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The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions’ experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6–21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.

To determine how the incorporation of PET-CT changes radiotherapy treatment in pediatric Hodgkin lymphoma.Fifty-three Hodgkin lymphoma patients with a median age of 14 years (6-21 years) underwent multiagent chemotherapy followed by involved field radiotherapy (IFRT) to initial sites of disease. All patients had conventional staging which included CT scan of the neck, chest, abdomen and pelvis, bone marrow biopsy ± MRI, Gallium scan and bone scan. All had an initial 18-F-fluoro-deoxy-D-glucose (FDG) PET-CT. When there was discordance between conventional staging and PET-CT staging, true sites of disease were determined either by biopsy or response to multiagent chemotherapy.In 19 of 53 (35.8%) patients, there was discordance between conventional staging and PET-CT findings. The most common location for the 23 sites of discordance were the spleen in 6 (26.1%), neck in 3 (13%), inguinal nodes in 3 (13%) and mediastinum in 3 (13%). A change in stage occurred in 5 (9.4%) as a result of PET-CT imaging. A change in IFRT fields occurred in 9 (17%); eight were more extensive while one was less extensive. For PET-CT, the specificity, sensitivity, positive predictive value and accuracy were 99.5%, 96.3%, 97.9%, and 98.9%.Incorporation of PET-CT information was found to influence IFRT design in 17% of patients, with most having more extensive radiotherapy fields.

Neurocognitive impairment occurs in 20-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy.Seventy-two childhood ALL survivors treated with chemotherapy alone underwent a neurocognitive battery consisting of: Trail Making Tests A (TMTA) and B (TMTB), Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, Digit Span subtest, and Verbal Fluency Test. We performed genotyping for: 10-methylenetetrahydrofolate reductase (MTHFR 677CT and MTHFR 1298AC), serine hydroxymethyltransferase (SHMT 1420CT), methionine synthase (MS 2756 AG), methionine synthase reductase (MTRR 66AG), and thymidylate synthase (TSER). Student's two sample t-test and analysis of covariance were used to compare test scores by genotype.General impairment on the neurocognitive battery was related to MTHFR 1298AC (P = 0.03) and MS 2756AG (P = 0.05). Specifically, survivors with MTHFR 1298AC/CC genotypes scored, on average, 13 points lower on TMTB than those with MTHFR 1298AA genotype (P = 0.001). The MS 2756AA genotype was associated with a 12.2 point lower mean TMTA score, compared to MS 2756 AG/GG genotypes (P = 0.01). The TSER 2R/3R and 3R/3R genotypes were associated with an 11.4 point lower mean score on TMTB, compared to the TSER 2R/2R genotype (P = 0.03). Survivors with ≥6 folate pathway risk alleles demonstrated a 9.5 point lower mean TMTA score (P = 0.06) and 14.5 point lower TMTB score (P = 0.002) than survivors with6 risk alleles.Folate pathway polymorphisms are associated with deficits in attention and processing speed after childhood ALL therapy.

10004 Background: The strong dose-dependent association between anthracyclines and cardiomyopathy limits the therapeutic potential of this extremely effective class of agents, demanding identification of those at highest risk, such that anthracycline exposure may be tailored. Methods: In a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy in cancer survivors by using the ITMAT/Broad/CARe cardiovascular SNP-array to profile common SNPs in 2100 genes considered most relevant to de novo cardiovascular disease. All cases of cardiomyopathy fulfilled American Heart Association (AHA) criteria for cardiac compromise and were confirmed echocardiographically. Results: Using a matched case-control design (93 cases, 194 controls, all non-Hispanic white survivors of childhood cancer) we identified a common SNP rs2232228 in hyaluronan synthase (HAS3) gene that exerts a substantial modifying effect on anthracycline dose-dependent risk of cardiomyopathy. Among individuals with GG genotype, cumulative anthracycline exposure was not associated with cardiomypathy risk at any dose. Individuals with AA genotype, exposed to >250mg/m2 anthracyclines, had an 8.5-fold increased cardiomyopathy risk (95%CI, 2.0-35.6, p=0.004). Replication in an independent set of 76 patients (adult-onset and childhood cancer; all races) with anthracycline-related cardiomyopathy revealed the odds of cases with AA genotype in the high-dose anthracycline group to be 4.5-times higher (95%CI, 1.1-18.4, p=0.04). Hyaluronan (HA) – produced by HAS3 – is a ubiquitous component of extracellular matrix (ECM). ECM is involved in tissue remodeling; the extent of cardiac remodeling/repair after anthracycline-induced cardiac injury is possibly modulated by variability in HA production. Conclusions: The significant modifying effect of HAS3 genotype on the dose-dependent association between anthracycline and cardiomyopathy risk suggests that, upon confirmation in prospective studies, genotyping HAS3 may be considered when evaluating risk of anthracycline-related cardiomyopathy.