Outcomes of Referrals in Pediatric Patients With Peripheral Lymphadenopathy.

Lymphadenopathy is a common reason for referral to a subspecialist, which may result in significant anxiety for parents. Understanding which patients require a subspecialty referral for lymphadenopathy is key to streamlining health care utilization for this common clinical entity. This is an IRB-approved retrospective study examining pediatric patients consecutively referred to pediatric hematology oncology, otolaryngology, or surgery for lymphadenopathy from 2012 to 2021 at a free-standing tertiary-care children's hospital. Logistic regression was fitted to examine the association between the maximum size of the lymph nodes (LN) and a diagnosis of malignancy. The odds ratio, area under the receiver operator curve, sensitivity, and specificity were estimated. We found a significant association between LN size and cancer diagnosis. For every centimeter increase in the maximal dimension of LN, there was an estimated 2.3 times increase in the odds of malignancy (OR=2.3, 95% CI: 1.65-3.11; P<0.0001). The estimated area under the curve (0.84, 95% CI: 0.78-0.90) indicated that LN size correlated well with cancer diagnosis. A LN cut-off size of 2 cm resulted in an estimated sensitivity of 1.0 (95% CI: 0.87-1.00) and specificity of 0.54 (95% CI: 0.46-0.61). Maximum LN size may be a predictor of malignancy among pediatric patients with lymphadenopathy.

Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms.

During the past decade, the outcomes of pediatric patients with acute myeloid leukemia (AML) have plateaued with 5-year event-free survival (EFS) and overall survival (OS) of approximately 46 and 64%, respectively. Outcomes are particularly poor for those children with high-risk disease, who have 5-year OS of 46%. Substantial survival improvements have been observed for a subset of patients treated with targeted therapies. Specifically, children with KMT2A-rearranged AML and/or FLT3 internal tandem duplication (FLT3-ITD) mutations benefitted from the addition of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in the AAML0531 clinical trial (NCT00372593). Sorafenib also improved response and survival in children with FLT3-ITD AML in the AAML1031 clinical trial (NCT01371981). Advances in characterization of prognostic cytomolecular events have helped to identify patients at highest risk of relapse and facilitated allocation to consolidative hematopoietic stem cell transplant (HSCT) in first remission. Some patients clearly have improved survival with HSCT, although the benefit is largely unknown for most patients. Finally, data-driven refinements in supportive care recommendations continue to evolve with meaningful and measurable reductions in toxicity and improvements in EFS and OS. As advances in application of targeted therapies, risk stratification, and improved supportive care measures are incorporated into current trials and become standard-of-care, there is every expectation that we will see improved survival with a reduction in toxic morbidity and mortality. The research agenda of the Children's Oncology Group's Myeloid Diseases Committee continues to build upon experience and outcomes with an overarching goal of curing more children with AML.

Obesity in children with acute promyelocytic leukemia: What is its prevalence and prognostic significance?

OBJECTIVE: To compare outcomes of obese and nonobese pediatric patients with acute promyelocytic leukemia (APL) from the Cancer and Leukemia Group B trial (CALGB) 9710 and the Children's Oncology Group trial AAML0631. METHODS: Data including demographics, adverse events, overall and event-free survival (EFS) were analyzed. RESULTS: The prevalence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall and EFS in the obese population on multivariable analysis on AAML0631 but not on CALGB 9710. Eleven patients died during therapy or in follow-up. CONCLUSION: The prevalence of obesity is higher in pediatric patients with APL compared to the general population. The decreased EFS and OS in obese patients on AAML0631 suggest that the presence of obesity can influence outcomes using the most current treatment. These findings support the need for further research on the potential role of obesity in pediatric APL leukemogenesis.

Therapy-related Myeloid Neoplasms in Children: A Single-institute Study.

Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.

Time to Antibiotic for Pediatric Oncology Patients With Febrile Neutropenia at Regional Emergency Departments.

OBJECTIVES: We compared the time to antibiotic (TTA) for pediatric oncology patients with febrile neutropenia (FN) presenting at regional emergency departments (EDs) with those presenting at a pediatric referral ED, and examined its association with need for aggressive medical care. METHODS: We abstracted data for pediatric oncology patients (age, <21 years) admitted for FN between August 2012 and August 2017 at a single children's hospital and compared the TTA between those referred from a regional ED across the state and those admitted via the referral ED at the children's hospital. Factors associated with delay in antibiotic administration (TTA, >60 minutes) were estimated using generalized linear modeling with generalized estimating equations (GEEs). Delay in antibiotic administration was examined for its association with the need for aggressive medical care (>1 fluid bolus, intensive care unit admission, inotropic or invasive ventilator support) within 24 hours of admission as an exploratory aim. RESULTS: Three-hundred eighty-nine FN admissions (regional ED, 26.7%; referral ED, 73.3%) occurred in 205 eligible patients. Median TTA was significantly (P < 0.0001) greater among patients presenting at a regional ED (117.5 minutes [range, 9-722 minutes]) vs referral ED (46 minutes [range, 6-378 minutes]). Presentation at regional ED was the only factor associated with delay in antibiotic administration (odds ratio, 9.73; 95% confidence interval, 5.37-17.63; P < 0.0001). Delay in antibiotic administration was not associated with greater need for aggressive medical care (odds ratio, 1.34; 95% confidence interval, 0.55-3.29; P = 0.5). CONCLUSIONS: Pediatric oncology patients with FN presenting to regional EDs have longer TTA as compared with those presenting to a referral ED at a children's hospital.

Recurrent Skin Langerhan Cell Histiocytosis Successfully Treated With Indomethacin Monotherapy.

Langerhans cell histiocytosis (LCH) often has a recurrent and refractory course despite multiagent treatment modalities. Common relapse treatments include intense or prolonged cytotoxic chemotherapy regimens. There are a few prior reports that the nonsteroidal anti-inflammatory drug indomethacin demonstrated activity against bone LCH. Here we report indomethacin as a successful treatment for a case of chronic skin LCH that failed multiple prior chemotherapy regimens. This experience supports the need for trials to investigate indomethacin as a treatment for LCH both in the relapsed or refractory setting as well as potential combination or maintenance therapy in newly diagnosed patients.

Outcome for pediatric acute promyelocytic leukemia patients at Children's Oncology Group sites on the Leukemia Intergroup Study CALGB 9710 (Alliance).

BACKGROUND: Acute promyelocytic leukemia (APL) is a unique leukemia subtype requiring specialized treatment including all-trans retinoic acid (ATRA). A prior report demonstrated worse outcome among young children <5 years old compared with older children. METHODS: We evaluated outcomes for pediatric patients (<18 years old; N = 83) with APL treated on North American intergroup study CALGB 9710 at Children's Oncology Group sites. Induction and consolidation included ATRA, cytarabine, and anthracyclines. Patients ≥15 years old were randomized to addition of arsenic trioxide (ATO) consolidation. All patients were randomized to ATRA maintenance with versus without oral chemotherapy. RESULTS: The estimated 5-year overall survival (OS) rate was 82%, and the event-free survival (EFS) rate was 54%. Seven patients (8.4%) died during induction due to coagulopathy. Maintenance randomization demonstrated that addition of oral chemotherapy to ATRA significantly reduced relapse rate, but difference in EFS did not reach statistical significance (P = 0.12; 5-year rates [95% CI]: 41% [17%-64%] ATRA only vs 72% [56%-88%] ATRA plus chemotherapy). There was no difference (P = 0.93) in EFS for age <5 years versus 5-12.99 years versus 13-17.99 years (5-year rates: 56%, 47%, and 45%, respectively). Among adolescents 15-17.99 years old in the ATO randomization, there was a significantly lower relapse risk at 5 years for those receiving ATO (0% ATO vs 44% no ATO; P = 0.02). CONCLUSION: Our data demonstrate that intensified ATRA, cytarabine, and anthracycline chemotherapy is effective for pediatric APL including very young patients, but early deaths and relapses remain barriers to cure. Further improvements are likely with incorporation of ATO into pediatric APL regimens.

Risk Markers for Significant Bleeding and Thrombosis in Pediatric Acute Promyelocytic Leukemia; Report From the Children's Oncology Group Study AAML0631.

Acute promyelocytic leukemia (APL) is characterized by a heightened risk of coagulopathy with significant morbidity and mortality. Here we report our evaluation of presenting white blood cell (WBC) and the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scoring system as markers for early death and nonlethal coagulopathy in pediatric APL. We evaluated 79 pediatric patients treated on a Children's Oncology Group phase III clinical trial. There were 4 early deaths and 13 nonlethal, clinically significant (grade III to IV) coagulopathy events during induction. Elevated presenting WBC was significantly associated with early death but not with both lethal and nonlethal coagulopathy events. An ISTH DIC score of ≥5 (the original ISTH criteria for overt DIC) was not associated with either early deaths or coagulopathy events. An ISTH DIC score threshold of 6, however, was significantly associated with early death (12% score ≥6 vs. 0% score <6) and with both lethal and nonlethal coagulopathy events (35% score ≥6 vs. 11% score <6). In pediatric APL patients, the presenting WBC is a marker for risk of early death. Although the ISTH score using a cutoff of ≥6 showed improved correlation with adverse coagulation events during induction, the sensitivity was only 70.6% (95% confidence interval, 44.0%-89.7%) and the specificity was 64.5% (95% confidence interval, 51.3%-76.3%). Thus, there is a strong need to identify other biomarkers that can predict APL-associated coagulopathy.

Blinatumomab activity in a patient with Down syndrome B-precursor acute lymphoblastic leukemia.

Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B-precursor acute lymphoblastic leukemia (BP-ALL). Given the strong association of MRD and outcome in non-Down syndrome (non-DS) BP-ALL, it is likely that MRD levels are also of prognostic significance in DS BP-ALL. We report here the successful use of blinatumomab, a bispecific T-cell engager antibody construct, in a patient with DS BP-ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP-ALL. This patient had no significant toxicity and achieved MRD negativity after only one cycle of blinatumomab.

Acute myelogenous leukemia in adolescents and young adults.

The incidence of acute myelogenous leukemia (AML) increases progressively with age. Favorable genetic mutations are most prevalent in children, and unfavorable profiles increase proportionately in adolescents and young adults (AYA) and into later adulthood. Survival rates of AYA have improved over recent decades to 50-60%, but their accrual to clinical trials remains poor. In contrast to AYA with acute lymphoblastic leukemia, the prognostic benefit for AYA with AML enrolled in pediatric compared with adult trials is minor and only seen when different protocols are used. The distinctive needs of AYA, including intensive psychological services, call for their treatment within specialized centers that offer complex supportive care.

Protocol for Reducing Time to Antibiotics in Pediatric Patients Presenting to an Emergency Department With Fever and Neutropenia: Efficacy and Barriers.

OBJECTIVES: Patients with febrile neutropenia are at high risk of morbidity and mortality from infectious causes. Decreasing time to antibiotic (TTA) administration is associated with improved patient outcomes. We sought to reduce TTA for children presenting to the emergency department with fever and neutropenia. METHODS: In a prospective cohort study with historical comparison, TTA administration was evaluated in patients with neutropenia presenting to the Children's of Alabama Emergency Department. A protocol was established to reduce delays in antibiotic administration and increase the percentage of patients who receive treatment within 60 minutes of presentation. One hundred pre-protocol patient visits between August 2010 and December 2011 were evaluated and 153 post-protocol visits were evaluated between August 2012 and September 2013. We reviewed individual cases to determine barriers to rapid antibiotic administration. RESULTS: Antibiotics were administered in 96.9 ± 57.8 minutes in the pre-protocol patient group, and only 35% of patients received antibiotics within 60 minutes of presentation and 70% received antibiotics within 120 minutes. After implementation of the protocol, TTA for neutropenic patients was decreased to 64.3 ± 28.4 minutes (P < 0.0001) with 51.4% receiving antibiotics within 60 minutes and 93.2% within 120 minutes. CONCLUSIONS: Implementing a standard approach to patients at risk for neutropenia decreased TTA. There are numerous challenges in providing timely antibiotics to children with febrile neutropenia. Identified delays included venous access (time to effect of topical anesthetics, and difficulty obtaining access), physicians waiting on laboratory results, and antibiotic availability.

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921.

PURPOSE: Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS: In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS: Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 µg h/mL, 2.52 µg h/mL, and 2.66 µg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION: Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.

Characteristics and prognostic impact of IDH mutations in AML: a COG, SWOG, and ECOG analysis.

Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged between <1 month and 88 years treated on Children's Cancer Group/Children's Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): pediatric (0-17, 1744), adolescent/young adult (18-39, 444), intermediate-age (40-59, 640), older (≥60, 309). IDH mutations (IDHmut) were identified in 9.2% of the total cohort (n = 288; IDH1 [n = 123, 42.7%]; IDH2 [n = 165, 57.3%]) and were strongly correlated with increased age: 3.4% pediatric vs 21% older, P < .001. Outcomes were similar in IDHmut and IDH-wildtype (IDHWT) AML (event-free survival [EFS]: 35.6% vs 40.0%, P = .368; overall survival [OS]: 50.3% vs 55.4%, P = .196). IDH mutations frequently occurred with NPM1 (47.2%), DNMT3A (29.3%), and FLT3-internal tandem duplication (ITD) (22.4%) mutations. Patients with IDHmut AML with NPM1 mutation (IDHmut/NPM1mut) had significantly improved survival compared with the poor outcomes experienced by patients without (IDHmut/NPM1WT) (EFS: 55.1% vs 17.0%, P < .001; OS: 66.5% vs 35.2%, P < .001). DNTM3A or FLT3-ITD mutations in otherwise favorable IDHmut/NPM1mut AML led to inferior outcomes. Age group analysis demonstrated that IDH mutations did not abrogate the favorable prognostic impact of NPM1mut in patients aged <60 years; older patients had poor outcomes regardless of NPM1 status. These trials were registered at www.clinicaltrials.gov as #NCT00070174, #NCT00372593, #NCT01371981, #NCT00049517, and #NCT00085709.

FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group.

BACKGROUND: FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL). PROCEDURE: Diagnostic specimens from 104 pediatric APL patients were screened for FLT3/Mut (FLT3/ITD or FLT3/ALM). FLT3/Mut status was correlated with disease characteristics and clinical outcome for patients treated on CALGB C9710 (n = 50). RESULTS: Forty-two of the 104 patients (40%) had either FLT3/ITD (n = 28, 27%) or FLT3/ALM (n = 15, 14%). Median diagnostic WBC count was 23,400 cells/µl vs. 3,600 cells/µl for those with and without FLT3/Mut (P < 0.001), and similar results for the cohort of 50 patients treated on C9710 (P < 0.001). In patients treated on C9710, presence of a FLT3 mutation was highly correlated with diagnostic WBC count >10,000 (P = 0.004), microgranular variant histology (P = 0.035), and a lower remission rate (P = 0.009). In patients who received ATRA (C9710 or CCG-2911, n = 8), those with FLT3/Mut had an induction death rate of 30% (7/23) compared to 3% (1/35) in FLT3/WT patients (P = 0.005). In patients with high WBC counts (>10,000), those with FLT3/Mut had a significantly higher risk of induction death versus FLT3/WT patients (47% vs. 0%, P = 0.05). FLT3/Mut was not associated with adverse outcome in those who survived induction therapy. CONCLUSIONS: FLT3/Mut are prevalent in pediatric APL and are associated with high WBC count and increased induction death. This study provides further evidence for testing APL patients for FLT3/Mut and the potential role for FLT3 inhibitors in this disease.

Hematopoietic Cell Transplantation in the Treatment of Pediatric Acute Myelogenous Leukemia and Myelodysplastic Syndromes: Guidelines from the American Society of Transplantation and Cellular Therapy.

The role of allogeneic hematopoietic stem cell transplantation (HCT) in the treatment of acute myelogenous leukemia (AML) in children is reviewed and critically evaluated in this evidence-based review. Specific criteria were used for searching the published literature, grading the quality and strength of evidence, and assigning the strength of treatment recommendations. Genomic characterization and response to therapy have been critical in the risk stratification of pediatric AML. Although some children are cured with chemotherapy alone, allogeneic HCT offers a survival benefit in selected patients with certain unfavorable risk features and is the standard of care for children who relapse following initial treatment with chemotherapy. Important aspects of HCT include recipient characteristics, donor source, and preparative regimen. The goals of HCT are to reduce incidence of relapse, enhance graft-versus-leukemia (GVL) effects, and minimize graft-versus-host disease. Relapse following HCT remains a significant cause of treatment failure, and interventions pre- and post-HCT, especially those that may augment GVL, are an important focus of ongoing investigations.

Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial.

IMPORTANCE: All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL. OBJECTIVE: To assess whether treatment with an ATRA and arsenic trioxide-based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively. DESIGN, SETTING, AND PARTICIPANTS: The Children's Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children's Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/µL) and high-risk APL (white blood cell count ≥10 000/µL) cohorts. INTERVENTIONS: All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered. MAIN OUTCOMES AND MEASURES: Event-free survival (EFS) at 2 years after diagnosis. RESULTS: Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration was 24.7 months (range, 0-49.5 months) for patients with standard-risk APL and 22.8 months (range, 0-47.7 months) for patients with high-risk APL. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL). CONCLUSIONS AND RELEVANCE: In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide-based regimen that included 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02339740.

Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children's Oncology Group.

BACKGROUND: Mutations in the DNMT3A, TET2, IDH1, and IDH2 genes carry prognostic significance and occur frequently in adult acute myeloid leukemia (AML). Leukemic mutations in all four genes have recently been implicated in aberrant DNA methylation, a hallmark of neoplasia. We previously reported that IDH1 mutations were absent, whereas TET2 mutations were present in 6%, of pediatric AML patients; in the present study, we determined the prevalence of DNMT3A and IDH2 mutations in pediatric AML. METHODS: We screened for DNMT3A and IDH2 mutations by direct sequencing of diagnostic specimens from 180 children treated on the Children's Oncology Group clinical trial AAML03P1. Clinical characteristics, the presence of other leukemic mutations, and survival outcome was determined for mutation-positive patients. RESULTS: No disease-associated DNMT3A mutations were detected. IDH2 mutations were detected in 4/180 patients (2.2%), affecting codons R140 (n = 3) and R172 (n = 1). Two patients with IDH2 mutations harbored t(8;21), one patient harbored an MLL translocation, and one patient had a concomitant NPM1 mutation. FLT3, CEBPA, and WT1 mutations did not occur together with IDH2 mutations in our study. CONCLUSION: DNMT3A and IDH2 mutations are uncommon in pediatric AML. The low prevalence of methylation-associated mutations in our study highlights the differences in the pathogenesis of pediatric versus adult AML, at the genetic as well as potentially at the epigenetic level. The age-specific characteristics of AML underscore the importance of studying the molecular biology of both childhood and adult forms of this leukemia in parallel, as the development of novel therapeutics should account for these biologic differences.

B-cell acute lymphoblastic leukemia in patients with germline RUNX1 mutations.

Germline RUNX1 mutations underlie a syndrome, RUNX1-familial platelet disorder (RUNX1-FPD), characterized by bleeding symptoms that result from quantitative and/or qualitative defect in platelets and a significantly increased risk for developing hematologic malignancies. Myeloid neoplasms are the most commonly diagnosed hematologic malignancies, followed by lymphoid malignancies of T-cell origin. Here, we describe the first 2 cases of B-cell acute lymphoblastic leukemia (B-ALL) in patients with confirmed germline RUNX1 mutations. While 1 of the patients had a known diagnosis of RUNX1-FPD with a RUNX1 p.P240Hfs mutation, the other was the index patient of a kindred with a novel RUNX1 variant, RUNX1 c.587C>T (p.T196I), noted on a targeted genetic testing of the B-ALL diagnostic sample. We discuss the clinical course, treatment approaches, and the outcome for the 2 patients. Additionally, we describe transient resolution of the mild thrombocytopenia and bleeding symptoms during therapy, as well as the finding of clonal hematopoiesis with a TET2 mutant clone in 1 of the patients. It is critical to consider testing for germline RUNX1 mutations in patients presenting with B-ALL who have a personal or family history of thrombocytopenia, bleeding symptoms, or RUNX1 variants identified on genetic testing at diagnosis.