Stratified Treatment in Pediatric Anaplastic Large Cell Lymphoma: Result of a Prospective Open-Label Multiple-Institution Study.

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin's lymphoma Berlin-Frankfurt-Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% [95% Confidence Interval (CI), 69.0%-83.9%] and 92.3% (95% CI,86.1%-95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5%-95.5%, and 67.9% (95% CI, 55.4%-77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6%-19.0%), 65.7% (95% CI, 47.6%-78.9%), 55.7% (95% CI, 26.2%-77.5%), and 70.7% (95% CI, 48.6%-84.6%), respectively. At the end of follow-up, one of the 5 patients who received maintenance therapy with VBL relapsed, and seven patients receiving ALK inhibitor maintenance therapy did not experience relapse. Conclusion: This study has confirmed the poor prognostic of MDD (+) ，high risk site and SC/LH ,but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

MTHFD1 regulates the NADPH redox homeostasis in MYCN-amplified neuroblastoma.

MYCN amplification is an independent poor prognostic factor in patients with high-risk neuroblastoma (NB). Further exploring the molecular regulatory mechanisms in MYCN-amplified NB will help to develop novel therapy targets. In this study, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) was identified as the differentially expressed gene (DEG) highly expressed in MYCN-amplified NB, and it showed a positive correlation with MYCN and was associated with a poor prognosis of NB patients. Knockdown of MTHFD1 inhibited proliferation and migration, and induced apoptosis of NB cells in vitro. Mouse model experiments validated the tumorigenic effect of MTHFD1 in NB in vivo. In terms of the mechanism, ChIP-qPCR and dual-luciferase reporter assays demonstrated that MTHFD1 was directly activated by MYCN at the transcriptional level. As an important enzyme in the folic acid metabolism pathway, MTHFD1 maintained the NADPH redox homeostasis in MYCN-amplified NB. Knockdown of MTHFD1 reduced cellular NADPH/NADP+ and GSH/GSSG ratios, increased cellular reactive oxygen species (ROS) and triggered the apoptosis of NB cells. Moreover, genetic knockdown of MTHFD1 or application of the anti-folic acid metabolism drug methotrexate (MTX) potentiated the anti-tumor effect of JQ1 both in vitro and in vivo. Taken together, MTHFD1 as an oncogene is a potential therapeutic target for MYCN-amplified NB. The combination of MTX with JQ1 is of important clinical translational significance for the treatment of patients with MYCN-amplified NB.

Treatment Outcome of Response-Based Radiation Therapy in Children and Adolescents With Central Nervous System Nongerminomatous Germ Cell Tumors: Results of a Prospective Study.

PURPOSE: The optimal dose and range of radiation therapy for central nervous system nongerminomatous germ cell tumors (NGGCTs) have not been uniformly established. Therefore, this study aimed to investigate the effect of individualized radiation therapy, based on the response to induction chemotherapy combined with surgery, on the prognosis of patients with NGGCTs. METHODS AND MATERIALS: Based on the imaging examination and tumor markers after induction chemotherapy and pathologic results of second-look surgery, patients with NGGCT received different radiation therapy strategies, including 30.6 Gy whole ventricular irradiation + tumor-bed boost to 54 Gy, 30.6 Gy craniospinal irradiation + tumor-bed boost to 54 Gy, 36 Gy craniospinal irradiation + tumor-bed boost to 54 Gy, and 36 Gy craniospinal irradiation + 54 Gy tumor-bed boost with 45 Gy to metastatic spinal lesions. RESULTS: A total of 51 patients were enrolled between January 2015 and March 2021, with a median age of 10.3 years. The 3-year event-free survival and overall survival (OS) of the entire cohort were 70.2% ± 6.9% and 77.5% ± 6.0%, respectively. The 3-year OS of patients achieving partial response after induction chemotherapy was higher than that of patients with stable disease (P = .03) or progressive disease (P = .002). The 3-year event-free survival and OS of the 18 patients receiving 30.6 Gy whole ventricular irradiation and 54 Gy tumor-bed boost were 88.9% ± 7.4% and 94.4% ± 5.4%, respectively. CONCLUSIONS: The results suggest that an individualized radiation therapy strategy based on response to induction chemotherapy and surgery is a feasible and promising means of achieving reduction in dose and extent of radiation in patients while still providing good response.

The dual HDAC and PI3K inhibitor, CUDC­907, inhibits tumor growth and stem­like properties by suppressing PTX3 in neuroblastoma.

Neuroblastoma (NB) is one of the common solid tumors in childhood and poses a threat to the lives of children. Patients with advanced­stage or recurrent NB have a poor prognosis. CUDC­907, as a novel dual­target inhibitor of histone deacetylase (HDAC) and phosphatidylinositol­3­kinase (PI3K), has been proven to play an antitumor role in several types of tumors. However, the exact role of CUDC­907 in NB remains unclear. In the present study, in vivo and in vitro assays were performed to investigate the anti­NB activity of CUDC­907. Pentraxin 3 (PTX3) small interfering RNA (siRNA) and PTX3 overexpression plasmid were transfected into cells to define the underlying mechanisms of CUDC­907. Tumor tissues and clinical information were collected and immunohistochemistry (IHC) was conducted to analyze the association between the expression of HDAC1, HDAC2, HDAC3 and CD44, and the prognosis of patients with NB. The results indicated that CUDC­907 significantly inhibited the proliferation and migration, and induced the apoptosis of NB cells, downregulating the expression level of MYCN, and suppressing the PI3K/AKT and MAPK/ERK pathways. Furthermore, CUDC­907 suppressed the stem­like properties of NB cells by inhibiting PTX3, a ligand and upstream protein of CD44. IHC revealed that the high expression of HDAC1, 2, 3 and CD44 was associated with a poor prognosis of patients with NB. On the whole, these findings indicate that CUDC­907 may be developed into a possible therapeutic approach for patients with NB.

Long-term outcome of children with acute promyelocytic leukemia: a randomized study of oral versus intravenous arsenic by SCCLG-APL group.

Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As4S4), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.

Safety and clinical efficacy of sintilimab (anti-PD-1) in pediatric patients with advanced or recurrent malignancies in a phase I study.

The aim of this phase I study is to evaluate, for the first time, the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies. During the dose escalation phase, patients received a single intravenous infusion of sintilimab at varying doses of 1, 3, and 10 mg/kg. The primary endpoints included the identification of dose-limiting toxicities (DLTs) as well as the evaluation of safety and tolerance. Secondary endpoints focused on assessing objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 29 patients were enrolled, including 10 individuals diagnosed with Hodgkin lymphoma (HL) and 19 patients with various other tumor categories. Notably, diverse pathological types such as thymoma, choroid plexus carcinoma, and NK/T-cell lymphoma were also included in the study cohort. By the safety data cutoff, most adverse events were grade 1 or 2, with grade 3 or higher treatment-related adverse events (TRAE) occurring in 10% of patients. Among the 27 evaluated subjects, four achieved confirmed complete response (CR) while seven patients exhibited confirmed partial response (PR). Additionally, seven patients maintained disease (SD) during the study period. Notably, sintilimab demonstrated remarkable tolerability without DLTs and exhibited promising anti-tumor effects in pediatric HL. Whole-exome sequencing (WES) was conducted in 15 patients to assess the mutational landscape and copy number variation (CNV) status. The completion of this phase I study establishes the foundation for potential combination regimens involving sintilimab in childhood cancer treatment. The trial is registered on ClinicalTrials.gov with the identifier NCT04400851.

Treatment outcomes for response-based radiotherapy in children and adolescents with central nervous system germinoma: a prospective study.

PURPOSE: The optimal dose and range of radiotherapy for central nervous system (CNS) germinoma have not yet been established. This study aimed to investigate the effects of individualized radiotherapy on the prognosis of patients with germinoma. METHODS: Based on imaging examination, tumor markers, and pathologic results, patients with germinoma received different radiotherapy strategies, including R1 (24 Gy whole ventricular irradiation + tumor-bed boost to 40 Gy), R2 (24-30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy), R3 (24 Gy craniospinal irradiation + tumor-bed boost to 40 Gy), and R4 (30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy with 45 Gy to spinal metastasis). RESULTS: A total of 77 patients were enrolled in this study between January 2015 and March 2021. The 3-year event-free survival (EFS) and overall survival (OS) of the whole cohort were 94.7% ± 2.6% and 96.0% ± 2.3%, respectively. The 3-year EFS for patients with localized and metastatic disease were 96.6% ± 2.4% and 89.2% ± 7.2%, respectively. The 3-year EFS of patients receiving R1, R2, R3, and R4 radiotherapy were 100%, 94.1% ± 5.7%, 100%, and 86.2% ± 9.1%, respectively. CONCLUSION: Good prognosis was still achieved after reducing dose and extent of radiation for the patients who achieved complete response (CR) after induction chemotherapy or pathological CR after second-look surgery.

Efficacy and safety of programmed cell death receptor 1 inhibition-based regimens in patients with pediatric malignancies: the real-world study in China.

Background: Programmed death receptor 1 (PD-1) inhibition has shown durable response and mild adverse events (AEs) in adult malignancies. However, data on the clinical activity of PD-1 inhibition in pediatric patients are lacking. We comprehensively assessed the efficacy and safety of PD-1 inhibitor-based regimens for pediatric malignancies. Methods: We conducted a real-world, multi-institutional, retrospective analysis of pediatric malignancies treated with PD-1 inhibitor-based regimens. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints included disease control rate (DCR), duration of response (DOR), and AEs. The Kaplan-Meier method was used to calculate PFS and DOR. The National Cancer Institute Common Toxicity Criteria for AEs (version 5.0) were used to grade toxicity. Results: A total of 93 and 109 patients were evaluated for efficacy and safety, respectively. For all efficacy-evaluable patients, PD-1 inhibitor monotherapy, combined chemotherapy, combined histone deacetylase inhibitor, and combined vascular endothelial growth factor receptor tyrosine kinase inhibitor cohorts, the ORR and DCR were 53.76%/81.72%, 56.67%/83.33%, 54.00%/80.00%, 100.00%/100.00%, and 12.50%/75.00%, respectively; the median PFS and DOR were 17.6/31.2 months, not achieved/not achieved, 14.9/31.2 months, 17.6/14.9 months, and 3.7/1.8 months, respectively; the incidence rate of AEs were 83.49%, 55.26%, 100.00%, 80.00%, and 100.00%, respectively. One patient in the PD-1 inhibitor-combined chemotherapy cohort discontinued treatment due to diabetic ketoacidosis. Conclusions: This largest retrospective analysis demonstrate that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies. Our findings provide references for future clinical trials and practice of PD-1 inhibitors in pediatric cancer patients.

A multicenter phase II trial of primary prophylactic PEG-rhG-CSF in pediatric patients with solid tumors and non-Hodgkin lymphoma after chemotherapy: An interim analysis.

BACKGROUND: Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) can be used in pediatric patients. This study assessed the safety and efficacy of PEG-rhG-CSF as a primary prophylactic drug against neutropenia after chemotherapy in pediatric patients with solid tumors or non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: This phase II study (between October 2020 and March 2022) enrolled pediatric patients with solid tumors or NHL treated with high-intensity chemotherapy and with grade ≥3 myelosuppression for at least 14 days during chemotherapy. Prophylactic PEG-rhG-CSF was given at 100 µg/kg body weight (maximum total dosage of 6 mg) once 24-48 h following chemotherapy for two cycles. The primary endpoint was the incidence of PEG-rhG-CSF-related adverse events (AEs). The key secondary endpoints were the rates of grade 3/4 neutropenia and febrile neutropenia (FN). RESULTS: This study included 160 pediatric patients with a median age of 6.22 (0.29, 18.00) years. Fifty-eight patients (36.25%) were diagnosed with sarcoma. AEs potentially related to PEG-rhG-CSF included bone pain (n = 32), fatigue (n = 21), pain at the injection site (n = 21), and myalgia (n = 20). The rates of grade 3/4 neutropenia and FN during treatment were 57.28% and 29.45%, respectively. CONCLUSION: PEG-rhG-CSF is well tolerated and effective in pediatric patients with solid tumors or NHL. These findings should be substantiated with further trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04547829.

Oral vinorelbine and continuous low doses of cyclophosphamide in pediatric rhabdomyosarcoma: a real-world study.

Introduction: Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a lack of relevant data on its effectiveness in real-world situations. Methods: We retrospectively retrieved data of 459 patients < 18 years of age diagnosed with rhabdomyosarcoma at Sun Yat-sen University Cancer Center from January 2011 to July 2020 from our database. The MMT regimen was oral vinorelbine 25-40 mg/m2 for twelve 4-week cycles on days 1, 8, and 15, and oral cyclophosphamide 25-50 mg/m2 daily for 48 consecutive weeks. Results: A total of 57 patients who underwent MMT were included in the analysis. The median follow-up time was 27.8 (range: 2.9-117.5) months. From MMT to the end of follow-up, the 3-year PFS and OS rates were 40.6% ± 6.8% and 58.3% ± 7.2%, respectively. The 3-year PFS was 43.6% ± 11.3% in patients who were initially diagnosed as low- and intermediate-risk but relapsed after comprehensive treatment (20/57), compared with 27.8% ± 10.4% in high-risk patients (20/57) and 52.8% ± 13.3% in intermediate-risk patients who did not relapse (17/57). The corresponding 3-year OS for these three groups was 65.8% ± 11.4%, 50.1% ± 12.9%, and 55.6% ± 13.6%, respectively. Conclusion: We present a novel study of MMT with oral vinorelbine and continuous low doses of cyclophosphamide in real-world pediatric patients with RMS. Our findings showed that the MMT strategy significantly improved patient outcomes and may be an effective treatment for high-risk and relapsed patients.

Vincristine and dexamethasone pulses in addition to maintenance therapy among pediatric acute lymphoblastic leukemia (GD-ALL-2008): An open-label, multicentre, randomized, phase III clinical trial.

The efficacy and safety on the addition of vincristine (VCR) and dexamethasone (DEX) pulses to maintenance therapy among childhood acute lymphoblastic leukemia (ALL) remain uncertain. Herein, we perform an open-label, multicentre, randomized, phase III clinical trial that was conducted at nine major medical centers in Guangdong Province, China. Patients were randomly assigned either the conventional maintenance therapy (control group, n = 384) or the VCR/DEX pulse (treatment group, n = 375). When limited to the SR cohort, 10-year EFS was 82.6% (95% CI: 75.9-89.9) in the control group and 80.7% (95% CI: 74-88.1) in the treatment group (pnon-inferiority  = .0002). Similarly, patients with IR also demonstrated non-inferiority of the treatment group to the control group in terms of 10-year EFS (73.6% [95% CI: 67.6-80] vs. 77.6% [95% CI: 71.8-83.9]; pnon-inferiority  = .005). Among the HR cohort, compared with the control group, patients in the treatment group experienced a significant benefit in terms of 10-year EFS (61.1% [95% CI: 47.7-78.2] vs. 72.6% [95% CI: 55.6-94.7], p = .026) and a trend toward higher 10-year OS (73.8% [95% CI: 61.6-88.4] vs. 87.9% [95% CI: 579.2-97.5], p = .068). In the HR cohort, the total rate of drug-induced liver injury and Grade 3 chemotherapy-induced anemia were both lower for patients in the treatment group than in the control group (55.6% vs. 100%, p = .033; 37.5% vs. 60%, p = .036). Conversely, the total prevalence of chemotherapy-induced thrombocytopenia was higher for patients in the treatment group than in the control group (88.9% vs. 40%, p = .027). Pediatric acute lymphoblastic leukemia with high risk is suitable to VCR/DEX pulse during maintenance phase for the excellent outcome, while the standard-to-intermediate-risk patients could eliminate the pulses.

Long-term follow-up results of pediatric and adolescent patients with localized Ewing sarcoma treated based on stratified modalities.

BACKGROUND: Compared with other pediatric tumors, little advances were achieved in studies on the stratified treatment in localized Ewing sarcoma. Most pediatric oncology groups treated Ewing sarcoma according to whether there was an existing metastasis, without involving more prognostic factors. In this study, patients with localized Ewing sarcoma were divided into resectable and unresectable groups at diagnosis and received chemotherapy with different intensity, for the purpose of achieving good efficacy, avoiding overtreatment and reducing unnecessary toxicity. METHODS: A total of 143 patients with a median age of 10 years old diagnosed with localized Ewing sarcoma in this retrospective study were divided into two cohorts (Cohort 1, n = 42; Cohort 2, n = 101) and patients in Cohort 2 received chemotherapy with different intensity (Regimen 1, n = 52; Regimen 2, n = 49). Outcomes were analyzed using the Kaplan-Meier method to estimate event-free survival (EFS) and overall survival (OS), and the curves were compared using the log-rank test. RESULTS: The 5-year EFS and 5-year OS for all the patients were 69.0% and 77.5%. The 5-year EFS for Cohort 1 and Cohort 2 were 76.0% and 66.1% (p = 0.31), and the 5-year OS were 83.0% and 75.1% (p = 0.30), respectively. In Cohort 2, the 5-year EFS rate of patients treated with Regimen 2 was significantly higher than that of patients treated with Regimen 1 (74.5% vs. 58.3%, p = 0.03). CONCLUSIONS: According to whether a grossly complete resection was received at the time of diagnosis, localized Ewing sarcoma patients in this study were stratified into two groups and received different intensities of chemotherapy, which achieved good efficacy and avoided overtreatment and reduced unnecessary toxicity.

Relationship between methylenetetrahydrofolate reductase gene polymorphisms and methotrexate drug metabolism and toxicity.

Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of MTHFR C677T and A1298C genes and the toxicity responses of MTX. Methods: The MTHFR C677T and A1298C genotypes of 271 children with ALL who received HD-MTX chemotherapy in southern China from September 2017 to June 2021 were analyzed, and the toxicity of HD-MTX was evaluated and analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Results: The MTHFR C677T and A1298C gene polymorphisms were not correlated with the 48-hour MTX blood concentrations (P>0.05). Unconditional logistic regression model analysis also revealed that the risk of liver function impairment [odds ratio (OR) =1.656, 95% confidence interval (CI): 1.179-2.324, P<0.05] and mucosal damage (OR =1.508, 95% CI: 1.042-2.183, P<0.05) were 1.656 and 1.508 times higher for the heterozygous mutant (CT), and homozygous mutant (TT) mutant type than for the wild-type (CC), wild-type, respectively. The risk of neutropenia and liver function impairment were 0.498 (OR =0.498, 95% CI: 0.251-0.989, P<0.05) and 6.067 (OR =6.067, 95% CI: 1.183-31.102, P<0.05) times higher in low-risk children with CT+TT mutant genotypes than in those with CC wild genotypes, respectively. Furthermore, the risk of mucosal damage was 1.906 times higher in high-risk children with the CT+TT genotype than in those with the CC genotype (OR =1.906, 95% CI: 1.033-3.518, P<0.05). The MTHFR A1298C genotypes differed in the incidence of liver function damage and gastrointestinal toxic reactions in children with ALL. Nonetheless, no increased risk of liver function impairment nor gastrointestinal reactions in children with the heterozygous mutant (AC)+CC mutation was observed. Conclusions: Advancements in MTHFR genotype testing in children with ALL and the introduction of personalised treatments based on genotype results during HD-MTX chemotherapy will help to predict, prevent, and reduce the occurrence of adverse MTX-related toxic reactions.

Investigation of chemoresistance to first-line chemotherapy and its possible association with autophagy in high-risk neuroblastoma.

High-risk neuroblastoma (NB) is sensitive to chemotherapy but susceptible to chemoresistance. In this study, we aimed to analyze the incidence of chemoresistance in high-risk NB patients and to explore the role of autophagy in NB chemoresistance. We retrospectively analyzed the incidence of changing the chemotherapy regimen due to disease stabilization or disease progression during induction chemotherapy in high-risk NB patients, which was expressed as the chemoresistance rate. The autophagy levels were probed in tumor cells exposed to first-line chemotherapy agents. The sensitivity of tumor cells to chemotherapy agents and apoptosis rate were observed after inhibiting autophagy by transfection of shRNA or chloroquine (CQ). This study included 247 patients with high-risk NB. The chemoresistance rates of patients treated with cyclophosphamide + adriamycin + vincristine (CAV) alternating with etoposide + cisplatin (EP) (Group 1) and CAV alternating with etoposide + ifosfamide + cisplatin (VIP) (Group 2) was 61.5% and 39.9% (P = 0.0009), respectively. Group 2 had better survival rates than group 1. After exposure to cisplatin, cyclophosphamide, and etoposide, the autophagy-related proteins LC3-I, LC3-II, and Beclin-1 were upregulated, and the incidence of autophagy vesicle formation and the expression of P62 were increased. Chemotherapeutic agents combined with CQ significantly increased the chemotherapeutic sensitivity of tumor cells and increased the cell apoptosis. The downregulated expression of Beclin-1 increased the sensitivity of tumor cells to chemotherapeutics. Our results suggest that increasing the chemotherapy intensity can overcome resistance to NB. Inhibition of autophagy is beneficial to increase the sensitivity of NB to chemotherapy agents.

Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children's Leukemia Group.

Objectives: The prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children's Leukemia Group (SCCLG). Methods: A total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction. Results: The frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P <0.05) compared with non-CNSL patients. Moreover, CNSL status was associated with worse 3-year event-free survival (P = 0.030) and a higher risk of 3-year cumulative incidence of relapse (P = 0.008), while no impact was observed on 3-year overall survival (P = 0.837). Multivariate analysis revealed that CNSL status at diagnosis was an independent predictor with a higher cumulative incidence of relapse (hazard ratio = 2.809, P = 0.016). Conclusion: CNSL status remains an adverse prognostic factor in childhood B-cell ALL, indicating that additional augmentation of CNS-directed therapy is warranted for patients with CNSL at diagnosis.

The Efficacy and Safety of Anlotinib in Pediatric Patients With Refractory or Recurrent Solid Tumors.

Objective: Refractory or recurrent pediatric solid tumors lack effective treatments, and are associated with dismal outcomes. Hence, there is an urgent need for a novel therapeutic strategy. This study aimed to evaluate the efficacy and safety of anlotinib, a novel oral multi-kinase angiogenesis inhibitor, in pediatric patients with refractory or recurrent solid tumors. Methods: This single-institutional, observational retrospective study was conducted in Sun Yat-sen University Cancer Center, China. Refractory or recurrent pediatric solid tumor patients treated with anlotinib between 2018 and 2020 were evaluated. Results: Forty-one and 30 patients were enrolled to evaluate the efficacy and safety of anlotinib, respectively. There was partial response in five patients, stable disease in 22 patients, no patient with complete response, with an objective response ratio of 12.2% (5/41; 95% CI 1.7-22.7). The disease control rate was 65.9% (27/41; 95% CI 50.7-81) and the median progression-free survival was 2.87 months (95% CI 0.86-4.88). The incidence rates of any grade and grade 3-4 adverse events were 80% (24/30) and 23.3% (7/30), respectively. Bleeding (20%, 6/30), hand-foot syndrome (16.7%, 5/30), and diarrhea (13.3%, 4/30) were the most common adverse events. Grade 3-4 adverse events included hypertension, hand-foot syndrome, diarrhea, anemia, and thrombocytopenia. There were no adverse events-related deaths. Conclusion: For heavily pretreated pediatric solid tumors, anlotinib monotherapy and its combination with chemotherapy may be an effective treatment option with tolerable adverse events. It is necessary to monitor blood pressure when using anlotinib in children.

KDM5B promotes tumorigenesis of Ewing sarcoma via FBXW7/CCNE1 axis.

Ewing sarcoma (EwS) is an aggressive tumor that affects children and young adults. Patients with relapsed/refractory diseases have limited treatment options. Targeting the driver fusion oncoproteins of EwS remains a technical problem. Epigenetic mechanisms have been pointed out as key players and alternative therapeutic targets in EwS. Here, we reported that lysine demethylase 5B (KDM5B), a histone demethylase that specifically demethylates tri- and di-methylated H3 Lys-4 (H3K4), was upregulated in EwS and overexpressed KDM5B was correlated with poor outcomes of patients. KDM5B knockdown and KDM5B inhibitor AS-8351 suppressed EwS cell proliferation and induced cell cycle arrest. Bioinformatics analysis revealed that KDM5B mainly influenced the cell cycle pathways in EwS. In mechanistic studies, we found that overexpression of KDM5B resulted in increased CCNE1 protein level, but did not affect the mRNA level of CCNE1. KDM5B upregulation blocked the degradation pathway of CCNE1 by reducing the expression of FBXW7. KDM5B downregulated FBXW7 gene by demethylation of H3K4me3 at promoter region. Moreover, AS-8351 could inhibit tumor growth in nude mice models, indicating the antitumor effect of targeting KDM5B in EwS. Our study uncovered that KDM5B in EwS attenuated FBXW7 transcription and accumulated CCNE1 protein, leading to malignant proliferation of EwS. Epigenetic drug targeting KDM5B could be a potential treatment for EwS.

Vincristine, Irinotecan, and Temozolomide in Patients With Relapsed/Refractory Neuroblastoma.

Purpose: The combination of irinotecan, temozolomide and vincristine has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination for patients with relapsed and refractory neuroblastoma (NB). Patients and Methods: In this retrospective study, forty-six patients with relapsed or refractory NB were treated with the combination of vincristine (1.5 mg/m2 i.v. day 1), irinotecan (50 mg/m2/day i.v. days 1-5) and temozolomide (100 mg/m2/day p.o. days 1-5) (VIT) during the period 2011-2019. All toxicities were documented. Results: A total of 251 cycles (median 6 cycles/patient) were administered. A complete response (CR) was achieved in 5 patients, partial response (PR) in 27 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 6 patients, with an overall objective response rate (CR+PR) of 69.6%. Eighteen patients developed diarrhea with Grade 3 or less. Grade 1-2 hematologic toxicity occurred in 10 patients. Grade 3-4 hematologic toxicity developed in 32 patients. VIT was an effective regimen for different metastatic sites. UGT1A*28 genotyping performed in 7 patients revealed wild type. Diarrhea occurred in 4 of them. Conclusion: The shorter, 5-day VIT regimen is an active and well-tolerated salvage regimen in relapse/refractory NB.

Efficacy and safety comparison between R-CHOP and modified NHL-BFM-90 regimens in children and adolescents with diffuse large B-cell lymphoma.

Studies comparing the efficacy and safety of R-CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90 (NHL-BFM-90) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL) are lacking. Thus, we retrospectively analyzed 85 DLBCL patients aged ≤18 years from 2000 to 2020; 74 patients received the modified NHL-BFM-90 regimen, and 11 received the R-CHOP regimen. The 5-year OS and event-free survival (EFS) rates between the modified NHL-BFM-90 and R-CHOP regimens were 91.0% vs. 90.9% (P = 0.466) and 89.8% vs. 68.6% (P = 0.055), respectively. In the stratified analysis, the survival outcome of pediatric patients treated with the modified NHL-BFM-90 regimen was not significantly different from that of adolescent patients. The OS and EFS rates of patients with early-stage disease were both 100%. Patients in the advanced-stage group who were treated with the modified NHL-BFM-90 regimen had superior EFS rates (P < 0.05). The frequency of severe adverse events from the two regimens was similar. There were no treatment-related deaths. We concluded that the modified NHL-BFM-90 regimen has better efficacy than R-CHOP in DLBCL patients with advanced-stage disease. However, the R-CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical decisions about treatment.

Treatment barriers and clinical outcome of children with medulloblastoma in China: a report from the Chinese Children's Cancer Group (CCCG).

BACKGROUND: Medulloblastoma (MB) is the most common malignant central nervous system tumor of childhood. Management requires interdisciplinary care and is associated with unique challenges in developing regions. Here, we report the characteristics, clinical outcome and treatment barriers for Chinese children with MB based on a multi-institutional cohort from the Chinese Children's Cancer Group (CCCG). METHODS: Retrospective cohort study among 12 Chinese pediatric oncology units from the CCCG Brain Tumor Workgroup on patients aged <18 years diagnosed with MB from 2016 to 2019. RESULTS: 221 patients (male:female = 138:83) were included, 175 (79%) were ≥3 years of age, and 46 (21%) <3 years. 177 patients (80%) were completely staged, among which 50 (28%) had metastasis and 70 (40%) were considered to have high-risk (HR) disease. Gross/near-total resection was achieved in 203 patients (92%). In patients where molecular grouping could be assigned, 19 (16%), 35 (29%), and 65 (54%), respectively had WNT-activated, SHH-activated, and Group 3/4 MB. The median duration between resection and initiation of adjuvant therapy was 36 days. Respective 2-year PFS and OS rates were 76.0 ± 3.0% and 88.0 ± 2.3%. PFS was significantly associated with age, metastatic status and clinical risk grouping. Chemotherapy use during CSI or alkylator choice were not significant predictors for patient outcome. CONCLUSIONS: We reported the clinical profiles and outcome from the largest cohort of Chinese children with MB after multi-modal therapy. Strengths and limitations on the local provision of neuro-oncology service are identified.