Sandeep Batra

Background/Objectives: Acute leukemias in adolescents and young adults (AYAs) with Down Syndrome (DS) are understudied. Methods: This was a single-center, retrospective cohort study. Medical records for pediatric DS (n = 41) and AYA-DS (n = 7) treated with a pediatric chemotherapy regimen for acute leukemia were evaluated. Results: Two-year event-free survival (EFS) in AYA DS acute leukemia patients was lower than that in their pediatric DS counterparts (28.6% (Confidence Interval (CI) 4.1, 61.2) vs. 84.9% (CI 69.5, 92.9); p = 0.002). Conclusions: Additional research is needed to improve outcomes in AYA DS leukemia.

Somatic and epigenetic alterations contribute to myeloid leukemogenesis and play an important role in risk stratification and the optimization of treatment for myeloid malignancies. The significance of rare genetic alterations, such B-cell lymphoma-6 corepressor (BCOR) and B-cell lymphoma-6 corepressor-like protein 1 (BCORL1) mutations, in pediatric acute myeloid leukemias (AML) and myelodysplastic syndrome (MDS) is unknown. We present a case series of pediatric and adolescent patients, with de novo AML, harboring BCOR/BCORL1 mutations. Studies involving larger cohorts of patients are needed to further elucidate the role of BCOR/BCORL1 mutations in pediatric AML and MDS.

There are a variety of rare hematologic malignancies and germline predispositions syndromes that occur in children and adolescent young adults (AYAs). These entities are important to recognize, as an accurate diagnosis is essential for risk assessment, prognostication, and treatment. This descriptive review summarizes rare hematologic malignancies, myelodysplastic neoplasms, and germline predispositions syndromes that occur in children and AYAs. We discuss the unique biology, characteristic genomic aberrations, rare presentations, diagnostic challenges, novel treatments, and outcomes associated with these rare entities.

There is a lack of consensus for safely discharging adolescent and young adults (AYA) with newly diagnosed acute lymphoblastic leukemia. From 2017 to 2019 we evaluated predefined early discharge criteria for 41 AYA patients during induction chemotherapy. Only 17% (7/41) of patients met criteria for early discharge. Two (29%) patients who were discharged early were readmitted, but not to the pediatric intensive care unit (PICU). This outcome was compared to a historic cohort at our institution of 73 patients who were discharged without predefined discharge criteria. Twenty-seven (37%, p = 0.7) patients were readmitted, but 13 (48%) were readmitted to the PICU ( p = 0.004).

Journal of Adolescent and Young Adult Oncology

Acute venous thromboembolisms (VTEs) are serious complications that occur during acute lymphoblastic leukemia (ALL) chemotherapy. The data elucidating risk factors for developing VTEs are limited in adolescent and young adult patients being treated per pediatric ALL protocols. In a cohort of 66 patients, 14 (21%) experienced VTEs. The majority of VTEs occurred during induction chemotherapy after the first dose of asparaginase, and in the upper extremities. Five-year relapse-free and overall survival were not impacted by VTEs. Contrary to VTEs in adults, hypoalbuminemia and increased body mass index were not associated with an elevated risk of VTE.

Mixed-phenotype acute leukemias (MPAL) are rare in children and often lack consensus on optimal management. This review examines the current controversies and emerging paradigms in the management of pediatric MPAL. We examine risk stratification, outcomes of recent retrospective and prospective collaborative trials, and the role of transplantation and precision genomics, and outline emerging targets and concepts in this rare entity.

Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a nonessential amino acid, by L-asparaginase has been used in treating pediatric acute lymphoblastic leukemia (ALL) for decades. Of interest, unlike most solid tumor cells, ALL cells lack the ability to synthesize their own asparagine de novo effectively. However, only until recently, growing evidence suggests that solid tumor cells strive to acquire adequate amounts of asparagine to support tumor progression. This process is subjected to the regulation at various levels, including oncogenic signal, tumor-niche interaction, intratumor heterogeneity and dietary accessibility. We will review the literature on L-asparaginase-based therapy as well as recent understanding of asparagine metabolism in solid tumor progression, with the hope of shedding light into a broader cancer therapeutic strategy by perturbing its acquisition and utilization.

Hypogammaglobulinemia is a poorly described complication of chemotherapy in adolescents and young adults (AYAs, 15–39 years) with acute lymphoblastic leukemia (ALL). The majority of AYAs treated on a Berlin–Frankfurt–Munster-based ALL regimen experienced hypogammaglobulinemia (65.0% [13/20]). Febrile neutropenia episodes (throughout the treatment course) and infectious events during maintenance occurred more frequently in hypogammaglobulinemic patients compared with patients with normal immunoglobulin G levels ( n = 7) (median 1.0 vs. 0.0, p = 0.02; 7.0 vs. 3.0, p = 0.02, respectively). Hypogammaglobulinemia did not impact overall or event-free survival. Further studies are needed to elucidate the etiology of hypogammaglobulinemia and to establish criteria for immunoglobulin replacement in these patients.

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.