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Purpose To explore the outcome and prognostic factors between inv(16) and t(8;21) disrupt core binding factor (CBF) in acute myeloid leukemia (AML). Methods The clinical characteristic, probability of achieving complete remission (CR), overall survival (OS) and cumulative incidence of relapse (CIR) were compared between inv(16) and (8;21). Results The CR rate was 95.2%, 10-year OS was 84.4% and CIR was 29.4%. Subgroup analysis showed that patients with t(8;21) had significant lower 10-year OS and CIR than patients with inv(16). Unexpectedly, there was a trend for pediatric AML receiving five courses cytarabine to have a lower CIR than four courses cytarabine (19.8% vs 29.3%, P  = 0.06). Among the cohort of no-gemtuzumab ozogamicin(GO) treatment, inv (16) patients showed a similar 10-year OS (78.9% vs 83.5%; P  = 0.69) and an inferior outcome on 10-year CIR (58.6% vs 28.9%, P  = 0.01) than those patients with t(8;21). In contrast, inv (16) and t(8;21) patients receiving GO treatment had comparable OS (OS: 90.5% vs. 86.5%, P  = 0.66) as well as CIR (40.4% vs. 21.4%, P  = 0.13). Conclusion Our data demonstrated that more cumulative cytarabine exposure could improve the outcome of childhood patients with t(8;21), while GO treatment was beneficial to the pediatric patients with inv(16).

Purpose To evaluate the prognostic factors and outcome for acute lymphoblastic leukemia (ALL) in children with MLL rearrangement (MLL-r). Methods A total of 124 pediatric patients who were diagnosed with ALL were classified into two groups based on the MLL-r status by using a retrospective case-control study method from June 2008 to June 2020. Results The prevalence of MLL-r positive in the whole cohort was 4.9%. The complete remission (CR) rate on Day 33 in the MLL-r positive group was not statistically different from the negative group (96.8% vs 97.8%, P  = 0.736). Multivariate analysis showed that T-cell, white blood cell counts (WBC) ≥ 50 × 10 9 /L, MLL-AF4, and D15 minimal residual disease (MRD) positive were independent risk factors affecting the prognosis of MLL-r positive children. Stem cell transplantation (SCT) was a favorable independent prognostic factor affecting event-free survival (EFS) in MLL-r positive patients ( P  = 0.027), and there was a trend toward an independent prognostic effect on overall survival (OS) ( P  = 0.065). The 10-year predicted EFS for patients with MLL-AF4, MLL-PTD, MLL-ENL, other MLL partner genes, and MLL-r negative cases were 46.67 ± 28.61%, 85.71 ± 22.37%, 75 ± 32.41%, 75 ± 32.41%, and 77.33 ± 10.81%, respectively ( P  = 0.048). The 10-year predicted OS were 46.67 ± 28.61%, 85.71 ± 22.37%, 75 ± 32.41%, 75 ± 32.41%, and 85.2 ± 9.77%, respectively ( P  = 0.049). The 124 patients with ALL were followed up and eventually 5 (4%) cases relapsed, with a median relapse time of 3.9 years. Conclusion Patients with MLL-r positive ALL have moderate remission rates, but are prone to relapse with low overall survival. The outcome of MLL-r positive ALL was closely related to the partner genes, and clinical attention should be paid to screening for MLL partner genes and combining them with other prognostic factors for accurate risk stratification.

Activating FLT3 mutations are the most common mutations in acute myeloid leukemia (AML), but the optimal threshold of FLT3/ITD allelic ratio (AR) among pediatric AML patients remains controversial. Here, we present the outcome and prognostic significance of FLT3/ITD AR analysis among pediatric patients with AML from the TARGET dataset. Applying fitting curve models and threshold effect analysis using the restrictive cubic spline function following Cox proportional hazards models identifies the cut-off value of 0.5 on FLT3/ITD AR. Moreover, we observe that high FLT3/ITD AR patients have an inferior outcome when compared to low AR patients. Our study also demonstrates that stem cell transplantation may improve the outcome in pediatric AML patients with high FLT3/ITD AR and may be further improved when combined with additional therapies such as Gemtuzumab Ozogamicin. These findings underline the importance of individualized treatment of pediatric AML. Activating FLT3 mutations are the most common mutations in AML. Here, the authors explore the relationship between the FLT3/ITD allelic ratio and prognosis in pediatric AML patients and identify an optimal threshold to stratify patients.

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. For 11q23/KMT2A‐rearranged AML pediatric patients with FAB‐M5 morphology, patients with t(9;11)(p22;q23) demonstrated improved outcomes compared to those with other 11q23/KMT2A rearrangements. Patients with 11q23/KMT2A rearrangements have characteristic mutation patterns and varying clinical outcomes depending on different translocation partners.

Background The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70–85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL. Methods The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs. Results The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group ( n =7) was 28.6%, while in the MRD Day 33 negative group ( n =67) was 7.5% ( p =0.129). Conclusions The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

Purpose The current study aims to investigate the significance of N6-methyladenosine (m 6 A) methylationrelated genes in the clinical prognosis of childhood relapsed B-cell acute lymphoblastic leukemia (B-ALLL) patient. Methods Transcriptome data and corresponding clinical data on m 6 A methylation-related genes (including 20 genes) were obtained from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET) database. Results The bone marrow (BM) samples of 134 newly diagnosed (naive) and 116 relapsed B-ALL from TARGET were enrolled in the current study. Three genes (FTO, HNRNPC, RBM15B) showed significant up-regulation in relapsed B-ALL compared with that in naive B-ALL.The three genes had a significantly worse survival ( P  < 0.05). The LASSO Cox regression model was used to select the most predictive genes as prognostic indicators, and YTHDC1 and FTO were identified as prognostic factors for relapsed B-ALL. Finally, the results of multivariate regression analysis showed that the risk score of m 6 A methylation-related genes was an independent prognostic factor in relapsed B-ALL ( P  < 0.05). Conclusion We found that the expression levels of m 6 A methylation-related genes were different in naive and relapsed patients with B-ALL and correlated with survival and prognosis.This implies that m 6 A methylation-related genes may be promising prognostic indicators or therapeutic targets for relapsed B-ALL.

PurposeThe impact of myeloid sarcoma (MS) on clinical outcome of pediatric acute myeloid leukemia (AML) patients remains controversial. Moreover, little is known about the role of stem cell transplantation (SCT) in such patients.MethodsClinical data of patients with AML under 18 years of age were retrieved from the TARGET dataset. We analyzed the prevalence, clinical profile, molecular characteristics, and prognosis of MS in these patients.ResultsAmong 884 pediatric patients with AML, the frequency of MS was 12.3%. Pediatric AML with MS was associated with age under 1-year, abnormal cytogenetics, and KMT2A rearrangement. Moreover, MS was associated with a low complete remission rate, high induction death, poor 5-year EFS, and OS. KMT2A rearrangement had a negative impact on clinical outcome in AML patients with MS. In addition, SCT had no significant effect on the survival of AML patients with MS. Multivariate analysis revealed that MS was an unfavorable prognostic factor in pediatric AML in terms of EFS (Hazard ratio 1.670, P < 0.001) and OS (Hazard ratio 1.623, P = 0.004).ConclusionsThe presence of MS at diagnosis of pediatric AML is associated with poor clinical outcomes, particularly when associated with KMT2A rearrangements. Moreover, pediatric patients with AML and MS may not benefit from SCT.

ABSTRACT Background With the rapid development of diagnostic techniques and treatment strategies, there are notable improvements in pediatric acute myeloid leukemia (AML) prognosis. Nevertheless, the pathogenesis of AML remains largely unknown. This study aims to investigate the RAS pathway‐associated genes based on bioinformatics analysis, and investigate their underlying mechanisms in the initiation and progression of AML. Materials and Methods The UCSC Xena database was the source of the training set data, while the GSE192638 dataset was the source of the validation set data. Children in the training set were split up into two groups according to RAS pathway‐associated genes, and then differentially expressed genes (DEGs) of them were screened. To discover prognosis‐related genes and develop a prognostic risk‐scoring model, we employed One‐way Cox and LASSO regression analysis. The performance of the model was assessed by an independent validation dataset. Survival analysis was performed using the Kaplan‐Meier (K‐M) curve. Furthermore, we investigated the association between the prognostic risk‐scoring model and the correlation between immune infiltration and drug sensitivity. The expression levels of genes associated with reverse transcription‐polymerase chain reaction were quantified. Results We built a prognostic risk‐scoring model comprising 26 DEGs. Depending on the risk score, AML patients were split up into two groups: high‐ and low‐risk groups. Notably, compared with the survival time of patients in the high‐ risk group, that in the low‐risk group was substantially prolonged. Univariate (uniCox) as well as multivariate Cox (multiCox) regression analyses were carried out, demonstrating that the risk score emerged as a separate risk factor for prognosis. A nomogram that incorporates clinical factors and prognostic risk scores was proposed to increase the accuracy of survival rates estimation. Subsequent analyses revealed significant connections of the risk score with the immune infiltration and drug sensitivity. The experimental results demonstrated significantly elevated expression levels of GCSAML, MED12L, and TCF4 in AML samples compared to normal samples. Conclusion The developed prognostic risk‐scoring model, along with the identified key risk genes, holds promise as candidate prognostic biomarkers and treatment targets for pediatric AML.

Background This study was aimed to evaluate the value of DNA index(DI) among pediatric acute lymphoblastic leukemia (ALL) treated on Children’s Oncology Group (COG) protocols between 2000 and 2015. Methods Retrospective study were analysis among pediatric ALL patients from the TARGET dataset. Result Totally, 1668 eligible pediatric patients were enrolled in this study. Of them, 993 are male and 675 are female with a median age of 7.6 years old. The median follow-up for those patients was 7.7 years (range 0.1–15.7 years). The probability of 15-year EFS and OS were reported to be 67.5 ± 3.1% and 78.3 ± 2.5%, respectively. BCR/ABL1 fusion gene affected the early treatment response and the survival of childhood ALL. Moreover, those patients with ETV6/RUNX1 fusion gene were also significantly associated with better EFS ( HR  = 0.6, 95% CI 0.4–0.8, P  = 0.003) and OS ( HR  = 0.3, 95% CI 0.2–0.5, P  < 0.001) compared to patients with no ETV6/RUNX1. On the contrary, BM NR on Day+ 29 showed a significant decrease in EFS ( HR  = 3.1, 95% CI 2.1–4.5, P <  0.001) and OS ( HR  = 1.7, 95% CI 1.1–2.8, P =  0.026). Multivariate analysis showed that DI was significantly associated with better EFS and OS. The threshold effect of DI on poor outcome was significant after adjusting for potential confounders. The adjusted regression coefficient (Log RR) was 0.7 (95% CI 0.1–3.2, P  = 0.597) for DI < 1.1 while 8.8 (95% CI 1.4–56.0, P  = 0.021) for DI ≥ 1.2 and 0.0 (95% CI 0.0–0.8, P  = 0.041) for 1.1 ≤ DI < 1.2. Generalized additive models revealed that the lowest rates of the adverse outcomes estimated to occur among DI between 1.1 and 1.2. Conclusion For those childhood ALL treated on COG protocols between 2000 and 2015, ETV6/RUNX1 and BM NR were closely related to the prognosis. Moreover, the DI between 1.1 and 1.2 can serve as a significant cut-point discriminating the risk group, which indicated a favourable prognostic factor.

Background Umbilical cord blood transplantation (UCBT) from unrelated donors is one of the successful treatments for acute leukemia in childhood. The most frequent side effect of UCBT is peri-engraftment syndrome (PES), which is directly associated with the greater prevalence of acute and chronic graft-versus-host-disease (aGvHD and cGvHD). In haploidentical stem cell transplantation, posttransplant cyclophosphamide (PTCY) has been demonstrated to be an effective method against GvHD. However, the effects of PTCY as a GvHD prophylactic in UCBT had not been investigated. This study aimed to evaluate the effects of PTCY on the outcomes of UCBT for pediatric acute leukemia. Methods This retrospective study included 52 children with acute leukemia who underwent unrelated single-unit UCBT after myeloablative conditioning regimens. The results from the PTCY and non-PTCY groups were compared. Results The incidence of transplantation-related mortality in non-PTCY and PTCY were 5% and 10% ( p  =  0.525 ), respectively. The incidence of relapse in non-PTCY and PTCY were 5% and 23% ( p  =  0.095 ), respectively. Second complete remission status (CR2) was an independent risk factor for relapse-free survival ( hazard ratio  = 9.782, p  =  0.001 ). The odds ratio for sepsis or bacteremia incidence was significantly greater in the PTCY group (9.524, p  =  0.017 ). PTCY group had increased rates of cytomegalovirus activity and fungal infection. The incidence of PES, aGvHD, cGvHD, and hemorrhagic cystitis in the PTCY group was lower than that in the non-PTCY group, although it was not significantly different. Additionally, higher doses of PTCY (29 mg/kg and 40 mg/kg) were associated with lower incidences of aGvHD and severe GvHD (65% and 29%, respectively) than lower doses (93% and 57%, respectively). Engraftment time and graft failure incidence were similar across groups. Conclusion The results support the safety and efficiency of PTCY as part of PES controlling and GvHD prophylaxis in single-unit UCBT for children with acute leukemia. A PTCY dosage of 29 mg/kg to 40 mg/kg appears to be more effective in GvHD prophylaxis for UCBT patients.