Importance Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. Objective To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. Design, Settings and Participants An observational, consecutive case series (May 2012–October 2014) of 102 children and young adults (mean age, 10.6; median age, 11.5, range: 0–22 years) with relapsed, refractory, or rare cancer at a single major academic medical center. Exposures Each participant underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing along with genetic counseling. Results were discussed in a multi-disciplinary Precision Medicine Tumor Board (PMTB) and recommendations were reported to treating physicians and families. Main Outcomes and Measures Proportion of patients with potentially actionable findings (PAF), results of clinical actions based on integrative clinical sequencing (ICS), and estimated proportion of patients or their families at risk for future cancer. PAF was defined as any genomic findings discovered during sequencing analysis that could lead to a 1) change in patient management by providing a targetable molecular aberration, 2) change in diagnosis or risk stratification or 3) provides cancer-related germline findings, which inform patients/families about a potential future risk of various cancers; Results We screened 104 patients and enrolled 102 patients of which 91 (89%) had adequate tumor tissue available to complete sequencing and only these patients were included in all subsequent calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Overall, 42 (46%) patients had PAFs which changed patient management including, 54% (15/28) with hematological malignancies and 43% (27/63) with solid tumors. Overall, individualized actions were taken in 23 of the 91 (25%) patients and families based on actionable ICS findings, including change in treatment in 14 (15%) and genetic counseling for future cancer risk in 9 (10%) patients. 9/91 (10%) of these personalized clinical interventions resulted in ongoing partial clinical remission of 8–16 months duration or help sustain complete clinical remission of 6–21 months duration. All 9 (10%) patients and families with actionable incidental genetic findings agreed to formal genetic counseling and screening. Conclusions and Relevance In this single center case series of children and young adults with relapsed or refractory cancer, incorporation of data from integrative clinical sequencing into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling in a s...

Standard therapy in the United States for malignancy-associated hyperuricemia consists of hydration, alkalinization, and allopurinol. Urate oxidase catalyzes the enzymatic oxidation of uric acid to a 5 times increased urine soluble product, allantoin. Rasburicase is a new recombinant form of urate oxidase available for clinical evaluation. This multicenter randomized trial compared allopurinol to rasburicase in pediatric patients with leukemia or lymphoma at high risk for tumor lysis. Patients received the assigned uric acid-lowering agent for 5 to 7 days during induction chemotherapy. The primary efficacy end point was to compare the area under the serial plasma uric acid concentration curves during the first 96 hours of therapy (AUC 0-96 ). Fifty-two patients were randomized at 6 sites. In an intent-to-treat analysis, the mean uric acid AUC 0-96 was 128 ؎ 70 mg/dL.hour for the rasburicase group and 329 ؎ 129 mg/dL.hour for the allopurinol group (P < .0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% CI: 2.0-3.4) less exposure to uric acid. Four hours after the first dose, patients randomized to rasburicase compared to allopurinol achieved an 86% versus 12% reduction (P < .0001) of initial plasma uric acid levels. No antirasburicase antibodies were detected at day 14. This randomized study demonstrated more rapid control and lower levels of plasma uric acid in patients at high risk for tumor lysis who received rasburicase compared to allopurinol. For pediatric patients with advanced stage lymphoma or high tumor burden leukemia, rasburicase is a safe and effective alternative to allopurinol during initial chemotherapy. (Blood. 2001; 97:2998-3003)

Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 ؋ 2 factorial design to receive dexamethasone (6 mg/m 2 /d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m 2 /d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m 2 /d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous systemdirected therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous systemrelapse rate of 3.7% ؎ 0.8%, compared with 7.1% ؎ 1.1% for prednisone (P ‫؍‬ .01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% ؎ 2% for dexamethasone and 77% ؎ 2% for prednisone (P ‫؍‬ .002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse. (Blood. 2003;101:3809-3817)

A B S T R A C T PurposeDespite improvements in treatment, approximately 20% of patients with acute lymphoblastic leukemia (ALL) experience relapse and do poorly. The Therapeutic Advances in Childhood Leukemia (TACL) Consortium was assembled to assess novel drugs for children with resistant leukemia. We hypothesize that novel agents and combinations that fail to improve baseline complete remission rates in comparable populations are unlikely to contribute to better outcomes and should be abandoned. We sought to define response rates and disease-free survival (DFS) rates in patients treated at TACL institutions, which could serve as a comparator for future studies. Patients and MethodsWe performed a retrospective cohort review of patients with relapsed and refractory ALL previously treated at TACL institutions between the years of 1995 and 2004. Data regarding initial and relapsed disease characteristics, disease response, and survival were collected and compared with those of published reports. ResultsComplete remission (CR) rates (mean Ϯ SE) were 83% Ϯ 4% for early first marrow relapse, 93% Ϯ 3% for late first marrow relapse, 44% Ϯ 5% for second marrow relapse, and 27% Ϯ 6% for third marrow relapse. Five-year DFS rates in CR2 and CR3 were 27% Ϯ 4% and 15% Ϯ 7% respectively. ConclusionWe generally confirm a 40% CR rate for second and subsequent relapse, but our remission rate for early first relapse seems better than that reported in the literature (83% v approximately 70%). Our data may allow useful modeling of an expected remission rate for any population of patients who experience relapse.