Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia.

Not available.

Vincristine exposure in Kenyan children with cancer: CHAPATI feasibility study.

The low incidence of vincristine-induced peripheral neuropathy (VIPN) in Kenyan children may result from low vincristine exposure. We studied vincristine exposure in Kenyan children and dose-escalated in case of low vincristine exposure (NCT05844670). Average vincristine exposure was high. Individual vincristine exposure was assessed with a previously developed nomogram. A 20% dose increase was recommended for participants with low exposure and no VIPN, hyperbilirubinemia, or malnutrition. None of the 15 participants developed VIPN. Low vincristine exposure was seen in one participant: a dose increase was implemented without side effects. In conclusion, the participants did not develop VIPN despite having high vincristine exposure.

Childhood Cancer Awareness Program in Bungoma County, Kenya.

BACKGROUND: Awareness could play a key role in reducing underdiagnosis and accelerating referral of childhood cancer in low- and middle-income countries and ultimately improve outcomes. This study describes the implementation of a childhood cancer awareness program in Bungoma County in Kenya, containing five components: (1) baseline data collection of primary healthcare facilities; (2) live training session for healthcare providers (HCP); (3) early warning signs posters; (4) online SMS course for HCP; and (5) radio campaign. METHODS: This study was conducted between January and June 2023. All 144 primary healthcare facilities (level 2 and 3 health facilities) within Bungoma County were visited by the field team. RESULTS: All 125 level 2 (87%) and 19 level 3 (13%) facilities participated in the study. National Health Insurance Fund (NHIF) failed to cover services in 37 (26%) facilities. HCP were more often reported absent at level 3 (89%) than level 2 (64%) facilities (P = 0.034). The 144 live training sessions were attended by over 2000 HCP. Distribution of 144 early warning signs posters resulted in 50 phone calls about suspected childhood cancer cases. Sixteen children were later confirmed with childhood cancer and treated. Online SMS learning was completed by 890 HCP. Knowledge mean scores improved between pre-test (7.1) and post-test (8.1; P < 0.001). Finally, 540 radio messages about childhood cancer and a live question-and-answer session were broadcasted. CONCLUSION: This study described the implementation of a childhood cancer awareness program in Kenya involving both HCP and the general public. The program improved HCP's knowledge and increased the number of referrals for children with cancer.

Fertility-Preserving Treatments and Patient- and Parental Satisfaction on Fertility Counseling in a Cohort of Newly Diagnosed Boys and Girls with Childhood Hodgkin Lymphoma.

PURPOSE: The purpose of this study is to evaluate the use of fertility-preserving (FP) treatments and fertility counseling that was offered in a cohort of newly diagnosed children with classical Hodgkin lymphoma (cHL). METHODS: In this observational study, boys and girls with cHL aged ≤ 18 years with scheduled treatment according to the EuroNet-PHL-C2 protocol were recruited from 18 sites (5 countries), between January 2017 and September 2021. In 2023, a subset of Dutch participants (aged ≥ 12 years at time of diagnosis) and parents/guardians were surveyed regarding fertility counseling. RESULTS: A total of 101 boys and 104 girls were included. Most post-pubertal boys opted for semen cryopreservation pre-treatment (85% of expected). Invasive FP treatments were occasionally chosen for patients at a relatively low risk of fertility based on scheduled alkylating agent exposure (4/5 testicular biopsy, 4/4 oocyte, and 11/11 ovarian tissue cryopreservation). A total of 17 post-menarchal girls (20%) received GnRH-analogue co-treatment. Furthermore, 33/84 parents and 26/63 patients responded to the questionnaire. Most reported receiving fertility counseling (97%/89%). Statements regarding the timing and content of counseling were generally positive. Parents and patients considered fertility counseling important (94%/87% (strongly agreed) and most expressed concerns about (their child's) fertility (at diagnosis 69%/46%, at present: 59%/42%). CONCLUSION: Systematic fertility counseling is crucial for all pediatric cHL patients and their families. FP treatment should be considered depending on the anticipated risk and patient factors. We encourage the development of a decision aid for FP in pediatric oncology.

Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.

OBJECTIVE: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SETTING: Not applicable. PATIENTS: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0 × 10-8) and 16 genome-wide suggestive (<5.0 × 10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors.

Management of hyperleukocytosis in pediatric acute myeloid leukemia using immediate chemotherapy without leukapheresis: results from the NOPHO-DBH AML 2012 Protocol.

Hyperleukocytosis (HL) in pediatric acute myeloid leukemia (AML) is associated with severe complications and inferior outcome. We report results on HL patients included in the NOPHO-DBH AML 2012 study. We recommended immediate start of full dose chemotherapy (etoposide [ETO] monotherapy for 5 days as part of the first course), avoiding leukapheresis (LA) and prephase chemotherapy (PCT). Of 714 included patients, 122 (17.1%) had HL, and 111 were treated according to the recommendations with ETO upfront without preceding LA or PCT. The first dose was applied the same day as the AML diagnosis or the day after in 94%. ETO was administered via peripheral veins in 37% of patients without major complications. After initiation of ETO the remaining WBC on days 2-5 was 69%, 36%, 17% and 8% of the pre-treatment level. On day 3, 81% had a WBC.

A caregivers' perspective on social reintegration and stigma of childhood cancer survivors in Kenya.

OBJECTIVES: Childhood cancer survivors' social reintegration may be hampered in low and middle-income countries. The nature and extent of social challenges and prejudices that survivors encounter in such settings are largely unknown. This study explores caregivers' perspectives on social reintegration and stigmatization of Kenyan childhood cancer survivors. METHODS: Caretakers of childhood cancer survivors (<18 years) were interviewed using mixed-methods questionnaires during home or clinic visits between 2021 and 2022. Stigma was assessed with an adjusted Social Impact Scale and risk factors were investigated. RESULTS: Caretakers of 54 survivors (median age 11 years) were interviewed. Families' income (93%) decreased since start of treatment. Caretakers (44%) often lost their jobs. Financial struggles (88%) were a burden that provoked conflicts within communities (31%). School fees for siblings became unaffordable (52%). Families received negative responses (26%) and were left or avoided (13%) by community members after cancer disclosure. Survivors and families were discriminated against because the child was perceived fragile, and cancer was considered fatal, contagious, or witchcraft. Survivors repeated school levels (58%) and were excluded from school activities (19%) or bullied (13%). Performance limitations of daily activities (p = 0.019), male sex (p = 0.032), solid tumors (p = 0.056) and a short time since treatment completion (p = 0.047) were associated with increased stigma. Caretakers recommended educational programs in schools and communities to raise awareness about cancer treatment and curability. CONCLUSIONS: Childhood cancer survivors and their families experienced difficulties with re-entry and stigmatization in society. Increasing cancer and survivorship awareness in schools and communities should facilitate social reintegration and prevent stigmatization.

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.

Mitoxantrone Versus Liposomal Daunorubicin in Induction of Pediatric AML With Risk Stratification Based on Flow Cytometry Measurement of Residual Disease.

PURPOSE: Measurable residual disease (MRD) by using flow cytometry after induction therapy is strongly prognostic in pediatric AML, and hematopoietic stem-cell transplant (hSCT) may counteract a poor response. We designed a phase III study with intensified response-guided induction and MRD-based risk stratification and treated poor induction response with hSCT. The efficacy of liposomal daunorubicin (DNX) in induction was compared with mitoxantrone. METHODS: The study planned to randomly assign 300 patients, but the production of DNX ceased in 2017. One hundred ninety-four patients were randomly assigned to mitoxantrone or experimental DNX in induction 1. Ninety-three non-randomly assigned patients served as an observation cohort. Primary end point was fraction of patients with MRD <0.1% on day 22 after induction 1. Patients with MRD ≥15% after induction 1 or ≥0.1% after induction 2 or FLT3-ITD with NPM1 wildtype were stratified to high-risk therapy, including hSCT. RESULTS: Outcome for all 287 children was good with 5-year event-free survival (EFS5y) 66.7% (CI, 61.4 to 72.4) and 5-year overall survival (OS5y) 79.6% (CI, 75.0 to 84.4). Overall, 75% were stratified to standard-risk and 19% to high-risk. There was no difference in the proportion of patients with MRD <0.1% on day 22 after induction 1 (34% mitoxantrone, etoposide, araC [MEC], 30% DNX, P = .65), but the proportion increased to 61% for MEC versus 47% for DNX (P = .061) at the last evaluation before induction 2. EFS5y was significantly lower, 56.6% (CI, 46.7 to 66.5) versus 71.9% (CI, 63.0 to 80.9), and cumulative incidence of relapse (CIR) was higher, 35.1% (CI, 25.7 to 44.7) versus 18.8% (CI, 11.6 to 27.2) for DNX. The inferior outcome for DNX was only in standard-risk patients with EFS5y 55.3% (CI, 45.1 to 67.7) versus 79.9% (CI, 71.1 to 89.9), CIR 39.5% (CI, 28.4 to 50.3) versus 18.7% (CI, 10.5 to 28.7), and OS5y 76.2% (CI, 67.2 to 86.4) versus 88.6% (CI, 81.4 to 96.3). As-treated analyses, including the observation cohort, supported these results. For all high-risk patients, 85% received hSCT, and EFS5y was 77.7 (CI, 67.3 to 89.7) and OS5y was 83.0 (CI, 73.5 to 93.8). CONCLUSION: The intensification of induction therapy with risk stratification on the basis of response to induction and hSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior anti-leukemic effect than liposomal daunorubicin.

Discovering needs for palliative care in children with cancer in Indonesia.

BACKGROUND: Although most children with cancer die in low- and middle-income countries, palliative care receives limited attention in these settings. This study explores parents' perspectives on experiences and needs of children dying from cancer. METHODS: Home visits were conducted to interview parents of children, who were treated for cancer at an Indonesian academic hospital and died between 2019 and 2020, using semi-structured questionnaires. RESULTS: Parents of 49 children (response rate 74%) were interviewed. While all children died in hospital, 37% of parents stated their child preferred to die at home. The most common symptoms during final illness were breathing difficulties (82%), pain (80%), and appetite loss (80%). Psychological symptoms received the least support from the medical team. No intervention was given to 46% of children with depression, 45% of children with anxiety, and 33% with sadness. Boys suffered more often from anxiety (68%) than girls (37%; p = .030). Parents (57%) were not always informed about their child's condition, and doctors gave confusing information (43%). The families' choice of treatment while dying was relieving pain or discomfort (39%) and extending life (33%), while for 29% it was unknown. However, many parents (51%) did not discuss these treatment wishes with doctors. Many children (45%) felt lonely wanting more interactions with school (71%), friends (63%), and family (57%). CONCLUSION: Relieving suffering of children with cancer requires regular physical, psychological, social, and spiritual needs assessment. Families should actively participate in deciding whether to extend life or relieve pain and discomfort. This can importantly improve the quality of life of children and families.

Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia.

ABSTRACT: A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.

Model-Informed Precision Dosing to Reduce Vincristine-Induced Peripheral Neuropathy in Pediatric Patients: A Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis.

BACKGROUND: Vincristine-induced peripheral neuropathy (VIPN) is a common adverse effect of vincristine, a drug often used in pediatric oncology. Previous studies demonstrated large inter- and intrapatient variability in vincristine pharmacokinetics (PK). Model-informed precision dosing (MIPD) can be applied to calculate patient exposure and individualize dosing using therapeutic drug monitoring (TDM) measurements. This study set out to investigate the PK/pharmacodynamic (PKPD) relationship of VIPN and determine the utility of MIPD to support clinical decisions regarding dose selection and individualization. METHODS: Data from 35 pediatric patients were utilized to quantify the relationship between vincristine dose, exposure and the development of VIPN. Measurements of vincristine exposure and VIPN (Common Terminology Criteria for Adverse Events [CTCAE]) were available at baseline and for each subsequent dosing occasions (1-5). A PK and PKPD analysis was performed to assess the inter- and intraindividual variability in vincristine exposure and VIPN over time. In silico trials were performed to portray the utility of vincristine MIPD in pediatric subpopulations with a certain age, weight and cytochrome P450 (CYP) 3A5 genotype distribution. RESULTS: A two-compartmental model with linear PK provided a good description of the vincristine exposure data. Clearance and distribution parameters were related to bodyweight through allometric scaling. A proportional odds model with Markovian elements described the incidence of Grades 0, 1 and ≥ 2 VIPN overdosing occasions. Vincristine area under the curve (AUC) was the most significant exposure metric related to the development of VIPN, where an AUC of 50 ng⋅h/mL was estimated to be related to an average VIPN probability of 40% over five dosing occasions. The incidence of Grade ≥ 2 VIPN reduced from 62.1 to 53.9% for MIPD-based dosing compared with body surface area (BSA)-based dosing in patients. Dose decreases occurred in 81.4% of patients with MIPD (vs. 86.4% for standard dosing) and dose increments were performed in 33.4% of patients (no dose increments allowed for standard dosing). CONCLUSIONS: The PK and PKPD analysis supports the use of MIPD to guide clinical dose decisions and reduce the incidence of VIPN. The current work can be used to support decisions with respect to dose selection and dose individualization in children receiving vincristine.

Health-related quality of life and its determinants during and after treatment for paediatric acute lymphoblastic leukaemia: a national, prospective, longitudinal study in the Netherlands.

OBJECTIVES: Health-related quality of life (HRQoL) is impaired in paediatric patients with acute lymphoblastic leukaemia (ALL). Over the past decades, ALL treatment has successfully been adjusted to the risk of relapse, which is now reflected by the stratification of patients into three risk groups who receive treatment of differing intensities. This study is the first to evaluate the longitudinal course of HRQoL in light of these adjustments and identify determinants of HRQoL. DESIGN: Two prospective, national cohort studies (add-on studies within the two most recent treatment protocols for children with ALL (ALL-10 and ALL-11)). SETTING: Dutch paediatric oncology hospitals between October 2006 and October 2009 (ALL-10) and between August 2013 and July 2017 (ALL-11). PARTICIPANTS: Patients with ALL (2-18 years) are treated according to the ALL-10 or ALL-11 treatment protocol. Patients treated according to the ALL-10 protocol only completed a cancer-specific QoL measure and patients treated according to the ALL-11 protocol completed both a cancer-specific and generic QoL measure (see below). OUTCOME MEASURES: HRQoL, assessed with parent-proxy questionnaires (PedsQL Generic and Cancer module) within the first 5 months (T0), at 1 year (T1), 2 years (T2) and 3 years (T3) after diagnosis. The proportion of patients with clinically relevant generic HRQoL impairment was compared with healthy norm values. Multivariable mixed model analyses were used to evaluate the development of HRQoL over time and its medical and sociodemographic determinants (collected on enrolment). RESULTS: Of the ALL-10 cohort, 132 families participated and of the ALL-11 cohort, 136 families participated (268 total). Thus, cancer-specific HRQoL assessments were available for 268 patients (median age 5.3 years (IQR 6.15), 56.0% boys, 69.0% medium-risk ALL), and generic HRQoL assessments for 136 patients (median age 4.8 years (IQR 6.13), 60.3% boys, 75.0% medium-risk ALL). Generic HRQoL improved between timepoints T0 and T3 (total score B 16.1, 95% CI 12.2 to 20.1, p<0.001), but did not restore to normal 1 year after the end of treatment: 28.0% of children remained impaired compared with 16% in the general population (p=0.003). Cancer-specific HRQoL generally improved from T0 to T2 (Pain B 11.3, 95% CI 7.1 to 15.5; Nausea B 11.7, 8.4 to 15.1; Procedural Anxiety B 19.1, 14.8 to 23.4; Treatment Anxiety B 12.8, 9.5 to 16.0; Worry B 3.5, 0.6 to 6.3; Communication B 8.5, 5.0 to 11.9; all p<0.001 except for Worry (p=0.02)), while Physical Appearance and Cognitive Functioning remained stable. Higher treatment intensity and experiencing pain or simultaneous chronic illness were associated with lower HRQoL over time for multiple subscales. CONCLUSIONS: HRQoL impairment is prevalent during and after ALL treatment. Patients with standard-risk ALL and reduced treatment intensity have better HRQoL than patients in higher risk groups. Systematic monitoring of HRQoL is of utmost importance in order to provide timely psychosocial interventions and supportive care.

Randomized controlled trial on the effect of 1-hour infusion of vincristine versus push injection on neuropathy in children with cancer (final analysis).

INTRODUCTION: Vincristine is an integral component of treatment for children with cancer. Its main dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of 1-hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short-term outcomes (median follow-up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1-hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow-up 20 months), which includes treatment outcome as a secondary objective (follow-up 3 years). METHODS: VIPN was measured 1-7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed. RESULTS: Forty-five participants per randomization group were included. There was no significant effect of 1-hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one-hour group (rate ratio 0.52, 95% confidence interval 0.33-0.80, p = 0.003). Four patients in the one-hour group and one patient in the push group relapsed. Two patients in the one-hour group died. CONCLUSION: 1-hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1-hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile.

Impact of Physician Dual Practices on a Pediatric-Oncology Outreach-Program.

OBJECTIVE: Physician dual practices (PDP) can be defined as 'doctors combining clinical work in public and private health-sector.' This study explores the impact of PDP on a long-term pediatric-oncology outreach-program between large referral hospitals in the Netherlands, Indonesia and Kenya. METHODS: This cross-sectional descriptive study used a self-administered semi-structured survey.  The most senior doctor from each partner site was interviewed in June 2022. The survey contained 70 closed-ended and 7 open-ended questions and took 30-45 minutes to complete. Closed-ended questions were evaluated on 2-5 point rating scales. Informed consent was acquired and respondents endorsed the final report. RESULTS: In the Netherlands an estimated 0-20% of senior doctors combine work in public and private-sector, while 60-80% do so in Indonesia and Kenya according to the respondents. In Indonesia and Kenya, most of doctors are involved in PDP to augment low government salaries. Impact of PDP on pediatric-oncology care is minimal in the Netherlands, but detrimental in Indonesia and Kenya: shortage of experienced doctors, limited supervision of junior staff, slow diagnostics and delays in chemotherapy administration ultimately lead to undermining of the quality of care and adverse patient outcomes. CONCLUSIONS: PDP adversely impact patient care at the Indonesian and Kenyan partner sites of a pediatric-oncology outreach-program. Strategies addressing PDP in resource-poor settings are required to improve treatment outcomes and survival of children with cancer.

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.

Impact of undernutrition on the pharmacokinetics of chemotherapy in children with cancer: A systematic review.

OBJECTIVES: This systematic review provides an overview of the effect of undernutrition on the pharmacokinetics of chemotherapy in children with cancer. METHODS: PubMed, Embase, and Cochrane were searched to identify eligible studies. This study uses the definition for undernutrition from the World Health Organization and the Gomez classification. RESULTS: Four studies with a total of 668 children with cancer were included and n = 121 (18%) were undernourished. Significant decreased clearance rates were found for vincristine in undernourished children compared to children with a normal nutritional status. CONCLUSION: Presenting outcomes only show significant changes in the pharmacokinetics of vincristine in undernourished children with cancer. However, data are scarce, groups were small, and none of the studies included severely undernourished children. In order to improve outcomes for (severely) undernourished children with cancer, more pharmacokinetic research is needed. The ultimate goal would be to develop subgroups, and ultimately individualized drug dosing in order to improve outcomes for children with cancer worldwide.

Influence of health-insurance on treatment outcome of childhood cancer in Western Kenya.

BACKGROUND: Few governments in low and middle-income countries (LMIC) have responded favourably to the international plea for Universal Health Coverage. Childhood cancer survival in LMIC is often below 20%. Limited health-insurance coverage may contribute to this poor survival. Our study explores the influence of health-insurance status on childhood cancer treatment outcomes in a Kenyan academic hospital. METHODS: This was a retrospective medical records review of all children diagnosed with cancer at Moi Teaching and Referral Hospital between 2010 and 2016. Socio-demographic and clinical data was collected using a structured data collection form. Fisher's exact test, chi-squared test, Kaplan-Meier method, log-rank test and Cox proportional hazard model were used to evaluate relationships between treatment outcomes and patient characteristics. Study was approved by Institutional Research Ethics Committee. FINDINGS: From 2010-2016, 879 children were newly diagnosed with cancer. Among 763 patients whose records were available, 28% abandoned treatment, 23% died and 17% had progressive/relapsed disease resulting in 32% event-free survival. In total 280 patients (37%) had health-insurance at diagnosis. After active enrolment during treatment, total health-insurance registration level reached 579 patients (76%). Treatment outcomes differed by health-insurance status (P < 0.001). The most likely treatment outcome in uninsured patients was death (49%), whereas in those with health-insurance at diagnosis and those who enrolled during treatment it was event-free survival (36% and 41% respectively). Overall survival (P < 0.001) and event-free survival (P < 0.001) were higher for insured versus uninsured patients. The hazard-ratio for treatment failure was 0.30 (95% CI:0.22-0.39; P < 0.001) for patients insured at diagnosis and 0.32 (95% CI:0.24-0.41; P < 0.001) for patients insured during treatment in relation to those without insurance. INTERPRETATION: Our study highlights the need for Universal Health Coverage in LMIC. Children without health-insurance had significantly lower survival. Childhood cancer treatment outcomes can be ameliorated by strategies that improve health-insurance access.

Treatment outcomes of pediatric acute myeloid leukemia in Western Kenya before and after the implementation of the SIOP PODC treatment guideline.

PURPOSE: The Pediatric Oncology in Developing Countries (PODC) committee of the International Society of Pediatric Oncology (SIOP) published a pediatric acute myeloid leukemia (AML)-specific adapted treatment guideline for low- and middle-income countries. We evaluated the outcomes of children with AML at a large Kenyan academic hospital before (period 1) and after (period 2) implementing this guideline. PATIENTS AND METHODS: Records of children (≤17 years) newly diagnosed with AML between 2010 and 2021 were retrospectively studied. In period 1, induction therapy comprised two courses with doxorubicin and cytarabine, and consolidation comprised two courses with etoposide and cytarabine. In period 2, a prephase with intravenous low-dose etoposide was administered prior to induction therapy, induction course I was intensified, and consolidation was adapted to two high-dose cytarabine courses. Probabilities of event-free survival (pEFS) and overall survival (pOS) were estimated using the Kaplan-Meier method. RESULTS: One-hundred twenty-two children with AML were included - 83 in period 1 and 39 in period 2. Overall, 95 patients received chemotherapy. The abandonment rate was 19% (16/83) in period 1 and 3% (1/39) in period 2. The early death, treatment-related mortality, complete remission, and relapse rates in periods 1 and 2 were 46% (29/63) versus 44% (14/32), 36% (12/33) versus 47% (8/17), 33% (21/63) versus 38% (12/32), and 57% (12/21) versus 17% (2/12), respectively. The 2-year pEFS and pOS in periods 1 and 2 were 5% versus 15% (p = .53), and 8% versus 16% (p = .93), respectively. CONCLUSION: The implementation of the SIOP PODC guideline did not result in improved outcomes of Kenyan children with AML. Survival of these children remains dismal, mainly attributable to early mortality.

Treating CD33-Positive de novo Acute Myeloid Leukemia in Pediatric Patients: Focus on the Clinical Value of Gemtuzumab Ozogamicin.

Although survival in pediatric acute myeloid leukemia (AML) has increased considerably over the past decades, refractory disease and relapse rates remain high. Refractory and relapsed disease are difficult to treat, with overall survival rates less than 40-50%. Preventing relapse should, therefore, be one of the highest priorities. Current conventional chemotherapy regimens are hard to intensify due to associated toxic complications, hence more effective therapies that do not increase toxicity are needed. A promising targeted agent is the CD33-directed antibody-drug conjugate gemtuzumab ozogamicin (GO). Because CD33 is highly expressed on leukemic cells in the majority of AML patients, GO can be useful for a broad range of patients. Better relapse-free survival (RFS) after therapy including GO has been reported in several pediatric clinical trials; however, ambiguity about the clinical value of GO in newly diagnosed children remains. Treatment with GO in de novo AML patients aged ≥1 month, in combination with standard chemotherapy is approved in the United States, whereas in Europe, GO is only approved for newly diagnosed patients aged ≥15 years. In this review, we aimed to clarify the clinical value of GO for treatment of newly diagnosed pediatric AML patients. Based on current literature, GO seems to have additional value, in terms of RFS, and acceptable toxicity when used in addition to chemotherapy during initial treatment. Moreover, in KMT2A-rearranged patients, the clinical value of GO was even more evident. Also, we addressed predictors of response, being CD33 expression and SNPs, PgP-1 and Annexin A5. The near finalized intent-to-file clinical trial in the MyeChild consortium investigates whether fractionated dosing has additional value for pediatric AML, which may pave the way for a broader application of GO in pediatric AML.