Fine Motor Impairment and its Impact on Social Outcomes in Survivors of Pediatric Acute Lymphoblastic Leukemia: St Jude Lifetime Cohort Study.

OBJECTIVE: The impact of fine motor impairment among adult survivors of childhood acute lymphoblastic leukemia on life after treatment is unknown. METHODS: This study evaluated prevalence and utilized multivariate logistic regression to identify risk factors for fine motor impairment among survivors of acute lymphoblastic leukemia, and associations with educational attainment and social independence. Latent class analysis defined social independence (independent, moderately independent, dependent), using employment, independent living, personal care assistance, routine need assistance, driver's license status, and marital status inputs. RESULTS: Among 875 survivors who were ≥ 25 years old (age when most adults achieve independence) and ≥ 5 years from diagnosis (mean = 28.97 years), 33.6% had fine motor impairment, with scores at or below the 10th percentile of the scores of community controls (n = 460) on fine motor components of the Physical Performance Test and the Grooved Peg-Board Test. Survivors exposed to cranial radiation had more fine motor impairment than those without (45.8% vs 20.2%). Male sex (exposed: odds ratio [OR] = 2.55, 95.0% CI = 1.65-3.92; unexposed: OR = 3.02, 95.0% CI = 1.69-5.38), and lower scores on the Wechsler Abbreviated Scale of Intelligence (exposed: OR = 0.46, 95.0% CI = 0.36-0.58; unexposed: OR = 0.43, 95.0% CI = 0.31-0.58) were risk factors for neuropathy. A 1-point-higher total neuropathy score was associated with 8% (95.0% CI = 1%-17%) increased odds of fine motor impairment. Fine motor impairment was associated with less than a college education (less than high school: OR = 2.23, 95.0% CI = 1.20-4.14; high school diploma/general equivalency diploma: OR = 2.66, 95.0% CI = 1.65-4.30; vocational education: OR = 2.07, 95.0% CI = 1.38-3.13), and less social independence (moderately independent: OR = 1.80, 95.0% CI = 1.15-2.83; dependent: OR = 2.65, 95.0% CI = 1.25-5.64). CONCLUSION: Fine motor impairment in survivors of childhood acute lymphoblastic leukemia may interfere with optimal educational attainment and social independence. IMPACT: Early identification of survivors at risk for fine motor impairment, with timely intervention, may improve long-term outcomes.

Outcomes in patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies.

Children with ETV6::RUNX1 or high-hyperdiploid B-acute lymphoblastic leukemia (B-ALL) have favorable outcomes. The St. Jude (SJ) classification considers these patients low-risk, regardless of their National Cancer Institute (NCI) risk, except when there is slow minimal residual disease (MRD) response or central nervous system/testicular involvement. We analyzed outcomes in children (aged 1-18.99 years) with these genotypes in the SJ Total XV and XVI studies (2000-2017). Patients with ETV6::RUNX1 (n = 222) or high-hyperdiploid (n = 296) B-ALL had 5-year event-free survival (EFS) of 97.7% ± 1.1% and 94.7% ± 1.4%, respectively. For ETV6::RUNX1, EFS was comparable for NCI standard-risk and high-risk patients (97.8% ± 1.2% and 97.5% ± 2.6%, respectively; P = 0.917) and for SJ low-risk and standard-risk patients (97.4% ± 1.2% and 100.0%; P = 0.360). Thirty-seven of 40 NCI high-risk patients who received SJ low-risk therapy had excellent EFS (97.3% ± 2.8%). For high-hyperdiploid B-ALL, EFS was worse for NCI high-risk patients than for standard-risk patients (87.6% ± 4.5% and 96.4% ± 1.3%; P = 0.016). EFS was similar for NCI standard-risk and high-risk patients classified as SJ low-risk (96.0% ± 1.5% and 96.9% ± 3.2%; P = 0.719); however, EFS was worse for NCI high-risk patients than for NCI standard-risk patients receiving SJ standard/high-risk therapy (77.4% ± 8.2% and 98.0% ± 2.2%; P = 0.004). NCI high-risk patients with ETV6::RUNX1 or high-hyperdiploid B-ALL who received SJ low-risk therapy had lower incidences of thrombosis (P = 0.013) and pancreatitis (P = 0.011) than those who received SJ standard/high-risk therapy. Contemporary MRD-directed therapy yielded excellent outcomes, except for NCI high-risk high-hyperdiploid B-ALL patients with slow MRD response, who require new treatment approaches. Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with high-hyperdiploid B-ALL experienced excellent outcomes with a low-intensity regimen. These trials were registered at www.clinicaltrials.gov as #NCT00137111 and #NCT00549848.

The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Pharmacogenomic Score Effectively Personalizes Treatment of Acute Myeloid Leukemia.

PURPOSE: Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for more than five decades. Recent pharmacogenomics-based 10-SNP ara-C (ACS10) scores showed low ACS10 (≤0) to be associated with poor outcomes in patients with AML treated with standard chemotherapy. Here, we evaluated the ACS10 score in the context of three different induction I regimens in patients with pediatric AML. EXPERIMENTAL DESIGN: ACS10 score groups (low, ≤0, or high, >0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose ara-C (LDAC arm, n = 91), AML02 + AML08 high-dose ara-C (HDAC arm, n = 194), and AML08 clofarabine + ara-C (Clo/ara-C arm, n = 105) induction I regimens. RESULTS: Within the low-ACS10 score (≤0) group, significantly improved EFS and OS were observed among patients treated with Clo/ara-C as compared with LDAC (EFS, HR = 0.45; 95% CI, 0.23-0.88; P = 0.020; OS, HR = 0.44; 95% CI, 0.19-0.99; P = 0.048). In contrast, within the high-ACS10 score group (score >0), augmentation with Clo/ara-C was not favorable as compared with LDAC (Clo/ara-C vs. LDAC, EFS, HR = 1.95; 95% CI, 1.05-3.63; P = 0.035; OS, HR = 2.10; 95% CI, 0.96-4.59; P = 0.063). Personalization models predicted 9% improvement in the outcome in ACS10 score-based tailored induction (Clo/ara-C for low and LDAC for high-ACS10 score groups) as compared with nonpersonalized approaches (P < 0.002). CONCLUSIONS: Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcomes in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen.

Simultaneous Presentation of B-Acute Lymphoblastic Leukemia and Streptococcus agalactiae Meningitis in a 3-Year-old Girl.

Infection is a major cause of treatment-related morbidity and mortality in pediatric acute lymphoblastic leukemia (ALL). Most children with ALL who develop life-threatening bacterial infections do so during induction therapy. We describe a rare case of ALL presenting simultaneously with Streptococcus agalactiae group B Streptococcus bacteremia and meningitis in a 3-year-old girl. She received appropriate antimicrobial therapy and a 2-drug early induction regimen consisting of vincristine and dexamethasone, leading to slow neurologic recovery and a favorable initial response to anti-neoplastic therapy as evidenced by minimal residual disease of 1.12% on day 15 of induction.

Pediatric Erythroid Sarcoma Diagnostically Confirmed by Identification of a Recurrent NFIA::CBFA2T3 Fusion.

Erythroid sarcoma (ES) is exceedingly rare in the pediatric population with only a handful of reports of de novo cases, mostly occurring in the central nervous system (CNS) or orbit. It is clinically and pathologically challenging and can masquerade as a nonhematopoietic small round blue cell tumor. Clinical presentation of ES without bone marrow involvement makes diagnosis particularly difficult. We describe a 22-month-old female with ES who presented with a 2-cm mass involving the left parotid region and CNS. The presence of crush/fixation artifact from the initial biopsy made definitive classification of this highly proliferative and malignant neoplasm challenging despite an extensive immunohistochemical workup. Molecular studies including RNA-sequencing revealed a NFIA::CBFA2T3 fusion. This fusion has been identified in several cases of de novo acute erythroid leukemia (AEL) and gene expression analysis comparing this case to other AELs revealed a similar transcriptional profile. Given the diagnostically challenging nature of this tumor, clinical RNA-sequencing was essential for establishing a diagnosis.

Pharmacogenomics, Race, and Treatment Outcome in Pediatric Acute Myeloid Leukemia.

Importance: Disparities in outcomes exist between Black and White patients with acute myeloid leukemia (AML), with Black patients experiencing poorer prognosis compared with their White counterparts. Objective: To assess whether varying intensity of induction therapy to treat pediatric AML is associated with reduced disparities in treatment outcome by race. Design, Setting, and Participants: A comparative effectiveness analysis was conducted of 86 Black and 359 White patients with newly diagnosed AML who were enrolled in the AML02 trial from 2002 to 2008 or the AML08 trial from 2008 to 2017. Statistical analysis was conducted from July 2023 through January 2024. Interventions: Patients in AML02 were randomly assigned to receive standard low-dose cytarabine-based induction therapy or augmented high-dose cytarabine-based induction therapy, whereas patients in AML08 received high-dose cytarabine-based therapy. Main Outcomes and Measures: Cytarabine pharmacogenomic 10-single-nucleotide variant (ACS10) scores were evaluated for association with outcome according to race and treatment arm. Results: This analysis included 86 Black patients (mean [SD] age, 8.8 [6.5] years; 54 boys [62.8%]; mean [SD] leukocyte count, 52 600 [74 000] cells/µL) and 359 White patients (mean [SD] age, 9.1 [6.2] years; 189 boys [52.6%]; mean [SD] leukocyte count, 54 500 [91 800] cells/µL); 70 individuals with other or unknown racial and ethnic backgrounds were not included. Among all patients without core binding factor AML who received standard induction therapy, Black patients had significantly worse outcomes compared with White patients (5-year event-free survival rate, 25% [95% CI, 9%-67%] compared with 56% [95% CI, 46%-70%]; P = .03). By contrast, among all patients who received augmented induction therapy, there were no differences in outcome according to race (5-year event-free survival rate, Black patients, 50% [95% CI, 38%-67%]; White patients, 48% [95% CI, 42%-55%]; P = .78). Among patients who received standard induction therapy, those with low ACS10 scores had a significantly worse 5-year event-free survival rate compared with those with high scores (42.4% [95% CI, 25.6%-59.3%] and 70.0% [95% CI, 56.6%-83.1%]; P = .004); however, among patients who received augmented induction therapy, there were no differences in 5-year event-free survival rates according to ACS10 score (low score, 60.6% [95% CI, 50.9%-70.2%] and high score, 54.8% [95% CI, 47.1%-62.5%]; P = .43). Conclusions and Relevance: In this comparative effectiveness study of pediatric patients with AML treated in 2 consecutive clinical trials, Black patients had worse outcomes compared with White patients after treatment with standard induction therapy, but this disparity was eliminated by treatment with augmented induction therapy. When accounting for ACS10 scores, no outcome disparities were seen between Black and White patients. Our results suggest that using pharmacogenomics parameters to tailor induction regimens for both Black and White patients may narrow the racial disparity gap in patients with AML.

Diagnostic and treatment strategies for pediatric acute lymphoblastic leukemia in low- and middle-income countries.

The survival rate of children and adolescents with acute lymphoblastic leukemia (ALL), the most common pediatric cancer, has improved significantly in high-income countries (HICs), serving as an excellent example of how humans can overcome catastrophic diseases. However, the outcomes in children with ALL in low- and middle-income countries (LMICs), where approximately 80% of the global population live, are suboptimal because of limited access to diagnostic procedures, chemotherapeutic agents, supportive care, and financial assistance. Although the implementation of therapeutic strategies in resource-limited countries could theoretically follow the same path of improvement as modeled in HICs, intensification of chemotherapy may simply result in increased toxicities. With the advent of genetic diagnosis, molecular targeted therapy, and immunotherapy, the management of ALL is changing dramatically in HICs. Multidisciplinary collaborations between institutions in LMICs and HICs will provide access to strategies that are suitable for institutions in LMICs, enabling them to minimize toxicities while improving outcomes. This article summarizes important aspects of the diagnosis and treatment of pediatric ALL that were mostly developed in HICs but that can be realistically implemented by institutions in countries with limited resources through resource-adapted multidisciplinary collaborations.

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Choanephora infundibulifera Rhinosinusitis in Man with Acute Lymphoblastic Leukemia, Tennessee, USA.

Choanephora infundibulifera is a member of the Mucorales order of fungi. The species is associated with plants as a saprophyte or parasite and may be responsible for spoilage or disease but is an uncommon cause of human infection. We describe C. infundibulifera rhinosinusitis in a young man with leukemia in Tennessee, USA.

Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia.

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.

Germ line genetic NBN variation and predisposition to B-cell acute lymphoblastic leukemia in children.

ABSTRACT: Biallelic mutation in the DNA-damage repair gene NBN is the genetic cause of Nijmegen breakage syndrome, which is associated with predisposition to lymphoid malignancies. Heterozygous carriers of germ line NBN variants may also be at risk for leukemia development, although this is much less characterized. By sequencing 4325 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), we systematically examined the frequency of germ line NBN variants and identified 25 unique, putatively damaging NBN coding variants in 50 patients. Compared with the frequency of NBN variants in gnomAD noncancer controls (189 unique, putatively damaging NBN coding variants in 472 of 118 479 individuals), we found significant overrepresentation in pediatric B-ALL (P = .004; odds ratio, 1.8). Most B-ALL-risk variants were missense and cluster within the NBN N-terminal domains. Using 2 functional assays, we verified 14 of 25 variants with severe loss-of-function phenotypes and thus classified these as nonfunctional or partially functional. Finally, we found that germ line NBN variant carriers, all of whom were identified as heterozygous genotypes, showed similar survival outcomes relative to those with wild type status. Taken together, our findings provide novel insights into the genetic predisposition to B-ALL, and the impact of NBN variants on protein function and suggest that heterozygous NBN variant carriers may safely receive B-ALL therapy. These trials were registered at www.clinicaltrials.gov as #NCT01225874, NCT00075725, NCT00103285, NCI-T93-0101D, and NCT00137111.

Genomic and global gene expression profiling in pediatric and young adult acute leukemia with PICALM::MLLT10 Fusion.

PICALM: MLLT10 fusion is a rare but recurrent genetic driver in acute leukemias. To better understand the genomic landscape of PICALM::MLLT10 (PM) positive acute leukemia, we performed genomic profiling and gene expression profiling in twenty PM-positive patients, including AML (n = 10), T-ALL/LLy (n = 8), Mixed-phenotype acute leukemia (MPAL), T/B (n = 1) and acute undifferentiated leukemia (AUL) (n = 1). Besides confirming the known activation of HOXA, differential gene expression analysis compared to hematopoietic stem cells demonstrated the enrichment of genes associated with cell proliferation-related pathways and relatively high expression of XPO1 in PM-AML and PM-T-ALL/LLy. Our study also suggested PHF6 disruption as a key cooperating event in PICALM::MLLT10-positive leukemias. In addition, we demonstrated differences in gene expression profiles as well as remarkably different spectra of co-occurring mutations between PM-AML and PM-T-ALL/LLy. Alterations affecting TP53 and NF1, hallmarks of PM-AML, are strongly associated with disease progression and relapse, whereas EZH2 alterations are highly enriched in PM-T-ALL/LLy. This comprehensive genomic and transcriptomic profiling provides insights into the pathogenesis and development of PICALM::MLLT10 positive acute leukemia.

Ommaya reservoir use in pediatric ALL and NHL: a review at St. Jude Children's Research Hospital.

PURPOSE: The intraventricular route of chemotherapy administration, via an Ommaya Reservoir (OmR) improves drug distribution in the central nervous system (CNS) compared to the more commonly used intrathecal administration. We retrospectively reviewed our experience with intraventricular chemotherapy, focused on methotrexate, in patients with Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL). METHODS: Twenty-four patients (aged 7 days - 22.2 years) with 26 OmR placements were identified for a total of 25,009 OmR days between 1990 and 2019. Methotrexate cerebrospinal fluid (CSF) concentrations (n = 124) were analyzed from 59 courses of OmR therapy in 15 patients. Twenty-one courses involved methotrexate dosing on day 0 only, whereas 38 courses involved booster dosing on days 1, 2, or both. We simulated the time CSF methotrexate concentrations remained > 1 µM for 3 days given various dosing regimens. RESULTS: CSF methotrexate exposure was higher in those who concurrently received systemic methotrexate than via OmR alone (p < 10- 7). Our simulations showed that current intraventricular methotrexate boosting strategy for patients ≥ 3 years of age maintained CSF methotrexate concentrations ≥ 1 µM for 72 h 40% of the time. Alternatively, other boosting strategies were predicted to achieve CSF methotrexate concentrations ≥ 1 µM for 72 h between 46 and 72% of the time. CONCLUSIONS: OmR were able to be safely placed and administer intraventricular methotrexate with and without boost doses in patients from 7 days to 22 years old. Boosting strategies are predicted to increase CSF methotrexate concentrations ≥ 1 µM for 72 h.

COVID-19 in Pediatric Patients With Acute Lymphoblastic Leukemia or Lymphoma.

Importance: COVID-19 in pediatric patients with acute lymphoblastic leukemia or lymphoma (ALL/LLy) has not been described in detail and may affect chemotherapy administration and long-term outcomes. Objective: To describe the clinical presentation of COVID-19 and chemotherapy modifications in pediatric patients with ALL/LLy. Design, Setting, and Participants: This is a retrospective case series of patients at St Jude Children's Research Hospital and its affiliate sites with newly diagnosed ALL/LLy who were treated on the Total XVII protocol (NCT03117751) between March 30, 2020, and June 20, 2022. Participants included patients aged 1 to 18 years who were receiving protocol chemotherapy. Acute symptoms and chemotherapy modifications were evaluated for 60 days after the COVID-19 diagnosis, and viral clearance, adverse events, and second SARS-CoV-2 infections were followed up during the 27-month study period. Exposures: SARS-CoV-2; all patients were screened at least weekly and at symptom onset and/or after known exposure to SARS-CoV-2. Main Outcomes and Measures: Description of the spectrum of COVID-19 illness and chemotherapy modifications. Results: Of 308 pediatric patients, 110 (36%) developed COVID-19 at a median age of 8.2 (IQR, 5.3-14.5) years. Sixty-eight patients (62%) were male. Most patients were in the continuation/maintenance phase of chemotherapy (101 [92%]). Severe disease was rare (7 [6%]) but was associated with older age, higher white blood cell counts at ALL/LLy diagnosis, lower absolute lymphocyte counts at COVID-19 diagnosis, abnormal chest imaging findings, and SARS-CoV-2 reinfection. Rare but serious thrombotic events included pulmonary embolism and cerebral venous sinus thrombosis (n = 1 for each). No multisystem inflammatory syndrome in children or death was seen. SARS-CoV-2 reinfection occurred in 11 patients (10%) and was associated with older age and with receiving standard or high-risk vs low-risk ALL/LLy therapy. Chemotherapy interruptions occurred in 96 patients (87%) and were longer for patients with severe disease, SARS-CoV-2 reinfection, and/or a COVID-19 diagnosis during the pre-Omicron variant period vs the post-Omicron period (after December 27, 2021). Conclusions and Relevance: In this case series of COVID-19 in pediatric patients with ALL/LLy, severe COVID-19 was rare, but chemotherapy administration was affected in most patients. Long-term studies are needed to establish the outcomes of COVID-19 in this population.

Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.

BACKGROUND: Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. METHODS: MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-). RESULTS: Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP. CONCLUSION: We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

Quantitative computed tomography analysis of body composition changes in paediatric patients with acute lymphoblastic leukaemia.

Children with acute lymphoblastic leukaemia (ALL) are at risk for obesity and cardiometabolic diseases. To gain insight into body composition changes among children with ALL, we assessed quantitative computed tomography (QCT) data for specific body compartments (subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT], total adipose tissue [TAT], lean tissue [LT], LT/TAT and VAT/SAT at lumbar vertebrae L1 and L2) at diagnosis and at off-therapy for 189 children with ALL and evaluated associations between body mass index (BMI) Z-score and clinical characteristics. BMI Z-score correlated positively with SAT, VAT and TAT and negatively with LT/TAT and VAT/SAT. At off-therapy, BMI Z-score, SAT, VAT and TAT values were higher than at diagnosis, but LT, LT/TAT and VAT/SAT were lower. Patients aged ≥10 years at diagnosis had higher SAT, VAT and TAT and lower LT and LT/TAT than patients aged 2.0-9.9 years. Female patients had lower LT and LT/TAT than male patients. Black patients had less VAT than White patients. QCT analysis showed increases in adipose tissue and decreases in LT during ALL therapy when BMI Z-scores increased. Early dietary and physical therapy interventions should be considered, particularly for patients at risk for obesity.

Genomic analysis of venous thrombosis in children with acute lymphoblastic leukemia from diverse ancestries.

Venous thrombosis is a common adverse effect of modern therapy for acute lymphoblastic leukemia (ALL). Prior studies to identify risks of thrombosis in pediatric ALL have been limited by genetic screens of pre-identified genetic variants or genome- wide association studies (GWAS) in ancestrally uniform populations. To address this, we performed a retrospective cohort evaluation of thrombosis risk in 1,005 children treated for newly diagnosed ALL. Genetic risk factors were comprehensively evaluated from genome-wide single nucleotide polymorphism (SNP) arrays and were evaluated using Cox regression adjusting for identified clinical risk factors and genetic ancestry. The cumulative incidence of thrombosis was 7.8%. In multivariate analysis, older age, T-lineage ALL, and non-O blood group were associated with increased thrombosis while non-low-risk treatment and higher presenting white blood cell count trended toward increased thrombosis. No SNP reached genome-wide significance. The SNP most strongly associated with thrombosis was rs2874964 near RFXAP (G risk allele; P=4x10-7; hazard ratio [HR] =2.8). In patients of non-European ancestry, rs55689276 near the α globin cluster (P=1.28x10-6; HR=27) was most strongly associated with thrombosis. Among GWAS catalogue SNP reported to be associated with thrombosis, rs2519093 (T risk allele, P=4.8x10-4; HR=2.1), an intronic variant in ABO, was most strongly associated with risk in this cohort. Classic thrombophilia risks were not associated with thrombosis. Our study confirms known clinical risk features associated with thrombosis risk in children with ALL. In this ancestrally diverse cohort, genetic risks linked to thrombosis risk aggregated in erythrocyte-related SNP, suggesting the critical role of this tissue in thrombosis risk.