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Methotrexate (MTX) is the only chemotherapy drug that is routinely monitored by therapeutic drug monitoring service in Malaysia government hospitals. The patients with MTX plasma concentration exceeding 0.4 μM for 48 h are at higher risk to develop toxicities such as nephrotoxicity, hepatotoxicity, neurotoxicity, mucositis and myelosuppression. The aim of this study was to develop and validate the ultra-high performance liquid chromatography−tandem mass spectrometry (UHPLC−MS/MS) method for MTX quantitation in human serum. Our results show that the retention times of MTX and warfarin (internal standard) were 1.82 and 2.68 min, respectively. The linearity was obtained at the concentrations from 25 to 500 ng/mL with the regression equation of y = 1025x – 11757 and r2 of 0.9901. This analyte was stable in a freezer at –80°C for up to 90 days. As a conclusion, this UHPLC−MS/MS method is an optional technique for clinicians to quantitate the patient’s MTX levels in the hospital.

This is the first study evaluating the frequencies of nucleophosmin (NPM1) gene mutation according to the hyperleukocytosis (HL) grading score. The current two cut off values of this score in acute myeloid leukaemia (AML) patients are [1] those with 50–100 × 109/L and [2] those with ≥ 100 × 109/L total WBC count. The score represents the current clinically based definition of HL in patients with AML. A total of 90 patients with AML were included. AML patients were stratified into three groups: [1] those with a WBC count below 50 × 109/L (n = 33), [2] those with a WBC count 50–100 × 109/L (n = 29) and [3] those with a WBC above 100 × 109/L (n = 28). Complete blood cell count, immunophenotyping and PCR of the exon 12 of NPM1 gene followed by sequencing analysis were done. NPM1 mutations were detected in 20/90 (22.2%) of patients with AML involving exon 12 of NPM1 gene and showed significant correlations with some hematologic characteristics. Contrary to expectation, no statistically significant difference was found in the WBC counts according to the NPM1 gene the mutation status among the studied groups. Also, there were no significant differences in the WHO classification categories according to the HL grading score. The difference in the frequency of NPM1 mutation in Asian compared to Western patients might be attributed to biology and aetiology variation of the disease in different population. The current two cut off values defining the HL are molecularly unreliable in spite of being clinically defined.

Background and objectives: Haemoglobin E β-thalassaemia has a variable clinical presentation. This study describes the clinical spectrum of these patients in two thalassaemia centers in Malaysia in addition to determining the prevalence of selected primary and secondary genetic modifiers which may influence its phenotype. Methods: A total of 99 patients were recruited in this cross-sectional study. Clinical parameters and severity scoring were determined. Molecular analysis was performed: Sanger sequencing and MLPA for β globin mutations; multiplex PCR for α-globin gene deletions and RFLP-PCR for XmnI polymorphism.Results: Patients with mild HbE β-thalassaemia were diagnosed at a later age as compared to the severe group (mean 3.14 and 1.6 years, p = 0.03). Haemoglobin level at diagnosis was higher for the mild group as compared to severe group (7.9 g/dL ± 1.97 and 6.0 g/dL ± 1.00, p = 0.02). The commonest β mutation in Malays were IVS1-5 (51.69%) and CD41/42 (20.2%) whereas in the Chinese, IVS2-654(44.4%) and CD41/42(33.4%). Single α-gene deletion (-α3.7/αα) was found in 4% of patients and none were homozygous for XmnI (+/+) polymorphism. Conclusion: Age at presentation and haemoglobin level at initial diagnosis is useful as clinical predictors of disease severity. The majority of our patients had β° gene mutation i.e. IVS1-5 and CD41/42, which accounted for the moderate to severe phenotype based on clinical severity scoring.

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months’ pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti–FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.

The risk of contact infection among susceptible individuals in a randomly mixed population can be reduced by the presence of immune individuals and this principle forms the fundamental of herd immunity. The conventional susceptible-infectious-recovered (SIR) model features an infection-induced herd immunity model, but does not include the reducing risk of contact infection among susceptible individuals in the transmission model, therefore tends to overestimate the transmission dynamics of infectious diseases. Here we show that the reducing risk of contact infection among susceptible individuals can be achieved by incorporating the proportion of susceptible individuals (model A) or the inverse of proportion of recovered individuals (model B) in the force of infection of the SIR model. We numerically simulated the conventional SIR model and both new SIR models A and B under the exact condition with a basic reproduction number of 3·0. Prior to the numerical simulation, the threshold for the eradication of infectious disease through herd immunity was expected to be 0·667 (66·7%) for all three models. All three models performed likewise at the initial stage of disease transmission. In the conventional SIR model, the infectious disease subsided when 94·0 % of the population had been infected and recovered, way above the expected threshold for eradication and control of the infectious disease. Both models A and B simulated the infectious disease to diminish when 66·7% and 75·6% of the population had been infected, showing herd immunity might protect more susceptible individuals from the infectious disease as compared to the projection generated by the conventional SIR. Our study shows that model A provides a better framework for modelling herd immunity through vaccination, while model B provides a better framework for modelling herd immunity through infection. Both models overcome the insufficiency of the conventional SIR model in attaining the effect of herd immunity in modelling outputs, which is important and relevant for modelling infectious disease, such as the COVID-19 in a randomly mixed population.

Effective prevention of β-thalassemia (β-thal) requires strategies to detect at-risk couples. This is the first study attempting to assess the prevalence of silent β-thal carriers in the Malaysian population. Hematological and clinical parameters were evaluated in healthy blood donors and patients with β-thal trait, Hb E (HBB: c.79G>A)/β-thal and β-thal major (β-TM). β-Globin gene sequencing was carried out for 52 healthy blood donors, 48 patients with Hb E/β-thal, 34 patients with β-TM and 38 patients with β-thal trait. The prevalence of silent β-thal carrier phenotypes found in 25.0% of healthy Malaysian blood donors indicates the need for clinician's awareness of this type in evaluating β-thal in Malaysia. Patients with β-TM present at a significantly younger age at initial diagnosis and require more blood transfusions compared to those with Hb E/β-thal. The time at which genomic DNA was extracted after blood collection, particularly from patients with β-TM and Hb E/β-thal, was found to be an important determinant of the quality of the results of the β-globin sequencing. Public education and communication campaigns are recommended as apparently healthy individuals have few or no symptoms and normal or borderline hematological parameters. β-Globin gene mutation characterization and screening for silent β-thal carriers in regions prevalent with β-thal are recommended to develop more effective genetic counseling and management of β-thal.

ObjectiveThalassaemia is the most common inherited blood disorder in Malaysia. This study aims to report the current status of thalassaemia in Malaysia and provide a comprehensive understanding of the disease through data obtained from the Malaysian Thalassaemia Registry.DesignData were extracted from the Malaysian Thalassaemia Registry, a web-based system accessible to enrolled users through www.mytalasemia.net.my.SettingThe Malaysian Thalassaemia Registry data was recorded from reports obtained from 110 participating government and university hospitals in Malaysia.ParticipantsThe patients were those attending the 110 participating hospitals for thalassaemia treatment.InterventionData were collected from the Malaysian Thalassaemia Registry from 2007 until the fourth quarter of 2018.Primary outcome measure7984 out of 8681 patients with thalassaemia registered in the Malaysian Thalassaemia Registry were reported alive.ResultsMajority of the patients were reported in the state of Sabah (22.72%); the largest age group affected was 5.0–24.9 years old (64.45%); the largest ethnic group involved was Malay (63.95%); and the major diagnosis was haemoglobin E/β-thalassaemia (34.37%). From the 7984 patients, 56.73% were on regular blood transfusions and 61.72% were on chelation therapy. A small fraction (14.23%) has undergone splenectomy, while the percentage of patients with severe iron overload (serum ferritin ≥5000 µg/L) reduced over time. However, cardiac complications are still the main cause of death in patients with thalassaemia.ConclusionData gathered into the registry can be used to understand the progression of the disorder, to monitor iron overload management and to improve the outcomes of treatment, to enhance preventive strategies, reduce healthcare burden and improve the quality of life. Sustainability of the Malaysian Thalassaemia Registry is important for surveillance of thalassaemia management in the country and help the national health authorities to develop more effective policies.

Aplastic anemia is characterized by the development of peripheral blood pancytopenia associated with hypocellularity of the bone marrow. Treatment strategies for aplastic anemia include immunosupressive therapy and hematopoietic stemcell transplantation. The choice of therapy depends on the severity of the disease, patient’s age and availability of a human leukocyte antigen (HLA) matched sibling donor. To describe the clinical characteristics and outcomes of all patients diagnosed with severe aplastic anemia who were treated with allogenic hematopoietic stemcell transplantation at IPHKL. All patients with SAA who had underwent matched sibling hematopoietic stemcell transplantation at IPHKL from January 2002- December 2013 were identified. Retrospective data was collected with regards to patient’s characteristics, transfusion history, conditioning regime, time of engraftment, length of stay, complication and outcomes of patients. In this study there were 36 patients with SAA who underwent allogenic hematopoietic stemcell transplantation. Of the 36 patients, 20 (55.6%) were boys and 16 (44.4%) were girls. The most regimes used for conditioning was combination of fludarabine, cyclophosphamide and ATG horse in 19 patients (52.8%). Mostly the granulocyte engraftment at 10 days after transplantation, while platelet engraftment occurred at 12 days after transplantation. Complications that occurred after transplant were febrile neutropenia in 32 patients (88.9%), mucositis in 25 patients (69.4%), fungal infection in 4 patients (11.1%) and only 2 patients had GvHD. No patients died after underwent allogenic hematopoietic stemcell transplantation. Thirty four patients (94.4%) were cured after a single hematopoietic stemcell transplantation, and only 2 patients (5.6%) had late graft rejection, but all were cured after having the second transplantation The outcomes of patients with severe aplastic anemia who had underwent allogenic hematopoietic stemcell transplantation in bone marrow transplantation ward IPHKL were good. All patients were cured from the disease.

Background: Having a child with acute lymphoblastic leukemia represents challenges to the family which may impact their quality of life. In such circumstances, parents use various coping strategies to face this stressful situation, and understanding the relation of coping strategies on quality of life among parents of children with acute lymphoblastic leukemia may provide professionals with ideas about how to support them which in turn may improve their quality of life. Aim: The aim of the present study was to assess the correlation between coping strategies and the health related quality of life of parents whose children are suffering from acute lymphoblastic leukemia. Study design: A cross-sectional design using guided self-administered questionnaire by a single researcher was used. Methods: A universal sample consisted of 299 parents of children with acute lymphoblastic leukemia (ALL) was recruited from Hospital Universiti Kebangsaan Malaysia and Kuala Lumpur Institute Pediatrics. The response rate was 98%. The data collection tools were WHOQOL BREF which is the World Health Organization Quality of Life shorter version and Brief COPE questionnaires. Results: The results revealed that half of the parents perceived their health related quality of life as good. The highest scores for parents were reported on the social relationship domain meanwhile the lowest were reported on the environmental health domain. In regard to the coping strategies, it was found that religion was most frequently used while humor was the least to be used. Moreover, there was a significant positive relationship between quality of life of the parents and problem-focused coping style and a significant negative relationship with emotion-focused coping style. Conclusion: On the basis of the finding of present study, an appropriate intervention could be design to include program that promote the use of problem-focused copings such as active coping and planning and discourage the use of emotion-focused copings such as self-blaming to enhance parents’ health related quality of life.

This is the first report of quadrupole time-of-flight (Q-TOF) mass spectrometric identification of the hemoglobin (Hb) subunits, α, β, δ and γ peptides, derived from enzymatic-digestion of proteins in the early unknown peaks of the cation exchange chromatography of Hb. The objectives were to identify the unknown high performance liquid chromatography (HPLC) peaks in healthy subjects and in patients with β-thalassemia (β-thal). The results demonstrate the existence of pools of free globin chains in red blood cells (RBCs). The α-, β-, δ- and γ-globin peptides were identified in the unknown HPLC peaks. The quantification and role of the free globin pool in patients with β-thal requires further investigation. Identification of all types of Hb subunits in the retention time (RT) before 1 min. suggests that altered Hbs is the nature of these fast-eluting peaks. Relevancy of thalassemias to the protein-aggregation disorders will require review of the role of free globin in the pathology of the disease.

This is the first report of QQQ-mass spectrometric identification and quantification of the Hb subunits, alpha, beta, delta and gamma globin peptides, derived from enzymatic-digestion of proteins in the early unknown peaks of the Bio-Rad cation-exchange chromatography of haemoglobin. The objectives were to assess the relationship of the quantity of the free alpha, beta, delta and gamma globin chains with the phenotypic diversity of beta-thalassaemias (β-thal). The results demonstrate that the pools of free globin chains in red blood cells were correlating with the severity of the disease in patients with different phenotypes of β-thal. The mechanism and the regulation of synthesis of free globin chains pool in a normal individual and in patients with different β-thal phenotypes could arise from several mechanisms which will require further investigation. The role of the free globin pool in patients with β-thal for development of novel therapeutic approaches based on these potential targets requires further investigation. Pertinent biomarkers improves the diagnosis of the β-thal, especially in low-income countries where they are most common and allows more effective therapeutic intervention leading to more successful therapeutic outcome. Keywords: Anaemia, Thalassemia, Mass spectrometry, Globin chain, Quantification, HPLC, Unknown peaks

Abnormal immune reactivity in patients with beta-thalassemia (beta-thal) major can be associated with poor prognosis. Immunome protein-array analysis represents a powerful approach to identify novel biomarkers. The Sengenics Immunome Protein Array platform was used for high-throughput quantification of autoantibodies in 12 serum samples collected from nine beta-thal major patients and three non-thalassemia controls, which were run together with two pooled normal sera (Sengenics Internal QC samples). To obtain more accurate and reliable results, the evaluation of the biological relevance of the shortlisted biomarkers was analyzed using an Open Target Platform online database. Elevated autoantibodies directed against 23 autoantigens on the immunome array were identified and analyzed using a penetrance fold change-based bioinformatics method. Understanding the autoantibody profile of beta-thal major patients would help to further understand the pathogenesis of the disease. The identified autoantigens may serve as potential biomarkers for the prognosis of beta-thal major.

Purpose. In this study, we aim to describe and compare the demographical, clinical and laboratory features of leptospirosis and dengue co-infections (LDCI) against single leptospirosis infections in Malaysia. Methodology. Data of patients admitted to various hospitals in Malaysia from 2011 to 2015 diagnosed with leptospirosis in our laboratory were obtained from their admission records. Co-infection with dengue was determined by collecting dengue serology results. Multivariate analysis and multiple logistic regression were used to differentiate features between single leptospirosis infection and confirmed LDCI. Results/Key findings. Only 602 (29.11 %) out of 2068 leptospira-positive patients were concurrently tested for dengue during their admission in which 44 (7.31 %) patients had positive non-structural protein 1 (confirmed LDCI) while 140 (23.26 %) were positive for dengue IgM (probable LDCI) with the highest number of cases recorded in high-density suburban districts. Myalgia and arthralgia were the only significant distinguishing clinical feature of LDCI while significant laboratory features were thrombocytopenia and high levels of alanine and aspartate transaminases. Only thrombocytopenia displayed a predictive value for LDCI from analysis of multiple logistic regression. Death occurred in 19 (3.16 %) patients in this dataset studied but only three (0.50 %) were attributed to LDCI. Conclusion. There is a considerable prevalence of LDCI in this country of which overlapping demographic, clinical and laboratory presentations pose diagnostic and therapeutic challenges. Efforts to raise awareness regarding LDCI, better access to diagnostic services and further prospective studies are warranted.

Background and objectives: DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers. Methods: DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27 000 CpG sites microarray chips. Subsequently, methylation-specific polymerase chain reaction (MSP) on selected hypermethylated genes was conducted on an additional 37 chemoresponsive and 9 chemoresistant B-ALL samples and 2 normal controls. Results: Both methods were found to be highly correlated. Unsupervised principal component analysis showed that the chemotherapy-responsive and -resistant B-ALL patients could be segregated from one another. Selection of segregated genes at high stringency identified two potential genes (CDH11 and ADAMTSL5). MSP analysis on the larger cohort of samples (42 chemoresponsive, 14 chemoresistant B-ALL samples and 6 normal controls) revealed significantly higher rates of hypermethylation in chemoresistant samples for ADAMTSL5 (93 vs. 38%; p = 0.0001) and CDH11 (79% vs. 40%, p Conclusion: Chemoresistant B-ALL patients are associated with increased methylation in ADAMTSL5 and CDH11. These findings need to be validated in a larger group of patients, and the functional biological and prognostic significance of differential methylation needs to be studied further.

Objective We aimed to identify factors contributing to ineffective prevention of thalassaemia in Malaysia by studying events leading to the births of children with transfusion-dependent thalassaemia (TDT) including their parents' reproductive choices. Methods Thirty children with TDT born in the year 2005 to 2012 were included. Their parents underwent a semi-structured, face-to-face interview in 2012 and were followed up until 2014 to evaluate the actual decisions made during subsequent pregnancy. Results In 70% of the cases (21/30), neither parent was aware of their carrier status until their child's diagnosis. Six of the remaining nine cases did not receive accurate information or support for prenatal diagnosis and the termination option. Of the 38 parents interviewed, 20 (52.6%) indicated that they would terminate an affected pregnancy. Notably, 52.2% of Muslims supported termination. Prenatal diagnosis was made in two of the five subsequent pregnancies, with thalassaemia traits diagnosed in both fetuses. Conclusion The current poor uptake of voluntary thalassaemia screening in Malaysia and inadequate access to counselling and prenatal diagnostic services contributed to ineffective prevention. A considerable number of Malaysian Muslims may accept the termination option if given access to comprehensive genetic counselling services. © 2014 John Wiley & Sons, Ltd.

Toxic epidermal necrolysis (TEN) is a rare but serious dermatological emergency characterized by diffuse exfoliation of skin and mucous membranes. It can be complicated with sepsis, renal impairmen...

Objective Genetic counseling for thalassemia carriers is conducted by nongeneticist health care workers (HCWs) in many countries. The aim of the study was to assess Malaysian HCWs' genetic counseling practices with regards to discussing prenatal diagnosis (PND) and termination of pregnancy (TOP) when counseling thalassemia carriers. Method A total of 118 Malaysian HCWs (52 doctors and 66 nurses) completed a structured questionnaire that enquired if they would discuss PND and TOP when counseling couples with thalassemia traits, and reasons for their responses were explored. Results All the nurses and 50 (96.1%) doctors were in favor of discussing PND. Only 29 (58%) doctors and 33 (50%) nurses were agreeable to discuss about the option of TOP. Main reasons given for declining to discuss TOP were views that “the condition was not serious enough” (54.9%), TOP is not permissible by their religion (17.6%) and abortion for this indication was illegal (13.7%). Conclusion The results showed that HCWs in Malaysia lacked the comprehensive information and necessary skills required when counseling thalassemia carriers. When nongeneticist HCWs are tasked with such responsibilities, their practices and attitudes should be regularly evaluated so that areas of deficiencies could be identified and addressed. © 2013 John Wiley & Sons, Ltd.

Cancer registries help to establish and maintain cancer incidence reporting systems, serve as a resource for investigation of cancer and its causes, and provide information for planning and evaluation of preventive and control programs. However, their wider role in directly enhancing oncology drug access has not been fully explored. We examined the value of cancer registries in oncology drug access in the Asia-Pacific region on three levels: (1) specific registry variable types; (2) macroscopic strategies on the national level; and (3) a regional cancer registry network. Using literature search and proceedings from an expert forum, this paper covers recent cancer registry developments in eight economies in the Asia-Pacific region - Australia, China, Hong Kong, Malaysia, Singapore, South Korea, Taiwan, and Thailand - and the ways they can contribute to oncology drug access. Specific registry variables relating to demographics, tumor characteristics, initial treatment plans, prognostic markers, risk factors, and mortality help to anticipate drug needs, identify high-priority research area and design access programs. On a national level, linking registry data with clinical, drug safety, financial, or drug utilization databases allows analyses of associations between utilization and outcomes. Concurrent efforts should also be channeled into developing and implementing data integrity and stewardship policies, and providing clear avenues to make data available. Less mature registry systems can employ modeling techniques and ad-hoc surveys while increasing coverage. Beyond local settings, a cancer registry network for the Asia-Pacific region would offer cross-learning and research opportunities that can exert leverage through the experiences and capabilities of a highly diverse region.

Summary Introduction: To study the s-gene mutations spectrum, the genotype/phenotype correlation, the modulatory effect of co-inherited factors such as α-gene mutations and of Xmn1 polymorphism in a large cohort of Malaysian patients. Methods: A total of 264 cases clinically diagnosed as Thalassemia major (TM) (111), Thalassemia intermedia (21), HbE-β Thalassemia (131), and 1 HbE homozygous were studied. The detection of α and s gene mutations and characterization of Xmn1 polymorphism were performed by multiplex PCR, amplification refractory mutation system (ARMS), DNA sequencing, and restriction fragment length polymorphism (RFLP)-PCR. Results: A total of 19 s Thalassemia mutations were characterized. CD26 and CD41/42 were the most common found in the Malay and Chinese population, respectively. The sensitivity of the clinical diagnosis for β TM, thalassemia intermedia, and HbE/β thalassemia was 94.0%, 15.2%, and 89.2%, respectively. Patients with Xmn1 heterozygosity [+/−] required less frequent transfusion compared with those without the polymorphism. Co-inheritance of α-thalassemia alleviates the severity of HbE-β thalassemia in our cohort. Conclusion: Molecular analysis should be used for a better diagnosis and management of β thalassemia.

The in vitro antifungal susceptibilities of 159 clinical isolates of Candida species from patients with invasive candidiasis in Kuala Lumpur Hospital, Malaysia, were determined against amphotericin B, fluconazole, voriconazole, itraconazole and caspofungin. The most common species were Candida albicans (71 isolates), Candida parapsilosis (42 isolates), Candida tropicalis (27 isolates) and Candida glabrata (12 isolates). The susceptibility tests were carried out using an E-test. The MIC breakpoints were based on Clinical Laboratory Standards Institute criteria. Amphotericin B and voriconazole showed the best activities against all the isolates tested, with MIC(90) values of ≤1 µg ml(-1) for all major species. Only one Candida lusitaniae isolate was resistant to amphotericin B, and all the isolates were susceptible to voriconazole. In total, six isolates were resistant to fluconazole, comprising two isolates of C. albicans, two of C. parapsilosis, one C. tropicalis and one C. glabrata, and all of these isolates showed cross-resistance to itraconazole. The MIC(90) of itraconazole was highest for C. glabrata and C. parapsilosis. Caspofungin was active against most of the isolates except for five isolates of C. parapsilosis. The MIC(90) of caspofungin against C. parapsilosis was 3 µg ml(-1). In conclusion, amphotericin B remains the most active antifungal agent against most Candida species except for C. lusitaniae. Voriconazole is the best alternative for fluconazole- or itraconizole-resistant isolates. Although five of the C. parapsilosis isolates showed in vitro resistance to caspofungin, more clinical correlation studies need to be carried out to confirm the significance of these findings. Currently, despite the increase in usage of antifungals in our hospitals, especially in the management of febrile neutropenia patients, the antifungal-resistance problem among clinically important Candida isolates in Kuala Lumpur Hospital is not yet worrying. However, continued antifungal-susceptibility surveillance needs to be conducted to monitor the antifungal-susceptibility trends of Candida species and other opportunistic fungal pathogens.

WOS: 000275981900009, PubMed ID: 19996412, Cardiac iron overload causes most deaths in beta-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with beta-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean +/- coefficient of variation) improved from a baseline of 11.2 ms (+/- 40.5%) to 12.9 ms (+/- 49.5%) (+ 16%; P < .001). LVEF (mean +/- SD) was unchanged: 67.4 (+/- 5.7%) to 67.0 (+/- 6.0%) (-0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (+/- 25.6%) to 32.5 ms (+/- 25.1%) (+ 2%; P = .57) and LVEF increased from baseline 67.7 (+/- 4.7%) to 69.6 (+/- 4.5%) (+ 1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821. (Blood. 2010; 115: 2364-2371), Novartis Pharma AG; Novartis Pharmaceuticals; British Heart FoundationBritish Heart Foundation [PG/09/074/27961]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0508-10081], This study was sponsored by Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.

Eighty-eight multi-ethnic Malaysian pediatric acute lymphoblastic leukemia (ALL) patients were screened for the TEL-AML1 rearrangement by reverse transcription-polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) was used as an independent screen for 30 cases and to confirm RT-PCR positive cases. Seventeen patients, or 19%, were found to be t(12;21) positive. Ethnically the group comprised 12 Malays, 4 Chinese, and 1 Indian. All patients, including 1 with an unusual blast cell morphology who suffered an early relapse and death, were characteristic TEL-AML1 cases in cell count, age, ALL subset classification, and fusion transcript expressed. This study shows that in Malaysia, TEL-AML1 is found in the same distinct ALL subset and at a similar frequency as in other diverse childhood ALL cohorts.

The purpose is to review the current knowledge and methods of determination of the free alpha hemoglobin with emphasis on its potential implications in patients with beta-thalassemia (β-thal).The severity of β-thal correlates with the extent of imbalance between α- and non-α-globin chains and the amount of the free alpha hemoglobin (free α- Hb) pool in the erythrocytes. To date, there is a lack of biomarkers that convey diagnostic and prognostic values in β-thal. Our ongoing research is aimed to evaluate the potential prognostic and diagnostic implications of free α-Hb to improve the care of patients with β-thal. Our ongoing research is aimed to quantify the free α-Hb for its potential prognostic and diagnosticimplications towards improving the care of patients with various β-thal types in the years to come.

The aims of this study were to review the deaths of Malaysian pediatric oncology patients in order to determine the major causes and the proportion of patients who received palliative care.This was a retrospective review from 2001-2007 of deaths at the Pediatric Institute, General Hospital Kuala Lumpur. Clinical data such as age, gender, disease, cause, and place of death were collected. The patients were divided into two groups: those who received palliative care and those who received curative treatment.Two hundred forty-seven patients were included. There were 148 males and 99 females. The age ranged from 2 months to 22 years (median, 4 years). One hundred thirty cases (53%) were still in the curative phase of treatment at the time of death. The most common cause of death was septicemia (62%), followed by hemorrhage (18%) and underlying cancer (14%). One hundred seventeen cases (47%) were in the palliative phase at the time of death. All palliative care deaths occurred in the oncology ward with one exception.Nearly half of all inpatient pediatric cancer deaths were palliative in nature. Septicemia and hemorrhage were the major causes of death in the others.

PubMed ID: 22271905, Background Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important. Design and Methods Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3 rd year, allowing cardiac iron removal to be analyzed over three years. Results Mean deferasirox dose during year 3 was 33.6±9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ±39.1% at baseline to 17.1 ms ±62.0% at end of study (P5 to

Thalassaemia is a public health problem in multi-ethnic Malaysia which mainly affects the Malays, Kadazan-Dusuns and Chinese. This study, the first in Malaysia, aims to evaluate the acceptability of prenatal diagnosis and abortion among Malaysian parents who have a child or children with thalassaemia major and the socio-demographic factors affecting their decision-making. A pre-structured questionnaire was distributed to parents of children with thalassaemia major. Response rate for completed surveys was 99.1 %. Out of 116 respondents, the majority (83/71.6 %) were agreeable for prenatal diagnosis, but only 33 (28.4 %) agreed to both prenatal diagnosis followed by termination of affected foetuses. Of parents who declined abortion, 77.6 % cited religious restriction as the main reason, and their religious background was a significant factor (p = 0.001), with 73.4 % of Muslim participants against termination compared to 25 % of Christians and 13.3 % of Buddhists. Gender, age, highest education level and number of children affected with thalassaemia were non-significant predictors in decision-making regarding abortion. The acceptance rate for termination of foetuses with thalassaemia major in Malaysia is low especially among the Muslims due to religious non-permissibility. Therefore, scholarly deliberations among the Malaysian Muslim religious authorities that result in a supportive stance in this issue may contribute to a more successful prevention programme.

Background Beta thalassemia represents a great heterogeneity as over 300 mutations have been identified and each population at-risk has its own spectrum of mutations. Molecular characterization with high accuracy, sensitivity and economics is required for population screening and genetic counseling. Methods We used the MALDI-TOF mass spectrometry (MS) platform to develop novel multiplex assays for comprehensive detection of 27 mutations in beta-thalassemia patients. Six multiplex assays were designed to detect 13 common known s-mutations, namely CD41/42, CD71/72, IVS1-5, IVS1-1, CD26, IVS2-654, CAP + 1, CD19, -28, -29, IVS1-2, InCD (T-G) and CD17; and 14 rare s-mutations, i.e. InCD (A-C), CD8/9, CD43, -86, CD15, Poly A, Poly T/C, IVS2-1, CD1, CD35/36, CD27/28, CD16, CD37, and 619bpDEL in 165 samples. We compared the efficiencies of genotyping by MS and Amplification Refractory Mutation System (ARMS). Discrepant results were confirmed by sequencing analysis. Results A total of 88.7% (260/293 allele) of MS and ARMS results was in agreement. More than fifty percent of the discrepant result was due to the false interpretation of ARMS results. Failed CD19 assay by MS method might be due to the assay design. The MS method detected 5 rare s-mutations (CD15, CD35/36, CD8/9, Poly A and Poly T/C) presented in 13 alleles, which were not included in the ARMS screening panel. Conclusion We revealed that the MS method is a sensitive, high-throughput, highly automated, flexible, and cost-effective alternative to conventional s-thalassemia genotyping methods.

Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients’ Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.

WOS: 000286902400010, PubMed ID: 21071497, Background The efficacy of cardiac iron chelation in transfusion-dependent patients has been demonstrated in one-year prospective trials. Since normalization of cardiac T2* takes several years, the efficacy and safety of deferasirox was assessed for two years in patients with beta-thalassemia major in the cardiac sub-study of the EPIC trial. Design and Methods Eligible patients with myocardial T2* greater than 5 to less than 20 ms received deferasirox, with the primary endpoint being the change in T2* from baseline to two years. Results Baseline myocardial T2* was severe (>5 to = 5%) increased serum creatinine, rash and increased alanine aminotransferase. Conclusions Continuous treatment with deferasirox for two years with a target dose of 40 mg/kg/d continued to remove iron from the heart in patients with beta-thalassemia major and mild, moderate and severe cardiac siderosis. (Clinicaltrials.gov identifier: NCT 00171821), Novartis Pharma AG; British Heart FoundationBritish Heart Foundation [PG/09/074/27961]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0508-10081], this study was sponsored by Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.

The aims of this study were to determine the types of cancers and hematological disorders in patients attending a pediatric hematology-oncology clinic. This was a prospective study at the Pediatric Institute, General Hospital Kuala Lumpur, Malaysia from June 2005-November 2006. During the 18-month study, 803 patients attended the clinic, 730 had oncological problems and 73 had hematological problems. The age range was from 2 months to 28 years (median 6 years). The patients were Malay (66%), Chinese (23%), Indian (10%) and other races (1%). Of the oncological patients, 51% had either leukemia (n=293) or lymphoma (n=77). The other most common diagnoses were retinoblastoma, followed by Wilm's tumor and germ cell tumors. Six patients (0.8%) developed a second malignant neoplasm. Of the hematological patients, 60% had platelet disorders, most commonly chronic immune thrombocytopenic purpura. Twenty-four per cent had bone marrow failure and 16% had red cell disorders.

Aims The aims of this study were to review the presenting features, treatment and outcome for Malaysian children with retinoblastoma currently. Subjects and Methods This was a prospective study, conducted at the General Hospital Kuala Lumpur from August 2001until October 2007. Clinical data were collected at presentation and follow-up. Results One hundred five children were diagnosed to have retinoblastoma. There were 55 males and 50 females, ranging in age from 1 month to 14 years (median 20 months). Seventy-six children were Malay in ethnic origin (73%), 14 Chinese (13%), 12 Indian (11%), and other races (3%). Sixty-four children presented with leukocoria (61%), followed by 23 with proptosis (22%), 13 with squint (12%), and 3 with orbital cellulitis (3%). Thirty-three children (31%) deferred treatment for 6 months or more. Overall, 56 children had extraocular disease (55%), 52 at presentation, 4 later. Seventy-one children (68%) underwent primary enucleation, 76 received chemotherapy (72%), and 23 radiotherapy (22%). Fifty-seven children are alive (54%), of whom 3 are blind (5%). Twenty-seven children were lost to follow-up (26%) and 21 have died (20%). Conclusion Retinoblastoma in Malaysia is still characterized by predominantly extraocular disease due to late presentation and high rates of abandonment. Pediatr Blood Cancer 2009;52:215–217. © 2008 Wiley-Liss, Inc.

In the last decade, chemotherapy in combination with focal therapy (chemoreduction) has been increasingly used in intraocular retinoblastoma to avoid enucleation and radiotherapy. The aim of this study was to assess the feasibility and outcome of chemoreduction in Malaysian children with retinoblastoma. This was a prospective study from August 2001 to January 2006. Twenty children (25 eyes) were given 4 cycles of chemoreduction, after which the response was assessed. Fourteen eyes showed a complete response, 10 eyes showed a partial response, and 1 eye had progressive disease. Twelve eyes developed progressive disease later, 9 after an initial complete response and 3 after a partial response. Overall, progressive disease occurred in 52%. There were 2 treatment failures, in Reese-Elsworth groups 3 and 4. Both eyes required enucleation. One eye in group 5 required second line chemotherapy to achieve a complete response. No eyes were irradiated. Five children (25%) defaulted follow-up, one of whom returned with disseminated disease. In conclusion, 4 cycles of chemoreduction achieved a durable complete response in only 12% of eyes. Chemoreduction is feasible in Malaysia but requires good patient compliance and close follow-up.

Background Health Related Quality of Life (HRQoL) studies on children with chronic illness such as thalassaemia are limited. We conducted the first study to investigate if children with thalassaemia have a lower quality of life in the four dimensions as measured using the PedsQL 4.0 generic Scale Score: physical, emotional, social and role (school) functioning compared to the healthy controls allowing for age, gender, ethnicity and household income. Methods The PedsQL 4.0 was administered to children receiving blood transfusions and treatments at Hospital Kuala Lumpur, Malaysia using PedsQL 4.0 generic Scale Score. Accordingly, the questionnaire was also administered to a control group of healthy school children. Socio-demographic data were also collected from patients and controls using an interview schedule designed for the study. Results Of the 96 thalassaemia patients approached, 78 gave consent to be interviewed giving a response rate of 81.3%. Out of 235 healthy controls approached, all agreed to participate giving a response rate of 100%. The mean age for the patients and schoolchildren is 11.9 and 13.2 years respectively. The age range for the patients and the schoolchildren is between 5 to 18 years and 7 to 18 years respectively. After controlling for age and demographic background, the thalassaemia patients reported having significantly lower quality of life than the healthy controls. Conclusion Thalassaemia has a negative impact on perceived physical, emotional, social and school functioning in thalassaemia patients which was also found to be worse than the children's healthy counterparts. Continuing support of free desferal from the Ministry of Health should be given to these patients. More understanding and support especially from health authorities, school authorities and the society is essential to enhance their quality of life.

Thalassaemia, a common inherited haemoglobinopathy in Malaysia1, causes significant morbidity due to chronic anaemia and complications of iron excess from regular blood transfusion. Short stature is one of the commonest complications in transfusion-dependent thalassaemia with prevalence of 31% to 75% 2,3. Causes of growth impairment include iron overload, nutritional deficiency, GH-IGF1 axis dysregulation, abnormal puberty and desferrioxamine toxicity4,5. We aim to determine the prevalence of short stature, defined as height z-score ≤ -2, and the factors affecting height in thalassaemia patients attending the Haematology clinic at a tertiary referral center. This observational cross-sectional study involved patients aged 3-19 years, needing blood transfusion at least every 8 weeks, and without co-morbidities or endocrinopathy which affect growth. Weight & height were measured. Puberty status was clinically assessed. Body mass index (BMI) was calculated as a marker of nutritional status. Mean of ferritin levels measured over the preceding one year was determined as a marker of iron overload. There were 52 boys (mean age 11.2y ± 4.8y, mean height z-score -1.67 ± 1.11, mean BMI z- score -0.87 ± 1.44, mean ferritin 3316 ± 2092 µg/L) and 47 girls ( mean age 11.8y ± 4.2y, mean height z-score -1.59 ± 0.97 , mean BMI z-score -0.83 ± 0.95, mean ferritin 3005 ± 2356 µg/L). Overall 35/99 (35%) were short while 64/99 (64%) had normal height. 19/52 (37%) boys and 16/47 (34%) girls were short. 16/19 (84%) short boys were aged ≥ 9 years, 15/16 (94%) short girls were aged ≥ 8 years. Only one boy (aged 15y) and one girl (aged 14y) had delayed puberty. They were both short with height z-score -3.41 and -2.26 respectively. Overall there was a moderate positive correlation between height z-score and BMI z- score (Pearson r = 0.388, p=0.00). There was no significant correlation between height z score and mean ferritin level (Pearson r = -0.044, p= 0.666). Significant proportion (35%) of our transfusion-dependent thalassaemia patients have short stature, majority of them in the pubertal age group. Height is significantly associated with nutritional status but not ferritin level. Improvement in nutrition may improve height in these patients.

Abstract 4276 Background: To date, the efficacy of various iron chelators in reducing cardiac iron, a leading cause of death in transfused patients with β-thalassemia major (TM), has been demonstrated in prospective controlled studies of up to 1-yr duration. Since removal of iron from the heart takes several years, it is important to assess longer-term effects of iron chelation therapy in terms of cardiac iron removal. We report here end-of-study (EOS) results from the EPIC cardiac substudy in TM patients treated with deferasirox for up to 3 yrs. Methods: Patients aged ≥10 yrs with myocardial T2* >5 to 2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dry weight (dw) and ≥50 lifetime transfused blood units were included in the study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the start of yr 2. Dose decreases were allowed for safety reasons. Primary endpoint was change in myocardial T2* from baseline (BL) to 3 yrs. Results: Seventy-one patients completed 2 yrs of treatment and entered the 3rd yr of the study. Mean age was 20.5 ± 7.4 yrs. BL cardiac T2* was >5 to 5 to After 3 yrs, 68.1% of patients with BL T2* 10 to 5 to Of 71 patients, 66 (93.0%) completed the 3rd yr. Reasons for discontinuation were unsatisfactory therapeutic effect (n=3) and consent withdrawal (n=2). There were no deaths during the 3-yr study. Drug-related AEs (≥5%) decreased year by year: increased blood creatinine (n=19 [26.8%] vs n=16 [22.5%] vs n=9 [12.7%]), rash (n=11 [15.5%] vs n=0 vs n=0), increased ALT (n=5 [7.0%] vs n=3 [4.2%] vs n=2 [2.8%]), increased AST (n=4 [5.6%] vs n=3 [4.2%] vs n=1 [1.4%]) and diarrhea (n=4 [5.6%] vs n=1 [1.4%] vs n=0). In yr 3, serious AEs included atrial fibrillation, chronic sinusitis, femur fracture, gastritis, muscle abscess and rheumatic fever (all n=1); none were considered deferasirox-related. Six patients (8.5%) had 2 consecutive increases in serum creatinine >33% above BL and upper limit of normal (ULN); 3 patients in the 1st yr and 3 in the 3rd yr. Two (2.8%) patients had 2 consecutive increases in ALT >10 × ULN; 1 patient in the 2nd yr and 1 patient in both the 2nd and 3rd yr. Conclusion: This is the first prospective study to report 3-yr data on cardiac iron removal for an iron chelator. Once-daily deferasirox monotherapy at doses of 30–40 mg/kg/day effectively removed cardiac iron, allowing 68% of patients with moderate-to-mild cardiac iron loading to normalize and 50% of patients with severe myocardial iron loading at BL to reduce their cardiac iron levels to the moderate-to-mild range, associated with a much lower risk of heart failure. Importantly, there were no reports of death during the study. The long-term improvements in cardiac iron loading with deferasirox at doses of >30 mg/kg/day were associated with a manageable safety profile, maintenance of normal cardiac function and a concomitant significant decrease in hepatic and total body iron burden by nearly 50% over the 3 yrs. Disclosures: Pennell: Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CVIS: Equity Ownership. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cappellini:Novartis: Speakers Bureau. Aydinok:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Honoraria. Li:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Viprakasit:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kattamis:Novartis: Honoraria, Research Funding, Speakers Bureau. Smith:Novartis: Consultancy, Research Funding. Habr:Novartis: Employment. Domokos:Novartis: Employment. Roubert:Novartis: Employment. Taher:Novartis: Honoraria, Research Funding.

Abstract 4062 Poster Board III-997 Background Over 70% of deaths in regularly transfused patients with β-thalassemia major (TM) are related to iron-induced cardiomyopathy. Deferasirox (Exjade®), in a sub-study of the 1-year multicenter prospective EPIC trial, demonstrated efficacy in reducing myocardial iron in TM patients with mild, moderate and severe cardiac siderosis, as evidenced by a statistically significant improvement in myocardial T2*. We herein report the extension phase results from the same study in patients who have received up to 2 years of deferasirox therapy. Methods Patients aged ≥10 years with myocardial T2* >5–2500 ng/mL, MR (R2) LIC >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units were included in the cardiac sub-study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the time patients had entered the 1-year extension. Dose decreases were allowed for safety reasons. The primary endpoint was change in myocardial T2* from baseline to 2 years. Results Out of 100 patients who entered the 1-year extension phase, 85 completed (85%); 24-month CMR data are available for 81 patients. Mean age was 20.6 ±7.3 years. Baseline cardiac T2* was Reasons for discontinuation were: unsatisfactory therapeutic effect (n=8), consent withdrawal (n=3), protocol violation (n=2), lost to follow up (n=1) and abnormal laboratory value (increased urinary protein/creatinine ratio) leading to consent withdrawal (n=1); no deaths were reported. Incidence of investigator-assessed drug-related AEs (≥5%) decreased overall from the core phase to the extension: increased blood creatinine (n=21 [21.0%] vs n=18 [18.0%]), rash (n=15 [15.0%] vs n=0), increased alanine aminotransferase (ALT) (n=6 [6.0%] vs n=4 [4.0%]) and increased aspartate aminotransferase (n=4 [4.0%] vs n=3 [3.0%]). There were no drug-related serious AEs over 2 years. In total, 4 patients (4.0%) had increased serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; 3 patients (3.0%) during the core and 1 (1.0%) during the extension. 4 (4.0%) patients had increased ALT >10xULN on two consecutive visits; 2 patients (2.0%) during the core and 2 (2.0%) during the extension; levels were already >ULN at baseline in these patients. Conclusions This is the first large prospective study to report 2-year data on cardiac iron removal for any iron chelator. Results show that continued therapy with deferasirox for up to 2 years at doses 30–40 mg/kg/day was effective in removing iron from the heart in TM patients with mild, moderate and severe cardiac siderosis. Myocardial T2* continued to improve in year 2 and the statistically significant improvement from baseline was associated with maintenance of normal cardiac function and a concomitant decrease in hepatic and total body iron burden. Overall, deferasirox was well tolerated. Disclosures: Pennell: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government : Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Smith:Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

Abstract 5106 Background Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients with β-thalassemia. Once-daily oral iron chelation therapy with deferasirox (Exjade®) has been shown to reduce body iron burden in patients with transfusion-dependent anemias, and the removal of myocardial iron has been demonstrated in several clinical studies including the prospective, multicenter EPIC study. Here we report for the first time an evaluation of right ventricular (RV) function assessed using magnetic resonance (MR) techniques in β-thalassemia patients with myocardial siderosis treated with deferasirox in the EPIC study. Methods The cardiac sub-study of EPIC enrolled patients with β-thalassemia aged ≥10 yrs who had MR myocardial T2* >5–2500 ng/mL, MR (R2) liver iron concentration (LIC) of >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/day and subsequent dose adjustments of 5–10 mg/kg/day were based on changes in SF, month-6 cardiac T2* and safety parameters. The following RV parameters were assessed using MR; ejection fraction (RVEF), volumes (end-systolic [RVESV] and end-diastolic [RVEDV]) and mass (RVM). All parameters were assessed at the CMR core laboratory in London, UK after 6 and 12 months of deferasirox treatment. Results 114 patients were enrolled in the cardiac sub-study (54 male, 60 female; mean age 20.9 ± 7.3 years). Baseline myocardial T2* was Conclusions To our knowledge, this is the first study to show a change in RV volumes and improvement in RV function associated with iron chelation. The RVEF improved with increased RVEDV and decreased RVESV, which is suggestive of improved RV and left ventricular compliance respectively resulting from removal of myocardial iron. However, improvements in pulmonary vascular resistance may also play a role. Disclosures Smith: Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Lee:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Research Funding; GPO-L-ONE clinical study sponsor by Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Hmissi:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.