Transfusion-dependent Hemoglobinopathies Research Articles

Pain Assessment among Egyptian Children with Transfusion-Dependent Hemoglobinopathies: Pilot Study

Pain Assessment among Egyptian Children with Transfusion-Dependent Hemoglobinopathies: Pilot Study

Pregnancy and assisted reproductive technology use in Australian female transfusion-dependent haemoglobinopathy patients: a 20-year retrospective analysis.

In the last few decades, the life expectancy of patients with transfusion-dependent thalassaemia (TDT) and sickle cell disease (SCD) has improved significantly, in part because of improved iron chelation. Fertility challenges and pregnancy complications have historically limited reproductive options in this group; however, improved multi-disciplinary care has made infertility a chronic disease complication requiring attention. Despite this, there are very few reports and no Australian data describing fertility and pregnancy outcomes in this population. To identify the rate of assisted reproductive technologies (ART) utilisation in our female transfusion-dependent haemoglobinopathy patients and to establish the nature of maternal and neonatal complications in this cohort. A 20-year retrospective analysis (1997-2017) at an Australian centre captured data on conception rates, use of assisted reproductive techniques (ART), and pregnancy and neonatal outcomes in female transfusion-dependent haemoglobinopathy patients. Conception was attempted in 14 women (11 TDT and three SCD) during the study period. A total of 28 pregnancies resulting in 25 live births were recorded. ART supported 13 conceptions. A positive association was not identified between elevated mean serum ferritin and ART use; however, all patients with an established diagnosis of hypogonadotropic hypogonadism (HH) required ART. Maternal complications included gestational diabetes mellitus and post-partum haemorrhage. There were no cardiac complications. Two-thirds of women underwent lower segment caesarean section, with prematurity complicating 20% of births. There were no neonatal or maternal deaths. Pregnancy is an achievable goal for women with transfusion-dependent haemoglobinopathies, although the support of ART may be required in a subset of patients.

Assessment of Sleep Disorders in Children with Transfusion-Dependent Hemoglobinopathies

Purpose: The aim of this study was to compare sleep problems between children with transfusion-dependent hemoglobinopathies and healthy controls.Methods: This study was a case-control survey of children with transfusion-dependent hemoglobinopathies. The sample consisted of 175 children in the patient group and 175 healthy children in the control group, with an age range of 8 to 18 years. Subjects were recruited from the Children’s Hospital of Mansoura University between February and July 2022. Children with transfusion-dependent hemoglobinopathies received consultations at the Department of Pediatric Hematology. The Children’s Sleep Habits Questionnaire (CSHQ) was used to evaluate sleep problems in both groups.Results: The mean age of the patient group was 11.22±2.39 years, and 52.57% (n=92) were girls. The control group had a mean age of 11.30±2.16 years, and 50.86% (n=89) were boys. The overall score (<i>P</i>=0.007) and the night waking (<i>P</i>=0.013), sleep duration (<i>P</i>=0.009), and sleep-disordered breathing (<i>P</i>=0.029) subscores were all substantially and statistically significantly higher in children with transfusion-dependent hemoglobinopathies than in healthy children.Conclusion: As children with transfusion-dependent hemoglobinopathies have more sleep problems than healthy children, more detailed studies are needed.

5613464 INTEGRATION OF PHARMACOKINETIC AND PHARMACODYNAMIC MODELS TO MULTI-CRITERIA DECISION ANALYSIS (MCDA) FOR PROSPECTIVE ASSESSMENT OF THE RISK-BENEFIT RATIO OF ORAL IRON CHELATORS IN PAEDIATRIC PATIENTS WITH TRANSFUSION-DEPENDENT HAEMOGLOBINOPATHIES

Background: Current therapies for the treatment of thalassaemia and other hereditary rare haemoglobinopathies are symptomatic and aim at controlling or reducing iron overload by chelation of iron from a very early age. Iron chelation ultimately prevents complications or comorbidities that can significantly reduce patient survival. Given the processes underlying iron homeostasis and current understanding of the chelation mechanism of available chelating agents, it may be possible to implement alternative, more efficient approaches for evidence generation in support of the dose rationale and their use across different populations affected by transfusion-dependent haemoglobinopathies. Aim: This study aimed to characterise the benefit-risk balance (BRB) of deferiprone in different populations, including children < 2 years old and paediatric sickle cell patients, using a nonlinear mixed effects modelling approach in conjunction extrapolation concepts and multicriteria decision analysis (MCDA). Methods: Based on the underlying pharmacokinetic-pharmacodynamic relationships as well as on the incidence of adverse events, extrapolation concepts were applied to predict the BRB of treatment in young adults, paediatric patients younger than 2 years, and paediatric sickle cell disease patients receiving deferiprone. Using individual patient-level data from a randomised controlled clinical trial (DEEP-2, EudraCT 2012-000353-31), preference elicitation methods were applied to select and prioritise endpoints or outcomes to be used in the evaluation of the BRB across the populations of interest. Subsequently, model parameter estimates obtained from each model/endpoint were used in a set of clinical simulation scenarios in which the effect of chelation therapy was evaluated during 12 months in a virtual cohort of patients. Results: Five endpoints were selected and ranked by the experts involved in the preference elicitation process (Fig.1). ‘Absence or prevention of complications (diabetes/hypothiroidism)’ and ‘occurrence of agranulocytosis’ were the most important criteria, while ‘incidence of arthralgia’ and ‘occurrence of neutropenia’ were considered less important. Clinical trial simulations revealed that the overall benefit score of deferiprone was higher for the treatment of paediatric SCD patient compared with the reference population (i.e. DEEP-2 study). Small but statistically significant differences were observed for the use of DFP in children younger than 2 years old and adolescents or young adults. Table 1 summarises the clinical and demographic baseline characteristics of the DEEP-2 study and virtual cohort of patients included in the different simulation scenarios. Conclusion: This study has shown that MCDA can be utilised in combination with modelling and simulation principles to prospectively assess the effect of interventions in subgroups of patients for which clinical data generation is challenging or not feasible. It also offers an opportunity to evaluate the implications of dose adjustment as well as changes in the clinical management of these patients, providing a less empirical basis for dose selection and treatment choices in rare paediatric conditions such as transfusion-dependent haemoglobinopathies. Table 1 - Demographics of the populations in the MCDA analysis. Reference population reflects the actual patients in the DEEP-2 study, whilst scenarios reflect the baseline characteristics from the virtual patient population. Population Age (years) Weight (kg) Blood consumption (mL/kg/year) Baseline ferritin (ng/mL) Reference population (DEEP-2 study) 8.9 (2.7-17.2) 26.5 (12.1-53.5) 155.4 (17.6-404.3) 1991 (586.2-6488.7) Scenario 1: Adolescents and young adults 17.6 (11.3-33.8) 58 (29-83.6) 139.7 (28.5-347.6) 1933 (432-10106) Scenario 2: Children < 2 years old 1.3 (0.6-1.9) 6.3 (1.1-9.3) 162.2 (21-382.9) 726.3 (253.3-1757) Scenario 3: Paediatric sickle cell patients 14.5 (12.4-17.8) 39 (30-62.4) 139.5 (23.8-338.2) 1598.4 (476.3-8993.9)

Prediction of long-term survival in patients with transfusion-dependent hemoglobinopathies: Insights from cardiac imaging and ferritin

AimsThe current study evaluated the association of echocardiography, cardiac magnetic resonance (CMR), and ferritin data with 10-year survival in thalassemia patients. MethodsDemographics, ferritin, echocardiography, and CMR parameters of stable consecutive thalassemia patients were prospectively collected. ResultsIn total, 75 patients (mean age 37 ± 11 years, 45% male) with thalassemia were included and dichotomized based on their survival status after a median follow-up period of 10.3 [9.6-10.9] years. Older age (HR: 1.071, p = 0.001), ferritin ≥2000 ng/ml (HR: 4.682, p = 0.007) and ≥1700 ng/ml (HR: 7.817, p = 0.002), elevated LV end-diastolic pressure (HR: 1.019, p = 0.044), TR Vmax >2.8 m/s (HR: 6.845, p = 0.005), and CMR T2∗ ≤20 msec (HR: 3.602, p = 0.043) and ≤34 msec (HR: 5.854, p = 0.026) were associated with increased all-cause mortality (primary endpoint). A baseline model including age was created and became more predictive of worse survival by adding TR Vmax >2.8 m/s instead of elevated LV end-diastolic pressure (C index 0.767 vs. 0.760, respectively), ferritin ≥1700 ng/ml instead of ≥2000 ng/ml (C index 0.890 vs. 0.807, respectively), or CMR T2∗≤34 msec instead of ≤20 msec (C index 0.845 vs. 0.839, respectively). Parameters associated with the combined endpoint of cardiac mortality/cardiac hospitalization (secondary endpoint) after adjusting for age were ferritin ≥1700 ng/ml (HR 3.770, p = 0.014), ratio E/A wave >2 (HR 3.565, p = 0.04), TR Vmax >2.8 m/s (HR 4.541, p = 0.049), CMR T2∗ ≤20 ms (HR 9.462, p = 0.001), and CMR T2∗ ≤34 ms (HR 11.735, p = 0.002). The model including age and T2∗ ≤34 ms instead of T2∗ ≤20 ms was more predictive of the secondary endpoint (C-index 0.844 vs 0.838, respectively). ConclusionsIn thalassemia patients, TR Vmax >2.8 m/s, ferritin ≥2000 ng/ml, and CMR T2∗ ≤20 ms were associated with worse long-term survival. In the current era of advanced chelation therapy, aiming for ferritin ≤1700 ng/ml and CMR T2∗ ≥34 ms may improve their prognosis.

New Perspectives and Challenges Regarding Fertility, Conception and Pregnancy in Hemoglobinopathies. a Multidisciplinary Report of 66 Outcomes

Introduction Major thalassemia (TM) and sickle cell disease (SCD), two common genetic hemoglobinopathies, were often fatal 50 years ago. Novel therapeutic and diagnostic methods are increasing lifespan and quality of life. Recent advances in iron chelation for transfusion-dependent hemoglobinopathies have significant improved patient prognosis. Young adult TM and SCD patients often ask about the possibility of conception and pregnancy. The increase in the worldwide movement of carriers and subjects has lead to new cultural, ethical and psychosocial aspects that must be taken into consideration. The present study investigated the fertility rate, maternity/paternity status, need for assisted reproductive techniques (ART), abortion rate, pregnancy/newborn complications in patients with hemoglobinopathies. Methods We followed 130 female (FPs) and male (MPs) patients (F:M=93:37); 75 with TM, 32 with thalassemia intermedia (TI), 13 with SCD and 10 with microdrepanocytosis (MDC). Median age is 55 yo (15-90) for TM+TI and 45 yo (18-79) for SCD+MDC. Pregnancy was reported in 37/52 FP of childbearing age (15-49 yo), and conception in 15 MP with fertility rates of 71% and 70%, respectively. Results We reviewed 66 conceptions from 1999 to 2020. Mother age at pregnancy was between 32-39 yo. Forty-seven pregnancies were spontaneous and 19 medically assisted. There were 3 ovodonations and 2 ICSI; 64% of pregnancies were planned. Pregnancy outcomes of 22 TM, 16 TI, 8 SCD and 3 MDC patients are described. There were 7 miscarriages in the first 12 weeks: 3 in TI, 1 in SCD FP; 1 in TM and 2 in SCD MP. Abortion rate was 9%, comparable to the general population. Intrauterine death at 24w occurred in a SCD FP for placental thrombosis and eclampsia. Sixty live healthy newborns were delivered;4 twin pregnancies occurred (1 TM MP, 3 TM FP). Only 1 malformation was observed, in an infant born after ovodonation in a TM FP who had minor gastroenteric and urinary malformations that were surgically corrected. Obstetric complications were eclampsia, disseminated intravascular coagulation, cardiac failure, and acute chest syndrome in SCD patients. One ovarian hyperstimulation syndrome in the 1st month of pregnancy with ascites and admission to the ER was reported. There were 30 (94%) caesarians (CD) and 3 vaginal deliveries (VG) in FP, with 7 preterm babies (22%). In partners of MPs there were 15 CD (56%), and 11 VG with 5 preterm babies (Table I). Births from MPs occurred between 34-40w with a median birth weight of 3 kg (2.17-4) and 30-41w in FPs with a median birth weight of 2,5 kg (1,1-3,4) . FPs were able to breast fed in 56% of cases for a medium time of 66 days (20-120), while female partners of MPs breastfed for 193 days (20-540). Newborn events includes 14 jaundices; 9 babies were placed in intensive care and required incubator use due to cerebral hemorrhage or infections requiring antibiotic therapy. Discussion Spontaneous pregnancies occur in well chelated and transfused patients but a relevant part of those patients are infertile due to hypogonadism due to transfusional hemosiderosis and may need ART. These patients present a base-line pro-coagulant state which can worsen during pregnancy, needing antithrombotic prophylaxis and require regular consultations, since pregnancies are considered high risk for both mother and baby. As osteopenia-osteoporosis are the common endocrine complications in hemoglobinopathies (67% of FPs), both cesarean delivery and breast feeding are strongly suggested. Even though chelating therapy during lactation does not alter iron excretion, our patients didn't receive chelating therapy when breastfeeding. Multidisciplinary programs including transfusions, cardiac and clinical evaluations should be monthly performed. Our Institution has a team of hematologists and other dedicated specialists that work together during the planning, conception, pregnancy, delivery and immediate post-delivery processes to assure best care to mother and child. Conclusions Survival of hemoglobinopathic patients in developed countries is improving and patients aspire to reproductive aims of their healthy peers. TM and SCD patients often request fertility and pregnancy information, including screening of partners. We provide insights regarding reproductive health experience of hemoglobinopathies in both genders. Detailed results, mothers and child follow up and practical management will be presented. Figure Disclosures Abruzzese: Incyte:Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Bms:Honoraria.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial

Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. EU Seventh Framework Programme.

No child with a transfusion-dependent haemoglobinopathy left unchelated: are we there yet?

Haemoglobinopathies such as thalassaemias and sickle cell disease pose substantial clinical and public health challenges across the world. 1 Shah FT Sayani F Trompeter S Drasar E Piga A Challenges of blood transfusions in β-thalassemia. Blood Rev. 2019; 37100588 Crossref PubMed Scopus (33) Google Scholar The Global Burden of Disease Study 2017 2 GBD 2017 Disease and Injury Incidence and Prevalence CollaboratorsGlobal, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018; 392: 1789-1858 Summary Full Text Full Text PDF PubMed Scopus (3032) Google Scholar estimates a prevalence of 411 000 and incidence of 106 300 new cases per year globally of clinically significant thalassaemias. Because most patients with β-thalassaemia major require regular blood transfusions for the treatment of severe anaemia, often starting within the first 2 years of life, most of these patients have transfusion-associated iron overload with its long-term sequelae. Allogeneic haematopoietic stem-cell transplantation is the only potentially curative therapeutic option; however, this treatment is limited by accessibility issues and its associated morbidity and mortality. Therefore, iron chelation therapy to mitigate the effects of transfusion-associated iron overload has been a standard of care in the treatment of transfusion-dependent haemoglobinopathies. 1 Shah FT Sayani F Trompeter S Drasar E Piga A Challenges of blood transfusions in β-thalassemia. Blood Rev. 2019; 37100588 Crossref PubMed Scopus (33) Google Scholar , 3 Di Maggio R Maggio A The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol. 2017; 178: 676-688 Crossref PubMed Scopus (16) Google Scholar Iron chelation therapy has been shown to improve outcomes, and the oral iron chelators deferiprone and deferasirox seem to be more effective and lead to greater compliance than the parenteral deferoxamine. 4 Pennell DJ Berdoukas V Karagiorga M et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood. 2006; 107: 3738-3744 Crossref PubMed Scopus (388) Google Scholar , 5 Pennell DJ Porter JB Piga A et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA). Blood. 2014; 123: 1447-1454 Crossref PubMed Scopus (82) Google Scholar , 6 Ladis V Chouliaras G Berdoukas V et al. Survival in a large cohort of Greek patients with transfusion-dependent beta thalassaemia and mortality ratios compared to the general population. Eur J Haematol. 2011; 86: 332-338 Crossref PubMed Scopus (43) Google Scholar Although data for patients as young as 2 years are available for deferasirox, there are few high-quality randomised studies in paediatric patients receiving deferiprone. Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trialIn paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. Full-Text PDF

Ethical Issues and Barriers for Multi-National Paediatric Clinical Trials: The Challenging Experience of the DEEP Project

Introduction: The procedures and requirements for the clinical trial application (CTA) to Ethics Committees (ECs) and/or Competent Authorities (CAs) are not fully harmonised, and this is even more evident when non-EU countries are involved. This lack of harmonisation makes more difficult the approach in the case of 'small populations', such as children and patients affected by rare diseases. A phase III efficacy-safety comparative trial (DEEP-2) involving paediatric patients affected by transfusion dependent haemoglobinopathies from seven European and non-European countries (Albania, Cyprus, Greece, Italy, United Kingdom, Egypt, Tunisia) was carried out in the context of a FP7 project (HEALTH-F4-2010-G.A. n. 261483) and included in an agreed Paediatric Investigation Plan. Aims: The aims of this paper are to describe in a complex multi-national/multi-ethnic framework the different provisions and procedures to authorise a paediatric trial in EU/non-EU countries and to evaluate the possible impact of the following key indicators on the timing of ECs approval and CAs authorisation: complexity of the national/local provisions and procedures to authorise a paediatric trial, including the number of ECs and CAs to be addressed; number and type of additional local/national documentation; number of queries from CAs and ECs; geographic setting (EU and non-EU). Methods: The following information was collected from official websites and through a survey addressed to Principal Investigators: The regulatory and legal frameworks in force at the time of the submission of DEEP-2 in each involved country;The procedures required at local/national level (i.e. number of ECs and CAs to be addressed, parallel or subsequent submission to the CA and the EC, preparation of the CTA form and documents required from CAs and ECs);The timing of ECs approval and CAs authorisation, including number and types of queries, were collected from DEEP-2 Trial Master File. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model (GLM) analysis were used to describe results and to analyse significance of the considered indicators. Results: In the EU countries, relevant legislative acts apply and include GCP and specific procedures for paediatric trials, in non-EU countries GCP guidelines apply but have not been implemented in the national laws regulating clinical trials. Moreover, within the 4 EU Member States a different approach was in place, even if under the same rules (i.e. Directive 2001/20/EC as implemented in the national law) with distinctive documents required for the CTA in almost all the EU countries compared with the EC provisions. The CTAs were performed in the period June 2012 - September 2015 in 23 trial sites. The EC approvals and CA authorisations were issued between January 2013 - September 2015. In the EU countries, the authorisation process was completed within 7,3 to 33,8 months (median = 15 months), while in non-EU countries, the authorisation process was completed by 7 months (median = 4 months) (figure 1). In particular, the comparison of the CA time authorisation shows a significant difference between EU and non-EU clusters (p = 0.001); however, if the statistical model is adjusted for the number of EC requests as covariate, the difference is not significant. Thus, it seems that the main factor influencing the time for EC approval is the number of requests for changes/clarifications (mainly on informed consent/assent, study protocol, insurance) (figure 2). Conclusion: Delays in completion of the authorisation phase in many countries seems to be a relevant issue and the timeframes for the authorisation in EU countries are not compliant with the European requirements (60 days for single opinion release and 30 days for its acceptance, as stated in Directive 2001/20/EC). The main reasons for delay is the complexity of the procedures and the requests from the ECs/CAs. In non-EU countries, procedures are different and faster with less requests from ECs and CAs. The upcoming application of a stronger set of rules, CT-Regulation (EU) 536/2014, is expected to harmonise practices in Europe and possibly outside Europe. The final aim of this change should be to assure a good balance between a timely approval and a high-level of children protection. Disclosures Reggiardo: CVBF: Consultancy. Tricta:ApoPharma: Employment.

Neutropenia in Children Treated with Deferiprone or Deferasirox: A Report of the Largest Randomized Trial of Oral Chelators in Transfusion-Dependent Pediatric Patients

Introduction: Agranulocytosis/severe neutropenia is an established adverse event during deferiprone (DFP) use. Less is known about milder episodes, which are frequently transient despite continuous deferiprone use. To provide further insight into this topic, we compared the incidence of neutropenia during DFP or deferasirox (DFX) treatment in the randomized Deferiprone Evaluation in Paediatrics (DEEP-2) trial, where blood neutrophil count was regularly monitored in patients randomized to be treated with DFP or DFX. Methods: DEEP-2 was a multicenter, randomized, 12-month, open-label trial comparing DFP vs DFX in pediatric (&amp;lt;18 years old) patients with transfusion-dependent hemoglobinopathies. 390 patients from 22 centers in 7 countries were randomized (1:1 DFP:DFX) and received at least one dose of the study medication (193 on DFP and 197 on DFX). Neutrophil count was regularly assessed every 7 +/-7 days in all patients. Neutrophil counts &amp;lt;500/mm3 were classified as agranulocytosis/severe neutropenia, 500 - &amp;lt;1,000 /mm3 as moderate neutropenia, and 1,000 - &amp;lt;1,500 /mm3 as mild neutropenia. The incidence of neutrophil counts below the threshold of neutropenia (1,500/mm3) and the rate of reported episodes of neutropenia as identified by the treating physician were compared between the two treatments. An ANOVA model was used to compare the time to neutropenia and time for its resolution between the two treatment groups. To compare the cumulative hazard curves was used the Kaplan-Meier log rank test. Results: 3579 and 4027 neutrophil counts were available for DFP- and DFX-treated patients, respectively. 47 (1.3%) of the total counts in 24 (12.4%) of the 193 DFP-treated patients versus 48 (1.2%) of the total counts in 27 (13.7%) of the 197 DFX-treated patients were below 1,500/mm3. Of these, 28 cases in 23 DFP-treated patients and 15 cases in 11 DFX-treated patients were reported by the treating physician as neutropenia, corresponding to a global incidence rate 11.9% for DFP and 5.6% for DFX (p=0.081, Chi-Square test). 23 (82.1%) of the 28 episodes of neutropenia during DFP use were considered drug related vs 2 (13.3%) of the 15 episodes during DFX use (p-value &amp;lt; 0.001, Fisher Exact test) (table 1). The mean (SD) treatment duration with either DFP or DFX prior to diagnosis of mild or moderated neutropenia was 127 (96.1) days and 101 (85.7) respectively. All those episodes, except for 2, resolved within a mean time of 13 days (1 - 42 days) in DFP-treated patients and 18 days (6 - 46 days) in DFX-treated patients. The 2 cases where neutropenia did not resolve were diagnosed as constitutional neutropenia and bone marrow suppression. There was no significant difference in those results between the two treatment groups as assessed by one-way ANOVA(p = 0.379), Log-Rank test (p = 0.065) or cumulative-hazard and Kaplan-Meier. During the study 3 events of agranulocytosis occurred, all in patients treated with DFP and not included in the present analysis. All 3 episodes resolved. Conclusion: Data from the largest randomized trial of oral chelators in transfusion-dependent pediatric patients provide evidence that, a drop in the neutrophil count below the threshold for mild neutropenia is very common (&amp;gt;10% of patients) for both DFP and DFX treated patients. All episodes of neutropenia, except for 2 with specific etiology, resolved, irrespective of their severity and of chelator used. A causal relationship of neutropenia to chelator use varied based on the chelator; the majority of events observed during DFP use were assessed by the clinician as drug related, whereas the majority of events observed during DFX use were assessed unrelated to its use. These data indicate that while agranulocytosis rate in DFP patients is not changed from previous reports, moderate/mild neutropenia represent discrete events in patients undergoing oral iron chelation therapy. Disclosures Tricta: ApoPharma: Employment. Della Pasqua:GlaxoSmithKline: Employment. Kattamis:Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reggiardo:CVBF: Consultancy. Spino:ApoPharma: Employment. Tsang:Apotex Inc.: Employment.

S144 A MULTICENTRE, RANDOMIZED, NON‐INFERIORITY TRIAL COMPARING THE EFFICACY OF DEFERIPRONE VERSUS DEFERASIROX IN PEDIATRIC PATIENTS AFFECTED BY TRANSFUSION‐DEPENDENT HEMOGLOBINOPATHIES (DEEP‐2 TRIAL)

Background:While the efficacy and safety of deferiprone (DFP) in adult patients with transfusion‐dependent hemoglobinopathies (TDH) has been extensively studied, data in children are sparse.Aims:We report results of DEferiprone Evaluation in Pediatrics‐2 (DEEP‐2), (EudraCT Number 2012‐000353‐31), a Phase III multicentre, randomized, open label study funded by the EU FP7 Research Program, to compare the efficacy of DFP liquid formulation versus deferasirox dispersible tablets (DFX).Methods:DEEP‐2 was a non‐inferiority, 12‐months, active‐controlled trial that included TDH patients, including sickle cell disease (SCD), of 1 month to &lt; 18 years of age. The primary composite efficacy endpoint was treatment success rate based on changes in serum ferritin (SF) levels (all patients) and cardiac iron concentration (MRI‐T2∗) (patients &gt;10 years able to undergo MRI). Predefined criteria (Figure) were used to determine treatment success for the per protocol (PP) population. The secondary endpoints were changes in SF level, cardiac MRI‐T2∗, liver iron concentration‐R2 (LIC‐R2) and safety profile. Non‐inferiority (NI) was based on the 2‐sided 95% confidence interval (CIL, CIU) of the difference in the success rate between the two arms and was established if CIL was greater than −0.125. In the intention‐to‐treat (ITT) analysis, treatment failure was strictly assigned to patients who withdrew from the study, irrespective of the ferritin response observed at the time of the study suspension.Results:21 sites from 7 countries participated in the trial between 3/2014 and 9/2017. 393 patients were randomized (1:1 DFP vs. DFX) and included 117 patients &lt; 6 years of age (30%), 38 with non β‐thalassemia TDH (mainly SCD) and 54 chelation‐naïve. DFP was non‐inferior to DFX based on the PP population (n = 271) while the NI criterion was not met for the ITT population (n = 390) due mainly to more patient withdrawals in the DFP arm, which were not mandated by the protocol (Figure). After 1year treatment (PP population) SF changed from 2468 to 2120 ng/ml in DFP arm and from 2822 to 2328 ng/ml in the DFX arm. Cardiac MRI T2∗ values changed from 31.3 to 32.4ms and from 30.8 to 32.0ms in DFP and DFX arm, respectively. Statistical analysis of the change in SF at the end of treatment also showed NI of DFP for the PP population (δ = −20, CIU = 317 ng/ml; NI criterion: &lt;400 ng/ml), but not for the ITT population when missing SF levels were not analyzed. No significant differences were seen between treatment arms for changes in MRI‐T2∗ and LIC. Overall, there were no statistically significant differences between the two arms in serious adverse events (SAEs) and drug‐related SAEs. 18 (9.3%) DFP and 11 (5.5%) DFX‐treated patients were reported with neutropenia, 3 reversible cases of agranulocytosis were detected in DFP arm, and 2 reversible renal failures in DFX arm.Summary/Conclusion:This FP7‐sponsored trial on chelation therapy in pediatric patients with TDH is the largest in this age group and the only one comparing the two oral chelating agents. The results of the study show that 1) oral iron chelation treatment is effective even in very young ages, 2) treatment with DFP was not inferior to DFX in patients who received 12 months treatment, 3) NI was not shown in the ITT analysis partially due to a different rate of withdrawal not necessarily mandated by the protocol, 4) the overall safety profile of both DFP and DFX was acceptable. The results of the DEEP‐2 trial provide evidence to support the use of DFP in pediatric patients.image

Prediction of ferritin response to chelation in patients affected by transfusion-dependent haemoglobinopathies

Prediction of ferritin response to chelation in patients affected by transfusion-dependent haemoglobinopathies

Deferasirox at therapeutic doses is associated with dose-dependent hypercalciuria

Deferasirox is an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies. Whilst initial long-term studies established the renal safety of deferasirox, there are now increasing reports of hypercalciuria and renal tubular dysfunction. In addition, urolithiasis with rapid loss of bone density in patients with β thalassemia major has been reported. We conducted a cross-sectional cohort study enrolling 152 adult patients comprising of β thalassemia major (81.5%), sickle cell disease (8%), thalassemia intermedia (2%), HbH disease (6.5%) and E/β thalassemia (2%). Cases were matched with normal control subjects on age, gender and serum creatinine. Iron chelator use was documented and urine calcium to creatinine ratios measured. At the time of analysis, 88.8% of patients were receiving deferasirox and 11.2% were on deferoxamine. Hypercalciuria was present in 91.9% of subjects on deferasirox in a positive dose-dependent relationship. This was not seen with subjects receiving deferoxamine. At a mean dose of 30.2±8.8mg/kg/day, deferasirox was associated with an almost 4 fold increase in urine calcium to creatinine ratio (UCa/Cr). Hypercalciuria was present at therapeutic doses of deferasirox in a dose-dependent manner and warrants further investigation and vigilance for osteoporosis, urolithiasis and other markers of renal dysfunction.

Clinical Emergencies Presented by Anemia

Anaemia affects 24.8% of the population worldwide. It has wide variety in terms of clinical manifestation of the disease severity. It can also ranges from almost asymptomatic to severe haemolytic anaemia. In contrast to all other nucleated cells, RBCs show very interesting biology. An alteration in any of the major factors in RBCs (eg. shape, size, and structural or functional or quantitional abnormalities in haemoglobin) usually results in compensatory changes in the other compensatory factors. Sometimes, the compensatory responses may fail because of severity of disease or due to underlying pathologic conditions. The result of failed compensatory responses is cellular dysfunction, tissue hypoxia and eventual cell death, which ultimately leads to severity in anaemia and emergency situations due to it. In this paper, we have concentrated to focus on how the extrinsic and intrinsic defects on RBCs cause severe haemolytic anaemia, leading to emergencies. We have also discussed the destructions of RBCs in both extra and intra vascular regions, contributing to severe haemolysis. Other than haemolytic anaemia, other structural and functional defects of haemoglobin, which can lead to life threatening conditions (e.g.: β thalassemia major and transfusion dependent haemoglobinopathies) are also being discussed here. In nutshell, this paper is an exclusive review on all forms of clinical emergencies due to anaemia’s and other haemoglobinopathies.

Vitamin D Insufficiency and Liver Iron Concentration in Transfusion Dependent Hemoglobinopathies in British Columbia

Patients with thalassemia major (TM) and other chronically transfused hereditary anemias are at increased risk of complications including endocrinopathies and bone disease due to iron overload. Vitamin D is important for bone health. Vitamin D deficiency is common in patients with transfusional iron overload, and the mechanism remains unclear. The first step in vitamin D metabolism, hydroxylation, occurs in the liver and liver iron overload may interfere with this step. This study investigates an association between degree of liver iron overload and vitamin D levels in patients with transfusion dependent hemoglobinopathies. Patients with TM, hemoglobin Eβ TM (Eβ TM), and congenital dyserythropiotc anemia (CDA) attending the Inherited Bleeding and Red Blood Cell Disorder Program in British Columbia (IBRBCD BC), Canada were identified. Included patients had an assessment of liver iron concentration (LIC) by MRI and endocrinology assessment including 25 hydroxy vitamin D level. Thirty patients were identified. The mean LIC was 5.13 mg/g dry weight (DW). Vitamin D deficiency/insufficiency was identified in 19 (63.3%). Eleven (36.7%) patients had an LIC ≥5 mg/gDW, 8 of whom had a vitamin D level 5 mg/gDW and vitamin D level <60nmol/L (P= 0.027) and there was a significant inverse correlation between LIC and vitamin D (R=-0.33). These results indicate an association between increased LIC and vitamin D insufficiency/deficiency, suggesting that liver iron overload may indeed affect vitamin D metabolism. Prospective trials are needed to confirm these results.

Effect of deferasirox on iron overload in patients with transfusion-dependent haemoglobinopathies

BackgroundPatients with haematopoietic disorders requiring long-term blood transfusions are at risk of iron overload. This study aimed to investigate the efficacy and safety of long-term deferasirox monotherapy in patients with transfusion-dependent anaemia in the routine clinical practice setting. MethodsThis was a retrospective analysis of patients who commenced deferasirox therapy at the Hospital Bianchi Melacrino Morelli in Reggio Calabria, Italy. Data collected included cardiac and hepatic iron load (assessed by magnetic resonance imaging); left ventricular ejection fraction (LVEF). Patients were divided into two groups for analysis: group A (baseline information collected prior to deferasirox initiation) and group B (baseline information collected after deferasirox initiation). ResultsForty-six patients were included (group A: n=25; group B: n=21). The overall population was 63% male, with a mean age of 33years. The majority of patients (65%) had thalassaemia major. In the overall population, cardiac iron levels between the baseline and first follow-up visits improved in both groups A and B (29.2 vs. 32.5ms; p=0.04 and 28.4 vs. 31.4ms; p=0.038). Liver iron levels improved significantly from baseline to visit 1 in group A (7.2 vs. 12.1ms; p<0.004) and from baseline to visit 3 (6.9 vs. 10.7; p=0.049) in group B. Generally, there was no correlation between cardiac and liver iron levels. LVEF remained stable throughout the study period. Deferasirox was well tolerated and was not associated with significant adverse events. ConclusionLong-term treatment with deferasirox is effective and safe in patients with transfusion-dependent haemoglobinopathies monitored in the clinical practice setting.

Utility of Transient Elastography (Fibroscan) in Estimating Hepatic Iron Concentration in Comparison to MRI in Patients with Transfusion Dependent Hemoglobinopathies

BackgroundPatients with severe hereditary anemias (e.g. β-Thalassemia Major) are transfusion-dependent for survival. Current guidelines suggest monitoring serum ferritin every three months and annual MRI to assess hepatic and cardiac iron load1. However, MRI, particularly the R2 sequence (FerriScan) which has high specificity and sensitivity in estimating the liver iron concentration, is expensive and not always readily available. Transient elastography (FibroScan) measures liver’s stiffness and predicts fibrosis. Previous studies have suggested its utility in other conditions that increase liver stiffness, such as amyloidosis2and perhaps iron overload.AimTo determine if FibroScan value correlates with hepatic iron concentration estimated using R2 MRI (FerriScan), and/or serum ferritin level.MethodsA prospective cross-sectional study was conducted at a university-affiliated tertiary care center (St. Paul’s Hospital, Vancouver, BC) in 2013 and 2014. Inclusion criteria: Age ≥ 19 years with transfusion-dependent hereditary anemias. Exclusion criteria: liver cirrhosis, primary liver disease (e.g. Wilson’s disease, hereditary hemochromatosis), and chronic viral hepatitis (e.g. Hepatitis B, C and HIV). In addition to having annual MRI and ferritin levels monitored every three months, subjects underwent FibroScan within six months of MRI in 2013. In 2014, participants were invited to undergo repeat FibroScan within three months of the annual MRI. Linear regression analysis was used to determine if there is any correlation/linear fit between FibroScan result, MRI result, and ferritin levels. This study was approved by the University of British Columbia Research Ethics Board.Results20 subjects have been recruited as of August 1, 2014, with 35 and 33 complete FibroScan and MRI results, respectively. 14 (70%) were female. Mean age was 30.7±9.8 years. Most common primary diagnosis was transfusion-dependent beta-thalassemia (Major and intermedia) (n=17).Linear regression analysis showed a weakly positive correlation between hepatic iron concentrations estimated with R2 MRI (FerriScan) and ferritin levels (R2=0.29; p=0.004), when they are performed within four weeks apart. The correlation remained statistically significant when all subjects were included regardless of time lapse between the two investigations (R2=0.30; p=0.001). However, FibroScan values did not appear to correlate with MRI, regardless of whether the scans are performed within six months (R2=0.011; p=0.58) or three months apart (R2=0.035; p=0.44). Similarly, there was no correlation between FibroScan and Ferritin (R2=0.022; p=0.49) when the investigations were performed within 4 weeks part.ConclusionInterim analysis did not demonstrate any correlation between FibroScan result and MRI-estimated hepatic iron concentration. A final analysis will be performed upon complete formal evaluation of the remaining MRI and FibroScan data.

Nephrolithiasis in Transfusion-Dependent Pediatric Patients

Background: The prolonged survival in patients with beta thalassemia major and other transfusion dependent disorders has exposed the multi-organ effects of multiple transfusions and chelation therapy. Renal deficits were described with the focus on tubular and glomerular function. Nephrolithiasis has not been systematically explored in these patients. Contributing factors to stone formation may include hypercalcuria, abnormal vitamin D homeostasis, and proximal tubulopathy.Objective: We analyzed hematologic and nephrologic parameters of 22 transfusion- dependent pediatric patients to investigate contributors to nephrolithiasis.Methods: The study included patients with beta thalassemia major (TM) (13), transfusion-dependent beta thalassemia intermedia (TDTI) (4), Diamond-Blackfan anemia (DBA) (3), other transfusion-dependent hemoglobinopathies (2). Patients’ ages were from 4-20 years (overall median -11 years, TM/TDTI median - 11.5, DBA median - 7.5 years). At the time of analysis 11 received iron chelation with deferasirox, 8 with combined desferoxamine & deferiprone, 2 with combined desferoxamine & deferasirox and one patient received desferoxamine alone. All patients had previously been treated with deferasirox alone and due to either significant adverse events or failure to control iron overload were switched to an alternate regimen. Seven patients were treated with vitamin D supplements for a median of 3 years (range: 0.2-4.3), 6 patients received vitamin D+calcium for a median of 4.5 years (range: 4.3-10). Venous blood samples, 24-hour urine collections and spot urine samples were collected to assess urine chemistry, vitamin D metabolism, electrolytes and renal function. Renal sonography and directed computerized tomography were used to diagnose nephrolithiasis/nephrocalcinosis.Results: Three patients, all with TM/TDTI, had symptomatic and radiographically identified renal stones, an additional TM patient had symptomatic nephrocalcinosis (Table 1). Among the entire cohort hypercalcuria was identified in 75% with increased Ca/Cr in 68%. 25(OH)D3 was abnormal in 81% of patients, mostly in the "insufficient" range (25-75 mmol/L). No significant relationship between presence of nephrolithiasis and chelation regimen, Ca mg/kg/d, Ca/Cr, renal fractional excretion (Fe) of phosphate (FePhos(, FeNa, FeUA, oxalate, cystein, citrate, 25(OH)D3, or treatment with vitamin D± calcium was identified, possibly in part due to the small sample size.Conclusions: The incidence rate of nephrolithiasis in our pediatric transfusion-dependent population was 1000x that published in various pediatric populations. Hypercalcuria and relatively low vitamin D levels were found in the majority of our patients, notably in all with nephrolithiasis. All 4 patients with nephrolithiasis/calcinosis were ≥ 13 years old, receiving vitamin D±calcium supplements and had received deferasirox chelation. Of note none of the patients not receiving vitamin D±calcium therapy presented with renal stones or calcinosis. The pathophysiology of nephrolithiasis/calcinosis is unclear among these adolescents; however the role of vitamin D±calcium supplemental therapy and the contribution of deferasirox must be further studied to find the proper formulation needed to maintain bone health without increasing the risk for renal stones.Abstract 4895. Table 1-Characteristics of patients with nephrolithiasis/nephrocalcinosisPatientDiagnosesAge at onset (years)Chelation (at onset)Duration of vitamin D+Ca supplement (years)Low vitamin D levels (mmol/L)Urine calcium (mg/kg/d) 1TM/NL16DFX2.3+7.62TM/NL16DFX5-6.93TDTI/NL13DFO&DFP (prior DFX)0.25 (vitamin D only)+4.44TM/NC18DFX4+2.7TM-thalassemia major, TDTI-transfusion-dependent thalassemia intermedia, NL-nephrolithiasis, NC-nephrocalcinosis, DFX-deferasirox, DFO-desferoxamine, DFP-deferiprone, Ca-calcium,normal values: vitamin D>75mmol/L, urine calcium<4mg/kg/d DisclosuresNo relevant conflicts of interest to declare.

Chelation Therapy with Oral Solution of Deferiprone in Transfusional Iron-Overloaded Children with Hemoglobinopathies

Iron overload in hemoglobinopathies is secondary to blood transfusions, chronic hemolysis, and increased iron absorption and leads to tissue injury requiring the early use of chelating agents. The available agents are parenteral deferoxamine and oral deferiprone and deferasirox. There are limited data on the safety and efficacy of deferiprone at a very young age. The aim of our study was the presentation of data regarding the use of oral solution of deferiprone in 9 children (mean age 6.5, range 2–10) with transfusion dependent hemoglobinopathies (6 beta thalassemia major, 1 thalassemia intermedia, and 2 sickle cell beta thalassemia). The mean duration of treatment was 21.5 months (range 15–31). All children received the oral solution without any problems of compliance. Adverse reactions were temporary abdominal discomfort and diarrhea (1 child), mild neutropenia (1 child) that resolved with no need of discontinuation of treatment, and transient arthralgia (1 child) that resolved spontaneously. The mean ferritin levels were significantly reduced at the end of 12 months (initial 2440 versus final 1420 μg/L, P < 0.001). This small study shows that oral solution of deferiprone was well tolerated by young children and its use was not associated with major safety concerns. Furthermore, it was effective in decreasing serum ferritin.

Association Between Increased Liver Iron Concentration and Vitamin D Deficiency in Patients with Transfusion Dependent Hemoglobinopathies in British Columbia

Abstract 3203 Background:Patients with transfusion dependent (TD) hemoglobinopathies are at risk of endocrinopathies and bone disease due to iron overload (IOL). Vitamin D is involved in regulation of calcium homeostasis, bone health and other clinical endpoints. Vitamin D deficiency is a common manifestation of patients with transfusional IOL; the mechanism remains unclear. Vitamin D hydroxylation occurs in the liver; whether liver IOL interferes with this step has not to date been addressed. This study investigates an association between liver iron concentration (LIC) and vitamin D levels in patients with TD hemoglobinopathies. Methods:Patients with TD b thalassemia major (TM), hemoglobin Eb TM (Eβ TM), and congenital dyserythropoetic anaemia (CDA) attending the Inherited Bleeding and Red Blood Cell Disorder Program at the adult (St. Paul’s Hospital) or pediatric (BC Children’s Hospital) programs in Vancouver, Canada were included if they had an assessment of LIC done by magnetic resonance imaging (MRI) and 25-hydroxyvitamin D3 (25 OH D3) levels between January 2009 and the 31st of December 2011. The analysis was restricted to patients >16 years of age to minimize confounding due to body mass. Clinical data collected included: gender, ethnicity, type of iron chelation therapy (ICT) and vitamin D and calcium supplementation. Laboratory data included: serum ferritin level, 25 OH D3, phosphorus (PO4), ionized calcium (Ca2+), parathyroid hormone (PTH) and thyroid stimulating hormone (TSH). Vitamin D insufficiency was: 25 OH D3 level <75 nmol/L and deficiency <60 nmol/L. Liver and cardiac iron assessment was done by T2* or R2* MRI. Liver iron was: LIC <2 mg/gmDW, normal; 2–5 mg/gmDW, mild; 5.1–7 mg/gmDW, moderate; >7 mg/gmDW severe. Cardiac IOL was: >20 ms, normal; 14–20 ms, mild; 8–15 ms, moderate; <8 ms, severe. Bone mineral density (BMD) was assessed by dual emission X-ray absorptiometry (DEXA) scans of the hip. BMD was: Z score <−1.5, osteopenia; and <−2.0, osteoperosis. Associations between variables were assessed using the Chi-square or Fischer’s exact test and the Pearson correlation. Results:26 patients with TD: βTM, n=21; Eβ TM, n=3; and CDA, n=2 were included, 21 adults and 5 from the pediatric program. Patients characteristics were: median age 24 (range 16–51) years and 11 (42.3%) were male. Ethnicities were: Asian, 11 (42.3%); Indian, 6 (23%); unclear ethnicity, 5 (19.2%); Middle Eastern, 3 (11.5%); and Caucasian, 1 (3.8%). The mean amount of blood received annually was 9633.9 (4677–14,508) mls/year. All patients were receiving ICT: deferasirox (DFX), 16 (61.5%); desferrioxamine (DFO), 8 (30.8%); and combination DFX+DFO, 2 (7.7%). 15 (57.7%) patients received vitamin D and calcium supplementation in variable doses and formulations. Median 25 OH D3 was 66.5 (18–125) nmol/L and vitamin D deficiency/insufficiency occurred in 15 (57.7%) patients: <75 nmol/L, n=15; and <60 nmol/L, n=10. Median Ca2+ was 2.37 (2.2–2.52) mmol/L, PO4 1.21 (0.78–1.71) mmol/L, AST 24.5 (16–46) U/L and ALT 18 (range10–50) U/L; all within normal. Median serum ferritin level was 693.5 (223–3553) mcg/L, LIC 4.25 (1.1–31.8) mg/g dry weight (DW) and median cardiac iron concentration was 35 (13–53.9) ms. Median BMD at the hip was −1.25 (−0.2–−3.7). There was a significant association between LIC >5 mg/gDW, and vitamin D level <60 nmol/L (P= 0.034), with 10 (38.5%) patients having an LIC ≥5 mg/gDW, 5 of whom had a vitamin D level <60 nmol/L. There was an inverse correlation between LIC and vitamin D level, with a Pearson coefficient of −0.33. There was no significant association between: vitamin D level and age, ethnicity, degree of transfusion requirement (DTR), ferritin level or type of ICT; or LIC and age, DTR, ferritin or BMD (P=NS for all). Conclusion:In this single center study of patients with transfusion dependent hemoglobinopathies, we found a significant association between LIC ≥5 mg/gDW and vitamin D level <60 nmol/L, with an inverse correlation between LIC and vitamin D level, suggesting that liver IOL may affect hepatic vitamin D metabolism and result in deficiency. These results warrant verification in larger numbers of patients and prospective trials and investigation of whether vitamin D insufficiency is linked to clinical endpoints. Patients may require intensification of vitamin D supplementation, and/or intensification of iron chelation therapy, particularly if a link to clinical consequences is demonstrated. Disclosures:Ezzat:Novartis: Honoraria. Leitch:Novartis: Honoraria, Speakers Bureau, participated in advisory boards Other.