Survival and Treatment Outcomes of Childhood Acute Lymphoblastic Leukemia in a Low-Middle Income Country: A Single-Center Experience in West Java, Indonesia.

Purpose: This study aimed to determine the survival rates and treatment outcomes of patients with childhood Acute Lymphoblastic Leukemia (ALL) in a single-center study at Indonesia. Patients and Methods: Factors contributing to the relapse and survival of ALL in Bandung, Indonesia, were evaluated. Data were collected from the medical record and the Indonesian Pediatric Cancer Registry (IPCAR). Subsequently, univariate and multivariate analyses were evaluated using Cox proportional hazard regression and Kaplan Meier was used for survival analysis. An analytic observational study was conducted on newly diagnosed children aged 1-18 with ALL from January 2019 to December 2022. Results: A total of 137 children were included in the analysis, 30 (21,9%) were dropped out during treatment and 60.5% died during the study period. Most of the deaths occurred after relapse in 32 (38.5%) with a high early relapse (70.5%), occurring mainly during the maintenance phase (42.4%). At the one-year mark, the observed overall survival (OS) rate was at 36%, while event-free survival (EFS) was lower, at 19%. Univariate Cox regression analysis showed that the leucocyte counts at diagnosis (p=0.005) and response to induction phase (p < 0.008) was associated with the death of ALL. Furthermore, a response to induction phase was significant [hazard ratio 4.67 (CI 95%: 1.64-13.29); p = 0.004] in the multivariate analysis. Conclusion: In conclusion, this study underscored the persistent challenges of high treatment discontinuation rates and the occurrence of very early relapses in low- to middle-income countries (LMICs), which significantly impacted the OS of children diagnosed with ALL.

Allergic Reactions to E. coli Asparaginase are Associated with Decreased Asparaginase Activity in an Indonesian Pediatric Population with ALL.

PURPOSE: The asparaginase's (ASP) utility for ALL treatment is limited by neutralizing antibodies, which is problematic in countries whose access limited to alternative preparations. ASP antibody levels and activity was measured during remission induction and associated with allergy manifestations. METHODS: E. coli ASP was dosed at 7500 IU/m2. ASP IgG antibody levels were quantified at the beginning and end of induction. ASP activity was measured 24 hours after 1st and 5th dose (standard-risk) or 7th dose (high-risk patients) administration, and within 24 hours in case of allergic reactions. Allergy was monitored by CTCAE version 3. Parametric and non-parametric was performed for data analysis. RESULTS: ASP antibody and activity levels were available in 41/63 consecutive patients. Allergic manifestations occurred in 13/41, with urticaria being the most frequent. There were no significant differences in subject characteristics based on allergic reactions. The 5th dose was the most frequent time of onset. Antibody levels in allergy group at the end of induction did not differ from those at baseline (p<0.05). Using a 24-hour level of 100 mU/mL as a threshold for adequate ASP activity, 6/13 patients with allergy had adequate levels compared to 26/28 patients without (p<0.05). The ASP activity level at the end of induction phase in both groups did not show a significant decrement. CONCLUSION: The E. coli ASP activity with adequate levels were significantly higher in non-allergy group. Its activity level was not accompanied by increment of IgG in allergic group indicates other factors might affect activity levels in allergy group.

Type of cancer and complementary and alternative medicine are determinant factors for the patient delay experienced by children with cancer: A study in West Java, Indonesia.

INTRODUCTION: Most pediatric cancer patients in developing countries present at an advanced stage due to delayed diagnosis, being an important barrier to effective care. The objective of this study was to evaluate the associated factor of patient delay and explore significant parental practice-associated risk factor to patient delay. METHODS: This was a sequential mixed methodology, utilizing data from the Indonesian Pediatric Cancer Registry for clinical variables and completed interviews with parents using structured questionnaires to obtain their sociodemographic data. A binary logistic regression analysis model was fitted to identify factors associated with patient delay. Additional semi-structured interviews related to parental practice of using complementary and alternative medicine (CAM) were administered to 30 parents. Thematic framework analysis was performed on qualitative data to explore determinant factors of parental practice of using CAM. RESULTS: We interviewed 356 parents with children with cancer. The median patient delay was 14 days (interquartile range [IQR]: 6-46.5 days). The most extended delay was in patients with malignant bone tumors (median 66, IQR: 14-126). In multivariable logistic regression analysis, solid cancer (odds ratio [OR] = 5.22, 95% confidence interval [CI]: 2.79-9.77, p < .001) and use of CAM (OR = 1.86, 95% CI: 1.13-3.08, p = .015) were associated with patient delay. Qualitative interviews highlighted key issues relative to determinant parental factors using CAM, including vague initial childhood cancer symptoms, parental health-seeking behavior, CAM availability and accessibility, also barriers of healthcare facilities. CONCLUSION: Type of cancer and use of CAM are essential factors that cause patient delay. It should be addressed in the future childhood cancer awareness and childhood cancer diagnosis pathway.

Identification of Potential Treatments for Acute Lymphoblastic Leukemia through Integrated Genomic Network Analysis.

The advancement of high-throughput sequencing and genomic analysis revealed that acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease. The abundance of such genetic data in ALL can also be utilized to identify potential targets for drug discovery and even drug repurposing. We aimed to determine potential genes for drug development and further guide the identification of candidate drugs repurposed for treating ALL through integrated genomic network analysis. Genetic variants associated with ALL were retrieved from the GWAS Catalog. We further applied a genomic-driven drug repurposing approach based on the six functional annotations to prioritize crucial biological ALL-related genes based on the scoring system. Lastly, we identified the potential drugs in which the mechanisms overlapped with the therapeutic targets and prioritized the candidate drugs using Connectivity Map (CMap) analysis. Forty-two genes were considered biological ALL-risk genes with ARID5B topping the list. Based on potentially druggable genes that we identified, palbociclib, sirolimus, and tacrolimus were under clinical trial for ALL. Additionally, chlorprothixene, sirolimus, dihydroergocristine, papaverine, and tamoxifen are the top five drug repositioning candidates for ALL according to the CMap score with dasatinib as a comparator. In conclusion, this study determines the practicability and the potential of integrated genomic network analysis in driving drug discovery in ALL.

Parental Factors Contribute to Childhood Cancer Abandonment Treatment During COVID-19.

Factors influence a person's health seeking behavior related to abandonment rate on pediatric oncology treatment during this pandemic is unknown. The aim is to identify factors influencing abandonment rates in early pandemic. This was a cross-sectional studies during early pandemic and analyze factors in parents whose children had treatment for malignancy contribute to their children's abandonment treatment rate through guided interview using questionnaire. The characteristic related significantly with treatment abandonment is maternal education. It is found that patients whose mother had education less than secondary school was 1.315 (CI 1.013-1.707) having risk experience abandonment treatment. Parental perception related to impact of COVID-19 was significantly related to treatment abandonment rate with RR 0.202 (CI 0.86-0.471). Patients whose parents have positive perception how abandonment treatment affect their child outcome, believe that doctor has taken step to prevent COVID-19 transmission during treatment, and receive information about COVID-19, having less risk being abandonment treatment.

Extended family thalassemia screening as a feasible alternative method to be implemented in identifying carriers in West Java, Indonesia.

The thalassemia screening program in Indonesia mostly conducted sporadically. Ideal prospective screening is still limited. This study aimed to compare thalassemia screening methods using the extended family approach with and without a history of severe thalassemia and the feasibility of implementing extended family screening method. A case control study was conducted in Dr. Hasan Sadikin General Hospital Bandung with 3 generations of extended families. Data were collected from 150 subjects of 8 extended families with severe thalassemia as an index case entry and 151 subjects of 12 families with no history of thalassemia. All subjects were examined for Hb, MCV, MCH, and peripheral blood smear (PBS) as initial laboratory examinations. Subjects with MCV < 80 fL, MCH < 27 pg, and suggestive findings on PBS continued hemoglobin analysis. Carrier status was determined by definition. All subjects consented to undergo screening and voluntarily participated. The proportion of thalassemia carriers and the participation rate between the 2 groups were compared. Sixty-four of 150 (42.7%) and 16 of 151 (10.6%) carriers were identified in both the case and control group (p < 0.001). The participation rate was 42-88 vs. 23-100% (p = 0.244). The mean age was 31.9 ± 21.2 vs. 31.1 ± 20.8 years (p = 0.782). The median family size was 28.5 vs. 20 subjects per family (p = 0.245). The types of identified thalassemia carrier in both groups consisted of ß-thalassemia, ß-thalassemia/HbE, suspected α-thalassemia, and ß-thalassemia Hb variant. All carriers continued the counseling process. The extended family method seems feasible to be implemented for thalassemia screening in West Java, Indonesia.

High-Risk Histopathologic Features of Retinoblastoma Treated at a Tertiary Hospital in West Java, Indonesia.

PURPOSE: To evaluate the histopathological characteristics of clinically advanced retinoblastoma (RB) and its relationship with tumor differentiation. METHODS: This was a cross-sectional study of primary enucleated group D/E intraocular RB using medical records from 2017 to 2020 in a tertiary referral hospital. Cases with incomplete histopathological results were excluded. Tumors were classified into well, moderately, and poorly differentiated and undifferentiated. High-risk histopathological features were classified as per Thaung and Karaa [Community Eye Health. 2018;31(101):17-3]. RESULTS: This study included 121 patients (129 eyes), of which 32.2% were diagnosed at 25-36 months. High-risk features (HRFs) were found in 100/129 eyes, and of 73 complete histopathological results, the 2 most common HRFs were postlaminar optic nerve invasion and massive choroidal invasion. RB was poorly differentiated in 69.9% and well differentiated in 12.3% of eyes. There was no statistically significant association between any HRFs and tumor differentiation, with age >2 years associated with tumor differentiation (p < 0.05). CONCLUSION: The frequency of HRFs is 77.5% of primary enucleated eyes, mainly poorly and undifferentiated cells, particularly in children aged >2 years old.

Serum TNF-α Level as a Possible Predictor of Inhibitor Levels in Severe Hemophilia A.

BACKGROUND: The development of factor VIII (FVIII) inhibitor in patients with hemophilia A (PWHA) is a great challenge for hemophilia care. Both genetic and environmental factors led to complications in PWHA. The development of inhibitory antibodies is usually induced by the immune response. Tumor necrosis factor α (TNF-α), one of the cytokines, might contribute to its polymorphism. In this study, we investigated the clinical factors, level of serum TNF-α, and polymorphism of c.-308G > A TNF - α gene in inhibitor development in severe PWHA. METHODS: A cross-sectional study was conducted among all PWHA in West Java province. The clinical parameters, FVIII, FVIII inhibitor, and serum TNF-α level were assessed. The genotyping of -380G > A TNF-α gene polymorphism was performed using polymerase chain reaction and Sanger sequencing. RESULTS: Among the 258 PWHA, 216 (83.7%) were identified as severe PWHA. The FVIII inhibitor was identified in 90/216 (41.6%) of severe PWHA, consisting of 45 high-titer inhibitors (HTI) and 45 low-titer inhibitors (LTI). There was a significant correlation between serum TNF-α level and the development of HTI (p = 0.043). The cutoff point of serum TNF-α level, which can be used to differentiate between HTI and LTI, was 11.45 pg/mL. The frequency of FVIII replacement therapy was significant only in HTI of severe PWHA regarding serum TNF-α level (p = 0.028). There is no correlation between polymorphisms of -380G > A TNF-α gene and inhibitor development (p = 0.645). CONCLUSIONS: The prevalence of FVIII inhibitor in severe PWHA in West Java, Indonesia, was 41.6%. The frequency of replacement therapy is a risk factor for inhibitor development. Serum TNF-α level might be used to differentiate between high and low inhibitor levels in severe hemophilia A, and this might support decision making regarding treatment options for inhibitor in severe hemophilia A.

Comparing measurement properties of EQ-5D-Y-3L and EQ-5D-Y-5L in paediatric patients.

BACKGROUND: The adult versions EQ-5D-3L and EQ-5D-5L have been extensive compared. This is not the case for the EQ-5D youth versions. The study aim was to compare the measurement properties and responsiveness of EQ-5D-Y-3L and EQ-5D-Y-5L in paediatric patients. METHODS: A sample of patients 8-16 years old with different diseases and a wide range of disease severity was asked to complete EQ-5D-Y-3L, EQ-5D-Y-5L, PedsQL Generic Core Scale, and selected, appropriate disease-specific instruments, three times. EQ-5D-Y-3L and EQ-5D-Y-5L were compared in terms of: feasibility, (re-)distribution properties, discriminatory power, convergent validity, test-retest reliability, and responsiveness. RESULTS: 286 participating patients suffered from one of the following diseases: major beta-thalassemia, haemophilia, acute lymphoblastic leukaemia, acute illness. Missing responses were comparable between versions of the EQ-5D-Y, suggesting comparable feasibility. The number of patients in the best health state (level profile 11111) was equal in both EQ-5D-Y versions. The projection of EQ-5D-Y-3L scores onto EQ-5D-Y-5L for all dimensions showed that the two additional levels in EQ-5D-Y-5L slightly improved the accuracy of patients in reporting their problems, especially if severe. Convergent validity with PedsQL and disease-specific measures showed that the two EQ-5D-Y versions performed about equally. Test-retest reliability (EQ-5D-Y-3L 0.78 vs EQ-5D-Y-5L 0.84), and sensitivity for detecting health changes, were both better in EQ-5D-Y-5L. CONCLUSIONS: Extending the number of levels did not give clear superiority to EQ-5D-Y-5L over EQ-5D-Y-3L based on the criteria assessed in this study. However, increasing the number of levels benefitted EQ-5D-Y performance in the measurement of moderate to severe problems and especially in longitudinal study designs.

Monitoring Of High-Dose Methotrexate (Mtx)-Related Toxicity and Mtx Levels in Children with Acute Lymphoblastic Leukemia: A Pilot-Study in Indonesia.

The administration of high-dose methotrexate (HD-MTX) requires an accurate monitoring of blood MTX levels to determine the regimen of leucovorin rescue and urine alkalinization to prevent toxicity. However, it is technically and logistically challenging to screen patients routinely in limited-resource settings. This study aimed to evaluate blood MTX levels at 24- and 48-hours from start of infusion in relation to clinical toxicity in childhood ALL. METHODS: A prospective cohort study was conducted on 32 consecutive children with acute lymphoblastic leukemia (ALL) who had received at least one cycle of 1 g/m2 HD-MTX intravenous infusion as a part of consolidation treatment based on the 2013 Indonesian ALL Protocol. In total, 68 cycles were evaluated. Serum MTX concentrations were measured using enzyme immunoassay. MTX toxicity was categorized using common toxicity criteria (CTCAE) 3.0 version. The association between MTX level and clinical toxicity was assessed by non-parametric analysis. RESULTS: The 24-hours MTX level was median 29.8 ng/mL (0.065 µmol/L) (IQR 8.1-390.6) with a modest decrease in 48-hours MTX serum level in all cycles (median 28.3 ng/mL and 0.062 µmol/L; IQR 0.35-28.7; p <0.05). The two most common toxicities were hepatotoxicity (32.2%) and neutropenia (30.9%). Nephrotoxicity and febrile neutropenia occurred in 8.8% and 5.8% of patients, respectively, with low percentage of mucositis (4.3%) and thrombocytopenia (5.6%) recorded.  No statistically significant association was found between MTX levels and clinical toxicity, except for liver toxicity. CONCLUSION: Serum MTX levels at 24-hours and 48-hours are low, followed by only 4.4% grade III/IV hepatotoxicity and 26,4% grade III/IV neutropenia. There is no significant association between the clinical toxicity and MTX levels at the two points of measurement. An attempt to increase the MTX dose and/or to introduce a loading dose should be considered in subsequent ALL protocol as supported by further pharmacokinetic MTX studies in the Indonesian population.

The Role of Ultrasonography forDiagnosing Wilms Tumor in Developing Country.

Background: Overall five-year survival rate of Wilm's Tumor (WT) in developing countries is still poor. Delayed diagnosis is one of the contributing factors, whereas early diagnosis is an important thing for the outcome. It is caused by the WT burden in developing countries that was not comparable with the number of facilities for diagnosis and treatment. Ultrasonography (USG) is the mandatory first-line imaging modality in children with a suspected abdominal mass and an overall sensitivity of 76%. Additionally, it can be found in many health facilities at a lower cost, quick, non-invasive, and carries no risk of radiation. Therefore, the relationship between USG and histopathology should be measured. Materials and Methods: A cross-sectional study with an analytical approach was performed in pediatric (0 untill 18 year of age) renal malignancy and neuroblastoma that admitted to Dr. Hasan Sadikin Hospital, Bandung between 2015-2018. Data were collected from medical records. Statistical analyses using Fisher exact test were done to determine the significance of the relationship between USG and histopathology. Results: Forty-three samples were obtained based on inclusion criteria, such as WT (n=33), neuroblastoma (n=6), renal clear cell carcinoma (n=2) and no specific type of renal malignancy (n=2). Fisher exact test revealed no-significant relationship between USG and histopathology with p-value > 0.05 Conclusion: There is no significant relationship between USG and histopathology. Therefore, centralized unity for USG interpretation is recommended.