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

Resistance to glucocorticoids (GC), 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-offunction 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 GC-resistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GC 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.

Understanding the Experience of Cancer Survivorship Among Pediatric and Adolescent Cancer Survivors and Their Parents Through Camera Lenses: A Photovoice Study.

OBJECTIVE: Although the relative survival rate of childhood cancer has increased substantially in recent years, the pursuit of successful outcomes is often accompanied by negative impacts on pediatric and adolescent cancer survivors and their parents' physical and psychological well-being. However, little is known about their experiences during the period of cancer survivorship. This study aimed to gain an understanding of the experience of cancer survivorship among pediatric and adolescent cancer survivors and their parents. METHODS: This study utilized a descriptive qualitative study employing the photovoice design. From September 2022 to March 2023, 17 pediatric and adolescent cancer survivors (9-18 years), who had completed active treatment at least 6 months before recruitment, participated in this study. A total of 217 photographs submitted by survivors and their parents and the interview data, were thematically analyzed to identify themes and subthemes. RESULTS: The analysis revealed five prominent themes: indelible marks, struggling with late effects, striving to return to normalcy, the strength of support, and living in the moment and hope for the future. CONCLUSION: The findings shed light on the experiences of pediatric and adolescent cancer survivors and their parents throughout the cancer journey, elucidating the influence on both negative and positive aspects. Additionally, the study highlighted that photovoice facilitated self-reflection, the discovery of values, and the recognition of strengths and can be a therapeutic strategy for pediatric and adolescent cancer survivors and their parents in further research.

Causes of death and treatment-related mortality in newly diagnosed childhood acute lymphoblastic leukemia treatment with Chinese Children's Cancer Group study ALL-2015.

To investigate the possible risk factors for death at post-treatment in children with acute lymphoblastic leukemia (ALL). A multivariate competing risk analysis was performed to retrospectively analyze the data of children with ALL who died after treatment with CCCG-ALL-2015 in China and to determine the possible risk factors for death at post-treatment in children with ALL. Age at the first diagnosis of ≥10 years; final risk level of high-risk; D19 minimal residual disease (MRD) (≥0.01%) and D46 MRD (≥0.01%); genetic abnormalities, such as KMT2A-rearrangement, c-Myc rearrangement, and PDGFRB rearrangement; and the presence of CNS3 (all P values, <0.05) were identified as independent risk factors, whereas the risk level at the first diagnosis of low-risk (LR) and ETV6::RUNX1 positivity was considered as independent protective factors of death in children with ALL. Among the 471 cases of death, 45 cases were treated with CCCG-ALL-2015 only, and 163 (34.61%) were treatment-related, with 62.42% due to severe infections. 55.83% of treatment-related mortality (TRM) occurred in the early phase of treatment (induction phase). TRM has a significant impact on the overall survival of pediatric patients with ALL. Moreover, the CCCG-ALL-2015 regimen has a better safety profile for treating children with ALL, with rates close to those in developed countries (registration number: ChiCTR-IPR-14005706; date of registration: June 4, 2014).

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.

Outcome prediction of chronic myeloid leukemia (CML) in children.

We evaluated the feasibility of existing risk assessment tools for chronic myeloid leukemia (CML) in children. Fifty-five patients with newly diagnosed CML between 1996 and 2019 were included. Forty-nine patients presented in chronic phase, thirty-six of whom were treated with upfront tyrosine kinase inhibitor (CP-TKI group); one presented in accelerated phase and four in blastic phase. Treatment, survival, responses, and tolerance were evaluated. All patients in the CP-TKI group received imatinib as their first TKI treatment. The 10-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of TKI-treated group was 97%, 91.4%, and 72.3%, respectively. At 60 months, the rates of major molecular response were 81.2% and deep molecular response was 67.5%. The EUTOS long-term survival (ELTS) risk grouping did not predict OS, PFS, or EFS. The IMAFAIL risk groups were correlated with the risk of imatinib failure. Further studies are required to modify the existing risk assessment tools for children.

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.

Acute Leukemia in Down Syndrome Children in Hong Kong: Retrospective Review.

BACKGROUND: Children with Down syndrome (DS) are at higher risk of developing acute leukemia. Treatment continues to evolve as we accumulate better understanding of the distinctive clinical and biological features of acute leukemia in DS patients. PROCEDURE: A retrospective review of the clinical features, treatment outcomes, and survival of DS children with acute leukemia in Hong Kong from 1993 to 2013 was conducted. Patients were identified from the registry of the Hong Kong Pediatric Hematology and Oncology study group. RESULTS: This cohort included a total of 29 patients with DS. Ten were diagnosed with acute lymphoblastic leukemia and 19 had acute myeloid leukemia (AML). The mean follow-up duration was 8.3 years (range, 0.6 mo to 18.1 y). The 5-year overall survival and event-free survival for DS-acute lymphoblastic leukemia and DS-AML were 65.6%, 54.9%, 89.5%, and 89.5%, respectively. CONCLUSIONS: The clinical characteristics and treatment outcomes of DS patients with acute leukemia in Hong Kong were comparable with results from other international study groups. Patients with DS-AML had a better prognosis.

The use of traditional, complementary and integrative medicine in Chinese adolescent and young adult patients with cancer: A multicenter cross-sectional study.

PURPOSE: Adolescent and young adult (AYA) patients with cancer often experience unique physical and psychosocial complications. They may turn to traditional, complementary and integrative medicines (TCIM) to address these concerns. To examine the pattern of TCIM use among AYA patients with cancer and explored their preferences regarding TCIM education. METHODS: Between August 2021 and December 2022, 246 patients diagnosed with cancer between 15 and 39 years old were recruited from hospitals in Hong Kong. They completed a structured questionnaire on TCIM use, symptom burden, psychological status and preference on education content. Multivariable logistic regression was used to identify predictors of TCIM use, adjusting for age and sex. RESULTS: Overall, 60.2% reported TCIM use, most commonly vitamins (24.0%) and Chinese herbal medicine (22.0%). The most common reasons for using TCIM were to improve general health (70.9%) and manage chronic symptoms (33.1%). Among patients on active treatment, TCIM users tend to report higher anxiety symptoms (aOR = 1.13, 95% CI = 1.02-1.27). TCIM users who were post-treatment were more likely to have chronic comorbidities (aOR = 3.54, 95% CI = 1.29-11.5). AYA patients indicated that they would like TCIM information to address specific needs, particularly fatigue (53.7%) and psychological problems (54.1%). CONCLUSIONS: The use of TCIM is common among AYA patients with cancer, especially among patients with high symptom burdens. A tailored education programme should be provided based on patients' preferences and needs. Healthcare professionals including oncologists and oncology nurses should communicate with AYA patients about TCIM use and address their needs by making evidence-based referrals/recommendations based on treatment status and symptom burden.

The incidence, risk factors, and outcomes of symptomatic avascular necrosis of bone among Chinese pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: Avascular necrosis (AVN) of bone is a debilitating complication of pediatric patients with acute lymphoblastic leukemia (ALL). While it is extensively studied and reported in Western population, studies focused on Orientals are limited. This study aims to evaluate the incidence, risk factors, and clinical outcomes of AVN among Chinese children with ALL. METHODS: This study is a retrospective, territory-wide population-based cohort study of pediatric patients with ALL enrolled on one of the three consecutive ALL study protocols (ALL-IC-BFM 2002, CCLG-ALL 2008, and CCCG-ALL 2015). RESULTS: A total of 24 out of 533 pediatric subjects with ALL (4.5%) had symptomatic AVN. Age was the single most important risk factor associated with the development of AVN. Only three patients were below age of 10 at the time of diagnosis of ALL. The incidences of AVN in patients aged above and below 10 years were 18.2% ± 3.6% and 0.8% ± 0.5%, respectively, and were significantly different (p < 0.005). Treatment protocol, immunophenotype, and gender were not predictive of AVN. Among the 24 patients, five required orthopedic interventions in view of progressive and severe disease. For subjects with hip joints involvement, follow-up assessments showed 12 of 22 hip joints had radiological progression over a median duration of 3.63 years. Seventeen of them did not have pain at the latest follow-up and among patients with pain (n = 7), five did not experience any limitation on activities of daily living while two required use of walking aids or wheelchair. CONCLUSION: The incidence of symptomatic AVN in Chinese ALL patients was comparable to other studies in Western population. Adolescent age more than 10 years old was recognized to be the most important factor for development of AVN. Significant proportion of patients had radiological progression over time with a small percentage of subjects had daily activities affected.

Prognosis and outcome of relapsed acute lymphoblastic leukemia: a Hong Kong Pediatric Hematology and Oncology Study Group report.

BACKGROUND: In 2000, the Hong Kong Pediatric Hematology Oncology Study Group started a new relapsed acute lymphoblastic leukemia (ALL) treatment protocol based on modified ALL-REZ BFM 96 protocol aiming at improving the treatment outcome in Chinese children. PROCEDURE: All patients in Hong Kong with first relapse of childhood ALL were included. Patients were stratified into four risk groups (S1, S2, S3, and S4) and the treatment consisted of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation, if indicated. RESULTS: Fifty-six patients were recruited and median age at diagnosis of ALL was 4.6 (range, 0.3-17) years. The median time from initial diagnosis to relapse was 2.5 (range, 0.3-9.1) years and follow-up time was 2.7 (range, 0-9.9) years. Forty-nine patients (87.5%) achieved second complete remission (CR2). CR2 rates for S1, S2, S3, and S4 groups were 100%, 93%, 90%, and 67%, respectively. Five-year overall survival (OS) was 50.5 ± 6.9% and event-free survival (EFS) was 41.5 ± 7.1%. There was no significant difference in survival among S1, S2, and S3 groups but S4 patients performed significantly worse with 5-year OS and EFS of 8% and 0%, respectively. CONCLUSION: Children with relapsed ALL of S1-S3 risk groups could be successfully treated with intensified treatment protocol. The S4 high risk group needs more innovative approach to improve treatment outcome.

R4 RGS proteins as fine tuners of immature and mature hematopoietic cell trafficking.

G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors. They are involved in almost every physiologic process and consequently have a pivotal role in an extensive number of pathologies, including genetic, neurologic, and immune system disorders. Indeed, the vast array of GPCRs mechanisms have led to the development of a tremendous number of drug therapies and already account for about a third of marketed drugs. These receptors mediate their downstream signals primarily via G proteins. The regulators of G-protein signaling (RGS) proteins are now in the spotlight as the critical modulatory factors of active GTP-bound Gα subunits of heterotrimeric G proteins to fine-tune the biologic responses driven by the GPCRs. Also, they possess noncanonical functions by multiple mechanisms, such as protein-protein interactions. Essential roles and impacts of these RGS proteins have been revealed in physiology, including hematopoiesis and immunity, and pathologies, including asthma, cancers, and neurologic disorders. This review focuses on the largest subfamily of R4 RGS proteins and provides a brief overview of their structures and G-proteins selectivity. With particular interest, we explore and highlight, their expression in the hematopoietic system and the regulation in the engraftment of hematopoietic stem/progenitor cells (HSPCs). Distinct expression patterns of R4 RGS proteins in the hematopoietic system and their pivotal roles in stem cell trafficking pave the way for realizing new strategies for enhancing the clinical performance of hematopoietic stem cell transplantation. Finally, we discuss the exciting future trends in drug development by targeting RGS activity and expression with small molecules inhibitors and miRNA approaches.

A scoping review of nausea, vomiting and retching measurement methods in children with cancer.

Evaluation of chemotherapy-induced nausea and vomiting (CINV) in the pediatric population is subject to diverse approaches. This scoping review summarizes the methods used in clinical studies that assessed nausea, vomiting or retching in children with cancer. We conducted a literature search of studies indexed in EMBASE and Ovid MEDLINE after 2000. Studies were included if they involved patients ≤18 years of age diagnosed with cancer, and had nausea, vomiting or retching as a primary study outcome. We excluded studies that reported only parent- or clinician-proxy measures without including the child's self-reported NVR, and those without specifying the NVR data collection process. The literature search identified twenty-four studies evaluating pediatric nausea, vomiting or retching. In the assessment of NVR, structured surveys were the most commonly used instrument for NVR assessment (75%) and the use of patient diaries (50%). Nine studies (38%) relied solely on self-reports from children as the outcome measure, while fifteen studies (62%) solicited input from parents/ caregivers and healthcare providers in addition to children's self-reports. Almost all the studies reported the frequency (n = 24) and/or severity (n = 23) of NVR symptoms and the use of antiemetic therapy (n = 19). Fewer studies evaluated distress caused by the symptoms (n = 2) and the effects of symptoms on activities of daily living (n = 4). Incorporating NVR measurement tools as part of standard of care for pediatric patients undergoing chemotherapy is strongly advocated. Based on the age group, we recommend the use of such tools comprising Likert scale, pictorial scales and structured scripts to assess various dimensions of a child's NVR experience.

Medication Burden Among Pediatric Cancer Survivors: Analysis of a Population-Wide Electronic Database in Hong Kong.

BACKGROUND: Few studies have evaluated the medication burden borne by survivors of pediatric cancer. This study aimed to describe the drug utilization pattern of chronic medications in a cohort of young pediatric cancer survivors. METHODS: This was a population-based study of patients diagnosed with cancer at age 18 years or younger between 2000 and 2013 in Hong Kong and who had survived at least 5 years postdiagnosis. The primary outcome is the use of any chronic medication (medications that were prescribed for ≥30 consecutive days within a 6-month period). Multivariable log-binomial models were used to identify factors associated with chronic medication use. Kaplan-Meier analysis was used to present the cumulative proportion of survivors initiated on a chronic medication across time from cancer diagnosis. RESULTS: Of the 2444 survivors (median age = 22 years, interquartile range = 16-27 years), 669 (27.4%) required at least 1 chronic medication at least 5 years postdiagnosis. Survivors who developed a chronic health condition (CHC) had a 5.48 (95% confidence interval [CI] = 4.49 to 6.71) times higher risk of taking a chronic medication than those without CHC. At 10 years postdiagnosis, the cumulative proportion of survivors being initiated a chronic medication was 33.4% (95% CI = 31.1% to 35.6%) for the overall cohort. Higher cumulative proportions were observed in survivors with endocrine (74.6%, 95% CI = 68.4% to 79.6%), renal (68.8%, 95% CI = 54.2% to 78.7%), neurological (58.6%, 95% CI = 46.1% to 68.1%), and cardiovascular (54.7%, 95% CI = 44.0% to 63.4%) disorders. CONCLUSION: Survivors with certain CHCs had a higher risk of starting a prescription medication in the early phase of survivorship. Future studies include examining the impact of medication burden on survivors' functional status.

Integrating Complementary Medicine Into the Care of Childhood Cancer Survivors: A Brief Report on the Preliminary Framework and Implementation of an Educational Program.

Background: Existing educational programs typically include limited information on traditional, complementary, and integrative medicine (TCIM) for survivors of childhood cancer. Objectives: This brief report presents the preliminary results of an educational program that aims to promote the safe and effective use of Chinese medicine (CM) among survivors in Hong Kong. Methods: Survivors of childhood cancer, their caregivers, and oncology practitioners were invited to participate in a program that consists of two didactic seminars and a written educational booklet that disseminated information on the use of CM. A structured questionnaire was used to evaluate participants' receptivity toward and perceived relevance of the program. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to discuss the impact of the intervention. Results: Reach: A total of 174 participants attended the seminars, and the seminar recording received over 380 views on social media platforms since April 2021. The hardcopy of the educational booklet was distributed to 43 recipients. The web-version of the booklet was sent to 67 participants and downloaded 143 times. Efficacy: The majority found that the content of the seminar useful (mean score = 5.04/6 points), especially the CM exercise (mean score = 4.88/6 points) and dietary advice (mean score = 4.99/6 points). Intention to adopt: The survivors (or their caregivers) reported that they would adopt advice on food therapies (83.3%) and traditional Chinese health exercises (55.6%) during survivorship. Conclusion: The preliminary data on patient preferences will be applied to further develop educational materials and to establish a TCIM referral network within the cancer survivor community.

Treatment Adherence and Health-Related Quality of Life in Patients with Hemophilia in Hong Kong.

Background: This study aims to identify factors affecting health-related quality of life (HRQoL) in Chinese patients with hemophilia in Hong Kong, and to examine the association between treatment adherence and HRQoL outcomes. Methods: Patients with hemophilia A or B from a non-governmental organization reported their HRQoL and treatment adherence to prophylactic therapy using validated tools. Univariate tests and multivariable regression analysis were used to compare differences in outcomes across clinically relevant subgroups. Results: Fifty-six patients were recruited (mean age 30.4 [17.4] years; majority hemophilia A: 75%; moderate-to-severe severity: 88%). Patients who received prophylactic treatment reported fewer work/school problems (25.8 [18.9] versus 51.5 [26.3]; p = 0.001) than those who received on-demand therapy. The multivariable model showed that older age (B = 0.42, 95% CI = 0.093−0.75) and living in public housing (B = 10.24, 95% CI = 0.70−19.77) were associated with worse HRQoL. Older age was associated with treatment non-adherence (r = 0.66, p < 0.0001). Patients with poor adherence tended to report worse functioning in sports/leisure (r = 0.31, p = 0.033). Conclusions: Our results suggest that patients who were older, had lower education attainment and received on-demand treatment had poorer perception of their health. Improving adherence may lead to better HRQoL. Future work includes evaluating the occupational needs prospectively in this population.

Perceptions of Infertility Risk Among Chinese Parents of Children with Cancer: A Qualitative Study.

Objective: Anticancer treatment may be associated with damage to the reproductive organs and risk of infertility in children with cancer. The collectivist cultural norms of Asian societies may lead Chinese parents to have unique concerns regarding infertility. This qualitative study explored the perceptions of infertility risk and parenthood among parents of childhood cancer survivors in Hong Kong. Methods: Thirteen parents were recruited via a snowball sampling approach from a nongovernmental organization in Hong Kong, representing nine survivors of childhood cancer (leukemia n = 5, solid tumors n = 4). The in-depth semistructured interviews were audiotaped and transcribed verbatim. A thematic analysis was performed using ATLAS.ti 8. Results: Parents mostly perceived their children's fertility status as a distant concern (n = 11, 85%) but emphasized the need for timely information from clinicians when their children reach young adulthood (n = 8, 62%). They reported receiving inconsistent fertility information from different oncology practitioners (n = 9, 69%). A few parents acknowledged that under the influence of the Chinese culture, their children, especially sons, have an important duty to continue the family lineage. However, even if the cancer treatment were associated with infertility risk, almost all parents (n = 12, 92%) stated that it would still not affect their willingness to let their child undergo treatment because survival and cure were still their highest priority. Conclusion: Our findings suggest the need to proactively provide fertility information to parents both during active treatment and when survivors reach reproductive age. Future studies should evaluate the benefits of developing culturally relevant decision-making aids to address parents' informational needs regarding fertility issues.

A prospective multicenter study on varicella-zoster virus infection in children with acute lymphoblastic leukemia.

Background and methods: The study evaluated prognostic factors associated with varicella-zoster virus (VZV) infection and mortality in children with acute lymphoblastic leukemia (ALL) using data from the multicenter Chinese Children's Cancer Group ALL-2015 trial. Results: In total, 7,640 patients were recruited, and 138 cases of VZV infection were identified. The incidence of VZV infection was higher in patients aged ≥ 10 years (22.5%) and in patients with the E2A/PBX1 fusion gene (11.6%) compared to those aged < 10 years (13.25%, P = 0.003) or with other fusion genes (4.9%, P = 0.001). Of the 10 deaths in children with ALL and VZV infection, 4 resulted from VZV complications. The differences between groups in the 5-year overall survival, event-free survival, cumulative recurrence, and death in remission were not statistically significant. The proportion of complex infection was higher in children with a history of exposure to someone with VZV infection (17.9% vs. 3.6%, P = 0.022). Conclusion: VZV exposure was associated with an increased incidence of complex VZV infection and contributed to VZV-associated death in children with ALL.

Pharmacogenomic Profiling of Pediatric Acute Myeloid Leukemia to Identify Therapeutic Vulnerabilities and Inform Functional Precision Medicine.

Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacologic profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene-expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug clinical data set that could be leveraged to research the unique biology of pediatric AML and sets the stage for realizing functional precision medicine for the clinical management of the disease. SIGNIFICANCE: We conducted integrated drug and genomic profiling of patient biopsies to build the functional genomic landscape of pediatric AML. Age-specific differences in drug response and new gene-drug interactions were identified. The feasibility of functional precision medicine-guided management of children with high-risk AML was successfully demonstrated in two evaluable clinical cases. This article is highlighted in the In This Issue feature, p. 476.