Children's Oncology Group Phase Research Articles

Impact of Propofol Exposure on Neurocognitive Outcomes in Children With High-Risk B ALL: A Children's Oncology Group Study.

Many children treated for ALL develop long-term neurocognitive impairments. Increased risk of these impairments is associated with treatment and demographic factors. Exposure to anesthesia is an additional possible risk factor. This study evaluated the impact of cumulative exposure to anesthesia on neurocognitive outcomes among a multicenter cohort of children with ALL. This study was embedded in AALL1131, a Children's Oncology Group phase III trial for patients with high-risk B-ALL. In consenting patients age 6-12 years, prospective uniform assessments of neurocognitive function were performed during and at 1 year after completion of therapy. Exposure to all episodes of anesthetic agents was abstracted. Multivariable linear regression models determined associations of cumulative anesthetic agents with the primary neurocognitive outcome reaction time/processing speed (age-normed) at 1 year off therapy, adjusting for baseline neurocognitive score, age, sex, race/ethnicity, insurance status (as a proxy for socioeconomic status), and leukemia risk group. One hundred and forty-four children, 76 (52.8%) males, mean age of 9.1 (min-max, 6.0-12.0) years at diagnosis, underwent a median of 27 anesthetic episodes (min-max, 1-37). Almost all patients were exposed to propofol (140/144, 97.2%), with a mean cumulative dose of 112.3 mg/kg. One year after therapy, the proportion of children with impairment (Z-score ≤-1.5) was significantly higher compared with a normative sample. In covariate-adjusted multivariable analysis, cumulative exposure to propofol was associated with a 0.05 Z-score decrease in reaction time/processing speed per each 10 mg/kg propofol exposure (P = .03). In a multicenter and uniformly treated cohort of children with B-ALL, cumulative exposure to propofol was an independent risk factor for impairment in reaction time/processing speed 1 year after therapy. Anesthesia exposure is a modifiable risk, and opportunities to minimize propofol use should be considered.

Chromatin Profiles Are Prognostic of Clinical Response to Bortezomib-Containing Chemotherapy in Pediatric Acute Myeloid Leukemia: Results from the COG AAML1031 Trial.

The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%, p = 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%, p = 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy.

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy.

Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML. Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy. This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562.

Impact of Molecular Risk on Efficacy of Blood and Marrow Transplantation for Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Outcomes for children and adolescents with newly diagnosed acute myeloid leukemia (AML) have only shown modest improvement over the past three decades. Additionally, outcomes for relapsed disease continue to be poor. As a result, there is a pressing need to optimize consolidation therapy to ensure deep and persistent remissions and prevent future relapse. In particular, the utility of bone and marrow transplant (BMT) for consolidation in pediatric AML has been debated for decades. A prior Children's Oncology Group (COG) study risk-stratified patients on the basis of cytogenetic alterations and demonstrated that consolidative BMT performed in first complete remission (CR1) improved long-term outcomes specifically in patients diagnosed with intermediate-risk disease, but found no survival benefit in patients with either low- or high-risk disease. Since then, whole genome and transcriptome sequencing have uncovered a large number of somatic mutations and cryptic fusions that carry prognostic significance in pediatric AML. Combining these molecular features with traditional cytogenetic risk stratification results in the re-classification of a significant number of patients. While this cytomolecular risk stratification is now being used in contemporary clinical trials (e.g., AAML1831/NCT04293562), the merits of consolidative BMT have not been rigorously re-assessed using these newly defined risk strata. To address this gap, we analyzed clinical and biological data from patients enrolled on COG phase 3 clinical trials AAML0531/NCT00372593 and AAML1031/NCT01371981. We filtered the resulting 2,024 patients to include those who had sufficient diagnostic data to ascertain their cytomolecular risk stratification. Additional inclusion criteria were achieving CR1; completing induction I, induction II, and intensification I; and undergoing BMT after intensification I, which was the recommended time point for BMT on both protocols. Our final analysis included 1,004 patients who met all inclusion criteria. BMT versus chemotherapy alone in CR1 was recommended based on indications provided by AAML0531 or AAML1031, which differ from one another (e.g., AAML1031 incorporated measurable residual disease). Clinical outcomes were assessed using Kaplan-Meier analysis and differences between groups were determined using log-rank testing. Clinical outcomes were superior for patients in the cytomolecular high-risk cohort who underwent BMT in CR1 relative to those who received chemotherapy alone. Specifically, high-risk patients who underwent BMT had a significantly improved five-year OS of 60.8 ± 9.3% (versus 41.3 ± 7.7%; p = 0.002) ( Fig. 1A) and DFS of 55.9 ± 9.4% (versus 30.6 ± 7.2%; p &amp;lt; 0.001) (data not shown). We also observed a decreased incidence of relapse in high-risk patients who received BMT, with a RR of 31.8 ± 8.8% relative to 64.5 ± 7.5% for patients in the chemotherapy only group (p &amp;lt; 0.001) ( Fig. 1B). Conversely, there was no difference in any of these outcome measures for patients in the low- and intermediate-risk groups who underwent BMT in CR1 versus receiving chemotherapy alone. Subsequent and ongoing analysis preliminarily indicates that while a subset of high-risk cytomolecular subtypes benefit from BMT in CR1, others do not. Increased availability of high-throughput sequencing has facilitated the identification of numerous molecular features that have prognostic importance in pediatric AML, leading to more accurate risk stratification and opportunities to better allocate patients to appropriate risk-adapted therapy. In this study, we demonstrate that incorporation of these molecular features into the traditional risk stratification schema significantly impacts the clinical indications for BMT as consolidation therapy in pediatric AML. Whereas BMT was previously found to benefit only those patients with intermediate-risk disease, our data suggest that patients with contemporary high-risk cytomolecular alterations benefit significantly from consolidative BMT. Notably, our current analysis does not yet address the potential bias that patients who reach BMT systematically differ from those patients who did not reach BMT (e.g., toxicity that precludes BMT), which we will address with multivariable analysis using BMT as a time varying exposure. These findings support the need for further prospective studies evaluating the role of BMT in high-risk pediatric AML.

Correlation of Minimal Residual Disease (MRD) at the End of Induction (EOI) and Event Free Survival (EFS) in T-Cell Lymphoblastic Lymphoma (T-LL), a Report from the Children's Oncology Group (COG) Trial AALL1231

Background: Defining prognostic variables that correlate to EFS in T-LL remains a clinical challenge. Traditional variables such as stage or radiologic response to therapy have failed to correlate with EFS in recent trials. AALL1231 was a COG phase 3 clinical trial for newly diagnosed with T Acute Lymphoblastic leukemia (T-ALL) or T-LL patients that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone with no bortezomib (Arm A) or with bortezomib (Arm B) during induction and delayed intensification (DI) (1.3mg/m2 x 4 doses per block). T-LL patients were stratified as standard (SR), intermediate (IR), or very high risk (VHR), based upon minimal detectable disease (MDD) in the bone marrow at diagnosis, prior steroid pre-treatment and radiographic response at the end of induction. Bone marrow (BM) samples to assess MRD by flow cytometry at the EOI were an optional submission for T-LL participants and those collected were analyzed to assess its correlation to EFS. Results: AALL1231 accrued 209 T-LL patients from 2014 until closure in 2017. At the end of induction, 43.6% were in radiologic remission, 55.4% had a partial response and 1% had stable disease or no response. There were 86 (41%) patients for whom EOI samples for MRD assessment were submitted. Patients with MRD <0.1% (n=75) at EOI had a superior EFS versus those with MRD >0.1% (n= 11), (89.0 + 4.4% verses 63.6 + 17.2%, p= 0.025). Overall survival did not significantly differ between the two groups (88.9 + 4.4% versus 72.7 + 15.5% p= 0.15). As previously reported, Arm B demonstrated a superior outcome for both EFS and OS for the entire cohort. Within risk groups, IR and SR patients had similar EFS outcomes (Arm A 73.9 + 7.5% versus 80.4 + 6.7, Arm B 87.2 + 5.8 % versus 90.5 + 4.8%) with only two patients the VHR, both in Arm B. Cox regression for EFS using Arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (Hazard Ratio, HR = 3.73 (1.12-12.40, p = 0.032), (Table 1) which was independent of treatment arm assignment. OS failed to reach statistical significance for patients MRD EOI ≥0.1%, HR = 2.714 (0.72-10.44, p=0.14). Furthermore, Cox regression failed to demonstrate a superior EFS with decreasing MDD at diagnosis (>5% versus 1-5%, versus <1%), HR=2.67 (0.336-21.145, p=0.141, HR= 0.830 (0.255-2.699, HR= 0.57 (0.289-1.073, p= 0.080)(Table 2). Conclusions: In this pediatric T-LL trial, BM EOI MRD by flow cytometry was associated with improved EFS in in both arms (+/- bortezomib) in both univariate and multivariate analyses. In contrast, race, age, gender, risk group, MDD, stage and radiologic response to therapy were not prognostic. Consideration to incorporate MRD at EOI into the design of future trials will establish its value in defining risk groups for subsequent therapeutic trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Single-Cell Map of Childhood Acute Myeloid Leukaemia Using Variational Auto-Encoders

Acute myeloid leukaemia (AML) is a haematological cancer in the bone marrow, with accumulation and expansion of immature cells of the myeloid lineage. Standard treatment of childhood AML is chemotherapy, which does not achieve durable remission in many patients. Personalised medicine including immunotherapies against surface antigens can potentially target chemotherapy resistant cells and achieve long-term remission. Identifying AML blasts and suitable targets for AML therapy are hampered by the heterogeneity and complex clonal and phenotypic composition of the cancer, as well as its complex evolution as the disease progresses into relapse. Aberrant expression of surface antigens on AML blasts measured by flow cytometry is an established strategy to monitor measurable residual disease. Although the likelihood to find blasts is increased as more markers are included in a staining, manual interrogation of all possible combinations exceeding 10 markers becomes extremely difficult. We aim to identify malignant cells based on expression of 23 surface markers normally or aberrantly expressed during hematopoiesis using spectral flow cytometry and machine learning. The goal of this high-dimensional approach is to distinguish leukaemia cells from normal myeloid cells with high confidence, and to place the blasts along the normal myeloid developmental trajectory. We built a single-cell AML map from 20 paediatric AML patients enrolled in the Children's Oncology Group Phase III trial, AAML1031. All patients were treated with standard chemotherapy on Arm A and consented to provide tissue for research. Cryopreserved samples were obtained for three time-points: diagnosis, remission, and relapse. We assumed full remission samples to be healthy and used them to train variational auto-encoders with different hyper-parameters in a cross validated manner. These models subsequently learned to encode the expression of healthy cells in a reduced dimension and to reconstruct their expression from this latent space. We selected the top-10 models that best reconstruct the healthy cells and used it to encode and reconstruct cells from non-remission samples. Since the model works well for encoding and reconstructing healthy cells, we expect a good reconstruction of healthy cells in non-remission samples. For malignant cells we expect a poor reconstruction, as their expression pattern differs from healthy cells. Thus, we use the reconstruction error of cells from non-remission samples to classify them as healthy or malignant. We annotated some cells with clear aberrant expression as malignant and shuffled them with remission cells not used for model development. This resulted in multiple synthetic mixtures with known percentages of malignant cells (ranging from 10 to 90% blasts). Using these synthetic mixtures, we evaluated how well we can classify malignant cells based on their mean-squared reconstruction error. We can achieve an average area under the receiving operator curve of 0.9 over all synthetic mixtures (Fig. 1). The latent space of the variational auto-encoder captures the developmental trajectory of myeloid lineage bone marrow cells (Fig. 2), and we can use this to identify where among the developmental trajectory the leukaemia occurs. We aim to use the trajectory assignment to study the time evolution of the disease in terms of the distribution of malignant cells across the myeloid lineage as well as investigate differences between diagnosis and relapse. We expect that this work will reveal patterns of evolution from diagnosis to relapse that will inform the development of novel strategies to predict and prevent relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Brentuximab vedotin and association with event-free survival (EFS) in children with newly diagnosed high-risk Hodgkin lymphoma (HL): A report from the Children's Oncology Group phase 3 study AHOD1331 (NCT 02166463).

7504 Background: The anti-CD30 antibody drug conjugate, Brentuximab vedotin (Bv) is approved for adults with advanced stage HL but its use has not been established in children or adolescents. We compared the efficacy and safety of Bv with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (Bv-AVE-PC) to the standard pediatric dose intensive regimen ABVE-PC, inclusive of bleomycin. Methods: This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated HL, stages IIB + bulk, IIIB, IVA, IVB. Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days with granulocyte colony-stimulating factor support. Centrally reviewed PET-CT after 2 cycles (PET2) identified slow responding lesions (SRL) defined as Deauville score &gt; 3. Involved site radiotherapy (ISRT) was given to bulky mediastinal adenopathy and SRL. The primary objective was 3-year EFS; events include relapse/progression, second malignant neoplasm (SMN) or death. Final data cutoff was 31 December 2021. Results: 600 participants were enrolled across 151 institutions from March 2015 to August 2019; 587 were eligible. Median age was 15.6 yrs (range 3.4-21). Patient and disease characteristics were balanced across study arms. Histology was nodular sclerosing in 76.5%. Stage distribution: 20.6% IIB-bulk; 19.3% IIIB; 28.5% IVA; 31.7% IVB. At a median follow-up of 42.1 mos (0.1-80.9), 3-year EFS (95%CI) by intent-to-treat analyses was 82.5% (77.4, 86.5) with ABVE-PC and 92.1% (88.4, 94.7) with Bv-AVE-PC (HR 0.41 (0.25, 0.67), p = 0.0002). Median time to 1st event was 9.4 months for both arms but the range differs by arm (3.6-57.8 ABVE-PC; 1.3, 25.8 Bv-AVE-PC). Relapse rate was 17% following ABVE-PC and 7% with Bv-AVE-PC. One SMN is noted in each arm: thyroid cancer at 57.8 mos and acute myeloid leukemia at 20.3 mos. 3-year overall survival (95%CI) was 98.5% (96.0, 99.4) for ABVE-PC and 99.3% (97.3, 99.8) for Bv-AVE-PC (p = 0.38). PET2 SRL rates were comparable (ABVE-PC 19% vs. Bv-AVE-PC 18%, p = 0.8). As-treated ISRT receipt did not differ (ABVE-PC 55.7% vs. Bv-AVE-PC 52.7%, p = 0.69). No difference in grade 3/4 adverse events was observed; myelosuppression, reflected in a 32% incidence of &gt; grade 3 febrile neutropenia, did not differ by arm (p = 0.67). Only 19% of patients experienced &gt; grade 2 neuropathy by the Balis pediatric neuropathy scale, with no difference between arms (p = 0.86). Conclusions: Brentuximab vedotin with AVE-PC in a dose intensive regimen has superior efficacy to ABVE-PC for pediatric patients with high-risk HL. A 59% risk reduction in EFS was achieved with no increase in toxicity and with fewer patients receiving ISRT compared to prior pediatric trials for high-risk HL. Clinical trial information: 02166463.

An updated assessment of 43,110 patients enrolled in the Childhood Cancer Research Network: A Children's Oncology Group report.

The Childhood Cancer Research Network (CCRN) was established by the Children's Oncology Group (COG) as a resource for epidemiologic studies of childhood cancer. The objective of this study was to evaluate the representativeness of CCRN and identify factors associated with enrollment. The number of US childhood patients with cancer diagnosed <20 years of age enrolled in CCRN (2008-2015) was compared to expected counts, calculated from Surveillance, Epidemiology, and End Results incidence rates and US Census population estimates. Observed-to-expected ratios and corresponding 95% confidence intervals (CI) were estimated across sex, race, diagnosis age, calendar year, and cancer diagnosis groups. Multivariable linear regression models were generated to evaluate the association between open COG phase 3 therapeutic trials and CCRN enrollment rates. The 43,110 cases enrolled in CCRN represented 36% of the expected childhood cancers diagnosed from 2008 to 2015 (N = 120,118). CCRN enrollment ratios [95% CI] were highest among males (0.38 [95% CI, 0.37-0.38]), non-Hispanics (0.35 [95% CI, 0.35-0.36]), and those diagnosed from 1 to 4 years of age (0.50 [95% CI, 0.50-51]). Enrollment ratios varied by diagnosis group, with leukemia, myeloproliferative diseases, myelodysplastic diseases (0.55 [95% CI, 0.54-0.55]), and renal tumors (0.55 [95% CI, 0.53-0.58]) having the highest enrollment. After adjusting for year of diagnosis and cancer diagnosis, there was a 3.1% [95% CI, 0.6-5.6%] increase in CCRN enrollment during windows of open COG therapeutic trials. Despite enrolling only 36% of newly diagnosed cases, CCRN remains a valuable resource for investigators conducting childhood cancer etiology and survivorship research. The results of this study may inform efforts to improve enrollment on current and future COG nontherapeutic registry protocols.

Wee1 kinase inhibitor adavosertib with radiation in newly diagnosed diffuse intrinsic pontine glioma: A Children's Oncology Group phase I consortium study.

BackgroundChildren with diffuse intrinsic pontine gliomas (DIPG) have a dismal prognosis. Adavosertib (AZD1775) is an orally available, blood-brain barrier penetrant, Wee1 kinase inhibitor. Preclinical efficacy against DIPG is heightened by radiation induced replication stress.MethodsUsing a rolling six design, 7 adavosertib dose levels (DLs) (50 mg/m2 alternating weeks, 50 mg/m2 alternating with weeks of every other day, 50 mg/m2, then 95, 130, 160, 200 mg/m2) were assessed. Adavosertib was only given on days of cranial radiation therapy (CRT).The duration of CRT (54 Gy over 30 fractions; 6 weeks) constituted the dose limiting toxicity (DLT) period. Endpoints included tolerability, pharmacokinetics, overall survival (OS) and peripheral blood γH2AX levels as a marker of DNA damage.ResultsA total of 46 eligible patients with newly diagnosed DIPG [median (range) age 6 (3–21) years; 52% female] were enrolled. The recommend phase 2 dose (RP2D) of adavosertib was 200 mg/m2/d during days of CRT. Dose limiting toxicity included ALT elevation (n = 1, DL4) and neutropenia (n = 1, DL7). The mean Tmax, T1/2 and Clp on Day 1 were 2 h, 4.4 h, and 45.2 L/hr/m2, respectively. Modest accumulation of adavosertib was observed comparing day 5 versus day 1 AUC0-8h (accumulation ratio = 1.6). OS was 11.1 months (95% CI: 9.4, 12.5) and did not differ from historical control.ConclusionAdavosertib in combination with CRT is well tolerated in children with newly diagnosed DIPG, however, compared to historical controls, did not improve OS. These results can inform future trial design in children with high-risk cancer.

Crebbp Alterations Are Associated with a Poor Prognosis in De Novo AML

Introduction: The translocation, t(8;16)(p11;p13), results in the fusion between KAT6A and CREBBP and has been associated with a poor prognosis in both pediatric and adult acute myeloid leukemia (AML). This lesion has therefore been re-classified as high risk on the active Phase 3 Children's Oncology Group (COG) trial for de novo AML, AAML1831 (NCT04293562). Less is known about the prognostic significance of CREBBP sequence variants.Methods: CREBBP variant status was determined in patients with AML enrolled on 4 successive COG trials for de novo pediatric AML (NCT00003790, NCT00070174, NCT01407757, NCT01371981). Fusions involving CREBBP were prospectively obtained via conventional cytogenetics and retrospectively confirmed via RNAseq. Insertions and deletions (indels) leading to frameshift mutations and single nucleotide variants (SNVs) were retrospectively interrogated via next generation sequencing.Results: Of 2216 patients (age: 0-29.8 years), 55 (2.5%) patients had an alteration involving CREBBP. Sixteen (29%) of these were a fusion involving CREBBP (CREBBP/fus), with KAT6A being the most common translocation partner (n=15) and the remaining translocation involving ANK1. The remaining 39 patients (71%) had a CREBBP mutation (CREBBP/mut), including 19 with an indel (CREBBP/indel) leading to a frameshift mutation and 20 with a SNV (CREBBP/SNV).We compared clinical and biologic characteristics between the three cohorts. CREBBP/fus patients were significantly younger than CREBBP/indel and CREBBP/SNV patients (median ages of 2.6 vs. 7.8 vs. 11.9 years; p=0.027). There was a higher prevalence of t(8;21)/RUNX1-RUNX1T1 in CREBBP/indel patients compared to CREBBP/SNV patients (42.1% vs. 5%; p=0.008). In contrast, CREBBP/SNV patients were more likely to be associated with a normal karyotype (40% vs. 5.3%; p=0.02). There was a similar prevalence of co-occurring high-risk lesions in CREBBP/indel (n=5; CBFA2T3-GLIS2, KMT2A-AFF1, KMT2A-MLLT4, MLLT10-PICALM, NUP98-HOXA9) and CREBBP/SNV (n=7; DEK-NUP214, ETV6-FOXO1, FUS-ERG, NUP98-NSD1, ETV6-MNX1, FLT3-ITDx2) patients. There was otherwise no difference between presenting WBC count, FLT3-ITD, NPM1, CEBPA, remission rates or MRD status after Induction 1 therapy.Patients with any CREBBP alteration had a significantly worse 5-year event free survival (EFS) compared to patients without (25.9% vs. 45.2%; p=0.002) and this inferior EFS overlaps with contemporarily defined high-risk patients (Figure 1a). Evaluation of outcomes based on type of alteration demonstrated a similar 5-year EFS of 33.3% and 23.1% between CREBBP/fus and CREBBP/mut patients, respectively (Figure 1b; p=0.832). This poor EFS was maintained in the CREBBP/indel patients with a co-occurring t(8;21) (n=8, 5-year EFS 12.5%). When patients with co-occurring high-risk lesions were excluded from analysis, the remaining CREBBP/mut (n=27) patients maintained their poor EFS (29.6%). Despite their poor EFS, CREBBP/mut patients had an analogous overall survival (OS) to non-CREBBP patients (57.4% vs. 62.3%; p=0.499, Figure 1c), demonstrating that these patients could be successfully salvaged following relapse. In contrast, all patients with CREBBP/fus that relapsed subsequently died from their disease (OS 33.3%).Conclusions: In a large study of CREBBP alterations in pediatric patients with de novo AML, we show that these patients have a dismal EFS, regardless of alteration type. Further, despite enrichment of t(8;21), the favorable prognosis typically conferred by this alteration was abrogated by the co-occurrence of CREBBP/indel. Similarly, by excluding patients with co-occurring high-risk lesions from analysis, we show that these poor outcomes persist in a cohort of patients that would otherwise be considered low risk. Translocations between CREBBP and KAT6A in patients over 90 days of age are considered high risk on the active COG phase 3 trial. Given the inferior EFS and high salvage rates associated with other CREBBP alterations, intensification of upfront treatment, including hematopoietic stem cell transplant, should be considered in this population.The authors would like to acknowledge Astellas Pharma Global Development, Inc. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Significant Improvements in Survival for Patients with t(6;9)(p23;q34)/DEK-NUP214 in Contemporary Trials with Intensification of Therapy: A Report from the Children's Oncology Group

The occurrence of t(6;9)(p22;q34)/DEK-NUP214 is a rare subtype of pediatric AML that commonly co-occurs with FLT3-ITD mutations and is associated with poor outcomes, regardless of FLT3-ITD status. With increased recognition of the inferior prognostic impact of FLT3-ITD and to a lesser degree t(6;9), and with early identification of these lesions, these patients have been allocated to high risk intensive therapy on more contemporary clinical trials. Therefore we sought to interrogate the outcome of children with t(6;9) AML to determine if intensification of therapy, specifically the use of hematopoietic stem cell transplant (HSCT) in CR1, and FLT3 inhibitors for ITD+ patients, may have improved outcomes for this high risk group of patients.We evaluated the outcomes of all patients with t(6;9) detected by karyotype analysis on pediatric patients with de novo AML enrolled on the previous 7 Children's Oncology Group (COG) or its predecessor (POG or CCG) trials over 31 years (1988-2017). A total of 66 cases of t(6;9) AML were identified from CCG-2861 (n=2), CCG-2891 (n=5), POG-9421 (n=7), CCG-2961 (n=10), AAML03P1 (n=7), AAML0531 (n=17), and AAML1031 (n=18). For all studies prior to 2005 (CCG-2861, CCG-2891, POG-9421, CCG-2961) neither t(6;9) nor FLT3-ITD was used as a prognostic factor to adjust treatment, while on AAML0531 post an amendment in 2008 all patients on AAML1031 with high allelic ratio (HAR; >0.4) FLT3-ITD were allocated to HSCT in CR1, which continued on AAML1031 and this group of patients also received sorafenib.Among all 66 t(6;9) patients identified, 45 (68%) had known data for ITD. Among these, 69% (n=31) harbored a co-occurring FLT3-ITD mutation (AR range 0.07-13.35), while 31% (n=14) were FLT3-ITD negative. In the early phase of trials prior to recognition of FLT3-ITD (1988-2002; CCG-2861, CCG-2891, POG-9421, and CCG-2961), the 5-year event-free survival (EFS) and overall survival (OS) for all t(6;9) patients was dismal at 14% and 18%, respectively (Figure 1). Trials from 2006-2010 (AAML03P1, AAML0531), evaluated the addition of gemtuzumab ozogamicin (GO) to chemotherapy as well as the use of HSCT in CR1 for patients with matched related donors, and the 5-year EFS and OS for patients with t(6;9) improved to 48% and 58% (p<0.001 compared to 1998-2002, Figure 1). Among this group of patients, only 16% received HSCT in CR1. The prevalence and clinical implications of FLT3-ITD in childhood AML was reported early and was incorporated as a risk stratifying biomarker following an amendment to 0531 and for all FLT3-ITD patients with HAR disease on AAML1031; this cohort was considered high risk and allocated to intensified therapy, which in many cases significantly impacted the treatment of patients t(6;9) given the significant overlap. In the most recent trial (AAML1031, 2011-2017), the 5-yr EFS and OS for patients with t(6;9) was excellent at 71% and 94%, which was significantly improved compared to other trials (p<0.001; Figure 1). Among the 18 t(6;9) patients on 1031, 72% (n=13) were allocated to HSCT in CR1, the indication for 7 was HAR FLT3-ITD and they also received sorafenib and for 6 was presence of residual disease after induction 1 (4 with LAR FLT3-ITD, 2 ITD negative). The EFS and OS for the t(6;9)/FLT3-ITD HAR and t(6;9)/FLT3-ITD LAR/neg ITD groups who both received HSCT in CR1 were comparable and very good (EFS: 87.5% vs 100%, OS: 87.5% vs 100%, p=NS for both).We show that over the past 3 decades, outcomes of patients with t(6;9) AML have improved significantly on upfront trials. While general improvements in AML treatment and supportive care are an important aspect, our data with excellent EFS on AAML1031 suggest that the intensification of upfront therapy with HSCT, which occurred for many t(6;9) patients due to their co-occurrence with FLT3-ITD, was critical to these improvements. On the current COG phase III AAML1831 trial, all patients with t(6;9) regardless of ITD status are considered high risk and allocated to HSCT in CR1, while those with a FLT3 mutation also receive gilteritinib. Evaluation of the outcome of t(6;9) patients with this therapy will be important as while FLT3-ITD patients have been an example of a group whose poor outcomes have been shown to be abrogated with intensified therapy, it appears that t(6;9) patients may have benefitted from their co-occurrence pattern and are also a group whose outcomes can be significantly improved with an intensified upfront therapeutic approach. [Display omitted] DisclosuresPollard: Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees.

The effects of sample handling on proteomics assessed by reverse phase protein arrays (RPPA): Functional proteomic profiling in leukemia

Reverse phase protein arrays (RPPA) can assess protein expression and activation states in large numbers of samples (n > 1000) and evidence suggests feasibility in the setting of multi-institution clinical trials. Despite evidence in solid tumors, little is known about protein stability in leukemia. Proteins collected from leukemia cells in blood and bone marrow biopsies must be sufficiently stable for analysis. Using 58 leukemia samples, we initially assessed protein/phospho-protein integrity for the following preanalytical variables: 1) shipping vs local processing, 2) temperature (4 °C vs ambient temperature), 3) collection tube type (heparin vs Cell Save (CS) preservation tubes), 4) treatment effect (pre- vs post-chemotherapy) and 5) transit time. Next, we assessed 1515 samples from the Children's Oncology Group Phase 3 AML clinical trial (AAML1031, NCT01371981) for the effects of transit time and tube type. Protein expression from shipped blood samples was stable if processed in ≤72 h. While protein expression in pre-chemotherapy samples was stable in both heparin and CS tubes, post-chemotherapy samples were stable in only CS tubes. RPPA protein extremes is a successful quality control measure to identify and exclude poor quality samples. These data demonstrate that a majority of shipped proteins can be accurately assessed using RPPA. SignificanceRPPA can assess protein abundance and activation states in large numbers of samples using small amounts of material, making this method ideal for use in multi-institution clinical trials. However, there is little known about the effect of preanalytical handling variables on protein stability and the integrity of protein concentrations after sample collection and shipping. In this study, we used RPPA to assess preanalytical variables that could potentially affect protein concentrations. We found that the preanalytical variables of shipping, transit time, and temperature had minimal effects on RPPA protein concentration distributions in peripheral blood and bone marrow, demonstrating that these preanalytical variables could be successfully managed in a multi-site clinical trial setting.

Cranial Radiation Can be Eliminated in Most Children with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Bortezomib Potentially Improves Survival in Children with T-Cell Lymphoblastic Lymphoma (T-LL): Results of Children's Oncology Group (COG) Trial AALL1231

Cranial Radiation Can be Eliminated in Most Children with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Bortezomib Potentially Improves Survival in Children with T-Cell Lymphoblastic Lymphoma (T-LL): Results of Children's Oncology Group (COG) Trial AALL1231

Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group.

New therapeutic strategies are needed for pediatric acute myeloid leukemia (AML) to reduce disease recurrence and treatment-related morbidity. The Children’s Oncology Group Phase III AAML1031 trial tested whether the addition of bortezomib to standard chemotherapy improves survival in pediatric patients with newly diagnosed AML. AAML1031 randomized patients younger than 30 years of age with de novo AML to standard treatment with or without bortezomib. All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. For those randomized to the intervention arm, bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each chemotherapy course. For those randomized to the control arm, bortezomib was not administered. In total, 1,097 patients were randomized to standard chemotherapy (n=542) or standard chemotherapy with bortezomib (n=555). There was no difference in remission induction rate between the bortezomib and control treatment arms (89% vs. 91%, P=0.531). Bortezomib failed to improve 3-year event-free survival (44.8±4.5% vs. 47.0±4.5%, P=0.236) or overall survival (63.6±4.5 vs. 67.2±4.3, P=0.356) compared with the control arm. However, bortezomib was associated with significantly more peripheral neuropathy (P=0.006) and intensive care unit admissions (P=0.025) during the first course. The addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival. These data do not support the addition of bortezomib to standard chemotherapy in children with de novo AML. (Trial registered at clinicaltrials.gov NCT01371981; https://www.cancer.gov/clinicaltrials/ NCT01371981).

Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433

Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. The children’s Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between March 2007 and October 2013 AALL0433 enrolled 275 participants with late bone marrow or very early isolated central nervous system (iCNS) relapse of childhood B-ALL. Patients were randomized to receive standard versus intensive vincristine dosing; this randomization was closed due to excess peripheral neuropathy in 2010. Patients with matched sibling donors received allogeneic hematopoietic cell transplantation (HCT) after the first three blocks of therapy. The prognostic value of minimal residual disease (MRD) was also evaluated in this study. The 3-year event free and overall survival (EFS/OS) for the 271 eligible patients were 63.6±3.0% and 72.3±2.8% respectively. MRD at the end of Induction-1 was highly predictive of outcome, with 3-year EFS/OS of 84.9±4.0% and 93.8±2.7% for patients with MRD <0.1%, versus 53.7±7.8% and 60.6± 7.8% for patients with MRD ≥0.1% (P<0.0001). Patients who received HCT versus chemotherapy alone had an improved 3-year disease-free survival (77.5±6.2% vs. 66.9 + 4.5%, P=0.03) but not OS (81.5±5.8% for HCT vs. 85.8±3.4% for chemotherapy, P=0.46). Patients with early iCNS relapse fared poorly, with a 3-year EFS/OS of 41.4±9.2% and 51.7±9.3%, respectively. Infectious toxicities of the chemotherapy platform were significant. The AALL0433 chemotherapy platform is efficacious for late bone marrow relapse of B-ALL, but with significant toxicities. The MRD threshold of 0.1% at the end of Induction-1 was highly predictive of the outcome. The optimal role for HCT for this patient population remains uncertain. This trial is registered at clinicaltrials.gov (NCT# 00381680).

Prognostic Significance of FOXO3 in Pediatric Acute Myeloid Leukemia (AML) Patients Treated with Bortezomib Addition to Standard Therapy: Results from a Children's Oncology Group Phase 3 Clinical Trial

The proteasome degrades unneeded and damaged proteins. Tumor cells highly depend on increased protein production and their degradation suggesting that malignant cells with a high proliferation index will be more sensitive to proteasome inhibition. The addition of the proteasome inhibitor Bortezomib (Velcade, 'BTZ') to standard pediatric AML chemotherapy (cytarabine, daunorubicin and etoposide, 'ADE') depleted leukemia-initiating cells in a phase 2 clinical trial in pediatric AML (pedi-AML) patients. A randomized phase 3 clinical trial was then conducted by the Children's Oncology Group (COG) comparing ADE and ADE+BTZ treatment regimes in pedi-AML (AAML1031). To determine if there were specific protein expression profiles that correlated with response to BTZ-containing chemotherapy, we analyzed key components of the proteome of pedi-AML that participated in the trial using reverse phase protein arrays (RPPA). RPPA-based expression of 293 validated antibodies was tested in 500 leukemia samples and compared to expression in CD34+ samples from healthy individuals (n=30). Among all proteins, FOXO3 expression was identified as the protein with the highest influence on outcome in the ADE group. The expression of FOXO3 was prognostic for event-free survival (EFS) in both univariate (HR = 0.56, 95% CI = 0.34-0.90, P = 0.017) and multivariate (HR = 0.55, 95% CI = 0.34-0.88, P = 0.013) analysis. All patients were divided into two clusters (low and high) based on their FOXO3 expression level using median FOXO3 expression in normal CD34+. Kaplan-Meier survival analysis showed poor OS (3 year OS 65.3% vs. 73.9%, P = 0.03) and EFS (3 year EFS, 42.8% vs. 55%, P = 0.01) in low FOXO3 expressors (n=119) compared to patients with high FOXO3 expression (n=291) (fig. 1A). Notably, the poor prognostic effect of low FOXO3 for OS was seen in ADE (3 year OS 60% vs. 72.3%, P = 0.03), but not in ADE-BTZ (3 year OS 70.3% vs. 75.3%, P = 0.23) (fig. 1B). This suggests that in particular patients with low FOXO3 may be eligible candidates for BTZ-addition. To validate our findings, we performed knockdown (KD) of FOXO3 using a short hairpin approach in OCI-AML3 (p53WT) and THP-1 (p53null) cell lines. KD FOXO3 in OCI-AML3 had a short-term growth advantage compared to controls (Day 4, P = 0.004), but not KD FOXO3 THP-1 cells suggesting a role for p53 in the FOXO3 functional pathway. KD FOXO3 cells were more resistant to doxorubicin and etoposide combination therapy than controls (P = 0.04), confirming our clinical observations. Since therapeutic regimes in AML are currently shifting towards Bcl-2 inhibition by Venetoclax (ABT-199, 'ABT'), we were eager to test whether BTZ and ABT could act in synergy, and if this is related to FOXO3 expression. Single low dose BTZ and ABT did not reduce cell numbers after 3 days, but were effective when used in combination (&lt;12% survival, P &lt; 0.001) in OCI-AML3 and THP-1. Although cell counts were lower regardless FOXO3 status in both cell lines, flow cytometry analysis using Annexin V staining revealed significant more apoptosis in KD FOXO3 THP-1 compared to controls. Using RPPA-based profiling, we identified a cluster of pedi-AMLs that benefitted from BTZ-addition to standard therapy. We hypothesize that AML patients with low FOXO3 levels have less activation of their apoptotic transcriptional programs and that this subgroup may benefit from proteasome blockage to prevent FOXO3 proteasomal degradation. The use of FOXO3 as potential biomarker may identify a prognostically adverse cluster in pedi-AML that could stratify patients for ADE+BTZ therapy. Patients with low FOXO3 expression may potentially benefit from ADE+BTZ in combination with ABT, a novel and promising combination approach in AML that warrants further investigation. Figure 1. A. Kaplan meier analysis comparing overall survival (OS) and event-free survival (EFS) between low (n=119, blue) and high (n=291, red) FOXO3 expression in pedi-AML patients. Children with low FOXO3 had significantly poorer OS (P = 0.033, Wilcoxon) and EFS (P = 0.011, Wilcoxon). B. Overall survival between ADE (solid) and ADE+BTZ (dashed) treated patients based on low (blue) or high (red) FOXO3 protein expression. The poor prognostic effect of FOXO3 is present in ADE, but not in ADE+BTZ treated patients (P = 0.028, Wilcoxon). Figure 1 Disclosures No relevant conflicts of interest to declare.

Response to Sorafenib in FLT3/ITD AML Is Depedent on Co-Occurring Mutational Profile

FLT3/ITD mutations are among the most common in AML and are associated with adverse outcome. The addition of FLT3 inhibitors (FLT3-I) to cytotoxic therapy has provided improvements in outcome. We have previously shown that co-occurring mutations impact the clinical implications of FLT3/ITD, where those with NUP98-NSD1 fusions and/or WT1 mutations do particularly poorly (Figure 1A), regardless of ITD allelic ratio (AR). FLT3-I act on mutated and aberrantly activated FLT3, thus may be most effective in AML that is primarily driven by overactive FLT3 signaling. Given the significant overlap between FLT3/ITD and WT1 and NUP98-NSD1, we questioned whether response to FLT3-I may be modulated by these co-occurring variants. The Children's Oncology Group phase III trial AAML1031 treatment arm for patients with high AR (HAR; &amp;gt;0.4) FLT3/ITD mutations evaluated the safety and efficacy of the FLT3-I sorafenib in combination with chemotherapy and hematopoietic stem cell transplant (HSCT). A total of 136 patients with HAR ITD were enrolled, 92 patients treated on the sorafenib arm (+SOR) with complete clinical and biologic (n=88) data available. An additional 42 patients were included in the primary randomization of +/- bortezomib and consolidation HSCT without sorafenib (w/o SOR). As equivalent outcomes were observed in the primary randomization, this cohort was combined for further analysis to serve as a control to evaluate outcomes of patients not receiving sorafenib. In addition to conventional karyotyping and mutational profiling (determination of the FLT3/ITD and respective AR by fragment length analysis), all patients were evaluated for NUP98-NDS1 by RNAseq and WT1 profiling by NGS or, hotspot sequencing of exons 7 and 9. Response to sorafenib was measured by 3-year overall survival (OS), event-free survival (EFS), and relapse risk (RR). We compared outcomes for patients +SOR to w/o-SOR to according to co-occurring mutations, specifically NUP98-NSD1, WT1, and triple positive (TP; ITD/NUP98-NSD1/WT1). Patients treated +SOR experienced a combined OS of 62% vs. 68% w/o-SOR (p=0.562). Patients with ITD+/NUP98-NSD1+ disease (WT1+ patients excluded) treated +SOR and w/o-SOR had similar poor outcomes with 3-year EFS of 22% and 20% respectively (p=0.912; Figure 1B). Among patients treated w/o SOR, NUP98-NSD1+ had significantly inferior outcomes compared to NUP98-NSD1-negative (neg) patients (EFS: 20% vs. 65%, p=0.02). NUP98-NSD1+ patients had similar dismal outcomes +SOR treatment, and inferior to NUP98-NSD1-neg patients treated +SOR (p=0.015; Figure 1B). Thus, sorafenib treatment did not improve outcomes of HAR ITD+/NUP98-NSD1+ patients. Analysis of the impact of co-occurring WT1 mutations (NUP98-NSD1+ patients excluded) demonstrated that ITD+/WT1+ patients had an adverse outcome w/o-SOR (EFS 0% and RR 100%), which was significantly inferior to WT1-neg patients treated w/o-SOR (p=0.002 and p=0.003 respectively; Figure 1C). However, WT1+ patients treated +SOR had much improved outcomes with an EFS of 50% and corresponding RR of 27%, which was comparable to WT1-neg patients treated +SOR (Figure 1C). Thus, sorafenib treatment resulted improved outcomes for ITD+/WT1+ patients. Combining all NUP98-NSD1+ patients, TP patients experienced poor EFS of 23%, similar to 21% for ITD+/NUP98-NSD1+/WT1-neg. Thus, we show that NU98-NSD1 fusions drive the dismal prognosis, as ITD+/NUP98-NSD1+ patients, regardless of additional mutations, experienced significantly inferior outcomes compared to other ITD+ patients, including WT1+, that was not improved by treatment with sorafenib in combination with chemotherapy and HSCT (Figure 1D). We show that sorafenib improved outcomes among the HAR ITD+/WT1+ patients, as this group of patients who did not receive sorafenib had very inferior outcomes, in line with previous findings for this poor risk cohort, while patients treated with sorafenib did much better with outcomes similar to other ITD+ patients. However, sorafenib failed to improve outcomes for NUP98-NSD1+ patients, further highlighting that novel therapeutic strategies will be needed for this group of patients. As the addition of FLT3-I is investigated in HAR FLT3/ITD+ patients, evaluation of its impact across patients with additional oncogenic mutations will be critical to determine which patients will derive the most benefit from this strategy. Disclosures No relevant conflicts of interest to declare. Off Label Disclosure: Sorafenib in FLT3/ITD-positive AML

MRI Features of Histologically Diagnosed Supratentorial Primitive Neuroectodermal Tumors and Pineoblastomas in Correlation with Molecular Diagnoses and Outcomes: A Report from the Children's Oncology Group ACNS0332 Trial.

Supratentorial primitive neuroectodermal tumors and pineoblastomas have traditionally been grouped together for treatment purposes. Molecular profiling of these tumors has revealed a number of distinct entities and has led to the term "CNS-primitive neuroectodermal tumors" being removed from the 2016 World Health Organization classification. The purpose of this study was to describe the MR imaging findings of histologically diagnosed primitive neuroectodermal tumors and pineoblastomas and correlate them with molecular diagnoses and outcomes. Histologically diagnosed primitive neuroectodermal tumors and pineoblastomas were enrolled in this Children's Oncology Group Phase III trial, and molecular classification was retrospectively completed using DNA methylation profiling. MR imaging features were systematically studied and correlated with molecular diagnoses and survival. Of the 85 patients enrolled, 56 met the inclusion criteria, in whom 28 tumors were in pineal and 28 in nonpineal locations. Methylation profiling revealed a variety of diagnoses, including pineoblastomas (n = 27), high-grade gliomas (n = 17), embryonal tumors (n = 7), atypical teratoid/rhabdoid tumors (n = 3), and ependymomas (n = 2). Thus, 39% overall and 71% of nonpineal tumor diagnoses were discrepant with histopathology. Tumor location, size, margins, and edema were predictors of embryonal-versus-nonembryonal tumors. Larger size and ill-defined margins correlated with poor event-free survival, while metastatic disease by MR imaging did not. In nonpineal locations, only a minority of histologically diagnosed primitive neuroectodermal tumors are embryonal tumors; therefore, high-grade glioma or ependymoma should be high on the radiographic differential. An understanding of molecularly defined tumor entities and their relative frequencies and locations will help the radiologist make more accurate predictions of the tumor types.

Quality of Life in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Background: Objectives were to describe guardian proxy-reported quality of life (QoL) during chemotherapy for pediatric acute myeloid leukemia (AML) and to identify treatment and demographic factors associated with worse QoL.Methods: Children's Oncology Group phase 3 AAML1031 study was a randomized trial for de novo AML patients age 0-30 to receive standard AML therapy with and without bortezomib. Patients with high risk FLT3-internal tandem duplication high allelic ratio (ITD HAR) were allocated to receive sorafenib in addition to the standard chemotherapy. Patients enrolled on the AAML1031 study who were 2-18 years of age at diagnosis with English or Spanish-speaking guardians were eligible to participate in the QoL portion of the study which included the PedsQL 4.0 Generic Core Scales, PedsQL 3.0 Acute Cancer Module and PedsQL Multidimensional Fatigue Scale. QoL assessments were obtained at four timepoints - at diagnosis and following completion of second, third and fourth (final) course of therapy. Guardians provided proxy assessments for all patients, while self-report for patients 5 years of age or older who could understand English was optional. This analysis focused on guardian proxy-reported QoL for patients who did not have FLT3-ITD HAR. In addition to demographic and treatment related factors, the total number of non-hematological grade 3-4 CTCAE (Common Terminology Criteria for Adverse Events) toxicities occurring during the time frame of QoL assessments was examined as a potential predictor of QoL.Results: There were a total of 4105 QoL submissions and there were 3513 non-hematological grade 3-4 CTCAE toxicities reported: 1339 submissions at diagnosis with 1088 toxicities reported, 1112 submissions following the second course with 721 toxicities, 929 submissions following third course with 911 toxicities, and 725 submissions following the fourth course with 793 toxicities.In repeated measures linear regression the number of submitted CTCAE toxicities was significantly associated with worse physical health (β±standard error (SE) -3.00±0.69; P<0.001) and general fatigue (β±SE -2.50±0.66; P<0.001). Older age was significantly associated with general fatigue (β±SE -0.58±0.25; P=0.022). In contrast, gender, risk status, bortezomib assignment, duration of neutropenia, private insurance status, white race and Hispanic ethnicity were not associated with physical health, psychosocial health or fatigue.Conclusions: The number of CTCAE toxicities was an important factor influencing physical QoL and fatigue among children on treatment for AML. Identifying novel approaches for reducing toxicities should be a priority to potentially improve QoL. DisclosuresNo relevant conflicts of interest to declare.

Productivity Loss Among Parent Caregivers Is Associated with Poor Health-Related Quality of Life (HRQL) at the Intial Diagnosis of Pediatric Advanced Stage Hodgkin Lymphoma (HL)

▪Background: Financial hardship is the combined effect of medical expenditures, out of pocket expenses, and the impact of a cancer diagnosis and treatment on work. Productivity loss is a measure of work engagement, specifically missed time and/or altered performance, experienced by parent caregivers of children with cancer in the form of missed time from work and/or altered performance at work. Health-related quality of life (HRQL) is an important indicator of the disease process and its functional consequences among children at the time of initial diagnosis with cancer. The association of parental productivity loss with the child's HRQL is unknown.Methods: Two hundred ninety-one parent caregivers of children and adolescents, ages 5-17.9 years with newly diagnosed advanced stage Hodgkin Lymphoma (HL) were invited to participate in a study to assess costs of care as part of a larger Children's Oncology Group Phase III trial. Consenting parents completed the Caregiver Work Limitations Questionnaire (CG WLQ) and the Child Health Ratings Inventories (CHRIs)-Global Health measure prior to start of therapy. The CG WLQ is a validated 23-item measure, which quantifies the percent of time respondents had difficulty performing four key dimensions of work because of caregiving: physical tasks, mental-interpersonal tasks, output tasks, and time management. Mean scale scores (SD), ranging from 0-100, indicate the percentage of time the respondent reported work limitations by dimension in the month prior to diagnosis. The estimated productivity loss score, expressed as a percentage of time, is calculated from the weighted sum of the four scale scores, using an established algorithm validated in the generic WLQ. This is then monetized by multiplying the productivity loss score by the national average wage index of $50,000. The 10-item CHRIs-Global is a parent-proxy report of child HRQL and yields scores that range from 0-100, with higher scores indicating better HRQL. To describe how CG WLQ varied by child global HRQL, CG WLQ scores were reported separately for the lowest quartile of HRQL scores (Q1) and quartiles 2-4 combined (Q2-4). Mean (SD) productivity loss scores were compared using the two-sample t-test.Results: Two hundred eighty-two parents of trial participants (282/291, 97%) completed any baseline measures. Of the 242 parents who initiated the CG WLQ, 159 (66%) reported working at a paying job and were eligible to complete the remainder of the measure. The average age (SD) of caregiver respondents was 43.8 (6.9) years with 75.3% female, 74.7% White and 63.7% with at least some college education. The average age of the child with HL was 15 (2.8) years and 55% were male. The mean HRQL score was 65.2 (21.9). On average CG WLQ scores indicated that the caregiving role resulted in disrupted work tasks at least 31.4% (27.6) of the time (Table). The average percent of time that caregiving disrupted mental-interpersonal tasks, output tasks, and time management was higher in working caregivers of children with HRQL scores in the lowest quartile compared to higher quartiles. The productivity loss score was higher for caregivers whose children had lower HRQL, resulting in larger annual productivity costs.Conclusions: Family caregivers of child and adolescent HL patients are vulnerable to productivity loss, which is costly to the families, employers and the nation. High productivity losses noted at initial diagnosis indicate that financial hardship begins prior to the start of cancer treatment. Provider understanding of the association of the child's HRQL on the caregiver's work will inform strategies to maximize adherence to intensive chemotherapy and improve patients' HRQL. DisclosuresParsons:Seattle Genetics: Research Funding. Henderson:Seattle Genetics: Research Funding.