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Thalassaemia is characterized by ineffective erythropoiesis and anaemia, which can precipitate bone marrow expansion and extramedullary haematopoiesis. The mainstays of treatment are blood transfusion and chelation therapy, which can cause an array of complications. Only recently, however, has pain been recognized as a clinical component of thalassaemia (Trachtenberg, et al 2010). Sixty-nine per cent of 265 participants in the Thalassaemia Clinical Research Network (TCRN) Thalassaemia Longitudinal Cohort reported bodily pain (Trachtenberg, et al 2010). Additionally, 34% of transfused thalassaemia patients participating in the TCRN Low Bone Mass Observational Study reported that transfusions helped reduce or eliminate their pain (Vogiatzi, et al 2009). We hypothesized that the effects of ineffective erythropoiesis are mitigated by transfusion and thus incidence of pain will vary throughout the transfusion cycle. The Assessment of Pain Survey study, conducted by the TCRN, was initiated to address increasing reports of pain. The primary aim of this substudy was to assess whether reports of pain vary over the transfusion cycle. Secondary aims were to assess whether the length of the transfusion cycle affects the level of pain and whether pain varies by pre-transfusion haemoglobin (Hb) level and reticulocyte count. The TCRN of the National Heart, Lung and Blood Institute is a clinical research network, funded by the National Institutes of Health (Appendix 1). The protocol was approved by the TCRN Data and Safety Monitoring Board and by the ethical review boards of all TCRN institutions. All participants signed informed consent. Transfusion-dependent subjects (≥8 transfusions within the last 12 months) with β-thalassaemia or Hb E β-thalassaemia participating in the Assessment of Pain Survey study who reported at least mild pain in the last month as measured by Brief Pain Inventory (BPI; Cleeland 2009) were enrolled. The BPI provides information on the intensity of pain and the degree to which pain interferes with function. It has been used previously to assess pain in osteoporotic thalassaemia patients and its use has been validated in cancer patients (Cleeland 2009; Dworkin, et al 2005; Keller, et al 2004; Tan, et al 2004). Subjects were stratified into two cohorts: age 18–29 years vs. 30+ years. Stratification was chosen based on observation that patients aged 30+ years tend to have more pain than younger patients (Haines, et al 2013). Target enrolment was 25–35 subjects. Subjects completed a daily pain assessment during three non-consecutive transfusion cycles, separated by at least three months and no more than four months apart. Subjects were transfused according to their clinical need; cycles lasted two to four weeks. Transfusion cycles were not altered for participation. Daily pain was assessed using the BPI Short Form (BPI-SF) by daily telephone call provided by Interactive Performance Technologies in association with Telecare Management of Pain (Cambridge, MA). The BPI-SF consists of 10 questions in which participants rate their worst, least and average pain in the past 24 h on a scale of 0–10 where 0 is “No pain” and 10 is “Pain as bad as you can imagine”. Variation over the transfusion cycle was modelled with repeated measures logistic regression (for pain prevalence) or regression (for pain severity) of time in pain, controlling for age, sex and transfusion cycle. An autoregressive [AR(1)] variance structure was assumed. Time was measured as percentage of transfusion cycle completed and quadratic effects of time were utilized. Length of transfusion cycle, pre-transfusion Hb level and reticulocyte counts were added to the model. Repeated measures models, controlling for age, were used to test for differences in reported causes of pain between patients reporting frequent (≥50% of study days) vs. infrequent pain. Thirty-two subjects enrolled, 56% were female, the mean age was 31.8 years (range, 18 – 55), and 59% were Caucasian. The average pre-transfusion Hb was 101 g/l (range, 73–128 g/l) and the average length of transfusion cycle was 23 days. Pain prevalence and severity increased with age (p 0.4), or differences over the three transfusion cycles (p>0.5). Thirty-four per cent of subjects reported pain on at least 50% of study days, confirming that pain is an important problem. Table I Pain prevalence, severity, and treatment over the thalassaemia transfusion cyclea. There was a non-significant trend towards lower prevalence of pain midway through the transfusion cycle compared to immediately pre-transfusion (31.3 vs. 42.2%, p=0.14; Figure 1, Table I). Pain reduction was more pronounced among subjects transfused less frequently (>4 weeks) (13.6 vs. 40.9%, p=0.026 for effect of length of transfusion cycle; Table I) whilst, there was no apparent variation among subjects transfused more frequently (≤2 week cycle); Table I). As fluctuation in Hb levels is greater with longer transfusion cycles, these effects may reflect improvement in anaemia and/or ineffective erythropoiesis. Figure 1 Pain prevalence over the thalassaemia transfusion cycle. Unexpectedly, prevalence of pain correlated with higher, not lower, pre-transfusion Hb (p=0.013) and also a lower reticulocyte count (p=0.05). Subjects transfused more frequently also reported more severe average pain compared to those with a longer transfusion cycle (3.8/10 for ≤2 week cycles vs. 0.7/10 for >4 weeks; p=0.031 for length of cycle). Although higher Hb could contribute to pain, it is also possible that patients are transfused more frequently in response to chronic pain or other complications. Nevertheless, it is likely that pain is multifactorial. Use of pain medications/treatments varied from 25–35% over the transfusion cycle (15–18% for those aged 18–29 years, 35–51% aged 30+ years; 14–32% for those transfused frequently, 40–50% transfused infrequently). Furthermore, midway through the transfusion cycle, pain severity was greater among subjects with frequent pain (5.1/10 vs. 0/10, p

Aim To assess the feasibility of collecting electronic pain data from thalassaemia patients, based on its acceptability and convenience to the participants and study team. Methods Participants in the Thalassemia Clinical Research Network Assessment of Pain Survey Study completed the Brief Pain Inventory (BPI) quarterly by paper or phone interview. Participants in a substudy completed the BPI Short Form daily over three non-consecutive transfusion cycles through an automated telephone system. Results The consent rate for the main study was 93%, with 93% retention. The substudy had 75% retention, with more than 75% of scheduled calls completed. Regular monitoring of enrolment, missed calls, data quality, and the performance of the subcontractor for the automated system was crucial to fulfillment of the study goals. Conclusions Use of electronic data collection for patient-reported outcomes was convenient for both patients and study personnel but required human interactions beyond the automated system to maximise data quantity and quality.

Pain reports have become increasingly common and problematic in thalassemia. As patients are living longer,there is a growing need to study pain and to explore its impact on patient lives. The Brief Pain Inventory(BPI) was used quarterly to assess pain and pain interference in patients with thalassemia in North America.The Medical Outcomes Study 36-Item Short Form Health Survey and the Hospital Anxiety and Depression Scale were used to assess quality of life, anxiety and depression. Of the 252 participants, 56% reported pain at least once over the course of this study, with 32% reporting severe pain (≥7/10); 16% reported pain at all four visits. Increased pain severity significantly interfered with daily life (P0.001; regression analysis) and participants with more sites of pain showed an increase in the amount of daily activities affected by pain(P50.001). Participants reporting more visits with pain reported a significantly higher impact on affective and physical function (P0.001). Physical quality of life decreased with increasing numbers of visits with pain (P0.001). Those who reported one or more sites of pain showed increased symptoms of both depression(P0.001) and anxiety (P50.003). Participants reporting at least two visits with pain had higher symptoms of anxiety (P50.002) and those with at least three visits reported higher symptoms of depression(P50.003). Pain is prevalent in thalassemia and is often a chronic condition that interferes with life. The study highlights the significance of pain in thalassemia and its impact, which should be considered in future research and treatments.

Pain is not a symptom generally associated with thalassaemia. However, providers have noted increasing patient reports of pain, creating an impetus for this prospective, observational assessment of pain in thalassaemia patients. The primary study goals were to assess pain prevalence, severity, location, and potential risk factors. This was a multicentre, prospective study of thalassaemia patients receiving care at 12 Thalassaemia Clinical Research Network sites. Pain was assessed using the Brief Pain Inventory. Two hundred and fifty-two thalassaemia patients ranging in age from 12 to 71 years (mean 28.8) were enrolled. Sixty-four per cent reported experiencing pain during the last 4 weeks, 22% of whom reported pain on a daily basis. Ordinal regression analysis of pain ratings demonstrated significant (P < 0.001) correlation of increased age with increased pain, irrespective of diagnosis, transfusion status, gender, bone density, chelator type or iron overload. Eighty-one per cent reported having pain for 1 year or longer and 31% reported pain for five or more years. Pain is a major cause of morbidity and an unrecognized problem for patients with thalassaemia. Age is the strongest predictor of frequency and severity. Little else is known about the aetiology and predictors of this pain syndrome.

The Thalassemia Clinical Research Network collected adherence information from 79 patients on deferoxamine and 186 on deferasirox from 2007 to 2009. Chelation adherence was defined as percent of doses administered in the last 4 weeks (patient report) out of those prescribed (chart review). Chelation history since 2002 was available for 97 patients currently on deferoxamine and 217 on deferasirox, with crude estimates of adherence from chart review. Self-reported adherence to both deferoxamine and deferasirox were quite high, with slightly higher adherence to the oral chelator (97 vs. 92%). Ninety percent of patients on deferasirox reported at least 90% adherence, compared with 75% of patients on deferoxamine. Adherence to both chelators was highest in children, followed by adolescents and older adults. Predictors of lower deferoxamine adherence were smoking in the past year, problems sticking themselves (adults only), problems wearing their pump, and fewer transfusions in the past year. Predictors of lower deferasirox adherence were bodily pain and depression. Switching chelators resulted in increased adherence, regardless of the direction of the switch, although switching from deferoxamine to deferasirox was far more common. As adherence to deferoxamine is higher than previously reported, it appears beneficial for patients to have a choice in chelators.

Background Understanding patients’ views about medication is crucial to maximize adherence. Thalassemia is a congenital blood disorder requiring chronic blood transfusions and daily iron chelation therapy. Methods The Beliefs in Medicine Questionnaire (BMQ) was used to assess beliefs in chelation in thalassemia patients from North America and London in the Thalassemia Longitudinal Cohort (TLC) of the Thalassemia Clinical Research Network (TCRN). Chelation adherence was based on patient report of doses administered out of those prescribed in the last four weeks. Results Of 371 patients (ages 5-58y, mean 24y), 93% were transfused and 92% receiving chelation (26% deferoxamine (DFO; a slow subcutaneous infusion via portable pump), 63% oral, 11% combination). Patients expressed high “necessity” for transfusion (96%), DFO chelation (92%) and oral chelation (89%), with lower “concern” about treatment (48%, 39%, 19% respectively). Concern about oral chelation was significantly lower than that of DFO (p Conclusions Despite their requirement for multimodal therapy, thalassemia patients have positive views about medicine, more so than in other disease populations. Patients may benefit from education about the tolerability of chelation and strategies to effectively cope with side effects, both of which might be beneficial in lowering body iron burden. Clinicaltrials.gov identifier NCT00661804

Abstract 257 Background. Advances in treatment of thalassemia have led to increased life expectancy for patients making outcomes such as health related quality of life (HRQOL) an important consideration of therapy. Little has been published about the HRQOL of pediatric patients with thalassemia. There are limited reports on how this illness impacts the family. Because the familial situation is the starting point for how patients learn to live with their condition, it is important to document this effect and how it changes over time. This report looks at changes in parental reported HRQOL from baseline (BL) to year 1 (Y1) in the Thalassemia Clinical Research Networks (TCRN) Thalassemia Longitudinal Cohort (TLC) study. Patients and Methods. The TCRN is a NIH-sponsored network of 16 major thalassemia centers in the US, Canada and London. We report here on the results from 77 patients under the age of 14 who completed BL and assessments at Y1. Overall the patients were 47% male with a mean age of 9 years (range 5–13). 94% were chronically transfused, and 69% had β-thalassemia, and 12% were E-β thalassemia patients. 57% used an oral chelator, while 29% were on desferoxamine (DFO). HRQOL was measured by self-report with the Children Health Questionnaire (CHQ), 28-item Parental Form (PF28). The 28 items derive 12 subscales that assess physical and psychosocial health. 2 summary scales assess overall physical health and psychosocial health. We defined a clinically significant change as a difference of at least 2 points on any subscale. Results. Clinical Changes: 45% saw a reduced number of transfusions from BL to year 1 (32% showed no change). 73% did not change chelator, while 18% changed from DFO to oral (2.6% other way). 5% began a chelation regimen. Only one percent of patients developed new secondary complications. 63% showed no change in their general adherence rate; 25% showed a decrease. HRQOL changes: As a population, mean HRQOL remained stable over the 1 year study period. Age appears to be significant for CHQ assessment of child's self esteem and behavior (and overall psychosocial assessment), but gender, country and ethnicity do not appear to be significant. The average number of scales with significant changes was eight. Only one CHQ assessment does not show any significant changes on any CHQ scale, while three reports showed changes on all 14 scales. The psychosocial scales showed more significant changes than physical health assessments. Figure 1 illustrates the reported changes by scale. Measures of overall general health, parental emotions and child behavior showed the most changes. Assessment of the child's physical and psychosocial roles and family cohesion showed the least change. The physical health assessments of function and pain showed lower significant changes than the psychosocial health assessments. More psychological health measures show a significant drop than familial assessments. When we examine scale changes by age groups, the youngest age group (5-7) showed modestly better physical and psychosocial scale changes. The 8–10 age group saw more than twice the number of parents seeing a decline in a physical or psychosocial health scale. The oldest age group (11-14) showed the fewest changes, with mainly higher physical health scale changes, but lower scores on the psychosocial scales. Clinical Associations: Changes in number of transfusions and adherence do not appear to impact CHQ assessment. However, changes in chelator appear to be significant for parental time (P=0.048) and the psychosocial summary scale (p=0.04). Changes in secondary complication appear to be associated with changes in the CHQ assessment of the child's behavior (p=.04). Conclusions. The dearth of clinical changes suggests that patients enrolled in TCRN are receiving optimized health care. The lack of changes on the CHQ's physical health scales is to be expected given the low number of clinical changes, and the reported changes in CHQ do not appear to be related to clinical changes. At this stage of data analysis, CHQ assessment in thalassemia appears to be associated with the normal effects a growing child has on the family. This would be the desired result of effective clinical intervention in thalassemia. Further analyses of changes are needed to understand the relationship between changes in HRQOL and specific changes in clinical measures. Disclosures: Neufeld: Novartis, Inc: Research Funding; Ferrokin, Inc: Research Funding.

Abstract 1533 Background: Advances in treatment of thalassemia have led to increased life expectancy for patients, making outcomes such as health related quality of life (HRQOL) an important consideration of therapy. However little has been published about the HRQOL of patients living with thalassemia, especially as it may change over time. Our study reports changes in patient-reported HRQOL from baseline to year 1 in the Thalassemia Clinical Research Networks (TCRN) Thalassemia Longitudinal Cohort (TLC) study. Methods: The TCRN is an NIH sponsored network of 16 major thalassemia centers in the US, Canada and London. We report here on the results from 220 patients (approximately 80% of the total cohort) over the age of 14 who completed baseline and year 1 assessments. HRQOL was measured by self-report with the Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF36v2). We defined a clinically significant change as a difference of at least 2 points on any SF-36 subscale. Results: Overall the patients were 46% male with a mean age of 29 years at baseline (range 14–58). Across the TLC population, mean self-reported HRQOL showed little change over the 1 year study period, with only social functioning showing a significant increase (p=0.04). However in each SF-36 domain over 50% of patients reported a signficant change in scores (an increase or decrease of more than 2 points) (Figure 1). All patients had a significant change on at least one domain, with a mean of 7 domains affected. Overall a small majority of patients (56%) reported that their health in general was “about the same” at year 1 as at baseline; 14% reported it was somewhat worse, 19% somewhat better, and 11% much better. Forty-nine % of patients reported requiring fewer transfusions in year 1, while 34% needed more, and 17% had no change. Most patients (82%) made no change in their chelator, although 8% changed from deferoxamine (DFO) to an oral chelator, fewer than 1% changed from oral to DFO, and 3% each stopped and started chelation. Most patients (61%) reported the same general adherence rate, although taken together there was slightly better reported adherence in year 1. Almost half of patients (47%) reported no change in chelator side effects, although again there was a slight overall decrease in reported side effects across the group. Most patients (92%) reported no new secondary complications in year 1. As expected, increasing age was associated with decreased HRQOL in the following domains: physical function, bodily pain, vitality, social function, mental health, and physical summary scales, although only bodily pain showed a clinically significant change (+2.1 points). Gender, race, change in number of transfusions, and change in chelator were not associated with change in HRQOL, although there was a trend towards improved general health in patients who made any change in chelation. A decrease in reported side effects from chelation was associated with an improvement in physical functioning (+2.8) and the mental summary score (+3.48), while development of a new complication during the one year study period was associated with a decrease in role-emotional (-8.2). Surprisingly an increase in reported adherence was associated with a decrease in social functioning (-5.1), role emotional (-7.7) and the mental summary score (-5.4). Conclusions: As a population, the TLC showed overall stability in clinical status and SF-36 scores over the 1 year study period. However individual patients reported significant changes, both positive and negative, in an average of 7 SF-36 domains. HRQOL appears to be most affected by age, with some association with changes in chelator, secondary complications, side effects and adherance. Further analysis is needed in order to fully understand these associations. Disclosures: Neufeld: Novartis, Inc: Research Funding; Ferrokin, Inc: Research Funding.

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.