SOHO State of the Art Updates and Next Questions: Novel Therapies in T-ALL: From CAR-T to Novel Targets.

While outcomes for children and adolescents with T-cell acute lymphoblastic leukemia (T-ALL) have improved significantly with contemporary therapy, outcomes for newly diagnosed adults and all patients with relapsed or refractory (r/r) disease remain poor. Improved understanding of T-ALL genomics and the integration of novel agents into treatment have the potential to improve outcomes further by enhancing risk stratification and improving salvage rates for those with r/r disease. In this review, we will discuss landmark genomic studies that have identified therapeutic targets in T-ALL, shed further light on the early-T precursor phenotype, and described novel genomic subtypes of T-ALL. We will further discuss recent clinical trials investigating the role of nelarabine and bortezomib into front-line therapy for T-ALL, highlighting the benefit of nelarabine for pediatric and adolescent/young adult patients with T-ALL seen on the Children's Oncology Group trial AALL0434 (4-year disease-free survival 92.2% for the Capizzi methotrexate + nelarabine arm). Finally, we will address new classes of targeted small molecule inhibitors, immunotherapeutics, and chimeric antigen receptor T-cell therapies under investigation in r/r T-ALL. We focus on recent trials incorporating novel immunotherapies, including a phase 2 trial of the anti-CD38 monoclonal antibody daratumumab in combination with chemotherapy which demonstrated an overall response rate of ∼80% as well as numerous early-phase chimeric antigen receptor T-cell trials with response rates exceeding 90%.