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ABSTRACTObjectives Cognitive-behavioral stress management (CBSM) is an effective psychological intervention to relieve psychological and symptomatic distress. This study aimed to investigate the effect of CBSM in anxiety, depression, and post-traumatic stress disorder (PTSD) in parents of pediatric acute myeloid leukemia (AML) patients.Methods Totally, 56 pediatric AML patients and 100 parents were randomized into the CBSM group (28 patients and 49 parents) and the normal control (NC) group (28 patients and 51 parents) to receive corresponding interventions for 10 weeks. The questionnaire scores were assessed at month M0, M1, M3, and M6.Results In parents of pediatric AML patients, self-rating anxiety scale score at M1 (p = 0.034), M3 (p = 0.010), and M6 (p = 0.003), as well as anxiety at M3 (p = 0.036) and M6 (p = 0.012) were decreased in the CBSM group versus the NC group. Self-rating depression scale score at M3 (p = 0.022) and M6 (p = 0.002), as well as depression at M6 (p = 0.019) were declined in the CBSM group versus the NC group. Symptom checklist-90 (a psychotic status questionnaire) score at M3 (p = 0.031) and M6 (p = 0.019) were declined in the CBSM group versus the NC group. Regarding PTSD, the impact of the events scale-revised score at M3 (p = 0.044) and M6 (p = 0.010) were decreased in the CBSM group versus the NC group. By subgroup analyses CBSM (versus NC) improved all outcomes in parents with anxiety at M0 and depression at M0 (all p 0.050).Conclusion CBSM reduces anxiety, depression, and PTSD in parents of pediatric AML patients.

Abstract Risk classification in pediatric acute myeloid leukemia (P-AML) is crucial for personalizing treatments. Thus, we aimed to establish a risk-stratification tool for P-AML patients and eventually guide individual treatment. A total of 256 P-AML patients with accredited mRNA-seq data from the TARGET database were divided into training and internal validation datasets. A gene-expression-based prognostic score was constructed for overall survival (OS), by using univariate Cox analysis, LASSO regression analysis, Kaplan–Meier (K-M) survival, and multivariate Cox analysis. A P-AML-5G prognostic score bioinformatically derived from expression levels of 5 genes (ZNF775, RNFT1, CRNDE, COL23A1, and TTC38), clustered P-AML patients in training dataset into high-risk group (above optimal cut-off) with shorter OS, and low-risk group (below optimal cut-off) with longer OS (p 3, p

Abstract Background Prompt response to induction chemotherapy is a prognostic factor in pediatric acute myeloid leukemia. In this study, we aimed to evaluate the prognostic significance of multiparametric flow cytometry-minimal residual disease (MFC-MRD), assessed at the end of the first and second induction courses. Methods MFC-MRD was performed at the end of the first induction (TP1) in 524 patients and second induction (TP2) in 467 patients who were treated according to the modified Medical Research Council (UK) acute myeloid leukemia 15 protocol. Results Using a 0.1% cutoff level, patients with MFC-MRD at the two time points had lower event-free survival and overall survival. Only the TP2 MFC-MRD level could predict the outcome in a separate analysis of high and intermediate risks based on European LeukemiaNet risk stratification and KMT2A rearrangement. The TP2 MFC-MRD level could further differentiate the prognosis of patients into complete remission or non-complete remission based on morphological evaluation. Multivariate analysis indicated the TP2 MFC-MRD level as an independent adverse prognostic factor for event-free survival and overall survival. When comparing patients with MFC-MRD ≥ 0.1%, those who underwent hematopoietic stem cell transplant during the first complete remission had significantly higher 5-year event-free survival and overall survival and lower cumulative incidence of relapse than those who only received consolidation chemotherapy. Conclusions The TP2 MFC-MRD level can predict the outcomes in pediatric patients with acute myeloid leukemia and help stratify post-remission treatment.

This retrospective study aimed to analyze the treatment effect and prognostic factors of pediatric acute myeloid leukemia (AML) patients with t(8;21). A total of 268 newly diagnosed pediatric AML (pAML) enrolled from 1 January 2005 to 31 December 2022 were retrospectively reviewed, and 50 (18.7%) patients harbored t(8;21) translocation. CR rate, OS, EFS, and RFS were assessed by multivariate Logistic and Cox regression models in these patients. Of the 50 patients, 2 patients abandoned treatment during the first induction course. Of the remaining 48 patients who received double-induction therapy and were included in the final analyses, CR1 and CR2 were 75.0% (36/48) and 95.8% (46/48), respectively. The overall three-year OS, EFS, and RFS were 68.4% (95% CI, 55.0–85.1), 64.2% (95% CI, 50.7–81.4), and 65.5% (95% CI, 51.9–82.8), respectively. The presence of loss of sex chromosome (LOS) at diagnosis (n = 21) was associated with a better 3-year OS [87.5% (95% CI, 72.7–100) vs. 52.7% (95% CI, 35.1–79.3), p = 0.0089], 3-year EFS [81.6% (95% CI, 64.7–100) vs. 49.7% (95% CI, 32.4–76.4), p = 0.023], and 3-year RFS [81.6% (95% CI, 64.7–100) vs. 51.7% (95% CI, 33.9–78.9), p = 0.036] than those without LOS (n = 27), and it was also an independent good prognostic factor of OS (HR, 0.08 [95% CI, 0.01–0.48], p = 0.005), EFS (HR, 0.22 [95% CI, 0.05–0.85], p = 0.029), and RFS (HR, 0.21 [95% CI, 0.05–0.90], p = 0.035). However, extramedullary leukemia (EML) featured the independent risk factors of inferior OS (HR, 10.99 [95% CI, 2.08–58.12], p = 0.005), EFS (HR, 4.75 [95% CI, 1.10–20.61], p = 0.037), and RFS (HR, 6.55 [95% CI, 1.40–30.63], p = 0.017) in pediatric individuals with t(8;21) AML. Further analysis of combining LOS with EML indicated that the EML+LOS− subgroup had significantly inferior OS (92.9%, [95% CI, 80.3–100]), EFS (86.2%, [95% CI, 70.0–100]), and RFS (86.2%, [95% CI, 80.3–100]) compared to the other three subgroups (all p < 0.001). LOS and EML are independent prognostic factors of OS, EFS, and RFS with t(8;21) pAML patients. LOS combined with EML may help improve risk stratification.

Abstract Background Alterations of 11q23/KMT2A are the most prevalent cytogenetic abnormalities in acute myeloid leukemia (AML) and the prognostic significance of 11q23/KMT2A‐rearranged AML based on various translocation partners varies among different studies. However, few studies evaluated the molecular characteristics of 11q23/KMT2A‐rearranged pediatric AML. We aim to analyze the mutational landscape of 11q23/KMT2A‐rearranged AML and assess their prognostic value in outcomes. Methods The mutational landscape and clinical prognosis of 105 children with 11q23/KMT2A‐rearranged AML in comparison with 277 children with non‐11q23/KMT2A‐rearranged AML were analyzed using publicly accessible next‐generation sequencing data from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset. Results Pediatric AML patients with 11q23/KMT2A‐rearrangements harbored a low number of mutations (Median, 1 mutation/patient, range, 1‐22), 58% of which involved in RAS pathway mutations (KRAS, NRAS, and PTPN11) and 10.5% of which comprised of SETD2 mutations. Compared with non‐11q23/KMT2A‐rearranged AML, the incidence of KRAS (32.4% vs. 10.1%, P〈0.001) and SETD2 (10.5% vs. 1.4%, P=0.001) gene mutations in 11q23/KMT2A‐rearranged AML was significantly higher. Both KRAS and SETD2 mutations occurred more often in t(10;11)(p12;q23). KRAS mutations were correlated with worse 5‐year event‐free survival [EFS] (Plog‐rank = 0.001) and 5‐year overall survival [OS] (Plog‐rank = 0.009) and the presence of SETD2 mutations increases the 5‐year relapse rate (PGray = 0.004). Multivariate analyses confirmed KRAS mutations in 11q23/KMT2A‐rearranged AML as an independent predictor for poor EFS (hazard ratio [HR] = 2.10, P=0.05) and OS (HR = 2.39, P=0.054). Conclusion Our findings show that pediatric patients with 11q23/KMT2A rearrangements have characteristic mutation patterns and varying clinical outcomes depending on different translocation partners, which could be utilized to develop more accurate risk stratification and tailored therapies.

Abstract 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.

Abstract Background Pediatric acute myeloid leukemia (AML) is a challenging disease to treat in low‐ and middle‐income countries (LMICs). Literature suggests that survival in LMICs is poorer compared with survival in high‐income countries (HICs). Aims This study evaluates the outcomes of Kenyan children with AML and the impact of sociodemographic and clinical characteristics on outcome. Methods and Results A retrospective medical records study was performed at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Kenya, between January 2010 and December 2018. Sociodemographic and clinical characteristics, and treatment outcomes were evaluated. Chemotherapy included two “3 + 7” induction courses with doxorubicin and cytarabine and two “3 + 5” consolidation courses with etoposide and cytarabine. Supportive care included antimicrobial prophylaxis with cotrimoxazole and fluconazole, and blood products, if available. Seventy‐three children with AML were included. The median duration of symptoms before admission at MTRH was 1 month. The median time from admission at MTRH to diagnosis was 6 days and to the start of AML treatment 16 days. Out of the 55 children who were started on chemotherapy, 18 (33%) achieved complete remission, of whom 10 (56%) relapsed. The abandonment rate was 22% and the early death rate was 46%. The 2‐year probabilities of event‐free survival and overall survival were 4% and 7%, respectively. None of the sociodemographic and clinical characteristics were significantly associated with outcome. Conclusion Survival of Kenyan children with AML is dismal and considerably lower compared with survival in HICs. Strategies to improve survival should be put in place including better supportive care, optimization of the treatment protocol, and reduction of the abandonment rate and time lag to diagnosis with sooner start of treatment.

Background: To establish a comprehensive differential gene profile for pediatric acute myeloid leukemia patients (pAML) based on two independent databases and verify the differentially expressed genes using in vitro and in vivo analyses.Methods: The mRNA and miRNA sequencing information of GSE2191 and GSE35320, clinically recruited pAML individuals, and human AML cell line (NB4 cells) were utilized in the study.Results: Compared with the control sample, pAML patients demonstrated a total of 778 differentially expressed genes, including 565 upregulated genes and 213 downregulated genes. The genes including ZC3H15, BCLAF1, PPIG, DNTTIP2, SRSF11, KTN1, UBE3A, PRPF40A, TMED5, and GNL2 were the top 10 potential hub genes. At the same time, 12 miRNAs demonstrated remarkable differential expressions in pAML individuals compared with control individuals, as five upregulated and seven downregulated miRNAs. The hsa-miR-133, hsa-miR-181, and hsa-miR-195 were significantly downregulated. Building a miRNA–mRNA regulatory network, hsa-miR-133 regulated ZC3H15, BCLAF1, SRSF11, KTN1, PRPF40A, and GNL2. Using the NB4 cell model, hsa-miR-133 treatment inhibited cell proliferation capacity, which could be attenuated by a single mRNA transfection or a combination of ZC3H15 and BCLAF1. At the same time, hsa-miR-133 mimic treatment could significantly accelerate cell apoptosis in NB4 cells, which was also ZC3H15- and BCLAF1-dependent. The concentrations of ZC3H15 and BCLAF1 were investigated in peripheral blood using the ELISA method for the clinical control and pAML samples. In pAML samples, the expression levels of ZC3H15 and BCLAF1 were significantly enhanced (p < 0.01), regardless of the classification.Conclusion: Collectively, this study hypothesized several promising candidates for pAML formation.

Background: The prognostic roles of ferroptosis-related mRNAs (FG) and lncRNAs (FL) in pediatric acute myeloid leukemia (P-AML) patients remain unclear.Methods: RNA-seq and clinical data of P-AML patients were downloaded from the TARGET project. Cox and LASSO regression analyses were performed to identify FG, FL, and FGL (combination of FG and FL) prognostic models, and their performances were compared. Tumor microenvironment, functional enrichment, mutation landscape, and anticancer drug sensitivity were analyzed.Results: An FGL model of 22 ferroptosis-related signatures was identified as an independent parameter, and it showed performance better than FG, FL, and four additional public prognostic models. The FGL model divided patients in the discovery cohort (N = 145), validation cohort (N = 111), combination cohort (N = 256), and intermediate-risk group (N = 103) defined by the 2017 European LeukemiaNet (ELN) classification system into two groups with distinct survival. The high-risk group was enriched in apoptosis, hypoxia, TNFA signaling via NFKB, reactive oxygen species pathway, oxidative phosphorylation, and p53 pathway and associated with low immunity, while patients in the low-risk group may benefit from anti-TIM3 antibodies. In addition, patients within the FGL high-risk group might benefit from treatment using SB505124_1194 and JAK_8517_1739.Conclusion: Our established FGL model may refine and provide a reference for clinical prognosis judgment and immunotherapies for P-AML patients.

Non-relapse mortality due to GVHD and infections represents a major source of morbidity and mortality in pediatric HSCT recipients. Post-transplant cyclophosphamide (PTCy) has emerged as an effective and safe GVHD prophylaxis strategy, with improved GVHD and relapse-free survival in matched (related and unrelated) and mismatched haploidentical HSCT adult recipients. However, there are no published data in pediatric patients with acute myeloid leukemia who received matched-donor HSCT with PTCy. We demonstrate, in this case series, that the use of PTCy in this population is potentially safe, effective in preventing acute GVHD, does not impair engraftment, is associated with reduced non-relapse mortality, and does not hinder immune reconstitution post HSCT.

Pediatric MLL-rearranged acute myeloid leukemia (AML) has a generally unfavorable outcome, primarily due to relapse and drug resistance. To overcome these difficulties, new therapeutic agents are urgently needed. Yet, implementing novel drugs for clinical use is a time-consuming, laborious, costly and high-risk process. Therefore, we applied a drug-repositioning strategy by screening drug libraries, comprised of >4000 compounds that are mostly FDA-approved, in a high-throughput format on primary MLL-rearranged AML cells. Here we identified pyrvinium pamoate (pyrvinium) as a novel candidate drug effective against MLL-rearranged AML, eliminating all cell viability at