No clear benefit of preventive cranial radiotherapy in childhood Philadelphia-positive acute lymphoblastic leukemia: a retrospective analysis of the EsPhALL2010 study.

Not available.

Outcome of infants with acute lymphoblastic leukemia treated with the Chinese Children's Cancer Group Acute Lymphoblastic Leukemia 2015 study protocol.

Not available.

CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.

Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-of-function experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

Prognosis of pediatric BCP-ALL with IKZF1 deletions and impact of intensive chemotherapy: Results of SCCLG-2016 study.

BACKGROUND: IKZF1 deletion (IKZF1del) is associated with poor prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). But the prognosis of IKZF1del combined with other prognostic stratification factors remains unclear. Whether intensified treatment improves BCP-ALL prognosis has not been determined. METHODS: A retrospective analysis was performed on 1291 pediatric patients diagnosed with BCP-ALL and treated with the South China Children's Leukemia 2016 protocol. Patients were stratified based on IKZF1 status for comparison of characteristics and outcome. Additionally, IKZF1del patients were further divided based on chemotherapy intensity for outcome assessments. RESULTS: The BCP-ALL pediatric patients with IKZF1del in south China showed poorer early response. Notably, the DFS and OS for IKZF1del patients were markedly lower than IKZF1wt group (3-year DFS: 88.7% [95% CI: 83.4%-94.0%] vs. 93.5% [95% CI: 92.0%-94.9%], P = .021; 3-year OS: 90.7% [95% CI: 85.8% to 95.6%] vs. 96.1% [95% CI: 95% to 97.2%, P = .003]), with a concurrent increase in 3-year TRM (6.4% [95% CI: 2.3%-10.5%] vs. 2.9% [95% CI: 1.9%-3.8%], P = .025). However, the 3-year CIR was comparable between the two groups (5.7% [95% CI: 1.8%-9.5%] vs. 3.7% [95% CI: 2.6%-4.7%], P = .138). Subgroup analyses reveal no factor significantly influenced the prognosis of the IKZF1del cohort. Noteworthy, intensive chemotherapy improved DFS from 85.7% ± 4.1% to 94.1% ± 0.7% in IKZF1del group (P = .084). Particularly in BCR::ABL positive subgroup, the 3-year DFS was remarkably improved from 53.6% ± 20.1% with non-intensive chemotherapy to 100% with intensive chemotherapy (P = .026). CONCLUSIONS: Pediatric BCP-ALL patients with IKZF1del in South China manifest poor outcomes without independent prognostic significance. While no factor substantially alters the prognosis in the IKZF1del group. Intensified chemotherapy may reduce relapse rates and improve DFS in patients with IKZF1del subset, particularly in IKZFdel patients with BCR::ABL positive.

Prognostic factors of childhood acute lymphoblastic leukemia with TCF3::PBX1 in CCCG-ALL-2015: A multicenter study.

BACKGROUND: Contemporary risk-directed treatment has improved the outcome of patients with acute lymphoblastic leukemia (ALL) and TCF3::PBX1 fusion. In this study, the authors seek to identify prognostic factors that can be used to further improve outcome. METHODS: The authors studied 384 patients with this genotype treated on Chinese Children's Cancer Group ALL-2015 protocol between January 1, 2015 and December 31, 2019. All patients provisionally received intensified chemotherapy in the intermediate-risk arm without prophylactic cranial irradiation; those with high minimal residual disease (MRD) ≥1% at day 46 (end) of remission induction were candidates for hematopoietic cell transplantation. RESULTS: The overall 5-year event-free survival was 84.4% (95% confidence interval [CI], 80.6-88.3) and 5-year overall survival 88.9% (95% CI, 85.5-92.4). Independent factors associated with lower 5-year event-free survival were male sex (80.4%, [95% CI, 74.8-86.4] vs. 88.9%, [95% CI, 84.1-93.9] in female, p = .03) and positive day 46 MRD (≥0.01%) (62.1%, [95% CI, 44.2-87.4] vs. 87.1%, [95% CI, 83.4-90.9] in patients with negative MRD, p < .001). The presence of testicular leukemia at diagnosis (n = 10) was associated with particularly dismal 5-year event-free survival (33.3% [95% CI, 11.6-96.1] vs. 83.0% [95% CI, 77.5-88.9] in the other 192 male patients, p < .001) and was an independent risk factor (hazard ratio [HR], 5.7; [95% CI, 2.2-14.5], p < .001). CONCLUSIONS: These data suggest that the presence of positive MRD after intensive remission induction and testicular leukemia at diagnosis are indicators for new molecular therapeutics or immunotherapy in patients with TCF3::PBX1 ALL.

Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation.

To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).

Prevalence of anemia at diagnosis of pediatric chronic myeloid leukemia and prognostic impact on the disease course.

The clinical presentation of chronic myeloid leukemia (CML) at diagnosis differs in children compared to adults. At younger age, anemia appears to be frequent at diagnosis, but its prevalence and its impact on prognosis are not well known. In the International Registry of Childhood CML, we selected children and adolescents in chronic phase at diagnosis of CML and treated upfront with imatinib. We examined their hemoglobin level at diagnosis according to the WHO grades to assess the prevalence of anemia and its impact on response to tyrosine kinase inhibitors (TKIs). Data on 430 patients were included. Anemia at diagnosis was observed in 350 patients (81%), with a mean hemoglobin level of 96.4 g/l (SD 23.6). Among them, 182 patients (52%) presented with moderate anemia and 110 (31%) with severe anemia while 58 (17%) had mild anemia. Compared with mild and no anemia, moderate and severe forms were significantly associated with younger age at diagnosis, asthenia, splenomegaly, and increased leukocyte and basophil counts. Delays in achieving major and deep molecular responses were significantly increased for patients with moderate and severe anemia, and also failure of imatinib treatment was more frequent in these two sub-cohorts. However, hemoglobin level was not significantly associated with survival. Anemia at diagnosis of pediatric CML was frequent and may be considered as a prognostic factor.

Clinical, neuroimaging, and behavioural risk factors for neurocognitive impairment in Chinese patients with haemophilia: A multicentre study.

BACKGROUND: Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia. OBJECTIVES: To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors. METHODS: We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong. A neurocognitive battery was administered to evaluate their attention, memory, processing speed and cognitive flexibility performances. They also underwent magnetic resonance imaging to identify cerebral microbleeds. Validated self-reported questionnaires were administered to assess their mental health status and adherence to prophylactic treatment. General linear modelling was used to investigate the association of neurocognitive outcomes with risks factors, adjusting for age and education attainment. RESULTS: Forty-two patients were recruited (median age 32.0 years; 78.6% haemophilia A; 80.9% moderate-to-severe disease). Six patients (14.3%) had developed cerebral microbleeds. A subgroup of patients demonstrated impairments in cognitive flexibility (30.9%) and motor processing speed (26.2%). Hemarthrosis in the previous year was associated with worse attention (Estimate = 7.62, 95% CI: 1.92-15.33; p = .049) and cognitive flexibility (Estimate = 8.64, 95% CI: 2.52-13.29; p = .043). Depressive (Estimate = 0.22, 95% CI: 0.10-0.55; p = .023) and anxiety (Estimate = 0.26, 95% CI: 0.19-0.41; p = .0069) symptoms were associated with inattentiveness. Among patients receiving prophylactic treatment (71.4%), medication adherence was positively correlated with cognitive flexibility (p = .037). CONCLUSION: A substantial proportion of patients with haemophilia demonstrated cognitive impairment, particularly higher-order thinking skills. Screening for cognitive deficits should be incorporated into routine care. Future studies should evaluate the association of neurocognitive outcomes with occupational/vocational outcomes.

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.

Provision of a personalized survivorship care plan and its impact on cancer-related health literacy among childhood cancer survivors in Hong Kong.

PURPOSE: To evaluate the short-term effectiveness of a personalized survivorship care plan (SCP) in improving cancer-related literacy among childhood cancer survivors, and to identify characteristics of survivors who demonstrated minimal gain from the intervention. METHODS: We recruited survivors diagnosed with cancer at ≤18 years old and were >2 years post treatment. The intervention included a personalized SCP and 30-minute health risk counseling. The participants' knowledge of their cancer diagnosis and potential treatment-related late effects (LEs) was assessed at baseline, immediately post intervention, and 1-3 months post intervention. Generalized estimating equation was used to test for changes in the awareness scores, with interacting terms (time*factor) added to identify differences in the score trajectory across clinically relevant subgroups. RESULTS: In total, 248 survivors completed the intervention (mean age: 19.4 [SD = 6.7] years; 54.1% male; 66.1% hematological malignancies), of whom 162 completed all assessments. There was significant increase in survivors' awareness of their cancer diagnoses (mean adjusted score: baseline 66.9, post intervention 86.3; p < .001) and potential LEs (baseline 30.9, post intervention 66.3; p < .001). The proportion of survivors who demonstrated awareness of their potential LEs increased from 9.7% to 54.3%. The interaction analysis showed that there was significantly less improvement in awareness among survivors of non-central nervous system (non-CNS) solid tumors (p = .032), lower socioeconomic status (p = .014), and parents of pediatric survivors (vs. adult survivors; p = .013). CONCLUSIONS: The provision of a personalized SCP showed preliminary effectiveness in improving survivors' understanding of their treatment-related LEs. Health counseling with SCP should be reinforced in vulnerable subgroups. Future work includes evaluating its long-term impact on lifestyle and health outcomes.

Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

Extended vincristine and dexamethasone pulse therapy may not be necessary for children with TCF3-PBX1 positive acute lymphoblastic leukaemia.

The effect of prolonged pulse therapy with vincristine and dexamethasone (VD) during maintenance therapy on the outcome of paediatric patients with TCF3-PBX1 positive acute lymphoblastic leukaemia (ALL) remains uncertain. We conducted non-inferiority analysis of 263 newly diagnosed TCF3-PBX1 positive ALL children who were stratified and randomly assigned (1:1) to receive seven additional VD pulses (the control group) or not (the experimental group) in the CCCG-ALL-2015 clinical trial from January 2015 to December 2019 (ChiCTR-IPR-14005706). There was no significant difference in baseline characteristics between the two groups. With a median follow-up of 4.2 years, the 5-year event-free survival (EFS) and 5-year overall survival (OS) in the control group were 90.1% (95% confidence interval [CI] 85.1-95.4) and 94.7% (95% CI, 90.9-98.6) comparable to those in the experimental group 89.2% (95% CI 84.1-94.7) and 95.6% (95% CI 91.8-99.6), respectively. Non-inferiority was established as a one-sided 95% upper confidence bound for the difference in probability of 5-year EFS was 0.003, and that for 5-year OS was 0.01 by as-treated analysis. Thus, omission of pulse therapy with VD beyond one year of treatment did not affect the outcome of children with TCF3-PBX1 positive ALL.

ABCC4, ITPA, NUDT15, TPMT and their interaction as genetic predictors of 6-mercaptopurine intolerance in chinese patients with acute lymphoblastic leukemia.

Inter-individual variance in 6-mercaptopurine (6-MP) dose intensity is common in patients with acute lymphoblastic leukemia (ALL). We aimed to evaluate the association of common variants of ABCC4, ITPA, NUDT15, and TPMT with 6-MP dose intensity and toxicity in pediatric ALL patients. In this cohort, 13.8% of patients were intolerant to 6-MP with actual dosage less than 50% of scheduled dose. Twenty percent of patients were found to be heterozygous or homozygous mutated with NUDT15. NUDT15 c.415C > T and the genotype-predicted NUDT15 activity were significantly associated with 6-MP intolerance. TPMT*3C variants were not common in this cohort (2.8%). NUDT15 polymorphisms and genotype predicted NUDT15 activity were significantly associated with 6-MP dose intensity and leukopenia episodes. Combination of ABCC4 and ITPA variants (ABCC4 c.912G > T and ITPA c.94C > A) also showed significant positive association with 6-MP intolerance in Chinese children with ALL. Further study on pharmacogenetic screening for ALL patients to avoid 6-MP induced toxicity is recommended.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1973628.

Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial.

BACKGROUND: Vincristine plus dexamethasone pulses are generally used throughout maintenance treatment for childhood acute lymphoblastic leukaemia. However, previous studies remain inconclusive about the benefit of this maintenance therapy and the absence of randomised, controlled trials in patients with low-risk or high-risk acute lymphoblastic leukaemia provides uncertainty. We therefore aimed to determine if this therapy could be safely omitted beyond 1 year of treatment without leading to an inferior outcome in any risk subgroup of childhood acute lymphoblastic leukaemia. METHODS: This open-label, multicentre, randomised, phase 3, non-inferiority trial involved 20 major medical centres across China. We enrolled patients who were aged 0-18 years with newly diagnosed acute lymphoblastic leukaemia that was subsequently in continuous remission for 1 year after initial treatment. Patients with secondary malignancy or primary immunodeficiency were excluded. Eligible patients were classified as having low-risk, intermediate-risk, or high-risk acute lymphoblastic leukaemia based on minimal residual disease and immunophenotypic and genetic features of leukaemic cells. Randomisation and analyses were done separately for the low-risk and intermediate-to-high-risk cohorts. Randomisation was generated by the study biostatistician with a block size of six. Stratification factors included participating centre, sex, and age at diagnosis; the low-risk cohort was additionally stratified for ETV6-RUNX1 status, and the intermediate-to-high-risk cohort for cell lineage. Patients in each risk cohort were randomly assigned (1:1) to either receive (ie, the control group) or not receive (ie, the experimental group) seven pulses of intravenous vincristine (1·5 mg/m2) plus oral dexamethasone (6 mg/m2 per day for 7 days) during the second year of treatment. The primary endpoint was difference in 5-year event-free survival between the experimental group and the control group for both the low-risk and intermediate-to-high-risk cohorts, with a non-inferiority margin of 0·05 (5%). The analysis was by intention to treat. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-14005706. FINDINGS: Between Jan 1, 2015, and Feb 20, 2020, 6141 paediatric patients with newly diagnosed acute lymphoblastic leukaemia were registered to this study. Approximately 1 year after diagnosis and treatment, 5054 patients in continuous remission were randomly assigned, including 2923 (1442 in the control group and 1481 in the experimental group) with low-risk acute lymphoblastic leukaemia and 2131 (1071 control, 1060 experimental) with intermediate-to-high risk acute lymphoblastic leukaemia. Median follow-up for patients who were alive at the time of analysis was 3·7 years (IQR 2·8-4·7). Among patients with low-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (90·3% [95% CI 88·4-92·2] vs 90·2% [88·2-92·2]; p=0·90). The one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·024, establishing non-inferiority. Among patients with intermediate-to-high-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (82·8% [95% CI 80·0-85·7] vs 80·8% [77·7-84·0]; p=0·90), but the one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·055, giving a borderline inferior result for those in the experimental group. In the low-risk cohort, we found no differences in the rates of infections, symptomatic osteonecrosis, or other complications during the second year of maintenance treatment between patients in the control and experimental groups. Patients with intermediate-to-high-risk acute lymphoblastic leukaemia in the control group were more likely to develop grade 3-4 pneumonia (26 [2·4%] of 1071 vs ten [0·9%] of 1060) and vincristine-related peripheral neuropathy (17 [1·6%] vs six [0·6%]) compared with the experimental group. Incidence of grade 5 fatal infection was similar between the control group and the experimental group in both the low-risk cohort (two [0·1%] of 1442 vs five [0·3%] of 1481) and intermediate-to-high risk cohort (six [0·6%] of 1071 vs five [0·5%] of 1060). INTERPRETATION: Vincristine plus dexamethasone pulses might be omitted beyond 1 year of treatment for children with low-risk acute lymphoblastic leukaemia. Additional studies are needed for intermediate-to-high-risk acute lymphoblastic leukaemia. FUNDING: VIVA China Children's Cancer Foundation, the National Natural Science Foundation of China, the China fourth round of Three-Year Public Health Action Plan (2015-2017), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Neurocognitive impairment in Asian childhood cancer survivors: a systematic review.

Childhood cancer survivors are at higher risk of developing neurocognitive deficits due to the intensive treatment they received at an early age. Most studies on childhood cancer survivorship have so far focused on the Western populations. Due to the ethnic, genetic, environmental, and cultural differences, clinical data of the Western populations may not be representative of Asian countries. This scoping review systematically summarized the existing clinical evidence of the neurocognitive impairment of Asian childhood cancer survivors. We searched the Embase and Medline databases for studies assessing the neurocognitive functions of survivors in Asia, who were diagnosed with cancer before the age of 19 and completed active treatment. The literature search identified 13 studies involving 2212 participants from five Asian countries: South Korea (n = 4, 30.8%), Taiwan (n = 3, 23.1%), Japan (n = 3, 23.1%), Hong Kong (n = 2, 15.4%), and Thailand (n = 1, 7.7%). The included studies focused on CNS tumors (n = 10, 76.9%), hematological malignancies (n = 7, 53.8%), or heterogeneous cancer diagnoses (n = 3, 23.1%). Collectively, mild-to-moderate impairment in intelligence was observed in 10.0 to 42.8% of survivors, which seemed higher than the reported rate in Western survivors. We speculate that the ethnic and genetic variations in drug responses and susceptibility to adverse chronic toxicities may have contributed to the differences in the prevalence and severity of neurocognitive impairment between these two populations. To better understand the effects of culturally relevant and region-specific environmental risk factors on the post-treatment neurocognitive development in cancer survivors, a holistic approach that addresses the complex interactions between biological, physical, and psychosocial factors is needed. This will aid the development of effective intervention strategies to improve the functional and psychosocial outcomes of cancer survivors in Asian societies.

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series.

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22+ blasts was 72% (range 40-100%, n = 9). The median dose in the first course was 1.74 mg/m2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.

Reduced intensity of early intensification does not increase the risk of relapse in children with standard risk acute lymphoblastic leukemia - a multi-centric clinical study of GD-2008-ALL protocol.

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.

Double-unit unrelated cord blood transplantation for thalassemia major: Comparison with HLA-identical sibling bone marrow transplantation.

UCBT recipients with TM are at high risk of EF related to low number of stem cells and prior alloimmunization after multiple blood transfusions. Here, we evaluated the safety and efficacy of double-unit UCBT using TT-containing conditioning regimens in TM. Retrospective analysis of children who underwent double-unit UCBT for TM in the Prince of Wales Hospital between August 2007 and January 2017, and outcome of double-unit UCBT for TM was compared with outcome of HLA-matched sibling BMT. Ten patients, median age 4.2 years, received double-unit UCBT. All patients except one engrafted at a median of 19 days. None of the patients with successful engraftment had grade III or IV aGVHD. Among nine patients with successful engraftment, six of nine patients evaluable after day 100 developed cGVHD. All patients with cGVHD were well controlled after treatment with steroids and/or supportive care and maintained good quality of life. In comparison with patients receiving BMT, those given UCBT had slower platelet recovery, and more cGVHD. With a median follow-up of 272 months after BMT and 84 months after UCBT, the 8-year OS after BMT and UCBT was 92% and 90% (P = .84), whereas 8-year DFS after BMT and UCBT was 87% and 80% (P = .54). UCB could be an acceptable source of stem cells for transplantation of TM patients when HLA-matched family bone marrow donors are NA.

t(1;22)(p13;q13) Acute Megakaryoblastic Leukemia Complicated by Hepatic Fibrosis: Antifibrosis Therapy?

BACKGROUND: There is no established effective treatment for patients with t(1;22)(p13;q13) acute megakaryoblastic leukemia (AMKL) and hepatic fibrosis. OBSERVATION: Here we report the outcomes of 2 t(1;22)(p13;q13) AMKL patients with hepatic fibrosis. One patient died from liver failure despite the control of leukemia. The other patient was successfully treated with reduced-intensity chemotherapy and antifibrosis therapy with tretinoin and α-tocopheryl acetate, the hepatic fibrosis resolved and leukemia was in remission for 3 years. CONCLUSIONS: Reduced-intensity chemotherapy plus antifibrosis therapy with tretinoin and α-tocopheryl acetate could be a treatment option for these patients with t(1;22)(p13;q13) AMKL and hepatic fibrosis.

Awareness of diagnosis, treatment and risk of late effects in Chinese survivors of childhood cancer in Hong Kong.

BACKGROUND: For survivors of childhood cancer, awareness of personal health risks is a critical component of long-term health management. OBJECTIVE: To evaluate the awareness of the diagnosis, treatment and risk of late effects among survivors of childhood cancer in Hong Kong. METHODS: Between June 2019 and March 2020, this cross-sectional study recruited 155 adult survivors (mean age = 26.9, standard deviation [SD] = 6.4 years) and 45 parents of paediatric survivors (mean age = 11.1, SD = 3.6 years) from a long-term follow-up clinic. At >10 years post-treatment (mean = 13.4, SD = 7.6 years), they completed a structured questionnaire to report their cancer-specific knowledge. Multiple linear regression analysis was conducted to identify clinical, socioeconomic and behavioural factors associated with poor awareness. RESULTS: The majority of participants accurately recalled their diagnoses (73.5%) and major treatment modalities (chemotherapy 92.4%, radiation 82.9% and surgery 88.2%). However, less than half (45%) of the participants recognized more than 25% of the total late effects for which they were at risk. The highest levels of awareness were reported for endocrine problems (49%), neurocognitive impairment (44%) and secondary cancers (43%), and the lowest for peripheral neuropathy (21%) and vision problems (23%). Compared with survivors of haematological malignancies, those of central nervous system (CNS) tumours (standardized estimate [B] = -9.33, 95% confidence interval [95% CI]: -13.41 to -5.26) and non-CNS solid tumours (B = -8.47, 95% CI: -12.39 to -4.94) had less knowledge about their diagnosis. Retaining medical records (P < .0001) and better medical information-seeking habits (P = .048) were associated with better awareness. CONCLUSIONS: Survivors of childhood cancer in Hong Kong have deficient awareness of their personal health risks. They may benefit from the provision of a survivorship care plan and personalized education regarding treatment-related late effects. PATIENT CONTRIBUTION: Patients contributed in designing the study tools. Results were presented at a non-governmental organization.