Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors.

Long noncoding RNAs (lncRNA) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data for 1,044 pediatric leukemia and extracranial solid tumors and integrated paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. A total of 2,657 lncRNAs were robustly expressed across six pediatric cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multidimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell type-specific transcription factors further implicated distinct histotype-elevated and developmental lncRNAs. Integration of these analyses prioritized lncRNAs for experimental validation, and silencing of TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming the computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies. SIGNIFICANCE: Comprehensive characterization of lncRNAs in pediatric cancer leads to the identification of highly expressed lncRNAs across childhood cancers, annotation of lncRNAs showing histotype-specific elevated expression, and prediction of lncRNA gene regulatory networks.

Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631.

Purpose The Children's Oncology Group AAML0631 trial for newly diagnosed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to determine the survival of patients receiving arsenic trioxide (ATO) consolidation and reduced doses of anthracyclines. Patients and Methods Patients age 2 to 21 years with de novo APL confirmed by PML-RARα polymerase chain reaction were stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic WBC count. All patients received all-trans retinoic acid (ATRA) during induction, each consolidation course, and maintenance. All patients received two cycles of ATO therapy during consolidation 1, an additional two (SR) or three (HR) consolidation courses that included high-dose cytarabine and anthracycline, and maintenance therapy comprising ATRA, oral methotrexate, and mercaptopurine. Results One hundred one patients (66 SR and 35 HR) were evaluable for outcome. The 3-year overall survival was 94%, and event-free survival (EFS) was 91%. For SR and HR patients with APL, the overall survival was 98% versus 86% ( P = .003), and EFS was 95% versus 83% ( P = .03), respectively. The EFS for SR patients in AAML0631 was noninferior to that of patients in the AIDA 0493 historical control, which used a significantly higher anthracycline dose and did not include ATO consolidation. Relapse risk for patients in AAML0631 from end consolidation 1 (after ATO treatment) was only 4% at 3 years and did not differ significantly between SR and HR patients. Conclusion ATO consolidation cycles were well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both SR and HR patients with APL.

Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia.

BACKGROUND: FLT3/ITD is associated with poor outcomes in adult and pediatric acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) can improve cure rates, however relapse is still common. Recent studies demonstrate the activity of FLT3 inhibitors, including sorafenib, in targeting the underlying mutation. PROCEDURE: We conducted a retrospective study of 15 pediatric patients with FLT3/ITD+ AML treated with sorafenib within 18 months after receiving HSCT. Sorafenib was administered either as prophylaxis in patients considered at very high risk for relapse (n = 6) or at the time of disease recurrence (n = 9). RESULTS: Sorafenib was initiated at a median of 100 days post HSCT. Overall, 11/15 (73%) of patients experienced medically significant toxicities. Among patients who experienced toxicity, 6/11 (55%) received treatment at doses above what was later determined to be the maximum tolerated dose of sorafenib for pediatric leukemia. Importantly, sorafenib did not appear to exacerbate graft versus host disease. Our findings suggest that sorafenib may be of particular efficacy in patients with minimal residual disease (MRD); all patients who received sorafenib for MRD immediately prior to transplant or with emergence post-HSCT are alive and remain in complete remission at a median of 48 months post HSCT. CONCLUSIONS: Our case series suggests that sorafenib administration is feasible and tolerable in pediatric FLT3/ITD+ AML patients early post HSCT. Ongoing prospective controlled studies are needed to further define the dosing of sorafenib in the post-HSCT period and to determine the optimal context for this treatment approach.

Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia.

Acute myeloid leukemia (AML) has posed significant therapeutic challenges to pediatric oncologists. Despite intensive therapy, half of the children with AML relapse and die from their disease. Efforts to identify risk factors in AML are directed toward defining populations who may benefit from alternative therapies. Patients at lower risk for relapse may benefit from treatment de-escalation, sparing them adverse side effects. Management of high-risk patients may prove more difficult, as the nearly myeloablative nature of AML therapy leaves little room for therapy escalation short of stem cell transplantation. This review evaluates prognostic factors in pediatric AML and discusses the feasibility of using these factors in risk-adapted therapy regimens.