Recent Children's Oncology Group Research Articles

Outcome of Infants Treated on Total Therapy for Infants with Acute Lymphoblastic Leukemia I: Results from a Non-Randomized Multi-Center Study

Infants with KMT2A rearranged (KMT2Ar) acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival (EFS) of 33.6-36.9% on recent Children's Oncology Group and Interfant trials. In preclinical studies, we identified bortezomib and vorinostat as novel active agents in primary KMT2Ar infant ALL specimens that have not been included in infant regimens to date. Total therapy for infants with acute lymphoblastic leukemia I (TINI) evaluated this novel combination in a multi-institutional pilot trial for infants with de novo ALL. In this study, bortezomib and vorinostat were incorporated into an ALL chemotherapy backbone containing dexamethasone, mitoxantrone, and pegasparaginase during induction and reinduction chemotherapy cycles. A run-in dose escalation evaluated 3 dose levels of vorinostat which was then followed by a dose expansion phase. The primary endpoint of the study was tolerability; secondary endpoints included minimal residual disease (MRD), 3-year EFS and overall survival (OS). Fifty patients enrolled between 2017-2021. Median follow up was 3.4 years (range 1.6-6.8 years). The six patients in the dose escalation phase had no dose-limiting toxicities. Forty-four patients received vorinostat at the third dose level (DL3) of 180 mg/m 2/dose. 68% of patients treated at DL3 had CNS involvement at diagnosis. 68% of DL3 patients carried a KMT2Ar. The most frequent KMT2A partner genes were AFF1 (40%), MLLT1 (20%), and MLLT3 (13%). The most frequent grade 3-4 non-hematologic adverse events during induction include neutropenic fever (45%), hypertension (43%), infection (40%), anorexia (32%), diarrhea (18%) and perineal skin ulceration (16%). There were 3 episodes of sepsis and 1 induction death due to parainfluenza pneumonia. Fewer events and no deaths or proven sepsis occurred during reinduction, with only grade 3 hypertriglyceridemia exceeding 10% of patients affected (18%). 79% of all patients and 69% of KMT2Ar patients became MRD negative by flow cytometry on day 22 of induction following our investigational block. Following induction intensification with cyclophosphamide, cytarabine, and mercaptopurine, 77% and 66% of all patients and KMT2Ar patients respectively were MRD negative at the time of count recovery. Eight of the forty-four patients, all KMT2Ar, underwent stem cell transplant in first remission due to persistent MRD positivity at the end of consolidation. The 3-year EFS and OS probabilities (SE) of all forty-four DL3 patients were 56.5% (8.0) and 70.5% (7.3), respectively. The 3-year cumulative incidence of relapse (CIR) with death considered a competing event was 29.3% (6.9) and the cumulative incidence of death (CID) as a first event was 8.9% (4.5). Patients lacking a KMT2Ar had superior outcomes with 85.7% (9.4) EFS and 92.9% (6.9) OS. The EFS and OS of KMT2Ar patients were 44.8% (9.5) and 62% (9.1) respectively. CIR and CID for KMT2Ar patients was 43.5% (9.6) and 7.2% (5) respectively. KMT2Ar patients ≥90 days at diagnosis had superior outcomes compared to their younger counterparts with 59.1% (10.5) EFS and 77.3% (8.9) OS. End of induction MRD was predictive of an event in this subgroup, with 85.6% (9.4) EFS for MRD negative patients and 14.3% (13.2) EFS for MRD positive patients. In contrast, KMT2Ar patients < 90 days of age at diagnosis had poor outcomes irrespective of MRD with 12.5% (11.7) EFS and 25% (15.3) OS. Notably KMT2Ar patients < 90 days who were MRD negative at the end of induction had a median time to relapse of 600 days (range 282-969 days), a late time point for this malignancy that typically relapses within a year from initial diagnosis. This suggests the regimen effectively reduced tumor burden leading to an extended duration of remission but failed to sufficiently eradicate disease to prevent relapse. We conclude that the incorporation of bortezomib and vorinostat for treatment of infants with ALL was well tolerated. MRD responses in KMT2Ar patients were robust. Although the study was not powered to evaluate outcomes, EFS and OS in KMT2Ar patients suggest a clinical signal worth pursuing given the low proportion of patients transplanted in first remission. The successor study, TINI 2 (NCT05848687), will build upon the bortezomib/vorinostat backbone by incorporating 2 cycles of blinatumomab and the menin inhibitor ziftomenib in combination with chemotherapy during reinduction.

Children's Oncology Group's 2023 blueprint for research: Hodgkin lymphoma.

The goal of therapy in pediatric Hodgkin lymphoma (HL) is to maximize overall survival while minimizing the morbidity of curative therapy. Key findings from recent Children's Oncology Group (COG) trials include: (i) superior event-free survival with the addition of brentuximab vedotin (Bv) in frontline regimens for high-risk disease, (ii) successful reduction in myeloablative regimens with demonstrated safety and efficacy of Bv and checkpoint inhibitor therapy in relapsed disease, and (ii) the potential to select a population that can be salvaged after relapse without receiving a stem cell transplant. The COG HL committee will lead a National cancer Institute National Clinical Trials Network phase 3 trial to evaluate the combination of Bv/nivolumab in early-stage disease. Ongoing advances in technology and blood biomarkers are increasing the ability to deliver biologically driven, personalized treatment for HL.

Survival of patients with orbital and eyelid rhabdomyosarcoma treated on Children's Oncology Group studies from 1997 to 2013: A report from the Children's Oncology Group.

Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I-III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported. Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non-low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n=169; 77.5%), <5cm (n=213; 97.7%), group III (n=170; 78.0%), and without lymph node involvement (N0; n=215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%-94.0%) and 95.6% (95% CI, 90.8%-100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%-100.0%) and 97.6% (95% CI, 90.0%-100.0%), respectively. Twenty-six patients with non-low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%-100.0%) and 95.8% (95% CI, 87.7%-100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%-88.8%). Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non-low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.

Patterns of Locoregional Relapse after Radiotherapy for High-Risk Neuroblastoma: A Multi-Institutional Study

<h3>Purpose/Objective(s)</h3> In high-risk neuroblastoma (HRNBL), locoregional relapse (LRR) is a significant contributor to treatment failure despite intensive multimodal therapy, including radiotherapy (RT). A recent Children's Oncology Group study found no benefit to boost RT for gross residual disease. Thus, we sought to characterize patterns of LRR after RT for patients (pts) with HRNBL. <h3>Materials/Methods</h3> The Institutional Review Boards approved this multi-institutional retrospective cohort study of pts who received ≥1 autologous stem cell transplant (ASCT) and external beam RT for HRNBL from 1997-2021. Pts who progressed prior to ASCT were excluded. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. In-field and marginal recurrences were defined as sites receiving >12 Gy and ≤12 Gy, respectively. Follow-up (FU) was from end of RT. Event-free survival (EFS) and overall survival (OS) were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse, secondary cancer, and death with Gray's test. <h3>Results</h3> We identified 311 pts with median age at diagnosis of 3.0 years (range: 0.02-28.7). The most common primary site was adrenal/abdominal (n=280, 90.0%). 271 (87.1%), 126 (40.5%) and 240 (77.2%) pts had metastatic disease at diagnosis, <i>MYCN</i> amplification, and unfavorable histology, respectively. 108 pts (34.7%) received proton RT. Of the 167 (53.7%) pts who underwent tandem ASCT, 68 (40.7%) received TBI-based conditioning. No pts received TBI after 2012. Of the 115 (37.0%) pts with subtotal resection (STR), 54 (47.0%) received ≥36 Gy. 202 (65.0%) received post-Consolidation anti-GD2 immunotherapy. Median FU was 6.5 years (range: 0.01-22.4). For the cohort, 5-year CILP, EFS and OS were 10.8%, 66.7% and 78.9%, respectively. After STR, ≥36 Gy did not decrease 5-year CILP (11.8% vs. 13.1%, p=0.80). 5-year CILP was significantly lower for pts receiving immunotherapy (6.4% vs. 21.5%, p<0.001). For pts receiving immunotherapy, 5-year CILP was similar for photon and proton RT (6.1% vs. 6.6%, p=0.78). Of the 29 pts with LRR and imaging for review, 13 (44.8%) were in-field only, 6 (20.7%) were marginal only, and 10 (34.5%) were both in-field and marginal. In pts receiving immunotherapy, 4 LRRs were in-field only, 3 were marginal only, and 4 were both in-field and marginal with 6/7 (85.7%) marginal recurrences occurring at sites of disease present at diagnosis with complete response after induction chemotherapy. <h3>Conclusion</h3> LRR contributes to treatment failure in HRNBL with most occurring in-field. CILP was lower for pts receiving immunotherapy and there was no difference in CILP between photon and proton RT. In pts receiving immunotherapy, approximately 25% of LRRs were marginal only. Future studies are needed to examine the optimal RT fields and dose in the era of anti-GD2 immunotherapy.

Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group.

Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker. Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor MYCN status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2). Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with MYCN amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2 MYCN nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months (MYCN) or 12-18 months (MYCN, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively. A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.

Outcomes Based on CNS Disease Status in Pediatric Acute Myeloid Leukemia and the Role of Peripheral Blood Contamination in Diagnostic Lumbar Punctures; A Report from the Children's Oncology Group Studies AAML0531 and AAML1031

The diagnosis and treatment of CNS leukemia in AML differs between pediatric and adult oncology. Adult AML patients generally receive no prophylactic intrathecal (IT) treatment. Here we evaluate an approach utilized on 2 recent Children's Oncology Group (COG) clinical trials for pediatric AML which included CNS prophylaxis and a low threshold to initiate CNS leukemia directed therapy.A total of 2119 patients with de novo AML were evaluable from COG trials AAML0531 and AAML1031. Patients with FLT3/ITD on AAML1031 are excluded as that cohort remains eligible for ongoing accrual. The median (range) follow-up time was 7.1 (0 - 10.5) years for AAML0531 and 2.5 (0 - 5.7) years for AAML1031. All patients received IT cytarabine once with each induction and intensification cycle (except for one of the intensification cycles with high dose cytarabine). An LP to determine CNS status was performed at start of induction therapy. CNS positive (CNSpos) leukemia was treated with twice weekly IT cytarabine until 2 negative CSF samples were obtained (minimum 4 and maximum 6 ITs). CNSpos was defined similarly on both trials (Table 1). In order to understand the role of traumatic LP in CNS status and outcomes, CNS status in this analysis was further classified according to criteria used for ALL (Table 1). Comparing the ALL criteria to the AML CNS definition, CNS1 patients are CNS negative (CNSneg) and CNS3 patients are CNSpos, however among patients with CNS2 by ALL criteria, the AML CNS definition does not take into account the number of CSF WBCs in an atraumatic LP and also uses a higher CSF RBC number (100 versus 10) to require use of the Steinherz/Bleyer algorithm.The rate of CNS relapse (isolated CNS and combined CNS and bone marrow) was evaluated separately on each trial since the protocols differed in number of chemotherapy courses and SCT allocation. On AAML0531, the 5 year CNS relapse rate was lower for CNS1 (4.5 ± 1.7%) compared to CNS2 (9.1 ± 4.5%) or CNS3 (17.7 ±9.4%), P<0.001. This finding was replicated in the AAML1031 outcomes; CNS relapse rates were 4.9 ± 1.8% (CNS1), 11.7 ± 5.0% (CNS2) and 19.3 ±8.8% (CNS3), P<0.001. Patients who were CNSpos had a higher 5 year CNS relapse rate on both studies (CNSpos 13.2 ± 5.1% vs. CNSneg 4.9 ± 1.7% on AAML0531, P<0.001; CNSpos 12.9 ± 4.3 % vs. CNSneg 5.6 ± 1.8% on AAML1031, P<0.001). Event free survival (combined AAML0531 and AAML1031) differed by CNS category (CNS1 51.2%, CNS2 43.5%, CNS3 37.7%, P<0.001) and AML CNS group (CNSneg 41.2%, CNSpos 49.9%, P<0.001), but overall survival did not differ significantly.We evaluated the role of peripheral blood contamination. For patients with CSF RBC ≥100, the majority of patients were classified by ALL criteria as CNS2 or CNS3, and the rate of CNS3 disease increased approximately two fold compared to those with CSF RBC <100 (Fig 1a). When considering the COG AML definition, CNSpos rate was substantially higher among those with CSF RBC 10-99 (41%) compared to those with CSF RBC <10 (24%) or RBC ≥100 (27%; Fig 1b). This difference is likely due to the presence of peripheral blood blasts without “correction” for this blood contamination because the Steinherz/Bleyer algorithm was not used to determine CNSpos when CSF RBC <100.The median blood WBC count was significantly lower in patients with CNS1 (14,650; 95% CI 13,200-15,900) compared to CNS2 (46,200; 95% CI 40,500-53,700) or CNS3 (32,400; 95% CI 21,900-43,500). Further, when this analysis was restricted to patients with an atraumatic tap (CSF RBC <10), those with CNS1 still had significantly lower WBC compared to those with CNS2 or CNS3 (median WBC [95% CI]: CNS1 15,100 [13,400-16,800]; CNS2 53,700 [45,800-62,000]; CNS3 35,500 [21,000-50,100]). This suggests that the biologic drivers resulting in leukocytosis may also increase the risk of CNS leukemia.This analysis demonstrates that CNS disease in AML is associated with a higher CNS relapse risk but caution must be used in interpreting disease status at diagnosis. Due to the worse prognosis associated with CNS disease, we advocate continued use of diagnostic lumbar punctures and intensified treatment for pediatric patients with CNS disease. However, we also speculate that deferring the initial diagnostic lumbar puncture until clearance of peripheral blasts (which usually occurs by day 5-8 of induction) may minimize the risk of false positive diagnosis of CNS disease resulting from high peripheral WBC and blast contamination of CSF samples. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High-Density Data Mining to Identify Unique Toxicities of Adolescent/Young Adult Cancer Treatment: A Report from the Children's Oncology Group

Background: Adolescent and young adult (AYA) cancer patients, 15-39 years of age, experience excess treatment-related toxicity compared to children. However, the relatively low number of AYAs enrolled on individual Children's Oncology Group (COG) clinical trials limits thorough toxicity analyses. Our objective was to delineate a detailed signature of drug- and dose-specific toxicities experienced by AYAs. We created a novel high-density data informatic method of clustering and analyzing toxicity data across multiple clinical trials that permits the comparison of outcomes in large populations of AYA versus younger cancer patients. In this pilot study, we aggregated four different COG acute lymphoblastic leukemia (ALL) trials to identify new and previously described toxicities that correlated with age and drug exposure, and validated our findings with previously published toxicity data as traditionally reported.Methods: Toxicity data from four recent COG trials for newly-diagnosed high-risk (CCG-1961, AALL0232) and standard-risk (CCG-1991, AALL0331) ALL trials were analyzed (n=13,436). First, disparate toxicity scoring systems were harmonized and re-mapped to a unified system based on the Common Terminology Criteria of Adverse Events (v.4.0), and then clustered in hierarchical fashion to enhance the power analysis. Differential rates of age-specific toxicities were determined in phases of treatment that were common to all protocols. AYA was defined as per NCI (15-39 y). Fisher's exact test was used to determine significant toxicity differences by treatment and age. Grade 3-5 events were included for all toxicities except osteonecrosis (ON), which included grade 2-5.Results: Across all phases of treatment, toxicity rates among AYAs vs children are summarized in Table 1. During Induction, hyperglycemia and hyperbilirubinemia were more common among AYAs (25.3% vs 8.1% and 10.4 vs 2.4%, respectively; both p < 0.0001). Metabolic disorders, including hypoalbuminemia, were also more common in AYA patients for both dexamethasone and prednisone in Induction (AYA: 8.7% vs 2.2%; children: 2.7% vs 1.5; both p < 0.05). Post-Induction, mucositis and peripheral neuropathy were more common among AYAs (15.5% vs. 4.5% and 6.1% vs 2.9%, respectively, both p<0.0001). ON appeared as a delayed manifestation during Maintenance in patients who received dexamethasone in Induction; patients (≥10 y) showed increased rates (21.4% (dex) vs 12% (pred), p< 0.0001). In addition, this large-scale cross-study analysis identified novel AYA toxicity signatures not previously described, including pancreatitis and thrombosis, which were more common in the AYAs compared to children (8.5% vs 5% and 3.9% vs 1.2 %, respectively; both p < 0.0001).Conclusions: We used high-density bioinformatics analysis to identify unique and novel toxicity signatures of AYA leukemia patients. We identified side effects previously published using traditional biostatistical analyses in individual trials, validating this approach. In addition, we identified novel toxicities. These findings suggest that large-scale data analyses are a sensitive and powerful method for simultaneous analyses of outcomes across multiple clinical trials, and in otherwise small populations. It provides a framework for a comprehensive understanding of toxicity and outcome differences among AYAs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The prognostic significance of anaplasia in childhood rhabdomyosarcoma: A report from the Children's Oncology Group.

Established prognostic indicators in rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, include several clinicopathologic features. Among pathologic features, anaplasia has been suggested as a potential prognostic indicator, but the clinical significance of anaplasia remains unclear. Patients enrolled on one of five recent Children's Oncology Group clinical trials for RMS (D9602, n=357; D9802, n=80; D9803, n=462; ARST0331, n=335; and ARST0531, n=414) with prospective central pathology review were included in this study. Clinicopathologic variables including demographic information, risk group, histologic subtype, and anaplasia were recorded along with overall survival (OS) and failure-free survival (FFS) with failure defined by recurrence, progression, or death. The log-rank test was used to compare OS and FFS. Anaplasia was more common in embryonal RMS (27% of all embryonal RMS) than other subtypes of RMS (11% for alveolar RMS, 7% for botryoid RMS, 11% for spindle cell RMS). On multivariate analyses, anaplasia was not an independent prognostic factor in RMS (OS:hazard ratio (HR)=1.12, p=0.43; FFS:HR=1.07, p=0.56) across all subtypes or within embryonal RMS only (OS:HR=1.41, p=0.078; FFS:HR=1.25, p=0.16). Among tumors with TP53 mutations, 69% had anaplasia, while only 24% of tumors with anaplasia had a tumoral TP53 mutation. Anaplasia is not an independent indicator of adverse outcomes in RMS. Emerging information on the prognostic significance of TP53 mutations raises the possibility that anaplasia may be a surrogate marker of TP53 mutations in some cases. Tumoral TP53 mutation status may be investigated as a prognostic indicator in future studies.

Area-Based Socioeconomic Disparities in Survival of Children with Newly Diagnosed Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Introduction: Income, education, and health insurance coverage have been shown to influence access to appropriate oncology care, impacting detection and treatment. We sought to evaluate the role of area-based measures of socioeconomic status in contributing to outcome disparities on the two most recent Children's Oncology Group (COG) Phase 3 clinical trials for acute myeloid leukemia (AML), AAML0531 and AAML1031. We hypothesized that pediatric AML patients from low income and low education zip codes have inferior five-year overall survival (OS) and event-free survival (EFS) relative to patients from middle income and more educated zip codes. Methods: Patients enrolled on AAML0531 and AAML1031 were included. Patients with Down syndrome (n=5), FLT3/ITD high allelic ratio (n=264), in AAML1031 Arm D (n=332), and patients whose zip code was not able to be mapped to a US Census area were excluded (n=60). Patients were observed from enrollment on study through last available follow up. Zip code level median annual household income was the primary exposure and was categorized as follows: Poverty: &amp;lt;$24,250 (federal poverty line); Low: $24,250-56,516; Middle/High &amp;gt;$56,516. Secondary exposures of interest included zip code level educational attainment and insurance type (Medicaid Only vs other insurance) at AML diagnosis. Standard descriptive statistics were used to compare patient characteristics by levels of exposure; the Kaplan Meier method was used to estimate OS (defined as time from study entry to death) and EFS (time from study entry until failure to achieve CR during induction, relapse, or death). Cox proportional hazards models were used to estimate hazard ratios (HR) for OS and EFS. Measures of association were adjusted for known risk factors for mortality including cytogenetic/mutation risk group, gemtuzumab (GO) receipt, race, and age. Logistic regression analyses were used to estimate odds ratios (OR) for early mortality (defined as death during induction). Results: Of 2387 patients enrolled on AAML0531 and AAML1031, 1726 met inclusion criteria for the overall analysis. Due to missing covariate data, 1467 patients were included in the final model. Race/ethnicity differed significantly by area-based income, area-based education, and insurance type with a higher proportion of Black and Hispanic patients living in poverty, low income, and low education areas, and having Medicaid only insurance. Lower area-based income was associated with lower OS (43% in poverty vs. 61% in low income vs. 68% in middle/high income; p = 0.004) and EFS (34% in poverty vs. 46% in low income vs. 54% in middle/high income; p = 0.005), shown in Figure 1. Lower area-based educational attainment was also associated with lower OS (58% in Quartile 4 (lower education) vs. 70% in Quartile 1 (higher education); p = 0.005 across quartiles) and EFS (44% in Q4 vs. 54% in Q1; p = 0.03 across quartiles). Patients with Medicaid Only insurance had lower OS (59 ± 5% vs. 66 ± 3%: p = 0.01) but similar EFS (48 ± 5% vs. 50 ± 3%: p = 0.33). In a full multivariable model, differences in survival by area-based educational attainment and insurance type resolved suggesting that observed crude associations were explained by confounding by area-based income combined with established risk factors. Patients from middle/high income areas experienced 25% lower risk of mortality compared to patients from low income areas (OS: crude HR 0.74 95% CI 0.62, 0.89; adjusted HR 0.79 95% CI 0.63, 0.99) with similar differences in EFS (crude HR 0.79 95% CI 0.69, 0.92; adjusted HR 0.77 95% CI 0.65, 0.89). There was no meaningful confounding of the income-survival association detected as evidenced by unchanged magnitudes of association following adjustment for area-based education, insurance, and established risk factors. Area-based low income was associated with both higher risk of early death (crude OR: 2.43 95% CI 1.04, 5.69) and treatment-related mortality on therapy (11.1 ± 10.5% vs. 3.7 ± 2.5%, p = 0.03) compared to area-based middle/high income. Conclusions: Lower area-based income and education were associated with significantly inferior EFS and OS among patients with AML on the last two Phase 3 COG trials. Moreover, zip-code based low SES is an independent risk factor for mortality in pediatric AML. Additional studies to understand mechanisms of observed socioeconomic disparities in treatment outcomes will inform interventions that may mitigate these inequities. Disclosures Fisher: Pfizer: Research Funding; Astellas: Other: Data Safety Monitoring Board Chair for an antifungal study; Merck: Research Funding.

Timing of Radiation Therapy in Pediatric Wilms Tumor: A Report From the National Cancer Database

Todetermine, using the National Cancer Database (NCDB), the impact of the surgery to radiation therapy interval (SRI) on survival in contemporary patients with Wilms tumor (WT). The NCDB was queried for patients aged ≤25years diagnosed from 2004 to 2013 with unilateral WT who underwent definitive surgery and radiation therapy. The SRI was calculated for each patient. A stratified analysis was performed based on presence of metastasis using logistic regression to calculate risk factors for prolonged SRI, with a focus on the recommended SRI according to recent Children's Oncology Group trials (by day 14) and National Wilms Tumor Study-5 (by day 9). Cox regression was performed to assess the association of SRI with overall survival. A total of 1488 patients were included; 32.1% had metastasis at diagnosis. Among both metastatic and nonmetastatic groups, older patients were more likely to have prolonged SRI. For those without metastasis, SRI > 14days was associated with increased risk of mortality (hazard ratio 2.13, P = .013). Analyzing SRI as a continuous variable also demonstrated an increased risk of death with longer SRI (hazard ratio 1.04 per day, P=.006) in this group. In contrast, among patients with metastasis, no significant association between SRI and mortality was found. Early initiation of radiation therapy remains a critical component of multimodal treatment for patients with nonmetastatic WT. For nonmetastatic patients, SRI ≤ 14days correlates with improved overall survival. However, no such association was noted for patients with metastases. These results may inform the development of future WT trials.

Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials.

Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent ≥1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab. From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( ± standard error) were 21% ± 2% and 6% ± 1%, respectively, whereas the 1-year and 4-year OS rates were 57% ± 3% and 20% ± 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial enrollment. This recent COG cohort of patients with recurrent/refractory neuroblastoma is inclusive and representative. To the authors' knowledge, the current study is the first meta-analysis of PFS, TTP, and OS within the context of modern therapy. These results will inform the design of future phase 2 studies by providing a) historical context during the search for more effective agents; and, b) factors prognostic of PFS and OS after disease recurrence to stratify randomization. Cancer 2017;123:4914-23. © 2017 American Cancer Society.

Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children's Oncology Group

To identify clinical and treatment variables associated with a higher risk of local failure in Ewing sarcoma patients treated on recent Children's Oncology Group protocols. Data for 956 patients treated with ifosfamide and etoposide-based chemotherapy on INT-0091, INT-0154, and AEWS0031 were analyzed. Local treatment modalities were defined as surgery, definitive radiation therapy (RT), or surgery plus radiation (S+RT). Five-year cumulative incidence of local failure was determined. The local failure rate for the entire cohort was 7.3%, with a 3.9% rate for surgery, 15.3% for RT (P<.01), and 6.6% for S+RT (P=.12). The local failure incidence was 5.4% for extremity tumors, 13.2% for pelvis tumors (P<.01), 5.3% for axial non-spine tumors (P=.90), 9.1% for extraskeletal tumors (P=.08), and 3.6% for spine tumors (P=.49). The incidence of local failure was 14.8% for extremity tumors and 22.4% for pelvis tumors treated with RT, compared with 3.7% for extremity tumors and 3.9% for pelvis tumors treated with surgery (P≤.01). There was no difference in local failure incidence by local treatment modality for axial non-spine, spine, and extraskeletal tumors. The local failure incidence was 11.9% in patients aged ≥18years versus 6.7% in patients aged <18years (P=.02). Age ≥18years (hazard ratio 1.9, P=.04) and treatment with RT (hazard ratio 2.40, P<.01) remained independent prognostic factors for higher local failure incidence on multivariate analysis. Tumor size (</≥ 8cm) was available in 40% of patients and did not correlate with local failure incidence. Local tumor control is excellent and similar between surgery and RT for axial non-spine, spine, and extraskeletal tumors. Age ≥18years and use of RT, primarily for pelvis and extremity tumors, are associated with the highest risk of local failure.Further efforts should focus on improving outcomes for these patients.

Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group

The prognostic impact of central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) has varied in past trials, and controversy exists over the degree of involvement requiring intensified CNS therapy. Two recent Children's Oncology Group protocols, AAML03P1 and AAML0531, directed additional intrathecal (IT) therapy to patients with CNS2 (≤5 white blood cell [WBC] with blasts) or CNS3 (>5 WBC with blasts or CNS symptoms) disease at diagnosis. We examined disease characteristics and outcomes of the 1,344 patients on these protocols, 949 with CNS1 (no blasts), 217 with CNS2, and 178 with CNS3, with the latter two receiving additional IT therapy. Young age (P = 0.003), hyperleukocytosis (P< 0.001), and the presence of inversion 16 (P< 0.001) were the only factors more prevalent in patients with CNS2 or CNS3 disease. Complete remission at the end of induction (EOI) 2 was achieved less often in patients with CNS involvement (P< 0.001). From diagnosis, event-free survival (EFS) for patients with CNS involvement was significantly worse (P< 0.001), whereas overall survival (OS) was not (P = 0.16). From the EOI1, there was a higher relapse rate (RR) and worse disease-free survival (DFS), but less impact on OS (CNS1:DFS 58.9%, RR 34.1%, OS 69.3%; CNS2:DFS 53.2%, RR 40.9%, OS 74.7%; CNS3:DFS 45.2%, RR 48.8%, OS 60.8%; P = 0.006, P< 0.001, P = 0.045, respectively). Multivariable analysis showed that independently CNS2 and CNS3 status adversely affected RR and DFS. Traumatic diagnostic lumbar puncture was not associated with worse outcome. CNS leukemia confers greater relapse risk despite more aggressive locally directed therapy. Novel approaches need to be investigated in this group of patients.

FLT3 Mutations in Pediatric Acute Promyelocytic Leukemia; A Report from the Children's Oncology Group AAML0631 Trial

BackgroundSurvival for acute promyelocytic leukemia (APL) has improved dramatically in recent decades through use of targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Early deaths, principally due to complications of APL coagulopathy, remain a significant barrier to cure. White blood cell (WBC) count at diagnosis is a well validated risk marker for early death and relapse. While APL is characterized by t(15;17), mutations of the FLT3 gene are prevalent. Prior reports in both adult and pediatric APL have demonstrated variable impact of FLT3 mutation status on outcomes. In a pediatric cohort from the Intergroup Study CALGB 9710, our group previously found an association of FLT3 mutations with early death. The more recent Children's Oncology Group (COG) APL trial AAML0631 included addition of two courses of arsenic trioxide (ATO) during consolidation. Relapse rate on this study was low, but survival, particularly for the high risk patients, was impacted by early deaths. In a prior analysis we reported that a significant proportion of patients on AAML0631 experienced clinically significant bleeding and clotting events. Here we report our analysis of the prevalence of FLT3 mutations and their association with outcomes for pediatric APL patients treated on the AAML0631 study.MethodsDiagnostic bone marrow samples were collected from consenting patients with newly diagnosed APL enrolling onto COG AAML0631. FLT3 mutation testing of these bone marrow samples included evaluation for internal tandem duplications (FLT3/ITD) of the juxta-membrane domain and point mutations of the activating loop (FLT3/ALM) of the tyrosine kinase domain. FLT3 mutation status was correlated with clinically significant bleeding/clotting, early death during induction and relapse. Significance of correlation was determined using the chi-square test and relapse risk for patients who achieved CR by end of Induction 1 was calculated using cumulative incidence.Eligible patients were age ≥ 2 years and < 22 years and required confirmation of PML-RARA by PCR testing. Risk group was defined by WBC at diagnosis: standard risk (SR) WBC < 10,000 and high risk (HR) WBC ≥ 10,000. Treatment regimen has been previously reported [Kutny et al, ASH Abstract, 2015].ResultsThere were 101 evaluable patients on AAML0631 including 35 HR APL and 66 SR APL. A total of 94 patients had specimens available for FLT3 mutation testing. Patients with unknown FLT3 status (3 HR and 4 SR) were excluded from the following analyses. FLT3 mutations were present in 43% (N=40) including 35% (N=33) with FLT3/ITD, 4% (N=4) with FLT3/ALM, and 3% (N=3) with both FLT3/ITD and FLT3/ALM. The median WBC was 24,450 for FLT3 mutant APL compared to 7,130 for FLT3 wild type, and the rate of FLT3 mutation was significantly higher in HR APL compared to SR APL (66% vs. 31%, P=0.001). Four patients died during induction (all HR APL with WBC of 16200-173800), but early death did not correlate with FLT3 mutation (2/4 patients had FLT3 mutations). We analyzed association of FLT3 mutations with prevalence of clinically significant (Grade III-IV) bleeding or clotting events during induction. There was no difference in prevalence of coagulopathy events (N= 19) between those with and without FLT3 mutations (18% vs. 22%, P=0.57).While OS and EFS were not significantly different, the relapse rate from end of Consolidation 1 was significantly higher at 6% (N=3) in FLT3 mutant patients versus 0% in FLT3 wild-type (P=0.039) [Figure 1].ConclusionsFLT3 mutations are highly prevalent (43%) in pediatric APL. The COG AAML0631 study represents the second largest group of pediatric APL patients with outcome data treated on a cooperative group trial and to our knowledge the current report is the largest group of pediatric APL patients evaluated for outcome based on FLT3 mutation status. This study failed to show an association of FLT3 mutations with early death or bleeding/clotting events in induction. With ATO consolidation, the relapse rate was low on this trial. However, it is of great interest that the relapse rate following ATO consolidation was significantly higher in FLT3 mutant patients. Evaluation of a larger (international) cohort of pediatric APL patients is warranted to further define of role of FLT3 in relapse risk, but the current results give further support to consideration of integrating FLT3 inhibitors into relapsed/refractory APL treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Comparative Evaluation of Normal Tissue Doses for Patients Receiving Radiation Therapy for Hodgkin Lymphoma on the Childhood Cancer Survivor Study and Recent Children's Oncology Group Trials

Survivors of pediatric Hodgkin lymphoma (HL) are recognized to have an increased risk of delayed adverse health outcomes related to radiation therapy (RT). However, the necessary latency required to observe these late effects means that the estimated risks apply to outdated treatments. We sought to compare the normal tissue dose received by children treated for HL and enrolled in the Childhood Cancer Survivor Study (CCSS) (diagnosed 1970-1986) with that of patients treated in recent Children's Oncology Group (COG) trials (enrolled 2002-2012). RT planning data were obtained for 50 HL survivors randomly sampled from the CCSS cohort and applied to computed tomography planning data sets to reconstruct the normal tissue dosimetry. For comparison, the normal tissue dosimetry data were obtained for all 191 patients with full computed tomography-based volumetric RT planning on COG protocols AHOD0031 and AHOD0831. For early-stage patients, the mean female breast dose in the COG patients was on average 83.5% lower than that for CCSS patients, with an absolute reduction of 15.5Gy. For advanced-stage patients, the mean breast dose was decreased on average by 70% (11.6 Gy average absolute dose reduction). The mean heart dose decreased on average by 22.9Gy (68.6%) and 17.6Gy (56.8%) for early- and advanced-stage patients, respectively. All dose comparisons for breast, heart, lung, and thyroid were significantly lower for patients in the COG trials than for the CCSS participants. Reductions in the prescribed dose were a major contributor to these dose reductions. These are the first data quantifying the significant reduction in the normal tissue dose using actual, rather than hypothetical, treatment plans for children with HL. These findings provide useful information when counseling families regarding the risks of contemporary RT.

Multimerin-1 (MMRN1) as Novel Adverse Marker in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

Exploratory gene expression array analyses suggested multimerin-1 (MMRN1) to be a predictive biomarker in acute myelogenous leukemia (AML). Following up on these studies, we evaluated the role of MMRN1 expression as outcome predictor in two recent Children's Oncology Group trials. We retrospectively quantified MMRN1 expression in 183 participants of AAML03P1 and 750 participants of AAML0531 by reverse-transcriptase PCR and correlated expression levels with disease characteristics and clinical outcome. In AAML03P1, the highest quartile of MMRN1 expression (expression ≥0.5 relative to β-glucuronidase; n = 45) was associated with inferior event-free survival (EFS; P < 0.002) and higher relapse risk (P < 0.004). In AAML0531, in which we quantified MMRN1 mRNA for validation, patients with relative MMRN1 expression ≥0.5 (n = 160) less likely achieved remission (67% vs. 77%, P = 0.006), and more frequently had minimal residual disease (43% vs. 24%, P = 0.001) after one induction course. They had inferior overall survival (OS; 44% ± 9% vs. 69% ± 4% at 5 years; P < 0.001) and EFS (32% ± 8% vs. 54% ± 4% at 5 years; P < 0.001) and higher relapse risk (57% ± 10% vs. 35% ± 5% at 5 years; P < 0.001). These differences were partly attributable to the fact that patients with high MMRN1 expression less likely had cytogenetic/molecular low-risk disease (P < 0.001) than those with low MMRN1 expression. Nevertheless, after multivariable adjustment, high MMRN1 expression remained statistically significantly associated with shorter OS (HR, 1.57; 95% confidence interval, 1.17-2.12; P = 0.003) and EFS (HR, 1.34; 1.04-1.73; P = 0.025), and higher relapse risk (HR, 1.40; 1.01-1.94; P = 0.044). Together, our studies identify MMRN1 expression as a novel biomarker that may refine AML risk stratification.

Highlights of This Issue

Exploratory gene expression array analyses by Laszlo and colleagues suggested that multimerin-1 (MMRN1) could be a novel predictive biomarker in acute myeloid leukemia (AML). To follow up on these findings, MMRN1 expression was studied in two recent Children's Oncology Group trials. Although associated with some adverse disease-risk features, high MMRN1 expression was independently associated with shorter overall- and event-free survival as well as a higher relapse risk. These data identify MMRN1 expression as a novel biomarker that may refine AML risk-stratification.Selective inhibitors of nuclear export system (NES) have been developed for cancer therapy, but the underlying mechanisms were not well understood. To clarify the mechanisms, Miyake and colleagues performed proteomic analyses and identified a previously unrecognized mechanism whereby inhibition of NES causes eukaryotic initiation factor 5A (eIF5A) accumulation in mitochondria and induces apoptosis; this effect is regulated by direct binding with insulin-like growth factor 2 mRNA binding protein (IGF2BP1). These data provide a new understanding of eIF5A regulation in response to inhibition of NES and provide a potent anticancer therapeutic strategy.FGFR-TACC gene fusions have emerged as frequent chromosomal translocations across different tumors. To explore their role as therapeutic targets, Di Stefano and colleagues designed a screen covering all FGFR-TACC variants. FGFR-TACC fusions cluster in IDH-wild type grade II-IV glioma, co-occur with CDK4/MDM2 amplification, are alternative to EGFR alterations, and are uniformly expressed in the positive tumors. Preclinical experiments with FGFR-TACC-positive glioma treated with a specific FGFR inhibitor show strong antitumor effects and treatment of two patients with recurrent glioblastoma result in clinical improvement and tumor shrinkage. These results validate the selection of FGFR inhibitors for the treatment of FGFR-TACC-positive cancer.Neuroblastoma is an often lethal embryonal tumor arising from sympathetic neuronal precursor cells. ALK mutations occur in 10% of all tumors, and clinical trials with ALK inhibitors are underway. Because tumors often become resistant to small molecule inhibitors, Lambertz and colleagues decided to unravel the signaling components downstream of ALK to identify additional targets for combination therapy. The authors identified RET regulated through the ALK-AKT-FOXO3a pathway and propose RET inhibition as a possible novel combination therapy. Furthermore, mutant ALK also installs a negative MAPK feedback loop that may have consequences for resistance to novel targeted treatments.

Abstract 5583: Integrative genomic analyses on pediatric acute myeloid leukemia

Abstract Background Acute myeloid leukemia (AML) is a complex and heterogeneous disease leading to a wide range of response variability to conventional therapy, excessive treatment related toxicity, and an overall poor outcome. The NCI supported Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative provided initial support for large-scale genomics to identify novel disease-associated genomic and epigenomic alterations that could be used to develop novel, targeted therapies for pediatric AML. Patients Diagnostic (Dx), remission (Rm), and relapse (Rel) samples were obtained from over 200 children with AML treated on the most recent Children's Oncology Group clinical trials. Data analyses were performed using Partek Genomics Suite 6.6 and Ingenuity Pathway Analysis. Results Methylation profiling (Illumina HumanMethylation27) identified 603 CpG sites significantly differentially methylated between Dx and Rm. In addition, 514 CpG sites were significantly differentially methylated between matched Rel and Rm (p&amp;lt;0.05 FDR, change in β≥0.25). Pathway analysis using genes associated with these CpG sites identified significant (p&amp;lt;0.01) over-representation of the WNT/β-catenin signaling pathway in Dx vs. Rm and in Rel vs. Rm. Gene expression profiling (Affymetrix Human Gene 1.1 ST) revealed 1,142 significantly differentially expressed between Dx and normal bone marrow obatined from the blood bank. Similarly, there were 1,242 significantly differentially expressed genes between Rel and normal bone marrow (p&amp;lt;0.05 FDR, fold-change≥2.00). Many expression differences were coordinated with methylation changes. Pathway analysis revealed 100 significantly (p&amp;lt;0.05) over-represented pathways in Dx vs. normal, Rel vs. normal, or both. Copy-number data analysis (Affymetrix Genome-Wide Human SNP 6.0) identified 180,379 significantly different regions in 254 Dx vs matched Rm. Similarly, 4,707 regions a significantly different in 49 Rel vs matched Rm (p&amp;lt;0.01). Many regions were distinct to either Dx or Rel groups. Whole-genome sequencing (Complete Genomics, Inc) was performed on 100 cases with matched Dx and Rm pairs and on 86 cases with matched Dx, Rel, and Rm samples. The frequencies of either somatic or germline variants were not significantly different when comparing Dx vs. Rel samples. Pathway analysis compared 1,528 mutated genes in the pediatric (TARGET) cohort with 1,963 mutated genes in adult de novo AML (TCGA cohort). Of the 85 and 80 significantly (p&amp;lt;0.05) over-represented canonical pathways, respectively, there are 44 pathways in common and many could be targeted by existing drugs. Conclusion A combination of genomic approaches have identified genes and pathways that appear deregulated in pediatric AML. Many changes are specific to Dx or Rel sample groups, or to pediatric vs. adult AML. Further study into these genes and pathways may reveal candidate targets for therapeutic intervention. Citation Format: Daniel H. Wai, Rhonda E. Ries, Michael Considine, David W. Lee, Sun-Mei Liu, Nicole M. O'Connor, Oliver Pepper, Ranjan Bista, Eiman Aleem, David O. Azorsa, Tanja M. Davidsen, Toni Farley, Jaime Guidry-Auvil, Jason E. Farrar, Malcolm A. Smith, Daniela S. Gerhard, MIchael F. Ochs, Spyro Mousses, Soheil Meshinchi, Robert J. Arceci. Integrative genomic analyses on pediatric acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5583. doi:10.1158/1538-7445.AM2014-5583

Abstract 998: Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukemia (B-ALL): A report from the children's oncology group (COG) - Target - St. Jude Pediatric Cancer Genome Project

Abstract Tumor clonal heterogeneity has been demonstrated in several cancers; however, the rise and fall of subclones under therapy have not been well characterized. To gain insight into the subclonal population architecture of pediatric B-ALL, we analyzed somatic lesions including sequence mutations, structural alterations and DNA copy number abnormalities derived from high coverage (200X) exome sequencing, whole-genome sequencing and SNP arrays of diagnosis (Dx)-remission-relapse DNA from 20 patients (median 7 yrs, range 2 to 19) treated on recent COG B-ALL trials. Cases were selected for analysis based upon occurrence of an early bone marrow relapse (median 19.2 months, range 3.8 to 35.7), which is associated with poor survival. We identified a high frequency of mutations in B-cell development (80%, e.g. PAX5, IKZF1, TCF3, BTG1, TOX, and EBF1 ), RAS signaling (65%, e.g. NRAS, KRAS, PTPN11 and FLT3), TP53 (60%, e.g. CDKN2A, TP53 and RB1), kinase signaling (25%, e.g. JAK2, CRLF2 and SH2B3) and chromatin remodeling (60%, e.g. WHSC1, MLL2, CREBBP, ARID2 and SETD2) pathways. Somatic lesions in these pathways were mostly retained (68%) between Dx and relapse. In contrast, mutations in the purine metabolism genes NT5C2 (45%) and NT5CB1 (15%) were relapse-specific. We constructed clonal lineage of somatic lesions for 15 cases based on subclonal population fractions estimated by a binomial mixture model that adjusts for sequence coverage of mutant alleles. The subclone number (median 3, range 1-5) at Dx was comparable to that at relapse (median=3, range 2-4). Notably, 6 Dx samples were observed with multiple subclones harboring distinct driver mutations in the same oncogene (e.g. NRAS, KRAS and JAK2). In almost all cases only one subclone from Dx arose to be the predominant clone present at relapse. Moreover, the mutation burden in an emergent subclone was comparable to those eradicated by therapy (P=0.43, Wilcoxon rank sum). In 80% of cases, the predominant clone at relapse originated from the smallest Dx subclone; in 45% of those cases, mutant allele present in relapse was detectable in remission DNA (∼0.1%) obtained at the end of the 1st month of therapy. Clonal lineage shows that the earliest acquired mutations at relapse are NT5C2 (n=5), NRAS (n=3), USH2A (n=3), WHSC1 (n=2), TP53 (n=2), IKZF1 (n=1) and CREBBP (n=1). Our study is the first that analyzes the genetic composition and population architecture of subclones that rise or fall after B-ALL therapy. The majority of the “rising” subclones are oligoclonal at Dx, which may explain acquisition of mutations such as those found in NT5C2 to confer growth advantage in relapse. Additional studies of patients who were cured of B-ALL are needed to determine if the presence of mutant clone at end induction might help to predict risk and tempo of relapse. Citation Format: Xiaotu Ma, Mignon L. Loh, Michael Rusch, Michael Edmonson, Richard C. Harvey, David A. Wheeler, Oliver A. Hampton, John Easton, Donald Yergeau, Bhavin Vadodaria, Gang Wu, William L. Carroll, I-Ming Chen, Daniela S. Gerhard, Julie M. Gastier-Foster, Mary V. Relling, Malcolm A. Smith, Meenakshi Devidas, Jaime M. Guidry Auvil, James R. Downing, Cheryl L. Willman, Charles G. Mullighan, Stephen P. Hunger, Jinghui Zhang. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukemia (B-ALL): A report from the children's oncology group (COG) - Target - St. Jude Pediatric Cancer Genome Project. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 998. doi:10.1158/1538-7445.AM2014-998

The Evolution of Pediatric Hodgkin Lymphoma Therapy: Contemporary Protocols Significantly Reduce Radiation Exposure of Normal Tissues

Background: Survivors of childhood Hodgkin Lymphoma (HL) are at an increased risk for radiation-related toxicity. However, most estimates of the magnitude of these risks are based on historical radiotherapy (RT) treatments that encompassed large volumes of normal tissue. We evaluated the normal tissue dose associated with two recent Children's Oncology Group (COG) trials and compared them with doses reconstructed from RT plans of HL survivors in the Childhood Cancer Survivors Study (CCCS).