Chana L. Glasser

Treatment for relapsed acute lymphoblastic leukemia (ALL) in children and young adults continues to evolve. Despite optimization of cytotoxic chemotherapeutic approaches and risk-adapted therapy, about 12% of pediatric patients still relapse, and survival rates in this population remain poor. Salvage therapy for relapsed patients continues to be challenging as attempts to further intensify chemotherapy have resulted in excessive toxicity without improving outcomes. Immunotherapy has profoundly impacted the landscape of relapsed ALL by harnessing the patient’s immune system to target and eliminate leukemia cells. In this review, we provide an overview and summary of immunotherapy agents that have been approved and remain under investigation for children, including blinatumomab, inotuzumab, daratumomab, and chimeric antigen receptor T-cell therapy. We discuss the landmark clinical trials that have revolutionized the field and provide an update on ongoing clinical trials involving these agents for children in the relapsed and upfront setting. The incorporation of these novel immunotherapies into ALL treatment, either as monotherapy or in combination with cytotoxic chemotherapy, has demonstrated promising potential to augment outcomes while decreasing toxicity. However, we also highlight the many challenges we still face and the research critically needed to achieve our goals for cure in children.

Pediatric acute myeloid leukemia (AML) is a devastating disease with a high risk of relapse. Current risk classification designates patients as high or low risk (LR) based on molecular features and therapy response. However, 30% of LR patients still suffer relapse, indicating a need for improvement in risk stratification. Cytokine levels, such as IL-6 and IL-10, have been shown to be prognostic in adult AML but have not been well studied in children. Previously, we reported elevated IL-6 levels in pediatric AML bone marrow to be associated with inferior prognosis. Here, we expanded our investigation to assess cytokine levels in diagnostic peripheral blood plasma (PBP) of pediatric AML patients and determined correlation with outcome. Diagnostic PBP was obtained from 80 patients with LR AML enrolled on the Children’s Oncology Group AAML1031 study and normal PBP from 11 controls. Cytokine levels were measured and correlation with clinical outcome was assessed. IL-6, TNFα, MIP-3a, and IL-1β were significantly higher in AML patients versus controls when corrected by the Bonferroni method. Furthermore, elevated TNFα and IL-10 were significantly associated with inferior outcomes. Our data demonstrate that in diagnostic PBP of LR pediatric AML patients, certain cytokine levels are elevated as compared to healthy controls and that elevated TNFα and IL-10 are associated with inferior outcomes, supporting the idea that an abnormal inflammatory state may predict poor outcomes. Studies are needed to determine the mechanisms by which these cytokines impact survival, and to further evaluate their use as prognostic biomarkers in pediatric AML.

Infections are responsible for most treatment-related morbidity and mortality in pediatric acute myeloid leukemia (AML). Children’s Oncology Group (COG) recommends hospitalization following chemotherapy until early absolute neutrophil count (ANC) recovery. No standard guidelines exist for antibiotic prophylaxis and discharge practices vary. Our objective was to report our institution’s experience with outpatient supportive care management following early discharge. A retrospective chart review of pediatric AML patients treated at our institution from 2010 to 2019 was conducted. Data was collected on length of hospitalization, antibiotics administered, infections, and neutropenia duration. Seventeen patients underwent 60 chemotherapy cycles. All were discharged after completion of chemotherapy if clinically stable. Patients were re-admitted for fever and discharged on empiric antibiotics if afebrile with negative cultures. Prophylactic antibiotics were administered in 55 cycles. There were 12 infections in 11 patients and no deaths due to infection. Patients remained outpatient for a mean of 15.8 neutropenia days per cycle. Outpatient supportive care for children with AML may be feasible and safe. Further studies are needed to establish outpatient supportive care guidelines.

Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 may present with fever, elevated inflammatory markers, and multiorgan involvement. Although the gastrointestinal system is commonly affected in MIS-C patients, associated necrotizing pancreatitis is rare. We present an 11-year-old boy with B-cell acute lymphoblastic leukemia in remission undergoing maintenance chemotherapy presenting with acute necrotizing pancreatitis. He developed fevers, fluid and electrolyte imbalance, respiratory distress, cytopenias, and coagulopathy, and was found to have markedly elevated inflammatory markers and positive SARS-CoV-2 antibodies. The patient met criteria for MIS-C and was treated with intravenous immunoglobulin with significant clinical improvement. This is the first known reported case of a child with B-cell acute lymphoblastic leukemia who met criteria for MIS-C presenting as acute pancreatitis, and highlights the importance of considering a broader differential for pancreatitis in children given the current SARS-CoV-2 pandemic.

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor–bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.

The relapse rate for children with acute myeloid leukemia (AML) remains high despite advancements in risk classification, multi-agent chemotherapy intensification, stem cell transplantation, and supportive care guidelines. Prognosis for this subgroup of children with relapsed/refractory AML remains poor. It is well known that the ceiling of chemotherapy intensification has been reached, limited by acute and chronic toxicity, necessitating alternative treatment approaches. In the last several years, our improved understanding of disease biology and critical molecular pathways in AML has yielded a variety of new drugs to target these specific pathways. This review provides a summary of antibody drug conjugates (ADCs), small molecule inhibitors, and tyrosine kinase inhibitors with an emphasis on those that are currently under clinical evaluation or soon to open in early phase trials for children with relapsed/refractory AML.