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PURPOSE To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment. MATERIALS AND METHODS Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial. RESULTS In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms). CONCLUSION Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

PURPOSE To identify effective and less toxic therapy for children with acute myeloid leukemia, we introduced clofarabine into the first course of remission induction to reduce exposure to daunorubicin and etoposide. PATIENTS AND METHODS From 2008 through 2017, 285 patients were enrolled at eight centers; 262 were randomly assigned to receive clofarabine and cytarabine (Clo+AraC, n = 129) or high-dose cytarabine, daunorubicin, and etoposide (HD-ADE, n = 133) as induction I. Induction II consisted of low-dose ADE given alone or combined with sorafenib or vorinostat. Consolidation therapy comprised two or three additional courses of chemotherapy or hematopoietic cell transplantation. Genetic abnormalities and the level of minimal residual disease (MRD) at day 22 of initial remission induction determined final risk classification. The primary end point was MRD at day 22. RESULTS Complete remission was induced after two courses of therapy in 263 (92.3%) of the 285 patients; induction failures included four early deaths and 15 cases of resistant leukemia. Day 22 MRD was positive in 57 of 121 randomly assigned evaluable patients (47%) who received Clo+AraC and 42 of 121 patients (35%) who received HD-ADE (odds ratio, 1.86; 95% CI, 1.03 to 3.41; P = .04). Despite this result, the 3-year event-free survival rate (52.9% [44.6% to 62.8%] for Clo+AraC v 52.4% [44.0% to 62.4%] for HD-ADE, P = .94) and overall survival rate (74.8% [67.1% to 83.3%] for Clo+AraC v 64.6% [56.2% to 74.2%] for HD-ADE, P = .1) did not differ significantly across the two arms. CONCLUSION Our findings suggest that the use of clofarabine with cytarabine during remission induction might reduce the need for anthracycline and etoposide in pediatric patients with acute myeloid leukemia and may reduce rates of cardiomyopathy and treatment-related cancer.

Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.

10004 Background: Venetoclax is an orally available BCL-2 antagonist with demonstrated activity in adults with newly diagnosed or relapsed acute myeloid leukemia (AML). Here, we describe the first use of venetoclax 1) in combination with high-dose cytarabine and idarubicin 2) in patients 2-22 years old with relapsed AML. Methods: Patients with relapsed AML or AML refractory to at least two courses of induction therapy were enrolled in this Phase 1 study with a rolling-six design. All patients received venetoclax (240 or 360 mg/m2) on days 1-28 and low-dose (LD: 100 mg/m2 every 12 hours x 20 doses) or high-dose (HD: 1000 mg/m2 every 12 hours x 8 doses) cytarabine beginning on day 8 (Table). Patients who had previously received < 270 mg/m2 of doxorubicin equivalents also received idarubicin 12 mg/m2 on day 8 in dose level 4; other patients were enrolled on the expansion cohort at dose level 3. Non-hematologic CTCAE grade 3 or higher toxicities were intensity limiting (ILT), excluding those anticipated with HD cytarabine. Results: Among 18 evaluable patients, a single ILT (prolonged hematological suppression beyond day 50) was observed (Table). Toxicities were consistent with the underlying cytotoxic chemotherapy, with 14 patients experiencing a total of 40 grade 3 toxicities including 6 documented infections and 23 episodes of febrile neutropenia. There was 1 grade 4 fungal sepsis. The recommended phase 2 dose of venetoclax was 360 mg/m2 (max 600 mg) when combined with HD cytarabine or HD cytarabine/idarubicin. Of the 12 patients with > 50% reduction in blasts following the 7-day venetoclax window therapy, end-of-cycle marrow responses included 7 CR/CRi and 3 PR. Minimal residual disease negative remissions occurred in 4 patients. BH3 profiling of samples and a phase 2 expansion of both dose levels 3 and 4 to further characterize the promising activity of these combinations are underway. Conclusions: Venetoclax combined with cytarabine or cytarabine/idarubicin is active and well tolerated in pediatric patients with relapsed/ refractory AML. Clinical trial information: NCT03194932. [Table: see text]

10027 Background: DNA methylation can alter gene expression by either creating binding sites for methylation-dependent repressor proteins, or by disrupting the binding of transcription factors to their target sequences. DNA methylation has been studied extensively and associated with survival in adults with AML. However, a detailed genome-wide study of epigenetic regulation of gene expression and its pharmacological and clinical impact in pediatric AML patients has not been performed. Methods: In this study, we obtained Illumina 450K methylation array profiles for 175 pediatric patients and Affymetrix U133A gene expression arrays for 166 pediatric patients treated in the multicenter AML02 clinical trial (NCT00136084). Results: We found a very significant canonical correlation of methylation with expression (FDR ≤ 0.01) in 1,978 genes with several of the top ranked genes having established roles in the biology and treatment of AML. An analysis adjusting for risk group found that the canonical correlation m...

10005 Background: Cytarabine (ara-C), a key component of AML therapy, is a prodrug that requires activation to ara-CTP, which inhibits DNA/RNA synthesis and triggers leukemic cell death. Thus, cellular pathways involved in ara-CTP metabolism and/or cell death are likely to influence treatment response. Methods: In the present study, we used a pathway-directed approach to identify the genetic predictors of ara-C response in 187 pediatric patients enrolled in the St. Jude AML02 trial. Patients were randomized to receive the first course of remission induction therapy containing either high- or low-dose ara-C, combined with daunorubicin and etoposide. SNPs in 14 key ara-C pathway genes were genotyped and screened for association with multiple endpoints, such as in vitro ara-C LC50 in diagnostic leukemic cells, minimal residual disease levels (MRD), event-free survival (EFS), overall survival (OS), and rate of relapse. Because AML is a very heterogeneous disease with multiple clinical, cytogenetic, and molecular features that are associated with response, we also evaluated SNPs in ara-C PK genes in the context of prognostic factors of proven clinical utility. Results: Ara-C pathway SNPs were significantly associated with clinical outcome. Known variables such as treatment, core-binding factor leukemia, MRD after one course of therapy, age at diagnosis, 11q23 rearrangements, megakaryoblastic leukemia without t(1;22), and FLT3-ITD accounted for 18.7% of variability in EFS. Additional variation in EFS could be explained by individual SNPs or a combination of SNPs within ara-C pathway genes. For instance, our analysis showed that incorporation of a DCTD SNP into existing model could enhance the percent total variation in EFS explained from 18.7% to 22.9%. Inclusion of all DCTD SNPs in the model increased the percent total variation in EFS explained from 18.7% to 29.7% Conclusions: Overall our results indicate that genetic variation in the ara-C pathway genes had a prognostic relevance that was similar to that of well-known factors. Understanding this variation can provide additional insights into the factors influencing treatment response and could lead to the identification of new prognostic markers.

10034 Background: In the setting of hematopoietic stem cell transplantation (HSCT), donor natural killer (NK) cells exhibit potent anti-leukemic effects without causing graft-versus-host disease. We hypothesized that the transplantation of purified haploidentical NK cells may be a safe and effective form of consolidation therapy that will reduce the risk of relapse among children with acute myeloid leukemia (AML) who are not treated with HSCT. In this pilot study, we assessed the safety, feasibility, and engraftment of NK cell infusions in 10 patients with AML in first remission.Methods: Patients received cyclophosphamide, 60 mg/kg on day -7; fludarabine, 25 mg/m2/day on days -6 through -2; and IL-2, 1 million units/m2, every other day for 6 doses starting on day -1. On day -1, the donor underwent apheresis and the product was purified for CD56+ cells by a two-step procedure. The entire purified product was infused on day 0.Results: The 10 patients had a median age of 2.5 years (range, 8 months to 21 years) and a median leukocyte count of 62 x 109/L (range, 4 to 487) at diagnosis. Leukemic cell genetic abnormalities included CBFβ-MYH11in 4 cases, RBM15-MKL1in 2 cases, MLL-ENL and MLL-AF9 in 1 case each; 2 cases had no detectable abnormalities. Patients received a median of 29 × 106/kg NK cells (range, 5 to 81 × 106/kg). All patients had detectable donor NK cells at one or more time points: donor NK cell chimerism ranged from 0% to 30% during the first 4 weeks after the infusions and was greater than 1% in 9 cases at week 1, 4 cases at week 2, 5 cases at week 3, and 3 cases at week 4. One patient had prolonged NK engraftment (189 days), but no non-hematological toxicity. Grade 3–4 non-hematological toxicity was limited to one respiratory viral infection and one episode of febrile neutropenia. Median length of hospitalization was 2 days (range, 0–3) and median time to neutrophil recovery was 12 days (range, 9–56). With a median follow-up time of 637 days, all patients remain in remission. Conclusions: Haploidentical NK cells can be safely administered to AML patients who are in remission. All patients demonstrated temporary engraftment, which may have antileukemic effects. We have recently opened a new trial to evaluate the efficacy of NK cell therapy in children in first remission of AML. No significant financial relationships to disclose.