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A recent study published in the Journal of Nature Genetics has expanded the molecular classification coverage of pediatric acute myeloid leukemia (pAML) from 68.5% to 91.4%, with implications for future treatment strategies. The study identified 23 molecular categories specific to pediatric cases, including new entities like UBTF tandem duplications and GLIS family rearrangements. The research highlights the importance of precise molecular diagnosis and risk stratification for pediatric AML, offering a predictive framework that combines molecular categories and minimal residual disease positivity for outcome forecasts. [Extracted from the article]

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 FROM AUTHOR]

Simple Summary: Bortezomib-containing chemotherapy did not improve the clinical outcome in the AAML1031 study in terms of overall survival and event-free survival compared to standard chemotherapy. We characterized epigenetically distinct proteomic profiles in a large cohort of pediatric patients that participated in this study using the reverse-phase protein array. We observed in the patient group that received standard therapy that a higher expression of 16 histone-modulating enzymes (HMEs) was an independent variable that predicted higher relapse risk three years after a second induction therapy compared to those with a lower HME protein expression. Also, there was significantly improved overall survival for those with a high HME expression who were treated with the bortezomib-containing chemotherapy, compared to high-HME patients treated without bortezomib. We also demonstrated that patients with a higher expression of HME had more open chromatin surrounding promoter sides compared to those with lower HME protein levels using ATAC-seq. The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%, p = 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%, p = 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

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 < 0.0001). Meanwhile, similar results were obtained in internal validation dataset (p = 0.005), combination dataset (p < 0.001), two treatment sub-groups (p < 0.05), intermediate-risk group defined with the Children's Oncology Group (COG) (p < 0.05) and an external Japanese P-AML dataset (p = 0.005). The model was further validated in the COG study AAML1031(p = 0.001), and based on transcriptomic analysis of 943 pediatric patients and 70 normal bone marrow samples from this dataset, two genes in the model demonstrated significant differential expression between the groups [all log2(foldchange) > 3, p < 0.001]. Independent of other prognostic factors, the P-AML-5G groups presented the highest concordance-index values in training dataset, chemo-therapy only treatment subgroups of the training and internal validation datasets, and whole genome-sequencing subgroup of the combined dataset, outperforming two Children's Oncology Group (COG) risk stratification systems, 2022 European LeukemiaNet (ELN) risk classification tool and two leukemic stem cell expression-based models. The 5-gene prognostic model generated by a single assay can further refine the current COG risk stratification system that relies on numerous tests and may have the potential for the risk judgment and identification of the high-risk pediatric AML patients receiving chemo-therapy only treatment. [ABSTRACT FROM AUTHOR]

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.

The efficacy of stem cell transplantation (SCT) in pediatric acute myeloid leukemia (pAML) remains unsatisfactory due to the limitations of existing prognostic models in predicting efficacy and selecting suitable candidates. This study aims to develop a cytomolecular risk stratification-independent prognostic model for SCT in pAML patients at CR1 stage. The pAML SCT model, based on age, KMT2A rearrangement (KMT2A-r), and minimal residual disease at end of course 1 (MRD1), effectively classifies patients into low-, intermediate-, and high-risk groups. We validate the effectiveness in an internal validation cohort and in four external validation cohorts, consisting of different graft sources and donors. Moreover, by incorporating the FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) allelic ratio, the pAML SCT model is refined, enhancing its ability to effectively select suitable candidates. We develop a simple and robust risk stratification model for pAML patients undergoing SCT, to aid in risk stratification and inform pretransplant decision-making at CR1 stage., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Circular RNAs (circRNAs) arise from precursor mRNA processing through back-splicing and have been increasingly recognized for their functions in various cancers including acute myeloid leukemia (AML). However, the prognostic implications of circRNA in AML remain unclear. We conducted a comprehensive genome-wide analysis of circRNAs using RNA-seq data in pediatric AML. We revealed a group of circRNAs associated with inferior outcomes, exerting effects on cancer-related pathways. Several of these circRNAs were transcribed directly from genes with established functions in AML, such as circRUNX1, circWHSC1, and circFLT3. Further investigations indicated the increased number of circRNAs and linear RNAs splicing were significantly correlated with inferior clinical outcomes, highlighting the pivotal role of splicing dysregulation. Subsequent analysis identified a group of upregulated RNA binding proteins in AMLs associated with high number of circRNAs, with TROVE2 being a prominent candidate, suggesting their involvement in circRNA associated prognosis. Through the integration of drug sensitivity data, we pinpointed 25 drugs that could target high-risk AMLs characterized by aberrant circRNA transcription. These findings underscore prognostic significance of circRNAs in pediatric AML and offer an alternative perspective for treating high-risk cases in this malignancy. • We systemically evaluated the prognosis significance of circRNA in pediatric AML. • We observed significant association between increased circRNA transcription and inferior prognosis of pediatric AML. • Results suggested RBP TROVE2 involved in circRNA processing and high TROVE2 expression related to inferior prognosis. • Our analysis identified potential effective drugs targeting high-risk AMLs with increased circRNA transcription. [ABSTRACT FROM AUTHOR]

The AML-05 study aimed to examine the efficacy and safety of a therapeutic strategy based on risk stratification for low-, intermediate-, or high-risk acute myeloid leukemia (AML) pediatric patients. Allogeneic hematopoietic cell transplantation (allo-HCT) was not indicated for low- or intermediate-risk AML patients in first complete remission. The present retrospective study for the AML-05 study aimed to identify prognostic factors for survival and to determine optimal allo-HCT according to multivariate analysis on overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR), and cumulative incidence of nonrelapse mortality for and between low- and intermediate-risk AML group patients in the AML-05 study who had undergone allo-HCT after its completion and relapse. The unique patient numbers (UPNs) of the AML-05 study were matched with the Transplant Registry Unified Management Program (TRUMP)-registered numbers, and the tied data on the AML-05 study's UPNs and the TRUMP-registered numbers were analyzed. The primary endpoint was 3-yr OS. Among 443 AML patients in the AML-05 study, 79 (32 low-risk AML and 47 intermediate-risk AML) were analyzed. The following statistically favorable prognostic factors were identified by multivariate analysis on the low- and intermediate-risk AML groups, respectively: UCB (OS-hazard ratio [HR], 0.105; 95% CI, 0.011 to 0.941; P = .004 and EFS-HR, 0.065, 95% CI, 0.007 to 0.577, P = .014) and late relapse (OS-HR, 0.212; 95% CI, 0.072 to 0.626; P = .005 and EFS-HR, 0.236; 95% CI, 0.088 to 0.630; P = .004). Three-year OS, 3-yr EFS, and 3-yr CIR were significantly different between the low- and intermediate-risk AML groups. UCB may be a safe and beneficial donor source for low-risk AML patients, while late relapse was a favorable prognostic factor for intermediate-risk AML patients. Intermediate-risk AML patients with late relapse and low-risk AML patients may benefit from allo-HCT after relapse., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The outcome of extramedullary infiltration (EMI) in pediatric acute myeloid leukemia (AML) is controversial, and little is known about the implications of stem cell transplantation (SCT) and gemtuzumab ozogamicin (GO) treatment on patients with EMI., Methods: We retrieved the clinical data of 713 pediatric patients with AML from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset, and analyzed the clinical and prognostic characteristics of patients with EMI at diagnosis and relapse., Results: A total of 123 patients were identified to have EMI at diagnosis and 64 presented with EMI at relapse. The presence of EMI was associated with age ≤2 years, M5 morphology, abnormal karyotype, and KMT2A rearrangements. Hyperleukocytosis and complex karyotype were more prevalent in patients with EMI at relapse. Additionally, patients with EMI at diagnosis had a reduced incidence of FLT3 ITD - /NPM1 + , whereas those with EMI at relapse displayed a lower frequency of FLT3 ITD + . Patients with EMI at diagnosis exhibited a lower complete remission (CR) rate at the end of Induction Course 1 and higher relapse incidence. Importantly, EMI at diagnosis independently predicted both shorter event-free survival (EFS) and overall survival (OS). Regarding relapse patients, the occurrence of EMI at relapse showed no impact on OS. However, relapse patients with myeloid sarcoma (MS)/no central nervous system (CNS) exhibited poorer OS compared to those with CNS/no MS. Furthermore, regarding patients with EMI at diagnosis, SCT failed to improve the survival, whereas GO treatment potentially enhanced OS., Conclusion: EMI at diagnosis is an independent adverse prognostic risk factor for pediatric AML, and GO treatment potentially improves survival for patients with EMI at diagnosis., (© 2024 Wiley Periodicals LLC.)

Background: Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed., Objectives: To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation., Design: Retrospective, single-arm study., Methods: From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023., Results: A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5-16.0) years. The median initial WBC count was 23.74 × 10 9 /L, 11 of whom ⩾100 × 10 9 /L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2-9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC < 100 × 10 9 /L ( n  = 59) and ⩾100 × 10 9 /L ( n  = 11) were 76.4% ± 5.7% and 45.5% ± 15% ( p  = 0.013), respectively. A total of 650 hospital infections occurred. The main causes of infection were respiratory tract infection (26.92%), septicemia (18.46%), stomatitis (11.85%), and skin and soft-tissue infection (10.46%)., Conclusion: This intensive treatment protocol with dual induction and ALL-like elements is effective and safe for childhood AML. Initial WBC ⩾ 100 × 10 9 /L was the only independent risk factor in this cohort., Trial Registration: It is a retrospective study, and no registration on ClinicalTrials.gov., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Acute myeloid leukemia (AML) accounts for approximately 25% of pediatric leukemia cases in Japan, with approximately 150 patients being newly diagnosed with AML annually. Pediatric acute myeloid leukemia is classified into three groups: myeloid leukemia associated with Down syndrome (ML-DS), acute promyelocytic leukemia (APL), and de novo AML. Patients with ML-DS have an event-free survival rate over 80%; however, relapsed patients have dismal outcomes, even if they receive hematopoietic cell transplantation. APL is curable with all-trans retinoic acid and arsenic trioxide. In de novo AML, 10% of patients fail to achieve remission, and approximately 30% of patients who successfully achieve remission subsequently experience AML relapse. This review highlights the therapeutic approach for these three diseases with context from past clinical studies in Japan, and shares promising new therapeutic options for relapsed/refractory de novo AML.