Sex-based disparities in outcome in pediatric acute lymphoblastic leukemia: a Children's Oncology Group report.

BACKGROUND: Boys with acute lymphoblastic leukemia (ALL) have historically experienced inferior survival compared to girls. This study determined whether sex-based disparities persist with contemporary therapy and whether patterns of treatment failure vary by sex. METHODS: Patients 1 to 30.99 years old were enrolled on frontline Children's Oncology Group trials between 2004 and 2014. Boys received an additional year of maintenance therapy. Sex-based differences in the distribution of various prognosticators, event-free survival (EFS) and overall survival (OS), and subcategories of relapse by site were explored. RESULTS: A total of 8202 (54.4% male) B-cell ALL (B-ALL) and 1562 (74.3% male) T-cell ALL (T-ALL) patients were included. There was no sex-based difference in central nervous system (CNS) status. Boys experienced inferior 5-year EFS and OS (EFS, 84.6% ± 0.5% vs 86.0% ± 0.6%, P = .009; OS, 91.3% ± 0.4% vs 92.5% ± 0.4%, P = .02). This was attributable to boys with B-ALL, who experienced inferior EFS (hazard ratio [HR], 1.2; 95% confidence interval [95% CI], 1.1-1.3; P = .004) and OS (HR, 1.2; 95% CI, 1.0-1.4; P = .046) after adjustment for prognosticators. Inferior B-ALL outcomes in boys were attributable to more relapses (5-year cumulative incidence 11.2% ± 0.5% vs 9.6% ± 0.5%; P = .001), particularly involving the CNS (4.2% ± 0.3% vs 2.5% ± 0.3%; P < .0001). There was no difference in isolated bone marrow relapses (5.4% ± 0.4% vs 6.2% ± 0.4%; P = .49). There were no sex-based differences in EFS or OS in T-ALL. CONCLUSIONS: Sex-based disparities in ALL persist, attributable to increased CNS relapses in boys with B-ALL. Studies of potential mechanisms are warranted. Improved strategies to identify and modify treatment for patients at highest risk of CNS relapse may have particular benefit for boys.

Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia.

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas include recommendations for the diagnosis and management of pediatric patients with primary mediastinal large B-cell lymphoma (PMBL) and sporadic variants of Burkitt lymphoma and diffuse large B-cell lymphoma. PMBL is now considered as a distinct entity arising from mature thymic B-cells accounting for 2% of mature B-cell lymphomas in children and adolescents. This discussion section includes the recommendations outlined in the NCCN Guidelines for the diagnosis and management of pediatric patients with PMBL.

Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL.

Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.

Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1-like ALL) in children with National Cancer Institute (NCI) intermediate- or high-risk (HR) ALL is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors. The prevalence, outcome, and potential for targeted therapy of Ph-like ALL in standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled in the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, and 67 patients with either BCR-ABL1 (n = 6) or ETV6-RUNX1 (n = 61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted reverse transcription polymerase chain reaction assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including CRLF2 rearrangements (29.5% of Ph-like), ABL-class fusions (1.4%), JAK2 fusions (1.4%), an NTRK3 fusion (0.7%), and other sequence mutations (IL7R, KRAS, NRAS; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared with non-Ph-like ALL (82.4 ± 3.6% vs 90.7 ± 1.0%, P = .0022), with no difference in overall survival (93.2 ± 2.4% vs 95.8 ± 0.7%, P = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia.

BACKGROUND: The BCL-2 inhibitor venetoclax (ven) has revolutionized the treatment of acute myeloid leukemia (AML) in elderly adults, leading to its recent FDA approval for this population in combination regimens. Although extensive data exist for adult myeloid malignancies, there are limited preclinical data on the efficacy and/or dosing of venetoclax for pediatric myelodysplastic syndrome (MDS) or AML and thus little information to guide use of this regimen in pediatric patients. Our objective was to describe our single-center experience with venetoclax in combination with the hypomethylating agent 5-azacitidine (aza) in pediatric patients with MDS or AML. PROCEDURE: We conducted a retrospective chart review of patients treated at Children's Hospital Colorado prior to March 2020 with at least one cycle of ven/aza. Patients were included if between the ages of 1 and 25 years with a diagnosis of high-grade MDS or AML. AML patients had relapsed or primary refractory disease or were deemed poor candidates for standard chemotherapy. RESULTS: Eight patients received ven/aza, two for high-grade MDS and six for AML. Ven/aza was well tolerated by all patients. The most common adverse events seen with this regimen were gastrointestinal and hematologic. Morphologic responses were seen in six patients including both patients with MDS. All four AML responders became minimal residual disease negative. Three responders have thus far proceeded to allogeneic hematopoietic stem cell transplant following ven/aza. CONCLUSIONS: Our clinical experience suggests that ven/aza is a safe and promising regimen that should be further explored with late-phase clinical trials.

Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children's Oncology Group study.

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, TPMT genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, P = .02; Asian, OR, 3.1, P = .02; African American, P < .001; paternal education less than college (OR, 1.4, P = .05); and 6MP nonadherence (OR, 9.4, P < .001). Self-report of 6MP intake in childhood ALL overestimates true intake, particularly in nonadherent patients, and should be used with caution.

Successful Use of EPOCH-R in 2 Young Adult Patients With Burkitt Lymphoma and Acute Kidney Injury: A Case Report.

Pediatric Burkitt lymphoma has historically been treated with intensive methotrexate-based chemotherapy, which improves patient survival while causing severe toxicities. Young patients typically have better outcomes with intensive therapies, while adults and immunocompromised patients have higher toxicities and worse outcomes. Newer treatment regimens, including etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab (EPOCH-R), show promise for these patients. However, few studies exist to demonstrate efficacy and improved toxicity profile with EPOCH-R. We present 2 cases: a 25-year-old male with Down syndrome and an 18-year-old male with Burkitt lymphoma and significant renal injury who were successfully treated with EPOCH-R with minimal toxicities.

Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia.

Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetics of osteonecrosis have focused on patients ≥10 years of age, leaving the genetic risk factors for the larger group of children <10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children <10 years. The discovery cohort comprised 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) standard-risk ALL protocol AALL0331 (NCT00103285, https://clinicaltrials.gov/ct2/show/NCT00103285), with results tested for replication in 817 children <10 years treated on COG protocol AALL0232 (NCT00075725, https://clinicaltrials.gov/ct2/show/NCT00075725). The top replicated single nucleotide polymorphisms (SNPs) were near bone morphogenic protein 7 [BMP7: rs75161997, P = 5.34 × 10(-8) (odds ratio [OR] 15.0) and P = .0498 (OR 8.44) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 (PROX1-AS1: rs1891059, P = 2.28 × 10(-7) [OR 6.48] and P = .0077 [OR 3.78] for the discovery and replication cohorts, respectively). The top replicated nonsynonymous SNP, rs34144324, was in a glutamate receptor gene (GRID2, P = 8.65 × 10(-6) [OR 3.46] and P = .0136 [OR 10.8] in the discovery and replication cohorts, respectively). In a meta-analysis, the BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the significance threshold of <5 × 10(-8). Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and analysis of annotated genes demonstrated enrichment in glutamate receptor and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis.

The ENTPD1 promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk.

Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1) degrades the purines ATP and ADP that are key regulators of inflammation and clotting. We hypothesized that NTPDase1 polymorphisms exist and that they regulate this pathway. We sequenced the ENTPD1 gene (encoding NTPDase1) in 216 subjects then assessed genotypes in 2 cohorts comprising 2213 humans to identify ENTPD1 polymorphisms associated with venous thromboembolism (VTE). The G allele of the intron 1 polymorphism rs3176891 was more common in VTE vs. controls (odds ratio 1.26-1.9); it did not affect RNA splicing, but it was in strong linkage disequilibrium with the G allele of the promoter polymorphism rs3814159, which increased transcriptional activity by 8-fold. Oligonucleotides containing the G allele of this promoter region bound nuclear extracts more avidly. Carriers of rs3176891 G had endothelial cells with increased NTPDase1 activity and protein expression, and had platelets with enhanced aggregation. Thus, the G allele of rs3176891 marks a haplotype associated with increased clotting and platelet aggregation attributable to a promoter variant associated with increased transcription, expression, and activity of NTPDase1. We term this gain-of-function phenotype observed with rs3814159 G "CD39 Denver."-Maloney, J. P., Branchford, B. R., Brodsky, G. L., Cosmic, M. S., Calabrese, D. W., Aquilante, C. L., Maloney, K. W., Gonzalez, J. R., Zhang, W., Moreau, K. L., Wiggins, K. L., Smith, N. L., Broeckel, U., Di Paola, J. The ENTPD1 promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk.

Risk factors for bacteremia and central line-associated blood stream infections in children with acute myelogenous leukemia: A single-institution report.

BACKGROUND: Central line-associated blood stream infections (CLABSIs) are a source of high morbidity and mortality in children with acute myelogenous leukemia (AML). PROCEDURE: To understand the epidemiology and risk factors associated with the development of CLABSI in children with AML. METHODS: We retrospectively reviewed all patients with AML over a 5-year period between 2007 and 2011 at the Children's Hospital Colorado. Cases and controls were classified on the basis of the presence of a CLABSI as defined by the National Healthcare Safety Network. RESULTS: Of 40 patients in the study, 25 (62.5%) developed at least one CLABSI during therapy. The majority of CLABSIs were due to oral or gastrointestinal organisms (83.0%). Skin organisms accounted for 8.5%. In a multivariable analysis, the strongest risk factors associated with CLABSI were diarrhea (odds ratio [OR] 6.7, 95% confidence interval [CI] 1.6-28.7), receipt of blood products in the preceding 4-7 days (OR 10.0, 95%CI 3.2-31.0), not receiving antibiotics (OR 8.3, 95%CI 2.8-25.0), and chemotherapy cycle (OR 3.5, 95%CI 1.4-8.9). CLABSIs led to increased morbidity, with 13 cases (32.5%) versus two controls (1.9%) requiring transfer to the pediatric intensive care unit (P < 0.001). Three (7.5%) of 40 CLABSI events resulted in or contributed to death. CONCLUSIONS: Intensified line care efforts cannot eliminate all CLABSIs in the patients with AML. Exploring the role of mucosal barrier breakdown and/or the use of antibiotic prophylaxis may be effective strategies for further prevention of CLABSIs, supporting ongoing trials in this patient population.

Prevalence and predictors of anxiety and depression after completion of chemotherapy for childhood acute lymphoblastic leukemia: A prospective longitudinal study.

BACKGROUND: The months immediately after the completion of treatment for childhood acute lymphoblastic leukemia (ALL) are often regarded as a stressful time for children and families. In this prospective, longitudinal study, the prevalence and predictors of anxiety and depressive symptoms after the completion of treatment were examined. METHODS: Participants included 160 children aged 2 to 9 years with standard-risk ALL who were enrolled on Children's Oncology Group protocol AALL0331. Parents completed standardized rating scales of their children's emotional-behavioral functioning and measures of coping and family functioning at approximately 1 month, 6 months, and 12 months after diagnosis and again 3 months after the completion of chemotherapy. RESULTS: At 3 months off therapy, approximately 24% of survivors had at-risk/clinically elevated anxiety scores and 28% had elevated depression scores, which are significantly higher than the expected 15% in the general population (P = .028 and .001, respectively). Patients with elevated anxiety 1 month after diagnosis were at greater risk of off-therapy anxiety (odds ratio, 4.1; 95% confidence interval, 1.31-12.73 [P = .022]) and those with elevated depressive symptoms 6 months after diagnosis were at greater risk of off-therapy depression (odds ratio, 7.88; 95% confidence interval, 2.61-23.81 [P = .0002]). In adjusted longitudinal analyses, unhealthy family functioning (P = .008) and less reliance on social support coping (P = .009) were found to be associated with risk of emotional distress. Children from Spanish-speaking families (P = .05) also were found to be at a greater risk of distress. CONCLUSIONS: A significant percentage of children experience emotional distress during and after therapy for ALL. These data provide a compelling rationale for targeted early screening and psychosocial interventions to support family functioning and coping skills. Cancer 2016;122:1608-17. © 2015 American Cancer Society.

Anxiety, pain, and nausea during the treatment of standard-risk childhood acute lymphoblastic leukemia: A prospective, longitudinal study from the Children's Oncology Group.

BACKGROUND: This prospective study describes the procedure-related anxiety, treatment-related anxiety, pain, and nausea experienced by children with standard-risk acute lymphoblastic leukemia (ALL) during the first year of treatment. METHODS: This study was undertaken at 31 Children's Oncology Group (COG) sites. Eligible children who were 2 to 9.99 years old were enrolled in a COG trial for patients with newly diagnosed standard-risk ALL from 2005 to 2009. Parents completed a demographic survey at the baseline and the Pediatric Quality of Life Inventory 3.0 Cancer Module (proxy version) and the General Functioning Scale of the Family Assessment Device 1, 6, and 12 months after the diagnosis. The association between patient-related (age, sex, ethnicity, and treatment), parent-related (marital status and education), and family-related factors (functioning, income, and size) and symptom scores was evaluated. RESULTS: The mean scores for procedure-related anxiety, treatment-related anxiety, and pain improved during the first year of treatment (P < .0389). The mean nausea score was poorer 6 months after the diagnosis in comparison with the other assessments (P = .0085). A younger age at diagnosis was associated with significantly worse procedure-related anxiety (P = .004). An older age (P = .0002) and assignment to the intensified consolidation study arm (P = .02) were associated with significantly worse nausea. CONCLUSIONS: Children with ALL experienced decreasing treatment-related anxiety, procedure-related anxiety, and pain during the first year of treatment. In comparison with scores at 1 and 12 months, nausea was worse 6 months after the diagnosis. Minimization of procedure-related anxiety in younger children and improved nausea control in older children and those receiving more intensified treatment should be prioritized.

6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children's Oncology Group study.

Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP). Adherence to oral 6MP among Asian-American and African-American children with ALL is unknown. We enrolled 298 children with ALL (71 Asian Americans, 68 African Americans, and 159 non-Hispanic whites) receiving oral 6MP for the maintenance phase. Adherence was measured electronically for 39 803 person-days. Adherence declined from 95.0% (month 1) to 91.8% (month 5, P < .0001). Adherence rates were significantly (P < .0001) lower in Asian Americans (90.0% ± 4.9%) and African Americans (87.1% ± 4.4%), as compared with non-Hispanic whites (95.2% ± 1.3%). Race-specific sociodemographic characteristics helped explain poor adherence (African Americans: low maternal education [less than a college degree: 78.9%, vs at least college degree: 94.6%; P < .0001]; Asian Americans: low-income households [<$50 000: 84.5%, vs ≥$50 000: 96.7%; P = .04]; households without mothers as full-time caregivers [85.6%] vs households with mothers as full-time caregivers [97.2%; P = .05]). Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P = .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00268528.

Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia or Chronic Myeloid Leukemia in Lymphoid Blast Crisis.

The clinical characteristics of chronic myeloid leukemia (CML) in lymphoid blast crisis (BC) can resemble those of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). Because of this, there can be concern as to whether a patient with newly diagnosed Ph leukemia has Ph ALL or CML in lymphoid BC. This distinction has significant potential therapeutic implications because most children with Ph ALL are now treated with chemotherapy plus a tyrosine kinase inhibitor, whereas allogeneic stem cell transplant is usually recommended for any patient with CML that presents in or later develops BC.

A prospective study of anxiety, depression, and behavioral changes in the first year after a diagnosis of childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

BACKGROUND: The authors prospectively assessed anxiety, depression, and behavior in children with standard-risk acute lymphoblastic leukemia (SR-ALL) during the first year of therapy and identified associated risk factors. METHODS: A cohort study was performed of 159 children (aged 2 years-9.99 years) with SR-ALL who were enrolled on Children's Oncology Group protocol AALL0331 at 31 sites. Parents completed the Behavior Assessment System for Children, the General Functioning Scale of the Family Assessment Device, and the Coping Health Inventory for Parents at approximately 1, 6, and 12 months after diagnosis. RESULTS: Overall, mean scores for anxiety, depression, aggression, and hyperactivity were similar to population norms. However, more children scored in the at-risk/clinical range for depression than the expected 15% at 1 month (21.7%; P= .022), 6 months (28.6%; P< .001), and 12 months (21.1%; P= .032). For anxiety, more children scored in the at-risk/clinical range at 1 month (25.2% vs 15%; P= .001), but then reverted to expected levels. On adjusted analysis, unhealthy family functioning was found to be predictive of anxiety (odds ratio [OR], 2.24; P= .033) and depression (OR, 2.40; P= .008). Hispanic ethnicity was associated with anxiety (OR, 3.35; P= .009). Worse physical functioning (P= .049), unmarried parents (P= .017), and less reliance on social support (P= .004) were found to be associated with depression. Emotional distress at 1 month predicted anxiety (OR, 7.11; P= .002) and depression (OR, 3.31; P= .023) at 12 months. CONCLUSIONS: Anxiety is a significant problem in a subpopulation of patients with SR-ALL immediately after diagnosis, whereas depression remains a significant problem for at least 1 year. Children of Hispanic ethnicity or those with unhealthy family functioning may be particularly vulnerable. These data suggest that clinicians should screen for anxiety and depression throughout the first year of therapy.

Pulmonary presentation of relapsed acute myeloid leukemia.

Extramedullary manifestations of acute myeloid leukemia (AML), often referred to as myeloid sarcoma (MS), occur relatively commonly in children with newly diagnosed or relapsed AML and have been associated with certain French-American-British morphologies and gene/chromosomal rearrangements. The most common locations of MS include the skin, orbit, skeleton, central nervous system, skin, and gut. Pulmonary MS is uncommon in adults and is extremely rare in children. We report the case of a 19-year-old man with French-American-British M5 AML, who before bone marrow transplant, presented with fever, hypotension, and respiratory symptoms that were ultimately attributed to pulmonary MS.

Household income and health-related quality of life in children receiving treatment for acute myeloid leukemia: Potential impact of selection bias in health equity research.

OBJECTIVE: Examine the influence of household income on health-related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). DESIGN: Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. EXPOSURE: Household income was self-reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. OUTCOME: Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. RESULT: Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2-20.2). Seven percent of enrolled patients presented with high acuity (ICU-level care in the first 72 h), and 16% had high toxicity (any ICU-level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction. CONCLUSIONS: While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research.

Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group.

PURPOSE: Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019. METHODS: We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials. RESULTS: Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 103/µL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005). CONCLUSION: Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.