Anthracycline-Free Protocol for Favorable-Risk Childhood ALL: A Noninferiority Comparison Between Malaysia-Singapore ALL 2003 and ALL 2010 Studies.

PURPOSE: To investigate whether, for children with favorable-risk B-cell precursor ALL (BCP-ALL), an anthracycline-free protocol is noninferior to a modified Berlin-Frankfurt-Muenster ALL-IC2002 protocol, which includes 120 mg/m2 of anthracyclines. PATIENTS AND METHODS: Three hundred sixty-nine children with favorable-risk BCP-ALL (age 1-9 years, no extramedullary disease, and no high-risk genetics) who cleared minimal residual disease (≤0.01%) at the end of remission induction were enrolled into Ma-Spore (MS) ALL trials. One hundred sixty-seven standard-risk (SR) patients (34% of Malaysia-Singapore ALL 2003 study [MS2003]) were treated with the MS2003-SR protocol and received 120 mg/m2 of anthracyclines during delayed intensification while 202 patients (42% of MS2010) received an anthracycline-free successor protocol. The primary outcome was a noninferiority margin of 1.15 in 6-year event-free survival (EFS) between the MS2003-SR and MS2010-SR cohorts. RESULTS: The 6-year EFS of MS2003-SR and MS2010-SR (anthracycline-free) cohorts was 95.2% ± 1.7% and 96.5% ± 1.5%, respectively (P = .46). The corresponding 6-year overall survival was 97.6% and 99.0% ± 0.7% (P = .81), respectively. The cumulative incidence of relapse was 3.6% and 2.6%, respectively (P = .42). After adjustment for race, sex, age, presenting WBC, day 8 prednisolone response, and favorable genetic subgroups, the hazard ratio for MS2010-SR EFS was 0.98 (95% CI, 0.84 to 1.14; P = .79), confirming noninferiority. Compared with MS2003-SR, MS2010-SR had significantly lower episodes of bacteremia (30% v 45.6%; P = .04) and intensive care unit admissions (1.5% v 9.5%; P = .004). CONCLUSION: In comparison with MS2003-SR, the anthracycline-free MS2010-SR protocol is not inferior and was less toxic as treatment for favorable-risk childhood BCP-ALL.

Haematopoietic stem cell transplantation for inborn errors of immunity: 25-year experience from University of Malaya Medical Centre, Malaysia.

AIM: Inborn errors of immunity (IEI) comprise a heterogeneous group of disorders of the immune system, most of which are curable by haematopoietic stem cell transplantation (HSCT). We present a 25-year audit of HSCT for IEI at a tertiary-level academic hospital in Malaysia. METHODS: Review of medical records of all cases of IEI who underwent HSCT between January 1993 and December 2018 at our centre. Diagnoses, complications, HSCT protocols and outcome data were studied. RESULTS: There were 20 patients (19 boys) with a median age at diagnosis of 11 months (range: 2 months to 12 years). Eleven of 19 (58%) had malnutrition at presentation. Donor sources were variable: 13 (65%) matched sibling donor (MSD), 4 (20%) human leukocyte antigen-haploidentical donor (HD) and 3 (15%) matched unrelated donor (MUD). Conditioning regimens were physician-dependent and adapted to each patient's clinical status. Grades III-IV acute graft-versus-host disease occurred in two of three cases who received MUD grafts, 50% in those who received HD, and 8% in the MSD group. Transplant-related mortality at day +100 was 5%. With a median follow-up of 7.5 years, 18 (90%) patients are alive and free of infections. CONCLUSION: Outcome of HSCT for IEI in our centre is comparable with international reports. HSCT results using HD and MUD grafts are also good despite challenges from acute graft-versus-host disease, providing a feasible alternative for patients without matched donors.

Intensifying Treatment of Childhood B-Lymphoblastic Leukemia With IKZF1 Deletion Reduces Relapse and Improves Overall Survival: Results of Malaysia-Singapore ALL 2010 Study.

Purpose Although IKZF1 deletion ( IKZF1del) confers a higher risk of relapse in childhood B-cell acute lymphoblastic leukemia (B-ALL), it is uncertain whether treatment intensification will reverse this risk and improve outcomes. The Malaysia-Singapore ALL 2010 study (MS2010) prospectively upgraded the risk assignment of patients with IKZF1del to the next highest level and added imatinib to the treatment of all patients with BCR- ABL1 fusion. Patients and Methods In total, 823 patients with B-ALL treated in the Malyasia-Singapore ALL 2003 study (MS2003; n = 507) and MS2010 (n = 316) were screened for IKZF1del using the multiplex ligation-dependent probe amplification assay. The impact of IKZF1del on the 5-year cumulative incidence of relapse (CIR) was compared between the two studies. Results Patient characteristics were similar in both cohorts, including IKZF1del frequencies (59 of 410 [14.4%] v 50 of 275 [18.2%]; P = .2). In MS2003, where IKZF1del was not used in risk assignment, IKZF1del conferred a significantly higher 5-year CIR (30.4% v 8.1%; P = 8.7 × 10-7), particularly in the intermediate-risk group who lacked high-risk features (25.0% v 7.5%; P = .01). For patients with BCR-ABL1-negative disease, IKZF1del conferred a higher 5-year CIR (20.5% v 8.0%; P = .01). In MS2010, the 5-year CIR of patients with IKZF1del significantly decreased to 13.5% ( P = .05) and no longer showed a significant difference in patients with BCR-ABL1-negative disease (11.4% v 4.4%; P = .09). The 5-year overall survival for patients with IKZF1del improved from 69.6% in MS2003 to 91.6% in MS2010 ( P = .007). Conclusion Intensifying therapy for childhood B-ALL with IKZF1del significantly reduced the risk of relapse and improved overall survival. Incorporating IKZF1del screening significantly improved treatment outcomes in contemporary ALL therapy.

Utility of labile plasma iron and transferrin saturation in addition to serum ferritin as iron overload markers in different underlying anemias before and after deferasirox treatment.

OBJECTIVES: Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overload; however, predictive utility may differ depending on underlying, transfusion-dependent, anemias. METHODS: Data were collected before and after 1 year of deferasirox treatment (end of study; EOS) from the large, 1-year EPIC (Evaluation of Patients' Iron Chelation with Exjade(®) ) study. Trends were evaluated between liver iron concentration (LIC), transferrin saturation (TfSat), predose labile plasma iron (LPI) and their relationship to SF categories in 1530 patients: thalassemia major (TM; n = 1114), myelodysplastic syndromes (MDS, n = 336), and sickle-cell disease (SCD, n = 80). RESULTS: Baseline and EOS SF values showed a clear and similar relationship to LIC for all disease groups. TfSat also showed a relationship to SF, most clearly in patients with SCD, where TfSat was lowest in the lowest relative SF category. Unlike SF or LIC, TfSat did not decrease at EOS in any disease group. Baseline LPI was raised in TM and MDS, but not in patients with SCD, decreasing at EOS in both patient groups. After 1 year of chelation therapy, there was a significant trend for greater LPI reduction in patients with TM achieving LIC <7 mg Fe/g dw (P = 0.0137). CONCLUSIONS: Despite limitations, SF showed the clearest relationship, of the plasma markers evaluated, to LIC before and after 1 year of deferasirox in patients with TM, MDS, and SCD. In patients with TM, changes in LPI with chelation show a significant relationship to EOS LIC and may provide an additional indicator of chelation response (clinicaltrials.gov identifier: NCT00171821).

Erratum to: Should All Children Admitted with Community Acquired Pneumonia have Blood Cultures Taken?

Erratum to: Indian J Pediatr DOI 10.1007/s12098-014-1565-6. In the original article, acknowledgement to a grant was missed. Below is the acknowledgement section. This study was partly funded by the UMR grant (no. UM.TNC2/RC/HTM/RP026-14HTM) awarded to AMN and JAdeB by University Malaya. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Should all children admitted with community acquired pneumonia have blood cultures taken?

OBJECTIVE: To evaluate the yield of blood cultures and the impact of blood culture results on the adjustment of empiric antibiotic treatment in children hospitalised with community acquired pneumonia (CAP). METHODS: This was a prospective study conducted at a tertiary hospital in Malaysia, from 1st August 2010 until 31st July 2011. Children aged between 1 mo and 12 y who were admitted for CAP and had blood cultures performed before starting intravenous antibiotics were recruited. Children with congenital pneumonia, immunodeficiency, chronic cardiac or respiratory disorders, nosocomial pneumonia or those on corticosteroids, were excluded. Decision for admission was made by the attending Accident and Emergency physician. RESULTS: One hundred and seventy-one children were enrolled. The median age was 13 mo (range: 38 d-10 y 3 mo) and 59 % were males. Blood cultures were positive in 1.2 % (2/171) of patients while the contamination rate was 1.8 % (3/171). Doctors altered antibiotics based on blood culture results in only one patient. CONCLUSIONS: Both the yield and the impact of blood culture results on the adjustment of empiric antibiotic treatment were very small. There was a high contamination rate. The recommended practice of performing blood cultures in all children admitted with CAP should be reviewed.

Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with ß-thalassemia major.

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 (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43 ± 1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ± 1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥ 20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n = 9, 12.7%). CONCLUSIONS: Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.

Analysis of 120 pediatric patients with nonmalignant disorders transplanted using unrelated plasma-depleted or -reduced cord blood.

BACKGROUND: Unrelated cord blood (CB) is an important stem cell source for unrelated hematopoietic cell transplantation (HCT) of patients with nonmalignant disorders. Processing methods to prepare red blood cell-reduced CB units incur significant nucleated cell loss. In contrast, plasma depletion or reduction (PDR) processing of CB units entails the removal of only a portion of the plasma with minimal nucleated cell loss. However, there are relatively limited data regarding outcomes of CB transplants using units processed by PDR. STUDY DESIGN AND METHODS: A Center for International Blood and Marrow Transplant Research (CIBMTR)-audited analysis was performed on 120 pediatric patients with nonmalignant disorders transplanted between November 2001 and January 2008 at 29 US and 17 international centers using PDR CB units from two CB banks. RESULTS: Transplant characteristics were as follows: median age, 3.5 years (range, 0.1-14 years); median patient weight, 15 kg (range, 4-61 kg); 58% male; HLA matches (intermediate-resolution HLA-A and HLA-B and high-resolution HLA-DRB1) of the units used in these patients six of six in 26, five of six in 48, four of six in 47, and three of six or two of six in 6; median prefreeze total nucleated cell dose, 10.5×10(7)/kg; median prefreeze CD34+ dose, 3.7×10(5)/kg; and nonmyeloablative regimen in 24%. The median times to myeloid and platelet engraftment were 21 and 49 days, respectively. The cumulative incidence of reported Grade II to IV acute graft-versus-host disease (aGVHD) was 38±5%, and 19±4% had Grade III to IV aGVHD. The Kaplan-Meier estimates of 3-year transplant-related mortality, overall survival, and disease-free survival were 20±4, 79±4, and 70±6%, respectively. CONCLUSION: These data demonstrate the effectiveness of PDR CB units for HCT.

Clinical efficacy and safety evaluation of tailoring iron chelation practice in thalassaemia patients from Asia-Pacific: a subanalysis of the EPIC study of deferasirox.

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.

Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children.

Severe combined immunodeficiencies (SCID) are a group of rare inherited disorders with profound defects in T cell and B cell immunity. From 2005 to 2010, our unit performed testing for IL2RG, JAK3, IL7R, RAG1, RAG2, DCLRE1C, LIG4, AK2, and ZAP70 mutations in 42 Chinese and Southeast Asian infants with SCID adopting a candidate gene approach, based on patient's gender, immune phenotype, and inheritance pattern. Mutations were identified in 26 patients, including IL2RG (n = 19), IL7R (n = 2), JAK3 (n = 2), RAG1 (n = 1), RAG2 (n = 1), and DCLRE1C (n = 1). Among 12 patients who underwent hematopoietic stem cell transplantation, eight patients survived. Complications and morbidities during transplant period were significant, especially disseminated bacillus Calmette-Guérin disease which was often difficult to control. This is the first cohort study on SCID in the Chinese and Southeast Asian population, based on a multi-centered collaborative research network. The foremost issue is service provision for early detection, diagnosis, management, and definitive treatment for patients with SCID. National management guidelines for SCID should be established, and research into an efficient platform for genetic diagnosis is needed.

Continued improvement in myocardial T2* over two years of deferasirox therapy in ß-thalassemia major patients with cardiac iron overload.

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 ß-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 < 10 ms) in 39 patients, and moderate-to-mild (10 to < 20 ms) in 62 patients. Mean deferasirox dose was 33.1 ± 3.7 mg/kg/d in the one-year core study increasing to 36.1 ± 7.7 mg/kg/d during the second year of treatment. Geometric mean myocardial T2* increased from a baseline of 11.2 to 14.8 ms at two years (P < 0.001). In patients with moderate-to-mild baseline T2*, an increase was seen from 14.7 to 20.1 ms, with normalization (≥ 20 ms) in 56.7% of patients. In those with severe cardiac iron overload at baseline, 42.9% improved to the moderate-to-mild group. The incidence of drug-related adverse events did not increase during the extension relative to the core study and included (≥ 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 ß-thalassemia major and mild, moderate and severe cardiac siderosis. (Clinicaltrials.gov identifier: NCT 00171821).

Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias.

UNLABELLED: Background Following a clinical evaluation of deferasirox (Exjade) it was concluded that, in addition to baseline body iron burden, ongoing transfusional iron intake should be considered when selecting doses. The 1-year EPIC study, the largest ever investigation conducted for an iron chelator, is the first to evaluate whether fixed starting doses of deferasirox, based on transfusional iron intake, with dose titration guided by serum ferritin trends and safety markers, provides clinically acceptable chelation in patients (aged >or=2 years) with transfusional hemosiderosis from various types of anemia. DESIGN AND METHODS: The recommended initial dose was 20 mg/kg/day for patients receiving 2-4 packed red blood cell units/month and 10 or 30 mg/kg/day was recommended for patients receiving less or more frequent transfusions, respectively. Dose adjustments were based on 3-month serum ferritin trends and continuous assessment of safety markers. The primary efficacy end-point was change in serum ferritin after 52 weeks compared with baseline. RESULTS: The 1744 patients enrolled had the following conditions; thalassemia (n=1115), myelodysplastic syndromes (n=341), aplastic anemia (n=116), sickle cell disease (n=80), rare anemias (n=43) and other transfused anemias (n=49). Overall, there was a significant reduction in serum ferritin from baseline (-264 ng/mL; P<0.0001), reflecting dosage adjustments and ongoing iron intake. The most common (>5%) adverse events were gastrointestinal disturbances (28%) and skin rash (10%). Conclusions Analysis of this large, prospectively collected data set confirms the response to chelation therapy across various anemias, supporting initial deferasirox doses based on transfusional iron intake, with subsequent dose titration guided by trends in serum ferritin and safety markers (clinicaltrials.gov identifier: NCT00171821).

Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia.

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.

Interaction of Hb South Florida (codon 1; GTG-->ATG) and HbE, with beta-thalassemia (IVS1-1; G-->A): expression of different clinical phenotypes.

INTRODUCTION: Interactions of different hemoglobin variants with thalassemia alleles can result in various clinical phenotypes. HbE-beta-thalassemia generally manifests with severe anemia where individuals exhibit beta-thalassemia major with regular blood transfusions or beta-thalassemia intermedia with periodic blood transfusions. This study presents a unique Malay family with three beta-globin gene defects-HbE, Hb South Florida, and IVS1-1 (G-->A). MATERIALS AND METHODS: HbE activates a cryptic splice site that produces non-functional mRNAs. Hb South Florida is a rare beta-hemoglobin variant, and its interactions with other beta-thalassemia alleles have not been reported. IVS1-1 is a Mediterranean mutation that affects mRNA processing giving rise to beta(o)-thalassemia. RESULTS AND DISCUSSION: Fifteen mutations along the beta-globin gene complex were analyzed using the amplification refractory mutation system. Hb South Florida was identified by direct sequencing using genomic DNA. CONCLUSION: The affected child with HbE/IVS1-1 produced a beta-thalassemia major phenotype. Compound heterozygosity for Hb South Florida/IVS1-1 produced a beta-thalassemia carrier phenotype in the mother.

Characterisation and confirmation of rare beta-thalassaemia mutations in the Malay, Chinese and Indian ethnic groups in Malaysia.

AIMS: In Malaysia, about 4.5% of the Malay and Chinese populations are heterozygous carriers of beta-thalassaemia. The initial identification of rare beta-globin gene mutations by genomic sequencing will allow the development of simpler and cost-effective PCR-based techniques to complement the existing amplification refractory mutation system (ARMS) and gap-PCR used for the identification of beta-thalassaemia mutations. METHODS: DNA from 173 beta-thalassaemia carriers and five beta-thalassaemia major patients from the Malay, Chinese and Indian ethnic groups were first analysed by ARMS and gap-PCR. Ninety-five per cent (174/183) of the 183 beta-globin genes studied were characterised using these two techiques. The remaining nine uncharacterised beta-globin genes (4.9%) were analysed using genomic sequencing of a 904 bp amplified PCR product consisting of the promoter region, exon 1, intervening sequence (IVS) 1, exon 2 and the 5' IVS2 regions of the beta-globin gene. RESULTS: The rare beta-globin mutations detected in the Chinese patients were CD27/28 (+C) and CD43 (GAG-TAG), and -88 (C-T) in an Indian patient. Beta-globin mutations at CD16 (-C), IVS1-1 (G-A), IVS2-1 (G-A), -86 (C-G) and Haemoglobin South Florida (CD1, GTG-ATG) were confirmed in the Malay patients. CONCLUSIONS: The seven rare beta-globin mutations and a rare haemoglobin variant confirmed in this study have been described in other populations but have not been previously described in Malaysian beta-thalassemia patients.

Molecular characterisation and frequency of Ggamma Xmn I polymorphism in Chinese and Malay beta-thalassaemia patients in Malaysia.

The molecular basis of variable phenotypes in P-thalassaemia patients with identical genotypes has been associated with co-inheritance of alpha-thalassaemia and persistence of HbF production in adult life. The Xmn I restriction site at -158 position of the Ggamma-gene is associated with increased expression of the Ggamma-globin gene and higher production of HbF This study aims to determine the frequency of the digammaferent genotypes of the Ggamma Xmn I polymorphism in P-thalassaemia patients in two ethnic groups in Malaysia. Molecular characterisation and frequency of the Ggamma Xmn I polymorphism were studied in fifty-eight Chinese and forty-nine beta-thalassaemia Malay patients by Xmn I digestion after DNA amplification of a 650 bp sequence. The in-house developed technique did not require further purification or concentration of amplified DNA before restriction enzyme digestion. The cheaper Seakem LE agarose was used instead of Nusieve agarose and distinct well separated bands were observed. Genotyping showed that the most frequent genotype observed in the Malaysian Chinese was homozygosity for the absence of the Xmn I site (-/-) (89.7%). In the Malays, heterozygosity of the Xmn I site (+/-) was most common (63.3%). Homozygosity for the Xmn I site (+/+) was absent in the Chinese, but was confirmed in 8.2% of the Malays. The ratio of the (+) allele (presence of the Xmn I site) to the (-) allele (absence of the Xmn I site)) was higher in the Malays (0.66) compared to the Chinese (0.05). The (+/-) and (+/+) genotypes are more commonly observed in the Malays than the Chinese in Malaysia.

Risks of seroconversion of hepatitis B, hepatitis C and human immunodeficiency viruses in children with multitransfused thalassaemia major.

OBJECTIVES: To estimate the risks of seroconversion of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency viruses (HIV) in children with multitransfused thalassaemia at a thalassaemic clinic in Kuala Lumpur, Malaysia. METHODS: Seventy-two children (39 males, median age 11.3 years, 2.5th-97.5th centile: 1.4-19.2 years) with thalassaemia major were studied. The risks of seroconversion of HBV, HCV and HIV were estimated by comparing the seroprevalences of hepatitis B surface antigen (HBsAg), anti-HCV and anti-HIV between a defined starting point and an end point. The end point was the point when latest serological results were available while the starting point was when regular transfusion was commenced, or approximately 5 years before the end point when the duration of transfusion was longer. RESULTS: The median duration of the study was 49 months (range 8-69 months, total 2953 patient-months). There were 2605 transfusion episodes and 4154 units of blood transfused (0.88 transfusion episode/patient per month, 1.41 units of blood transfused/patient per month). There were three new seroconversions for anti-HCV but none for HBsAg and anti-HIV. The risk of seroconversion for HCV was one in 1384 units of blood transfused (95% CI: 4000-472). The seroprevalence rates at the starting and end points were: HBsAg (1%, 1%), anti-HCV (10%, 13%) and anti-HIV (0%, 0%), respectively. CONCLUSIONS: The estimated risk of acquiring HCV infection in children receiving multiple blood transfusions in this study is surprisingly higher than the generally accepted estimated risk. Other routes of transmission may be important. A prospective, multicentre study to estimate such risks more precisely is needed.