Infection-related mortality and infection control practices in childhood acute myeloid leukemia in a limited resource setting: Experience with the Indonesian national protocol.

Background: In resource-limited settings, addressing infections remains a substantial challenge in the management of children with Acute Myeloid Leukemia (AML). In Indonesia, infection-related mortality (IRM) is thought to be high compared to high-income countries. However, there has been no previous study of infection profile and IRM in Indonesian patients with AML. Objective: This study aimed to describe infections and IRM in children with AML treated according to the Indonesian National AML protocol and to describe the implementation of infection control practices in resource-limited settings. Methods: This retrospective observational study used secondary data from the medical records of pediatric patients with AML treated with the National Protocol at Dr. Sardjito Hospital, Yogyakarta, Indonesia, from April 2012 to September 2018. Essential patient characteristics, time of IRM, and cause of death were recorded, and infection control practices were observed. Data were analyzed using descriptive statistics. Results: 113 patients with AML were treated with the National protocol, and 83 met the inclusion criteria. Infections occurred in 69 (83%) patients with a total of 123 episodes (mean 1.8/patient). Death was seen in 48 (58%) patients, with 19 (23%) IRM. The majority of infections were in the gastrointestinal tract (n = 51, 30.5%), sepsis (n = 29, 17%), and respiratory tract (n = 28, 17%). Infections mostly occurred during the first induction (41%). There were 90 (73%) episodes of clinically documented infection and 33 (27%) episodes of microbiologically documented infection. The positivity rate of blood cultures was only 27%. The majority of bacteria detected were gram-negative (n = 25, 69%), and among them were Klebsiella pneumonia (19%) and Escherichia coli (19%). Candida albicans was detected in 1 (2%) culture. Suboptimal infection prevention and control were found in the clinical practice. Conclusion: Infections and infection-related mortality in children with AML treated using the National protocol were frequent, mainly occurring during the first induction phase. Compliance with infection prevention and control measures needs improvement. Urgent attention is required for better supportive care, including isolation rooms, antibiotics, and antifungals. The predominance of Gram-negative bacterial infections highlights the necessity for further research into effective prophylaxis. Enhanced healthcare and nursing professional vigilance and tailored antibiotic strategies are vital. Improving compliance and ensuring adequate supportive care resources are essential, emphasizing nursing's pivotal role. Further research is crucial to drive advancements in infection control strategies.

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.

Chemo assist for children mobile health application to manage chemotherapy-related symptoms in acute leukemia in Indonesia: a user-centered design approach.

BACKGROUND: A mobile health (mHealth) application can encourage parents and pediatric patients to be involved in caring for their child's health condition by providing the ability to identify and actively manage chemotherapy-related symptoms in their child. Several monitoring systems available today are diverse in features and system basis. This study aimed to develop and trial the Chemo Assist for Children (CAC) mHealth application for symptom management in children with acute lymphoblastic leukemia (ALL). METHODS: In this study, the development of the CAC application went through multiple phases and methods. Study phases included: (1) development of the application's feature based on the need assessment, (2) creation of content of application based on literature review, (3) develop prototyping of CAC, (4) expert review and feedback on the application content, (5) usability testing by targeted end-user. RESULTS: Based on need assessment, it was determined that parents with leukemia children were interested in symptom management of chemotherapy and preferred mobile applications. Therefore, a mHealth application was designed to include features to identify symptoms and provide recommendation strategies to manage the symptom. Usability evaluation by end-user revealed that mHealth is a valid, accessible, and appropriate application for users. CONCLUSIONS: The CAC mHealth application developed can meet the needs of technology users to identify symptoms and manage chemotherapy-related symptoms in children with ALL. The CAC mHealth application can accommodate data not recorded at out-of-hospital care, increase the independence of symptom management, and improve communication between parents of children with ALL and health workers.

SIOP PODC adapted risk stratification and treatment guidelines: Recommendations for acute myeloid leukemia in resource-limited settings.

In low- and middle-income countries (LMICs), limited resources, suboptimal risk stratification, and disproportionate patient-to-infrastructure ratio result in low survival of patients with acute myeloid leukemia (AML). A high incidence of relapse, inherent to the biology, renders management arduous. The challenge of treating AML in LMICs is of balancing the intensity of myelosuppressive chemotherapy, which appears necessary for cure, with available supportive care, which influences treatment-related mortality. The recommendations outlined in this paper are based on published evidence and expert opinion. The principle of this adapted protocol is to tailor treatment to available resources, reduce preventable toxic death, and direct limited resources toward those children who are most likely to be cured.

Childhood acute lymphoblastic leukemia: Four years evaluation of protocols 2013 and 2016 in a single center in Indonesia, a lower-middle-income country.

BACKGROUND: The prognosis of childhood acute lymphoblastic leukemia (ALL) in Indonesia, a lower-middle-income country (LMIC), is lower than in high income countries (HICs). The Indonesian ALL2013 protocol resulted in too many toxic deaths (21%) and abandonments (11%). Therefore, we drafted an adapted protocol, ALL2016. Main changes: no anthracyclines in standard risk (SR), prednisone replaced dexamethasone at induction in high risk (HR), and anthracyclines and cyclophosphamide were rescheduled in HR. PROCEDURE: Patients (aged: 1-18 years) were stratified into SR and HR. HR was defined as age over 10 years, leucocyte count over 50 × 109 /L, central nervous system (CNS) involvement, mediastinal mass, T-cell phenotype, testicular involvement, or poor prednisone response. RESULTS: ALL2013 included 174 patients (106 SR and 68 HR) and ALL2016 188 (91 SR and 97 HR). Although the number of HR patients was significantly higher in ALL2016 (51.6% vs. 39.1%; p = .017), the outcome of ALL2016 improved over ALL2013 (4-year-probable overall survival (pOS) 60.1% vs. 50.0%; p = .042 and 4-year-probable event-free survival (pEFS) 49.5% vs. 36.8%; p = .018). ALL2016 showed a nonsignificant advantage for SR patients (4-year-pEFS 56.0% vs. 47.2%; p = .220 and 4-year-pOS 70.3% vs. 61.3%; p = .166), but less toxic deaths (7% vs. 20%; p = .011). In HR group, the outcomes were significantly better in ALL2016 (4-year-pEFS 43.3% vs. 20.6%; p = .004; 4-year-pOS 50.5% vs. 32.4%; p = .014) especially due to less relapses (31% vs. 62%; p = .001). Isolated CNS relapses went down from 18 to 8% in HR (p = .010) and 11 to 5% in SR (p = .474). Both SR and HR showed lower numbers of abandonment in ALL2016 (6% vs. 14%; p = .039). CONCLUSIONS: Overall ALL2016 results improved over ALL2013. Modest changes in protocol resulted in less initial toxicity and abandonments.

Development and Evaluation of Internet-based Health Technology in Pediatric Oncology: A Scoping Review.

OBJECTIVE: There is an increased awareness to identify symptomatic experiences in children undergoing chemotherapy. An Internet-based health technology accessible and friendly for children and parents to report health problems during chemotherapy has been well-developed in developed countries. The purpose of this scoping review is to provide a comprehensive view of relevant research related to the emergence of health applications in pediatric oncology so that it can provide information for design and evaluation in the future. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines support this scoping review. To investigate the evidence on the development of Internet-based health technology, Science Direct, Scopus, PubMed, EBSCOHOST Medline, IEEEXplore, ProQuest, and Nature databases were searched between 2015 and 2021. RESULTS: 14 articles met the inclusion criteria with nine Internet-based health technologies. Moreover, four of nine mobile health apps use a theoretical foundation (SPARK for children and family member, Empower Stars!, THRIVE, and Facebook-based "Healthy Teens for Soaam"), three apps apply four stages of development and testing, and all apps have met the category of the degree of attachment of patients to the application. CONCLUSION: The effect of Internet-based health technology through a scientific process by paying attention to the underlying theories, user needs, developer passion, application testing, and evaluation methods is the key to success.

Lag time to diagnosis as a predictor of mortality in children with extraocular retinoblastoma: Experience from a developing country.

AIM: To define the prevalence of mortality and identify factors associated with mortality in pediatric patients with extraocular retinoblastoma attending the tertiary hospital in Indonesia. METHODS: We retrospectively collected medical records from 2013 to 2019 of patients who were diagnosed with extraocular retinoblastoma. Cox proportional hazard regression analysis with 95% confidence interval (CI) was used to evaluate the association of mortality predictors with patient outcomes (Hazard Ratio [HR], 95% CI) with significance set as p < .05. RESULTS: Overall, 60 patients were included in this study for a retrospective chart review, with 55% males and 45% females. The median age at diagnosis was 13 (5-24) months. About 60% of the patients did not survive, while 2-year survival probability was 45%. The overall median survival time was 21.5 (7.25-40.75) months. Predictors of mortality were laterality (unilateral/bilateral): HR 2.15 (95% CI: 1.07-4.28; p = .03), nutritional status: HR 2.65 (95% CI: 1.34-5.25; p = .05), and lag time to diagnosis: HR 3.12 (95% CI: 1.56-6.2; p = .001). CONCLUSION: Laterality, nutritional status and lag time to diagnosis were identified to be mortality predictors in extraocular retinoblastoma. The 2-year survival for children with extraocular retinoblastoma was 45% with 21 months for median survival.

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.

Impact of universal health coverage on childhood cancer outcomes in Indonesia.

BACKGROUND: Starting from 2014, the Indonesian government has implemented Universal Health Coverage (UHC) with the aim to make healthcare services accessible and affordable to all Indonesian citizens. A major reason for childhood cancer treatment failure in low- and middle-income countries, particularly among families with low socioeconomic status (SES), is abandonment of expensive cancer treatment. Our study compared childhood cancer treatment outcomes of the overall, low, and high SES population before and after introduction of UHC at a large Indonesian academic hospital. METHODS: Medical records of 1040 patients diagnosed with childhood cancer before (2011-2013, n = 506) and after (2014-2016, n = 534) introduction of UHC were abstracted retrospectively. Data on treatment outcome, SES, and health-insurance status at diagnosis were obtained. FINDINGS: After introduction of UHC, the number of insured patients increased from 38% to 82% (P < 0.001). Among low SES population, insurance coverage increased from 40% to 85% (P < 0.001), and among high SES population from 33% to 77% (P < 0.001). In the overall population, treatment abandonment decreased from 36% to 22% (P < 0.001). Event-free survival estimates at four years after diagnosis of overall population improved from 16% to 22% (P < 0.001). Hazard ratio for treatment failure was 1.26 (CI: 1.07-1.48, P = 0.006) for uninsured versus insured patients. In the low SES population, treatment abandonment decreased from 36% to 19% (P < 0.001). Event-free survival estimates at four years after diagnosis of low SES population improved from 14% to 22% (P < 0.001). INTERPRETATION: Introduction of UHC in Indonesia contributed significantly to better treatment outcome and event-free survival of children with cancer from low SES families.

Paediatric cancer stage in population-based cancer registries: the Toronto consensus principles and guidelines.

Population-based cancer registries generate estimates of incidence and survival that are essential for cancer surveillance, research, and control strategies. Although data on cancer stage allow meaningful assessments of changes in cancer incidence and outcomes, stage is not recorded by most population-based cancer registries. The main method of staging adult cancers is the TNM classification. The criteria for staging paediatric cancers, however, vary by diagnosis, have evolved over time, and sometimes vary by cooperative trial group. Consistency in the collection of staging data has therefore been challenging for population-based cancer registries. We assembled key experts and stakeholders (oncologists, cancer registrars, epidemiologists) and used a modified Delphi approach to establish principles for paediatric cancer stage collection. In this Review, we make recommendations on which staging systems should be adopted by population-based cancer registries for the major childhood cancers, including adaptations for low-income countries. Wide adoption of these guidelines in registries will ease international comparative incidence and outcome studies.

Corruption in health-care systems and its effect on cancer care in Africa.

At the government, hospital, and health-care provider level, corruption plays a major role in health-care systems in Africa. The returns on health investments of international financial institutions, health organisations, and donors might be very low when mismanagement and dysfunctional structures of health-care systems are not addressed. More funding might even aggravate corruption. We discuss corruption and its effects on cancer care within the African health-care system in a sociocultural context. The contribution of high-income countries in stimulating corruption is also described. Corrupt African governments cannot be expected to take the initiative to eradicate corruption. Therefore, international financial institutions, health organisations, and financial donors should use their power to demand policy reforms of health-care systems in Africa troubled by the issue of corruption. These modifications will ameliorate the access and quality of cancer care for patients across the continent, and ultimately improve the outcome of health care to all patients.

Myeloid Antigen Expression in Childhood Acute Lymphoblastic Leukemia and Its Relevance for Clinical Outcome in Indonesian ALL-2006 Protocol.

The frequency of acute lymphoblastic leukemia (ALL) patients expressing myeloid antigens on their ALL cells varies between 5 and 36% in several different studies. The clinical relevance of myeloid antigen expression in childhood ALL is controversial. In Indonesian patients, no data were present. Therefore, in Yogyakarta, Indonesia, we analyzed 239 ALL patients who were immunophenotyped including myeloid markers (CD13, CD33, CD117, and/or cMPO). Myeloid antigen expression was found in 25% of patients. Expression of myeloid antigen in B-lineage leukemia was 27%, and in T-lineage leukemia, it was 18% (P = 0.15). No association was found between myeloid antigen expression and clinical or biological features. In the whole cohort of patients we did not find a significant association between myeloid antigen expression and survival, although leukemia-free survival at 3 years was higher in the myeloid-negative patients (73% ± 6%) compared to myeloid-positive patients (67% ± 8%). Interestingly, in T-ALL patients, expression of myeloid antigens was an independent adverse prognostic factor (hazard ratio: 3.26, 95% CI: 1.06-9.98, P = 0.04). Kaplan-Meier analysis for event-free survival was also significant (log rank P = 0.03) in this subgroup. In conclusion, in the Indonesian ALL population, in particular, myeloid antigen-expressing T-ALL patients had a higher chance of having induction failure.

Incidence of childhood leukemia in Yogyakarta, Indonesia, 1998-2009.

BACKGROUND: In most developing countries, incidence data for childhood cancers are less reliable, because very few population-based registries exist. The aim of this study was to present the epidemiology of childhood leukemia in the Dr. Sardjito Hospital (DSH) region, which catchment area extends beyond the boundaries of the Yogyakarta Special Province (YSP). PROCEDURE: Health records of children, 0-14 years of age, who were diagnosed with leukemia between January 1998 and December 2009, were reviewed. Diagnosis of leukemia was confirmed by morphological and histochemical examination of marrow samples. RESULTS: The estimated average annual incidence rate (AAIR) of childhood acute leukemia in DSH was 46.2 per million per year. Interestingly, the annual incidence rate (AIR) of childhood acute leukemia from the catchment area of DSH significantly increased from 35 in 1999 to 70 in 2009 (ANOVA, P = 0.003). The YSP population data, analyzed separately, showed an increase in AIR from 15.7 to 32.9 (ANOVA, P = 0.325) and an AAIR of 28.8. Remarkably, a relatively high frequency (25.5% in DSH and 27.7% in YSP) of children with AML was found in the group of acute leukemias. CONCLUSION: The DSH incidence calculations may be overestimated due to an underestimation of the population number. Since the population count for YSP is more precise, the data of YSP were used for comparison with developed countries. AAIR of ALL (20.8) is relatively low compared to Western countries (22.4-37.9). The AAIR of AML (8.0) is similar to Western countries (5.0-8.0) resulting a relatively high percentage of AML versus ALL (27.7%) in YSP.

Immunophenotypic patterns of childhood acute leukemias in Indonesia.

BACKGROUND: Immunophenotyping, as suggested by WHO, may improve diagnosis of childhood leukemia since it offers a better classification of the hematopoietic lineage of malignant cells as compared to morphology. Therefore, we aimed to determine the proportion of the immunophenotypic subtypes of acute leukemia in Indonesian children. METHODS: Samples were obtained from patients (0-14 years of age) in 4 hospitals in Indonesia. We analyzed 541 suspected leukemia samples presented over a 4-year period (March 2006 - July 2010) by flow cytometry. Immunophenotyping allowed classification into acute myeloid leukemia (AML) and ALL (B-lineage and T-lineage ALL). RESULTS: Of 541 samples, 136 were tested using a single color method and 405 with a three-color method. Concordance with morphology was very good (?=0.82) using the three-color method with a panel of 15 monoclonal antibodies (n=387). A relatively high percentage of acute leukemia was classified as AML (23%). Of the ALL samples 83% were B-lineage ALL and 17% T- lineage ALL. Nine out of 239 morphological ALL were labeled AML, and 12/79 morphological AML were in fact ALL. CONCLUSION: Immunophenotyping in a multi-center study proved feasible and appears particularly important for prognostic assessment of childhood leukemia in low income countries such as Indonesia.

Yogyakarta Pediatric Cancer Registry: an international collaborative project of University Gadjah Mada, University of Saskatchewan, and the Saskatchewan Cancer Agency.

INTRODUCTION: In July 2001, a 'twinning' project was undertaken between University Gadjah Mada, Indonesia, and the Saskatchewan Cancer Agency, Canada to create a computerised Pediatric Cancer Registry at Sardjito Hospital, Yogyakarta city. OBJECTIVES: To analyse information from the Yogyakarta Pediatric Cancer Registry (YPCR) in order to i) determine the prevalence of pediatric cancers in Yogyakarta Special Region and, ii) compare the demographics of pediatric malignancies in the Special Region (population: 3.3 million), with those of the Saskatchewan Cancer Registry in the province of Saskatchewan (population: 1 million). METHODOLOGY: In May 2001, a computer dedicated to the YPCR was installed at Sardjito Hospital. Bilingual (English/Indonesian) data capture forms were developed for data extraction from hospital health records. Data items were then entered into a data base using the Statistical Package For Social Sciences (SPSS) program. Two projects were initiated: i) a prospective study from 2000-2009 of pediatric cancer cases from the YPCR, and ii) a comparison of demographics from both Cancer Registries during the time period 1996-2003. Comparative data were obtained for age, sex, diagnoses, and referral patterns. Results were analysed using the SPSS software program. RESULTS: i) In the 10 year prospective study, 1,124 pediatriccancer cases were accrued in the Yogyakarta Registry, the majority being in the age group 0-5 years. Male:female: 7:1. Leukemias were the most common diagnosis, followed by retinoblastoma and neuroblastoma. The majority of patients (68%) were referred from outside the catchment area of Yogyakarta Special Region. ii) In the 8 year archival comparative analysis, the most striking contrasts were a higher proportion of children with retinoblastoma and negligible numbers of pediatric brain tumors in the Yogyakarta Registry. CONCLUSION: This is the first published report of a computerised pediatric cancer registry in Indonesia. The differences in diagnostic frequencies noted above may, in part, be due to comparisons between the population-based Saskatchewan Cancer Registry versus the hospital-based Yogyakarta Pediatric Cancer Registry. The contrasts in demographics are multifactorial, and require further investigation.

Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia.

Genetic variations in the polymorphic tandem repeat sequence of the enhancer region of the thymidylate synthase promoter (TSER), as well as in methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, influence methotrexate sensitivity. We studied these polymorphisms in children with acute lymphoblastic leukaemia (ALL) and in subjects without malignancy in Indonesia and Holland. The frequencies of TT and CT genotypes were two-fold higher in Dutch children. The TSER 3R/3R repeat was three-fold more frequent in the Indonesian children, while the 2R/2R repeat was only 1% compared to 21% in the Dutch children. No differences of these polymorphisms were found between ALL cells and normal blood cells, indicating an ethnic rather than leukemic origin. These results may have implications for treatment of Indonesian children with ALL.