates of cardiac iron accumulation and clearance could reconcile these differences. To test this hypothesis, we examined the longitudinal evolution of cardiac and liver iron in 38 thalassemia major patients, using previously validated magnetic resonance imaging (MRI) techniques. On cross-sectional evaluation, cardiac iron was uncorrelated with liver iron, similar to previous studies. However, relative changes in heart and liver iron were compared with one another using a metric representing the temporal delay between them. Cardiac iron significantly lagged liver iron changes in almost half of the patients, implying a functional but delayed association. The degree of time lag correlated with initial HIC (r ‫؍‬ 0.47, P < .003) and initial cardiac R2* (r ‫؍‬ 0.57, P < .001), but not with patient age. Thus, longitudinal analysis confirms a lag in the loading and unloading of cardiac iron with respect to liver iron, and partially explains the weak cross-sectional association between these parameters. These data reconcile several prior studies and provide both mechanical and clinical insight into cardiac iron accumulation. (Blood. 2008; 112:2973-2978) IntroductionDespite availability of iron chelation, iron-mediated cardiac toxicity remains the leading cause of death in thalassemia major patients. 1 Cardiac dysfunction, whether detected by radionuclide angiography, echocardiography, or magnetic resonance imaging (MRI), is often a late finding and carries an ominous prognosis. 2,3 Although intense chelation can rescue many patients, depleting cardiac iron burden often takes years and mortality is high with incomplete compliance. 3 Thus, prevention of cardiac iron accumulation and dysfunction is imperative. Initial studies in this area examined hepatic iron concentration (HIC), as measured by liver biopsy, and serum ferritin levels as potential predictors of cardiac toxicity. [4][5][6] This hypothesis was logical because HIC is an excellent indicator of iron balance and total body iron stores. 6,7 These early studies concluded that elevated liver iron and serum ferritin trends raise prospective risk of cardiac dysfunction, implying a correlation between cardiac and liver iron deposition. [4][5][6] Based upon this work, treatment algorithms for iron removal therapy based primarily on HIC and ferritin levels 8,9 were developed with the goal of minimizing cardiac and endocrine toxicities.However, the use of HIC and ferritin to infer cardiac iron has been challenged by recent MRI studies. 10-13 MRI allows organ iron concentrations to be easily and noninvasively measured and has been validated on both animals and humans. [14][15][16] Crosssectional analysis has demonstrated poor correlation between HIC or ferritin and cardiac iron. [10][11][12]13 In addition, some patients develop cardiac deposition and symptom...

Chronic blood transfusions start at a very young age in subjects with transfusion-dependent anemias, the majority of whom have hereditary anemias. To understand how rapidly iron overload develops, we retrospectively reviewed 308 MRIs for evaluation of liver, pancreatic, or cardiac iron in 125 subjects less than 10 years old. Median age at first MRI evaluation was 6.0 years. Median liver iron concentrations in patients less than 3.5 years old were 14 and 13 mg/g dry weight in thalassemia major (TM) and Diamond-Blackfan anemia (DBA) patients, respectively. At time of first MRI, pancreatic iron was markedly elevated (> 100 Hz) in DBA patients, and cardiac iron (R * 2 >50 Hz) was present in 5/112 subjects (4.5%), including a 2.5 years old subject with DBA. Five of 14 patients (38%) with congenital dyserythropoietic anemia (CDA) developed excess cardiac iron before their 10th birthday. Thus, clinically significant hepatic and cardiac iron accumulation occurs at an early age in patients on chronic transfusions, particularly in those with ineffective or absent erythropoiesis, such as DBA, CDA, and TM, who are at higher risk for iron cardiomyopathy. Performing MRI for iron evaluation in the liver, heart, and pancreas as early as feasible, particularly in those conditions in which there is suppressed bone marrow activity is very important in the management of iron loaded children in order to prescribe appropriate chelation to prevent long-term sequelae. Am. J. Hematol. 88:E283-E285,

Ferritin levels and trends are widely used to manage iron overload and assess the efficacy of prescribed iron chelation in patients with transfusional iron loading. A retrospective cohort study was conducted in 134 patients with transfusion-dependent anemia, over a period of up to 9 years. To determine whether the trends in ferritin adequately reflect the changes in total body iron, changes in ferritin between consecutive liver iron measurements by magnetic resonance imaging (MRI) were compared to changes in liver iron concentrations (LIC), a measure of total body iron. The time period between two consecutive LIC measurements was defined as a segment. Trends in ferritin were considered to predict the change in LIC within a segment if the change in one parameter was less than twofold that of the other, and was in the same direction. Using the exclusion criteria detailed in methods, the trends in ferritin were compared to changes in LIC in 358 segments. An agreement between ferritin trends and LIC changes was found in only 38% of the 358 segments examined. Furthermore, the change in ferritin was in opposite direction to that of LIC in 26% of the segments. Trends in ferritin were a worse predictor of changes in LIC in sickle cell disease than in thalassemia (P < 0.01). While ferritin is a convenient measure of iron status; ferritin trends were unable to predict changes in LIC in individual patients. Ferritin trends need to be interpreted with caution and confirmed by direct measurement of LIC.

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treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of the article.

2064 For patients with transfusion dependent anemias, in particular thalassemia major, as part of a compassionate –use program that was approved by the hospital's IRB, we report the efficacy and safety outcomes of combining therapy with deferasirox (DFX) and deferiprone (DFP). The combination of DFP and deferoxamine (DFO)has been shown to be effective in reducing cardiac iron overload but some patients are unable or unwilling to use DFO. DFP alone has also been reported to be cardioprotective. Based on concerns for their welfare in the presence of excessive cardiac iron load, a reduced left ventricular ejection fraction and either severe allergy or intolerance to DFO, 4 adult patients with thalassemia major have been treated with the combination of DFX and DFP for between 6 and 60 months (mean 18 months). All four patients were initially treated with DFO or DFX but DFP at 75–100 mg/kg/day was initiated because of severe cardiac iron overload. DFX at 15–40 mg/kg/day was added based upon high liver iron concentrations(LIC). Efficacy was evaluated by monthly ferritin levels and semiannual cardiac T2* and LIC estimates (using MRI R2 and R2*). All 4 patients had at least two MRI assessments. Table 1shows the changes in ferritin, cardiac T2*, LVEF and mean LIC. Cardiac T2* improved from 5.8 ±1.5 to 7.0 ± 1.5 ms., (p=0.15). If the T2* is recalculated as cardiac iron concentration then the change was from 4.1± 1.3 to 3.3± 1.1 mg/g dry weight (p=0.09). One patient who has been receiving the treatment for 6 months has shown a 1% per month deterioration in T2*. The patients who have been on the combination for 12, 24 and 60 months, have had reductions of 2.7%, 0.5% and 1.5% per month respectively. LVEF improved overall from the baseline value of 52.8% to 58.9% (p=0.02). Ferritin fell from a mean of 5826 to 5544 ng/L (p=0.86). LIC increased from a mean of 20.7 to 28.1 mg/g dry weight (p=0.36). Table 2 shows the baseline and minimum absolute neutrophil counts and baseline and final ALT (IU/L). No drug-related neutropenia (ANC of <1.5 ×109/L), agranulocytosis or arthralgia were observed. No patients demonstrated significant proteinuria and mean creatinine levels were unchanged. ALT's showed fluctuations that were compatible with the degree of LIC. It is important to note that compliance was extremely variable in that one patient (P3), only took DFX once monthly with many lapses in her DFP treatment as well. The other patients also had significant lapses in their compliance as well as long vacation periods during which they did not receive treatment. These results indicate that the combined use of the two oral chelators (DFP & DFX) prevented further cardiac iron loading with a tendency for its reduction, significant improvement in left ventricular ejection fraction, maintenance of ferritin levels and LIC. It is also possible that the DFP cardioprotective effect may be activated even in the presence of poor compliance with it. The combination was well tolerated and easier to manage. It is more acceptable for life-long chelation and positively influenced patients’ quality of life. It seems likely that maximum doses of both medications need to be prescribed for better outcomes and longer periods of follow up are essential. In particular, a prospective randomized study in patients with excessive cardiac iron will be necessary before this combination could be considered standard therapy. Disclosures: Berdoukas: ApoPharma Inc.: Consultancy. Wood:Novartis Inc.: Research Funding; ApoPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Coates:Novartis: Research Funding, Speakers Bureau.

3203 Ferritin trends are used as surrogates for change in total body iron in patients with transfusional iron overload who are on chelation therapy. They are often used to infer patient adherence with prescribed therapy and for recommending changes. Population studies of ferritin show a 70% correlation with liver iron. The aim of this study was to determine whether the trends in ferritin adequately reflect the change in liver iron concentration (LIC) in individual patients. We retrospectively evaluated ferritin and LIC for 10 years in 40 patients with transfusion dependent anemia (23 with transfusion dependent thalassemia, 12 with sickle cell anemia, 2 with congenital dyserythropoetic anemia, 2 with Diamond Blackfan Anemia and one with sideroblastic anemia). Ferritin levels are evaluated every three weeks at each transfusion and liver iron concentration (LIC) by MRI at approximately annual intervals. The LIC values in mg/g dry weight (dw) are derived by MRI. The trends for both LIC and ferritin were evaluated at each period between the sequential MRIs. We used the average of all ferritins in a four month window centered on the date of the MRI for comparison to the LIC. The overall correlation between ferritin and LIC was similar to other published results (r2=0.69). When ferritin and LIC were plotted against time for each patient, the ferritin trend clearly predicted the LIC trend during certain periods of time (Example figure 1 segment A) and did not during other periods (Figure 1 segment B). The trend in ferritin correctly predicted the trend in LIC all of the time in 55% of patients (22/40). In 45 % of the patients (18/40) the ferritin trend did not correlate with the LIC in over half of the observational periods. In 37.5 % (15/40) of patients during at least one observation period the direction of change was dramatically different. Of these, the direction of change was opposite in 12.5% (5/40). In 22.5 % (9/40) the changes were disproportionate. Six of these patients showed a period during which there was a slight decrease in ferritin but a significant decrease in LIC. In two there was a significant increase in LIC with only a minimal rise in ferritin. In one, with a significant increase in ferritin the LIC increased minimally. While the ferritin was decreasing the LIC and ferritin trends correlated much better than when the ferritin was increasing. This implies that when ferritin levels increase it is a particularly poor tool for assessing change in iron overload. It is clear from this analysis that over certain periods of time, even up to four years, the trends in ferritin can be opposite in direction to the change in total body iron, as derived from LIC. This could lead to inappropriate changes in therapy and incorrect assumptions by health care providers about patient adherence. It is accepted that poor compliance with chelation therapy is the greatest barrier to effective management of iron overload. If only ferritin is used to assess changes in total body iron, patients could be discouraged by their apparent poor response to therapy even though their LIC may actually be decreasing. Serial assessment of total body iron burden by direct measurement of LIC is essential for proper management of patients with transfusional iron overload. Disclosures: Berdoukas: ApoPharma Inc.: Consultancy. Carson:ApoPharma Inc.: Honoraria; Novartis Inc: Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coates:Novartis Inc: Speakers Bureau.

Introduction: Transition from pediatric to adult care for emerging adults with sickle cell disease (SCD) has been challenging due to limited availability of experienced adult providers and patient difficulty navigating the adult health care system. The purpose of this study was to determine among adults with SCD, healthcare utilization and their trust and satisfaction with their health care provider. Methods: We surveyed adult patients greater than 21 years old with SCD previously transitioned from Children's Hospital Los Angeles. Assessments of provider trust and satisfaction were conducted along with health care utilization and the transition experience. Results: Of 31 participants, 61% and 68% identified having an adult primary care provider (PCP) and adult hematologist respectively. Increased satisfaction with care was associated with increased trust in the adult hematologist (r=0.72 p<0.001) and PCP (r=0.76 p=0.001) and improved communication (p< 0.001). Trust in their hematologist was greater than PCP (76.5 vs 64.2, p = 0.058). For SCD complications, 65% of participants visited the ED, 80% of whom had negative experiences including sub-optimal pain management. Regarding transition experience, 55% felt unprepared for adult care. Discussion: More than 30% of adult SCD patients transferred out of pediatric care are not receiving regular hematology care for their SCD, resulting in fragmented medical care. Increased trust in their adult hematologist and clear communication are associated with higher levels of satisfaction with care. These findings will be utilized to develop a transition program to improve patient preparation and build on partnerships with adult providers to improve long-term outcomes. Introduction: Sickle cell disease (SCD) is one of the more common genetic conditions. It is characterized by intermittent exacerbation of vaso-occlusion by sickled red blood cells, leading to complications such as painful crisis, acute chest syndrome, stroke, and premature death. There are approximately 100,000 patients with this disease in the United States and as a result of its genetic predisposition, it disproportionately affects those of African and Hispanic descent. 1,2 With newborn screening, vaccinations, prophylactic antibiotics, and hydroxyurea, the mortality in children with SCD decreased by 68% from 1983 to 2002. 3,4 As a result, more than 90% of patients are living to age 20 and the median survival has increased, now 58 years of age in patients with hemoglobin SS or S-beta thalassemia zero and 66 years of age in hemoglobin SC or S-beta thalassemia plus disease. 5 However, studies have shown that morbidity and mortality increases dramatically in the 18-30 year old population, immediately after patients are transitioned from pediatric to adult centered care. 6,7 Transition of care for patients with rare, genetic conditions, like SCD, whose manifestations start early in childhood has additional layers of complexity due to the limited availability of adult specialists with the necessary domain expertise t...