Search

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas include recommendations for the diagnosis and management of pediatric patients with primary mediastinal large B-cell lymphoma (PMBL) and sporadic variants of Burkitt lymphoma and diffuse large B-cell lymphoma. PMBL is now considered as a distinct entity arising from mature thymic B-cells accounting for 2% of mature B-cell lymphomas in children and adolescents. This discussion section includes the recommendations outlined in the NCCN Guidelines for the diagnosis and management of pediatric patients with PMBL.

Osteosarcoma (OS) is a genetically diverse bone cancer that lacks a consistent targetable mutation. Recent studies suggest the IGF/PI3K/mTOR pathway and YAP/TAZ paralogs regulate cell fate and proliferation in response to biomechanical cues within the tumor microenvironment. How this occurs and their implication upon osteosarcoma survival, remains poorly understood. Here, we show that IGF-1R can translocate into the nucleus, where it may act as part of a transcription factor complex. To explore the relationship between YAP/TAZ and total and nuclear phosphorylated IGF-1R (pIGF-1R), we evaluated sequential tumor sections from a 37-patient tissue microarray by confocal microscopy. Next, we examined the relationship between stained markers, clinical disease characteristics, and patient outcomes. The nuclear to cytoplasmic ratios (N:C ratio) of YAP and TAZ strongly correlated with nuclear pIGF-1R (r = 0.522

Pediatric acute myeloid leukemia (AML) is a rare disease that is profoundly heterogeneous at a molecular and clinical level. Although, in recent clinical trials, the 5-year event-free survival rates for childhood AML ranged between 49% and 64%, bone marrow relapse still occurs in up to one-third of cases. New therapies are required to continue progress in this aggressive hematological disease. Optimistically, we anticipate that the next challenge may be not a lack of appropriate therapies but an abundance of potentially effective strategies and a question of how best to incorporate them into pediatric clinical practice.The focus of this review is to highlight all promising agents currently under investigation for pediatric AML, including nucleoside analogs, epigenetic modifiers, targeted small-molecule inhibitors, monoclonal antibodies, novel chemotherapeutics, and immunotherapies.While AML outcomes have improved over time for pediatric AML patients, our challenge is how to improve outcomes with our new knowledge of genetic and epigenetic aberrations. We posit to incorporate active therapy options into combination strategies and utilize targeted and immunotherapy approaches, as more opportunities are available.

Relapsed or refractory pediatric patients with B-acute lymphoblastic leukemia (B-ALL) have high rates of toxicities and relapse, and novel therapy is needed. We present a case of a 5-year-old male child with high-risk B-ALL that was refractory to several re-induction regimens. He was put into minimal residual disease-negative remission after re-induction with chemotherapy plus overlapping rituximab, inotuzumab ozogamicin, and blinatumomab, termed mini-hyper-CVD (cyclophosphamide, vincristine, and dexamethasone) plus CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab). This regimen was well tolerated, and he received his transplant and engrafted with no significant infections, toxicities, or sinusoidal obstruction syndrome. This is the first reported use of a condensed sequential immunotherapy/chemotherapy regimen in a pediatric leukemia patient.

Like several other translocation-positive sarcomas, Ewing sarcoma (ES) exists exclusively in a high-grade, undifferentiated state. We believe that the pathognomonic EWS-FLI1 fusion protein (FP) responsible for ES is intimately linked to cell fate, differentiation, and plasticity. Over the last two decades, an emerging body of research has begun the challenging task of deciphering how the FP - via its action as an aberrant transcription factor- blocks differentiation and promotes reprogramming toward a quasi-stem-like cell with features of neuroectodermal or mesenchymal stem cells. We compared ES transcriptome data to other cancers in an unsupervised comparison between the gene expression profile of cancer cells in the Cancer Cell Line Encyclopedia (CCLE) and tumor expression datasets. While ES is traditionally classified as a bone cancer, it does not cluster near other bone cancer subtypes (e.g., osteosarcomas) or soft-tissue sarcomas. To that end, we sought to better understand how targeting the FP affected ES differentiation and lineage. Using a CRISPR knockout (CRISPR-KO) model of A673, we targeted Exon 4 of the EWSR1 protein in the n-terminus of the FP and generated a clonal pool (EWSR1 CRISPR KO). We used single-cell RNA sequencing (scRNA-seq) to identify the transcriptional changes after FP knockout (FP KO). We identified five cell clusters in the data. We observed the expression of FP target genes (EWS-FLI1 On), PRKCB, and LIPI and saw robust expression in four of the clusters suggesting normal FP expression. Conversely, FP repressed genes (EWS-FLI1 Off), LOX and IGFBP3, were elevated in cluster 2, which contained only EWSR1 CRISPR KO cells. This suggests that the FP was successfully knocked out in cluster 2 (FP EWSR1 KO). Next, we asked how the FP KO changed the lineage/fate of A673 cells. We hypothesized that loss of the FP would induce mesenchymal/fibroblastic fate in ES cells. To answer this, we used SingleR, which compares the gene expression profile of query cells to the CCLE data set, to identify the nearest cell type. Interestingly, all clusters except the FP EWSR1 KO cluster identified closely with ES and related tumors. The FP EWSR1 KO cluster, which expressed EWS-FLI1 ‘off’ genes, did not resemble ES. Using a granular identification with cell lines, we confirmed that the highest score was A673 since these were A673 cell lines. However, the FP EWSR1 KO resulted in a phenotype unrelated to A673 and more closely resembled cell lines with fibroblastic phenotype. Our data suggest that targeting the FP significantly changed ES lineage. While the FP KO did not lead to cell death, our results suggest a novel gene regulatory network acts to sustain ES lineage. Further perturbations in this network may lead to a better understanding of ES treatment, particularly as novel EWS-FLI1-directed therapies emerge. Citation Format: Danh Truong, Sandhya Krishnan, Alexandar Lazar, David McCall, Joseph A. Ludwig. Understanding Ewing sarcoma cell fate. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3559.

Relapsed or refractive pediatric B-Acute Lymphoblastic Leukemia (B-ALL) patients have high rates of toxicities and relapse, and novel therapy is needed. We present a case of a 5-year-old male with high-risk B-ALL that was refractive to several re-induction regimens. He was put into MRD-negative remission after re-induction with chemotherapy plus overlapping rituximab, inotuzumab ozogamicin and blinatumomab, termed Mini-Hyper-CVD plus CRIB. This was well tolerated, and he received his transplant and engrafted with no significant infections, toxicities, or sinusoidal obstruction syndrome. This is the first reported use in pediatrics of a condensed sequential immunotherapy/chemotherapy regimen in a pediatric leukemia patient.

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have immediate clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.ONE SENTENCE SUMMARYWe demonstrate that DSRCT, an aggressive pediatric cancer, is an AR-driven malignancy capable of responding to androgen deprivation therapy.

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.

Simple Summary Pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoma (LBL) currently have unsatisfactory outcomes, and novel treatment options are needed. Venetoclax is approved for adult patients with several types of leukemia and is being investigated in the pediatric population. Here, we retrospectively reviewed the safety and efficacy of venetoclax for the treatment of ALL/LBL in the pediatric and young adult populations. The purpose of this study is to provide evidence that venetoclax is safe and effective to use in pediatric patients with ALL/LBL and should be considered in both the relapsed and upfront settings. Abstract Venetoclax is approved for adult patients with chronic lymphocytic leukemia and acute myeloid leukemia. Expanding its use to the pediatric population is currently under investigation, but more robust data are needed. We retrospectively analyzed the safety and efficacy of venetoclax in children/AYA with ALL/LBL. We identified 18 patients (T-cell ALL, n = 7; T-cell LBL, n = 6; B-cell ALL, n = 5) aged 6–22 years. No new venetoclax safety signals were identified; the most common toxicity was myelosuppression. No deaths occurred within 30 days from the start of the therapy. A mean of 2.6 (range 0–8) prior lines of therapy were given. The mean duration of venetoclax was 4.06 months (range 0.2–24.67 months). Complete remission was achieved in 11 (61%) patients. Of the eight patients who remain alive, four are continuing on venetoclax combination therapy, and four proceeded to hematopoietic stem cell transplantation. Three patients who initially achieved CR, later relapsed, and are deceased. Nine patients are deceased, and one patient was lost to follow-up. Overall survival is 9.14 months (range 1.1–33.1), and progression-free survival is 7.34 months (range 0.2–33.1). This is the largest cohort of pediatric/AYA patients who received venetoclax for ALL/LBL. Our data support the consideration of venetoclax-based regimens in pediatric patients with R/R ALL/LBL and its investigation as upfront therapy for T-cell ALL/LBL.