Event-free Survival In Children Research Articles

Effects of asparaginase-associated pancreatitis in children with haematological tumours.

Asparaginase-associated pancreatitis (AAP) is a major challenge for continuing asparaginase therapy. We aimed to investigate the acute and long-term complications and survival rates related to first and second AAP episodes in Chinese children with haematological malignancies. We retrospectively analysed clinical data of children with pancreatitis who received asparaginase chemotherapy for acute lymphoblastic leukaemia (ALL), acute mixed cell leukaemia, and non-Hodgkin's lymphoma at Shanghai Children's Medical Center from November 2013 to November 2023. Of the 76 children included in the study, 12 had local complications (15.79%), with no deaths recorded. Systemic complications manifested in 28 patients (36.84%), resulting in 3 deaths (3.95%). Four patients (5.26%) developed long-term complications (chronic pancreatitis or insulin-dependent diabetes mellitus). No significant differences in local or long-term complications were recorded between children in the asparaginase re-exposed (n=39) and non-re-exposed (n=45) groups. Among the re-exposed patients, eight (25.81%) experienced a second attack without fatalities or complications. Survival analysis of intermediate- to high-risk patients revealed a significantly higher event-free survival (EFS) rate for the re-exposed group than for the non-re-exposed group. The second AAP episode's occurrence and severity had no relation to the first AAP episode's severity, and the second AAP episode was significantly less severe than the first (p<0.001). The second AAP episode's occurrence is unrelated to the first AAP episode's severity, and the second AAP episode's severity is significantly lower than that of the first. Further, asparaginase therapy could improve EFS in children with intermediate and high-risk ALL.

Outcome of patients with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcomas enrolled in phase 2 cooperative group clinical trials: A report from the Children's Oncology Group.

The aim of this study was to estimate the event-free survival (EFS) of children and young adults with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) treated in nonrandomized phase 2 studies conducted by the Children's Oncology Group (COG) and predecessor groups to establish a benchmark EFS for future phase 2 NRSTS trials evaluating the activity of novel agents. A retrospective analysis of patients with recurrent or refractory NRSTS prospectively enrolled in nonrandomized phase 2 COG and predecessor group trials between 1994 and 2015 was conducted. EFS was defined as disease progression/relapse or death and calculated via the Kaplan-Meier method. The log-rank test and relative risk regression were used to compare EFS distribution by age at enrollment, sex, race, NRSTS histology, prior lines of therapy, calendar year of trial, and type of radiographic response. In total, 137 patients were enrolled in 13 phase 2 trials. All trials used radiographic response rate as a primary outcome, and none of the agents used were considered active on the basis of trial-specified thresholds. The estimated median EFS and 6-month EFS of the entire study cohort was 1.5 months (95% confidence interval [CI], 1.3-1.8 months) and 19.4% (95% CI, 12.7%-26%), respectively. No difference in EFS was observed by age at enrollment, sex, race, NRSTS histology subtype, prior lines of therapies, and trial initiation year. EFS significantly differed by radiographic response. The EFS for children and young adults with relapsed or refractory NRSTS remains suboptimal. Established EFS can be referenced as a benchmark for future single-agent phase 2 trials incorporating potentially active novel agents in this population.

The role of blinatumomab in the treatment of B-cell relapses of acute lymphoblastic leukemia in children: own experience

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Despite remarkable improvements in the treatment of pediatric acute lymphoblastic leukemia over last years, relapse still carries a poor prognosis with considerable morbidity and mortality. New immunotherapeutic approaches will change the way we treated our patients and the results we had. Blinatumomab is a bispecific T-cell-engaging antibody indicated for the treatment of relapsed/refractory B-cell lymphoblastic leukemia. The use of Blinatumomab in relapsed B-cell ALL has shown promising effects, especially as a bridging tool to hematopoietic stem cell transplantation. The therapy results for patients in the high risk group remain far from optimal due to refractoriness to chemotherapy, death from infectious complications, as well as acute chemotherapy toxicity. This article demonstrates the results of our experience of using Blinatumomab in children with the high-risk group relapsed B-cell ALL treated according to the ALL-REZ 2016 protocol. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The efficacy and toxicity of innovational blocks with the use of fludarabine and clofarabine with subsequent Blinatumomab infusion are shown. And we present the efficacy of autologous CD3+ lymphocytes infusion once a week during the continuous blinatumomab therapy. Also we demonstrate the results of using Blinatumomab for the treatment of patients with refractory to the first line therapy relapsed B-lymphoblastic leukemia and patients with a second relapse of B-cell ALL. The first line therapy in these patients was carried out according to the ALL-REZ 2014 protocol. Our results show an improved reduction in minimal residual disease in patients with refractory relapsed B-cell ALL as well as an increased event free survival in children with the high-risk group relapsed B-cell ALL.

Tumor size is an independent negative prognostic factor for event free survival in children with differentiated thyroid cancer.

BackgroundThe incidence of pediatric differentiated thyroid carcinoma (DTC) is increasing. Despite the advanced disease at presentation, the overall prognosis of DTC in children is excellent. The aim of this study is to investigate the risk stratifying factors for event free survival (EFS) of pediatric DTC from Middle Eastern ethnicity.MethodsEighty-eight patients aged ≤18 years with diagnosis of primary DTC were retrospectively analyzed. Cox proportional hazards model were used to calculate Hazard Ratios (HR) and Kaplan–Meier analysis were conducted to investigate EFS.ResultsEighty-eight (23 males and 65 females) pediatric DTCs who underwent surgery and radioactive iodine therapy had been reported (median age at diagnosis 15 years; range 5.9-17.9), with lymph node metastasis (LNM) noted in 70.5% and distant metastasis in 13.6%. Mean follow-up was 8.4 years. Ten-year overall survival rate was 98.4% while 10-year EFS was 79.2%. EFS was negatively impacted by the presence of LNM, distant metastasis and tumor size >4cm. American Thyroid Association risk stratification did not impact EFS in our cohort. Multivariate analysis revealed tumor size >4cm (HR = 5.34; 95% confidence interval (CI) = 1.36 – 20.22; p = 0.0177) and distant metastasis (HR = 8.73; 95% CI = 1.48 – 60.05; p = 0.0154) as independent negative prognostic factors for EFS.ConclusionsPrimary tumor size and the presence of distant metastasis at diagnosis are the only independent prognostic risk factors for EFS in pediatric DTC in Middle Eastern ethnicity. Children with tumor size over 4cm had poor EFS, which may justify the need of more aggressive treatment and frequent follow-up.

Overall and Event-free Survival in Children with Acute Lymphoblastic Leukemia and Evaluation of Treatment Related Acute Toxicity

Overall and Event-free Survival in Children with Acute Lymphoblastic Leukemia and Evaluation of Treatment Related Acute Toxicity

A higher tumor volume and undernutrition at diagnosis adversely affect the survival of children with Wilms tumor: A study of 200 patients.

Distinct prognostic factors for Wilms tumor (WT) in low- and middle-income countries need identification. Retrospective study of patients with WT managed by the International Society of Pediatric Oncology (SIOP) approach for over 11 years (2005-2016) at a single center in Chandigarh, India. The study included 200 patients (median age: 33.5 months). The tumor stage (SIOP) distribution included stage I (30%), II (36%), III (14%), IV (17%), and V (3%). The histology-risk groups were low (8%), intermediate (84%), and high risk (9%). At diagnosis, 68 out of 190 (36%) patients were underweight. The median tumor volume at diagnosis was 481ml (interquartile ratio [IQR]: 306.9, 686.8, n=146). Following neoadjuvant chemotherapy, it reduced to 110ml (IQR: 151.2, 222, n=77). Treatment was abandoned in 20.5% of the patients. Treatment-related mortality occurred in 13 of 179 (7.2%) patients. Relapse occurred in 26 of 158 (16.5%) patients. The 3-year overall survival (OS) and event-free survival (EFS) of patients who completed therapy were 78.3 and 72%, respectively. The stage (p=.013) and histology (p=.023) influenced OS. A lower OS in stage II (75.4%) versus stage III disease (83.7%) suggested understaging. Patients with a higher tumor volume at diagnosis (p=.005; odds ratio [OR]: 0.99; 95% confidence interval [CI]: 0.99-1.00) or a lower weight-for-age z-score (p=.002; OR: 1.68; 95% CI: 1.21-2.33) had an increased risk of death or relapse. The 3-year OS and EFS of children who completed therapy were 78.3 and 72%, respectively. A higher tumor volume and lower weight-for-age z-score at diagnosis were identified as distinct adverse prognostic factors. A likely suboptimal lymph node assessment (intraoperative and histopathology) contributed to the understaging of stage III to II disease and reduced survival.

Characteristics and prognostic effects of NOTCH1/FBXW7 gene mutations in T-cell acute lymphoblastic leukemia patients

Objective: To explore the characteristics, clinical features and prognostic effects of NOTCH1/FBXW7 gene mutations in T-cell acute lymphoblastic leukemia (T-ALL) patients. Methods: The clinical data of 61 T-ALL patients who underwent second-generation gene sequencing in Henan Provincial People's Hospital from March 2016 to March 2021 were retrospectively analyzed. There were 46 males and 15 females, with a median age [M (Q1, Q3)] of 18 (11, 30) years. The relationship between NOTCH1/FBXW7 gene mutation characteristics, clinical and laboratory parameters and their impact on event free survival (EFS) and overall survival (OS) were analyzed. Results: NOTCH1 gene mutations were found in 34 cases (55.7%, 34/61), including 22 cases of heterodimer domain (HD) mutations (64.7%), 7 cases of proline/glutamate/serine/threonine (PEST) mutations (20.6%), and 5 cases of both HD and PEST mutations (14.7%). FBXW7 gene mutations were detected in 9 cases (14.8%, 9/61), of which 5 cases had both NOTCH1 and FBXW7 gene mutations. Twenty-three (37.7%, 23/61) cases were wild type. The median white blood cell count of patients in NOTCH1/FBXW7 gene mutations group and wild-type group was 76.4×109/L (8.3×109/L, 149.2×109/L), 54.1×109/L (5.3×109/L, 156.6×109/L), respectively. Moreover, the hemoglobin was (89.1±27.1) g/L and (99.5±23.1) g/L, respectively, and the median proportion of bone marrow primordial cells was 84.5% (69.0%, 91.3%) and 60.0%(35.0%, 80.0%), respectively. The gene expression rate of SIL-TAL1, Hox11 and Hox11L2 was 7.9% (3/38) vs 17.4% (4/23), 18.4% (7/38) vs 4.3% (1/23), 5.3% (2/38) vs 13.0% (3/23), respectively (all P>0.05). However, the median platelet level in the NOTCH1/FBXW7 gene mutations group was 60.5×109/L (36.8×109/L, 100.3×109/L), which was lower than that in the wild-type group [116.0×109/L (63.0×109/L, 178.0×109/L)] (P=0.018). The median number of gene mutations in the group with NOTCH1/FBXW7 gene mutations group was 2.5 (1.8, 4.0), which was more than that in the group without NOTCH1/FBXW7 gene mutations group [0 (0, 1.0)] (P<0.001). The median EFS and OS of adult NOTCH1/FBXW7 gene mutations group were 28.0 (95%CI: 7.3-48.7) months and 30.0 (95%CI: 8.9-51.1) months, respectively, which were better than those of adult wild-type group [4.5 (95%CI: 0-11.6) months and 9.0 (95%CI: 0-19.1) months] (P=0.008 and 0.014).The median EFS and OS of children NOTCH1/FBXW7 gene mutations group were 12.0 (95%CI: 10.4-13.6) months and 19.0 (95%CI: 13.6-24.4) months, respectively, and those of wild-type group were 10.0 (95%CI: 8.9-11.1) months and 21.0 (95%CI: 0-51.4) months, respectively (P=0.673 and 0.434). Conclusions: The mutation rate of NOTCH1/FBXW7 gene is higher in T-ALL patients. Patients with NOTCH1/FBXW7 gene mutations group have lower platelet count and better EFS and OS. NOTCH1/FBXW7 gene mutation may be used as a hierarchical basis for individualized treatment of adult T-ALL patients.

The Correlation Between Busulfan Exposure and Clinical Outcomes in Chinese Pediatric Patients: A Population Pharmacokinetic Study.

Aims: The aims of the study were to 1) establish a population pharmacokinetic (Pop-PK) model for busulfan in Chinese pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and then estimate busulfan exposure and 2) explore the association between busulfan exposure and clinical outcomes. Methods: A total of 128 patients with 467 busulfan concentrations were obtained for Pop-PK modeling using nonlinear mixed effect model (NONMEM) software. Sixty-three patients who received the 16-dose busulfan conditioning regimen were enrolled to explore the correlations between clinical outcomes and the busulfan area under the concentration–time curve (AUC) using the Cox proportional hazards regression model, Kaplan–Meier method and logistic regression. Results: The typical values for clearance (CL) and distribution volume (V) of busulfan were 7.71 L h−1 and 42.4 L, respectively. The allometric normal fat mass (NFM) and maturation function (Fmat) can be used to describe the variability in CL, and the fat-free mass (FFM) can be used to describe the variability in V. Patients with AUCs of 950–1,600 µM × min had 83.7% (95% CI: 73.3–95.5) event-free survival (EFS) compared with 55.0% (95% CI: 37.0–81.8) for patients with low or high exposure (p = 0.024). The logistic regression analysis results showed no association between transplant-related toxicities and the busulfan AUC (p > 0.05). Conclusions: The variability in busulfan CL was related to the NFM and Fmat, while busulfan V was related to the FFM. Preliminary analysis results suggested that a busulfan AUC of 950–1,600 µM × min was associated with better EFS in children receiving the 16-dose busulfan regimen.

A Nomogram for Predicting Event-Free Survival in Childhood Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study.

ObjectiveEven though childhood acute lymphoblastic leukemia (ALL) has an encouraging survival rate in recent years, some patients are still at risk of relapse or even death. Therefore, we aimed to construct a nomogram to predict event-free survival (EFS) in patients with ALL.MethodChildren with newly diagnosed ALL between October 2016 and July 2021 from 18 hospitals participating in the South China children’s leukemia Group (SCCLG) were recruited and randomly classified into two subsets in a 7:3 ratio (training set, n=1187; validation set, n=506). Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were adopted to screen independent prognostic factors. Then, a nomogram can be build based on these prognostic factors to predict 1-, 2-, and 3-year EFS. Concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance and clinical utility of nomogram.ResultThe parameters that predicted EFS were age at diagnosis, white blood cell at diagnosis, immunophenotype, ETV6-RUNX1/TEL-AML1 gene fusion, bone marrow remission at day 15, and minimal residual disease at day 15. The nomogram incorporated the six factors and provided C-index values of 0.811 [95% confidence interval (CI) = 0.792-0.830] and 0.797 (95% CI = 0.769-0.825) in the training and validation set, respectively. The calibration curve and AUC revealed that the nomogram had good ability to predict 1-, 2-, and 3-year EFS. DCA also indicated that our nomogram had good clinical utility. Kaplan–Meier analysis showed that EFS in the different risk groups stratified by the nomogram scores was significant differentiated.ConclusionThe nomogram for predicting EFS of children with ALL has good performance and clinical utility. The model could help clinical decision-making.

Mutational spectrum and its prognostic significance in childhood acute lymphoblastic leukemia based on next-generation sequencing technology

目的分析儿童急性淋巴细胞白血病（ALL）的基因突变谱及其预后意义。方法回顾性分析2016年11月至2019年12月福建医科大学附属协和医院采用二代测序技术（NGS）行基因突变检测的141例初治ALL患儿的临床资料，分析基因突变谱及其对ALL患儿预后的影响。结果141例患儿中，83例（58.9％）检出体细胞突变，包括37个Ⅰ类及123个Ⅱ类突变位点。单核苷酸变异（SNV）为最常见的突变类型。KRAS（20/160，12.5％）为最常见的突变基因，其次为NOTCH1（11.9％）及NRAS（10.6％）。RAS通路（KRAS、FLT3、PTPN11）、PAX5及TP53突变仅在B-ALL患儿中检出，而FBXW7、PTEN突变仅在T-ALL患儿中检出；NRAS突变主要在B-ALL中检出，而NOTCH1突变主要在T-ALL中检出。每例T-ALL患儿检出的平均基因突变个数显著高于B-ALL患儿（4.16±1.33对2.04±0.92，P＝0.004）。按照有无遗传变异将患儿分为突变组和无突变组，两组的性别、年龄、初诊白细胞计数、微小残留病监测结果、预计3年无事件生存（EFS）率及总生存（OS）率差异均无统计学意义（P值均>0.05）；但突变组T-ALL以及融合基因阴性患儿的比例显著高于无突变组（P值分别为0.021和<0.001）。进一步亚组分析，在融合基因阴性的患儿中，有Ⅰ类突变的患儿预计3年EFS率显著低于无Ⅰ类突变的患儿（85.5％对100.0％，P＝0.039）；在B-ALL患儿中，伴TP53突变的患儿预计3年EFS率显著低于不伴有TP53突变的患儿（37.5％对91.2％，P<0.001）。结论体细胞突变在儿童ALL中较为常见，与临床表型及预后具有一定的相关性，NGS可作为传统MICM分型检查的重要补充。

Impact of Treosulfan Exposure on Early and Long-Term Clinical Outcomes in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Prospective Multicenter Study

Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationships between systemic treosulfan exposure and early and long-term clinical outcomes in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases remain unclear. In this a multicenter, prospective observational study, we assessed the association between treosulfan exposure and early and, in particular, long-term clinical outcomes. Our study cohort comprised 110 pediatric patients with nonmalignant diseases who underwent HSCT between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected, and treosulfan area under the receiver operating characteristic curve (AUC0-∞) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationships between treosulfan exposure and overall survival (OS) and event-free survival (EFS). The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days was evaluated using a multivariable logistic regression analysis. In the overall cohort, OS and EFS at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children age <2 years. The occurrence of grade II-IV acute graft-versus-host disease, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.26-13.68; P=.02) and all-grade mucositis (OR, 4.43; 95% CI, 1.43-15.50; P=.02), but not grade ≥2 mucositis (OR, 1.51; 95% CI, 0.52 to 4.58; P=.46) was related to high treosulfan exposure (>1750 mg*h/L). Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with nonmalignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring, thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether deescalation of treosulfan doses is possible to minimize early and long-term toxicity without compromising efficacy.

Gemtuzumab Ozogamicin (GO) In Children With De Novo Acute Myeloid Leukemia (AML) Improves Event-Free Survival (EFS) By Reducing Relapse Risk – Results From The Randomized Phase III Children's Oncology Group (COG) Trial, AAML0531

▪ BackgroundEscalation of treatment intensity for childhood acute myeloid leukemia has improved EFS but with excessive toxicity and toxic mortality (TM), compelling a search for more targeted less toxic alternatives. ObjectiveTo determine if the addition of GO to standard chemotherapy improves EFS in pediatric AML. MethodsPatients < 30 years of age were randomly assigned to receive standard therapy alone (noGO) or to receive two doses of GO 3 mg/m2/dose on day 6 of Induction I (IndI) and on day 7 of Intensification II (IntII) in a 5 cycle chemotherapy backbone previously piloted by COG (Cooper et al, Cancer 2012). Use of stem cell transplant (SCT) was stratified by overall risk group assignment (based on cytogenetics, FLT3-ITD high allelic ratio (HAR), and IndI response) in which high risk patients were allocated to best allogeneic donor SCT after Int I, low risk (LR) patients received chemotherapy only, and intermediate risk (IR) were assigned to SCT if there was a matched family donor (MFD). ResultsBetween 2006-2010, 1022 of 1070 enrolled non-DS pts were eligible for analysis; characteristics are presented in Table 1. Median follow-up was 3.6 (range 0-6.4) years for those alive.Protocol therapy was well tolerated with a TM of 2% in induction and 5% overall with no difference by study arm. VOD was observed in 3% (severe in 0.6%) with no difference by study arm. From time of enrollment, GO was significantly associated with better overall EFS (hazard ratio (HzR) 0.83 (95% CI: 0.7-0.99; p=.04) and relapse-free survival (HzR 0.74 (0.6-0.93; p=.01)) whereas OS was not significantly improved (HzR 0.91 (0.74-1.13)). At 3 yr, noGO v GO EFS was 47 v 53%, p=.05 and OS was 65 v 69%, p=.18. In multivariate analyses, GO was significantly associated with improved EFS than standard therapy after adjustment for significant adverse risk factors: age <2yr, initial WBC>100,000x109/L, and black race. GO was not associated with significantly better induction complete remission (CR) when compared to standard therapy (88% v 85%; p=NS). Table 2 illustrates the overall results by randomized arm and by overall risk group from time of CR showing a consistent reduction in relapse risk in all risk groups. Further risk group analysis found several unique results. In the LR group, relapse rates (RR) trended lower in the GO arm but the benefit was reduced by TM during Int 2 & 3 that was significantly worse in the GO arm (3 v 10%, p=.02). In the IR group, EFS, RR, and OS trended towards improvement with GO. However when pts were censored at the time of SCT (as treated), the outcomes were not significantly different between arms (log-rank p=.14 EFS and p=.81 OS). Table 1 shows an imbalance for SCT received in assigned IR pts with fewer actually receiving SCT in the noGO arm. As such, Table 2 shows outcomes by intent-to-treat for IR pts with MFD censored and by as treated for IR pts receiving MFD SCT. Noteworthy in the IR group alone who did receive a SCT, GO arm pts had a significantly better DFS than the noGO arm (intent to treat: p=.022; as treated: p=.044). However, for the IR pts randomized to the noGO arm, SCT failed to provide benefit. For HR pts achieving CR they as well trended towards better survival & RR in the GO arm. ConclusionGO improves EFS in children, adolescents and young adults with AML by reducing the risk of relapse among those achieving remission. Disclosures:No relevant conflicts of interest to declare.

Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: A report from CYP‐C

There are conflicting data about whether the development of cancer-associated thrombo-embolism (TE) negatively impacts survival in children. The objective was to determine whether TE during treatment was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). We performed a population-based retrospective cohort study using the Cancer in Young People-Canada registry. Children <15 years of age were diagnosed with de novo ALL (2000-2016). The primary exposure variable was radiologically-confirmed thrombo-embolism requiring medical intervention. Multivariable Cox regression models were used to determine the impact of thrombo-embolism on survival, where TE was time-dependent. We included 2006 children (median age: 4 years, 88.5% precursor B-cell ALL). Thrombo-embolism occurred in 113 patients (5.6%), at a median time of 107 days (interquartile range: 35-184 days) after ALL diagnosis. Among standard/low-risk patients, 41/1165 (3.5%) developed TE while among high/very high-risk patients, 72/841 (8.6%) developed TE. Patients with TE had a significantly worse OS (adjusted HR [aHR] of death: 2.61, 95% CI: 1.62-4.22, p< 0.001) and EFS (aHR of an event [death, relapse, second malignancy]: 2.03, 95% CI: 1.35-3.05, p= 0.001), compared with patients without TE. No statistically significant difference was seen in standard/low risk ALL for OS and EFS, but TE was associated with a significantly lower OS and EFS in children with high/very high-risk ALL (aHR of death: 2.90, 95% CI: 1.79-4.72, p< 0.001; aHR of an event: 2.02, 95% CI: 1.30-3.12, p= 0.002). Thus, TE led to a statistically significant reduction in OS and EFS in children with high risk/very high-risk leukemia.

Paediatric severe aplastic anaemia treatment: where to start?

Paediatric severe aplastic anaemia treatment: where to start?

Impact of Thromboembolism on Overall and Event-Free Survival in Children with Acute Lymphoblastic

Introduction: Thromboembolism (TE) is a well-known complication of cancer and its treatments. The impact of TE on survival outcomes remains unclear, especially in children. We assessed whether TE development was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). Methods: We performed a population-based retrospective cohort study using the national registry Cancer in Young People Canada (CYP-C). Children 0-&amp;lt;15 years of age diagnosed with ALL (2000-2018) and treated at one of 12 Canadian pediatric centers outside of Ontario were included. OS was defined as the time between the date of cancer diagnosis and death and, EFS, as the time between the date of cancer diagnosis and the date of relapse, subsequent malignancy or death (whichever came first). Patients were categorized as to whether they experienced a radiologically-confirmed TE during treatment graded 3, 4 or 5 as per the Common Terminology Criteria for Adverse Events v.4 (i.e. requiring medical treatment, life-threatening or fatal). Only TEs that occurred before relapse or subsequent malignancy were considered. The Kaplan-Meier survival method estimated the 5-year OS and EFS of children with TE compared to those without TE. Univariate and multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of death or an event between groups, adjusted for age, sex, and leukemia risk group. A sub-analysis stratified the analysis by leukemia risk group. Results: The study included 2,208 children (median age: 4 years [interquartile range: 2-7 years], 54.9% male). Precursor B-cell ALL was the most common diagnosis (1,789, 89.1%). Patients were stratified as standard/low risk ALL in 58.0% of cases, and high/very high risk ALL in 42.0%. Of these, 121 (6.0%) developed a TE, at a median time of 100 days (interquartile range: 30-183 days) after cancer diagnosis. Eight patients (0.4%) had a life-threatening or fatal TE. Patients with TE were more likely to be aged 10 years or older, to present with T-cell ALL, and to have high risk leukemia. The 5-year OS (95% CI) of patients with and without TE was 80.2% (72.9-87.5%) and 93.7% (92.5-94.9%) respectively (log-rank test: p&amp;lt;0.001, Figure 1). The adjusted HR (95% CI) of death in children with TE was 2.09 (1.33-3.27, p=0.001). Similarly, as shown in Figure 2, the 5-year EFS (95% CI) of patients with and without TE was 68.7% (59.7-77.7%) and 88.6% (87.1-90.1%), respectively (log-rank test: p&amp;lt;0.001). The adjusted HR (95% CI) of an event was 2.01 (1.39-2.90, p&amp;lt;0.001). When stratified by leukemia risk group, no statistically significant difference was seen in standard/low risk ALL for both OS and EFS but TE was associated with a significantly lower OS and EFS in children with high/very high risk ALL (Table 1). In this group, the increased risk of death was attributable to both deaths following relapsed disease (HR [95% CI]: 2.37 [1.39-4.04]) and death not following relapse (HR [95% CI]: 2.93 [1.35-6.35]). Sensitivity analyses in which 1) patients with very high risk ALL were removed and 2) only grade 3 or 4 TE were considered showed similar results. Conclusions: Clinically relevant TE led to a statistically significant reduction in OS and EFS in children with high risk/very high risk leukemia. Further research is needed to assess whether TE prevention may improve anti-cancer outcomes. Disclosures Brandao: Boehringer Ingelheim: Other: Member of a paediatric expert working group.

Predictors of Survival in Children with Osteogenic Sarcoma Undergoing Limb Salvage Surgery: Experience from a Tertiary Cancer Center in Rural India

Abstract Context: Osteogenic Sarcoma (OGS) is the fifth most common malignancy among adolescents aged 15–19. With multimodality therapy, the long-term survival has improved from 16% in the prechemotherapy era to around 70% in the postchemotherapy era. Aim: This study aims to determine the clinical profile and survival of children with OGS being treated with limb-salvage surgery (LSS). Subjects and Methods: This is a retrospective analysis of all cases of OGS (age ≤ 19) who underwent LSS at our center between June 2009 and February 2017. Baseline characteristics were noted and multivariate analysis was performed for various variables to identify predictors of survival. Results: Among 44 cases studied majority were boys (n = 27). Ninety-three percentage (n = 41) were adolescents. Stage 2 disease was 75% and Stage 3 disease was 25%. The estimated 3-year overall survival (OS) was 69% (95% confidence interval [CI] 55–86) and the estimated 3-year event-free survival (EFS) was 55% (95% CI = 41–74). OS was significantly improved in patients with &gt;90% necrosis postneoadjuvant chemotherapy (NACT) when compared with &lt;90% necrosis (3-year OS = 88% vs. 51%,P= 0.01) and in patients who received ≤4 cycles NACT versus &gt;4 cycles (78% vs. 60%,P= 0.04). EFS was significantly better in patients without lung metastasis at presentation (61% vs. 29%,P= 0.04), Stage 2 disease (59% vs. 38%,P= 0.04) and &gt;90% necrosis in the tumor post-NACT (69% vs. 35%,P= 0.02). Conclusion: Significant response to NACT predicted improved OS and EFS in children with OGS treated with LSS.

Prognostic significance of age in 5631 patients with Wilms tumour prospectively registered in International Society of Paediatric Oncology (SIOP) 93-01 and 2001.

BackgroundTo enhance risk stratification for Wilms tumour (WT) in a pre-operative chemotherapy setting, we explored the prognostic significance and optimal age cutoffs in patients treated according to International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) protocols.MethodsPatients(6 months-18 years) with unilateral WT were selected from prospective SIOP 93–01 and 2001 studies(1993–2016). Martingale residual analysis was used to explore optimal age cutoffs. Outcome according to age was analyzed by uni- and multivariable analysis, adjusted for sex, biopsy(yes/no), stage, histology and tumour volume at surgery.Results5631 patients were included; median age was 3.4 years(IQR: 2–5.1). Estimated 5-year event-free survival (EFS) and overall survival (OS) were 85%(95%CI 83.5–85.5) and 93%(95%CI 92.0–93.4). Martingale residual plots detected no optimal age cutoffs. Multivariable analysis showed lower EFS with increasing age(linear trend P<0.001). Using previously described age categories, EFS was lower for patients aged 2-4(HR 1.34, P = 0.02), 4-10(HR 1.83, P<0.0001) and 10–18 years(HR 1.74, P = 0.01) as compared to patients aged 6 months-2 years. OS was lower for patients 4–10 years(HR 1.67, P = 0.01) and 10–18 years(HR 1.87, P = 0.04), but not for 2–4 years(HR 1.29, P = 0.23). Higher stage, histological risk group and tumour volume were independent adverse prognostic factors.ConclusionAlthough optimal age cutoffs could not be identified, we demonstrated the prognostic significance of age as well as previously described cutoffs for EFS (2 and 4 years) and OS (4 years) in children with WT treated with pre-operative chemotherapy. These findings encourage the consideration of age in the design of future SIOP-RTSG protocols.

A phase II trial testing interventions to shorten time to diagnosis and reduce abandonment of treatment of children with Burkitt lymphoma in Kenya.

10032 Background: Burkitt Lymphoma (BL) is a common pediatric cancer in sub-Saharan Africa. Despite advances in care, prognosis is poor. The BL treatment protocol at our center in Kenya used since 2010, had a one-year survival of 29% (Martijn et al. BMJ Paed Open 2017). We hypothesized that financial burdens and delays in start of therapy impact outcomes. Methods: Our trial tested interventions aimed to: 1) Shorten time from presentation to start of treatment to improve survival; and 2) Support families during therapy to reduce abandonment. Initial eligibility included clinical suspicion of BL in a child 0-13 years of age. Patients with confirmed diagnosis of a mature B-cell lymphoma received support to complete therapy. Children with prior treatment of cancer were excluded. The trial was approved by human protection boards in Kenya and Indiana and consent was obtained prior to study entry. We enrolled 96 children with possible BL. Study personnel expedited routing of tissue samples to laboratories. Touch preps or smears were stained with Giemsa and reviewed by pathologists. Fresh tissue from all sources was used for flow cytometry. Tissue from core needle or incisional biopsies was processed for routine and immunohistochemical staining. Of 96 patients, 43 had BL confirmed by pathologic studies and were treated with combination chemotherapy given over 25 weeks. We paid families for transport costs for care, called after missed appointments, and provided direct monetary support (~$200 USD) for the 200 days children were on treatment. Results: Facilitating the biopsy shortened, by 3 days, the median time from admission to initiation of therapy for BL, because families did not need to raise funds for testing. Monetary support reduced abandonment of treatment by patients. Only 2 of 43 (5%) patients abandoned therapy, compared to abandonment by 22 of a cohort of 63 (35%) patients treated previously (p &lt; 0.001). The combination of rapid diagnosis, early therapy, and financial support and communication with families improved event free survival of children with BL to 50% at 1 year (p = 0.045). Conclusions: Simple interventions to improve efficiency of diagnosis and reduce abandonment leads to improved outcomes for children with BL in Kenya.

Effect of socio-economic status &amp; proximity of patient residence to hospital on survival in childhood acute lymphoblastic leukaemia

Background & objectives:Survival in paediatric acute lymphoblastic leukaemia (ALL) in lower/middle income countries continues to lag behind outcomes seen in high-income countries. Socio-economic factors and distance of their residence from the hospital may contribute to this disparity. This study was aimed at identifying the impact of these factors on outcome in childhood ALL.Methods:In this retrospective study, file review of children with ALL was performed. Patients were treated with the modified United Kingdom (UK) ALL-2003 protocol. Details of socio-economic/demographic factors were noted from a web-based patients’ database. Modified Kuppuswamy scale was used to classify socio-economic status.Results:A total of 308 patients with a median age of five years (range: 1-13 yr) were studied. Patients belonging to upper, middle and lower SE strata numbered 85 (28%), 68 (22%) and 155 (50%). Nearly one-third of the patients were underweight. There was no treatment abandonment among children whose mothers were graduates. Neutropenic deaths during maintenance therapy were lower in mothers who had passed high school. In patients who survived induction therapy, the five year event-free survival (EFS) of upper SE stratum was significantly better 78.7±4.9 vs. 59±7.2 and 58.1±4.6 per cent in middle and lower strata (P=0.026). Five year overall survival was higher in the higher SE group; being 91.2±3.5, 78.3±5.6 and 78.8±3.9 per cent (P=0.055) in the three strata. Survival was unaffected by a distance of residence from treating centre or rural/urban residence. High-risk and undernourished children had a greater hazard of mortality [1.80 (P=0.015); 1.98 (P=0.027)].Interpretation & conclusions:Our findings showed that higher socio-economic status contributed to superior EFS in children with ALL who achieved remission. Undernutrition increased the risk of mortality.

The effects of DLEU1 gene expression in Burkitt lymphoma (BL): potential mechanism of chemoimmunotherapy resistance in BL.

Following a multivariant analysis we demonstrated that children and adolescents with Burkitt lymphoma (BL) and a 13q14.3 deletion have a significant decrease in event free survival (EFS) despite identical short intensive multi-agent chemotherapy. However, how this deletion in the 13q14.3 region is associated with a significant decrease in EFS in children and adolescents with BL is largely unknown. The gene Deleted in Lymphocytic Leukemia 1 (DLEU1) is located in the region of 13q14.3. Here, we report that DLEU1 expression is implicated in the regulation of BL programmed cell death, cell proliferation, and expression of apoptotic genes in transcription activator-like effector nuclease (TALEN)s-induced DLEU1 knockdown and DLEU1 overexpressing BL cell lines. Furthermore, NSG mice xenografted with DLEU1 knockdown BL cells had significantly shortened survival (p < 0.05 and p < 0.005), whereas those xenografted with DLEU1 overexpressing BL cells had significantly improved survival (p < 0.05 and p < 0.0001), following treatment with rituximab and/or cyclophosphamide. These data suggest that DLEU1 may in part function as a tumor suppressor gene and confer chemoimmunotherapy resistance in children and adolescents with BL.