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Simple Summary: Childhood acute lymphoblastic leukemia (ALL) has seen significant advances in treatment, yet children classified as high-risk still face challenging outcomes. Traditionally, the severity of ALL was assessed using basic clinical information at diagnosis, but now a deeper understanding of specific biological markers—such as molecular profiles, genetic variations, and immune system characteristics—has become crucial. These markers are not just keys to understanding the disease's mechanisms, but also indicators of how it may progress and respond to treatment. For instance, the development of drugs like tyrosine kinase inhibitors can be used to target high-risk leukemia with certain genetic mutations. By focusing on the intricacies of high-risk childhood ALL, research is paving the way for more personalized and precise treatments, offering hope for better management of this complex disease. Childhood acute lymphoblastic leukemia (ALL) has witnessed substantial improvements in prognosis; however, a subset of patients classified as high-risk continues to face higher rates of relapse and increased mortality. While the National Cancer Institute (NCI) criteria have traditionally guided risk stratification based on initial clinical information, recent advances highlight the pivotal role of biological markers in shaping the prognosis of childhood ALL. This review delves into the emerging understanding of high-risk childhood ALL, focusing on molecular, cytogenetic, and immunophenotypic markers. These markers not only contribute to unraveling the underlying mechanisms of the disease, but also shed light on specific clinical patterns that dictate prognosis. The paradigm shift in treatment strategies, exemplified by the success of tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemia, underscores the importance of recognizing and targeting precise risk factors. Through a comprehensive exploration of high-risk childhood ALL characteristics, this review aims to enhance our comprehension of the disease, offering insights into its molecular landscape and clinical intricacies in the hope of contributing to future targeted and tailored therapies. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary treatment for pediatric, adolescent and young adult patients (AYA) with relapsed/refractory B-cell acute lymphoblastic leukemia. While the landscape of immunotherapy continues to rapidly evolve, widespread use of CAR T therapy is limited and many questions remain regarding the durability of CAR T therapy, methods to avoid CAR T therapy resistance and the role of consolidative stem cell transplant. Modified strategies to develop effective and persistent CAR T cells at lower costs and decreased toxicities are warranted. In this review we present current indications, limitations and future directions of CAR T therapy for ALL in the pediatric and AYA population. [ABSTRACT FROM AUTHOR]

The T‐cell engager monoclonal antibody, blinatumomab, is a potential therapeutic strategy for refractory B acute lymphoblastic leukemia after failure of CD 19 chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) therapies such as tisagenlecleucel, indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukemia (ALL), have been associated with striking treatment outcomes and overall survival. Yet, they are also associated with unique and potentially life-threatening complications. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are generally reversible complications of CAR therapies, but many patients may require critical care support especially if they are not promptly recognized and appropriately managed by frontline healthcare staff. As CAR therapies become more widely available, it is important that inter-professional staff members be aware of general principles regarding diagnosis and management. We hypothesized that an inter-professional education (IPE) simulation-based education intervention (CAR-TEAM) would improve knowledge base and confidence regarding complications of CAR therapies among inter-professional staff. Here, we demonstrate that following CAR-TEAM training, >90% of participants demonstrated knowledge proficiency and confidence in the IPE content area. CAR-TEAM training may serve as an important tool to establish initial and continued competency among sites introducing CAR therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: We present a case of a pediatric patient with symptomatic leukemia involving the heart without bone marrow involvement. The case is followed by a literature review of advances in leukemia treatment including immunotherapy, CAR T-cell therapy, improvement in the treatment of graft-versus-host disease, and the applicability of these treatments to leukemia involving areas outside of the bone marrow. We also explore the feasibility of treatments such as CAR T-cell therapy and blinatumomab and the associated risks for treating patients with leukemia infiltrating the heart. Isolated extramedullary relapse of acute lymphoblastic leukemia (ALL) occurs in soft tissues and various organs outside the testis and central nervous system. Treatments such as hematopoietic stem cell transplantation and more novel modalities such as immunotherapy have eradicated ALL at extramedullary sites. In some instances, survival times for relapsed ALL at these sites are longer than those for relapsed disease involving only the bone marrow. Isolated relapse of ALL in the myocardium is rare, especially in children, making diagnosis and treatment of it difficult. More recent treatment options such as chimeric antigen receptor T-cell therapy carry a high risk of cytokine release syndrome and associated risk of worsening cardiac function. Herein we present the case of an 11-year-old boy who presented with relapsed symptomatic B-cell ALL in the myocardium following allogeneic hematopoietic stem cell transplantation. This is an unusual presentation of relapsed ALL and this case demonstrates the associated challenges in its diagnosis and treatment. The case report is followed by a literature review of the advances in treatment of pediatric leukemia and their application to extramedullary relapse of this disease in particular. [ABSTRACT FROM AUTHOR]

Immune effector cell associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) are unique potentially life-threatening complications associated with immune effector cell (IEC) therapies. ICANS presents with varying symptoms ranging from confusion to seizure and cerebral edema. There is no consensus on the precise pathophysiology related to ICANS. The incidence of this toxicity may vary based on the specific product, underlying diagnosis and host factors. Here, we characterize ICANS in pediatric and adult young adolescent (AYA) patients receiving IEC therapy at our institution. We reviewed clinical characteristics, neurological severity and outcomes in pediatric and AYA patients who received IEC standard of care products from 2018-2019 at MDACC. Severity was retrospectively assessed based on ASTCT Consensus Criteria. Nine patients, median age 15.5 (range: 3-25) years received standard of care, chimeric antigen receptor (CART) IEC therapy. The primary diagnoses were pre-B cell acute lymphoblastic leukemia (ALL) (n=8) and primary mediastinal large B-cell lymphoma (n=1). Of these patients, 4 (44%) developed ICANS within a median of 8 (range: 3-27) days of CAR T cell infusion. ICANS was associated with CRS in all affected patients, occurring within a median of 6 (range: 2-7) days after CRS. Median CRS and ICANS severity grade was 2 (range 1-4) in all 9 patients. Symptoms included altered mental status (AMS) (5), seizure (1), aphasia (2), impaired ability to write a standard sentence (4). Neuroimaging did not correlate to ICANS symptoms or severity. EEG was obtained in 3 affected patients but only correlated to background slowing in one with aphasia. Lumbar puncture was performed in 2 patients with ICANS and was remarkable for lymphocytosis. All patients had received prophylactic anti-epileptic medication. All patients received tocilizumab for concomitant CRS and 3 received steroids. Almost half of pediatric patients receiving standard of care CART products may experience ICANS within one week CAR T cell infusion that is associated with CRS. Pleocytosis in the CSF may be due to CAR-T trafficking into the CSF and prospective studies may clarify its significance. Impaired ability to write a standard sentence and the Cornell Assessment of Pediatric Delirium (CAPD) may be early indicators of ICANS in pediatric/AYA patients. [ABSTRACT FROM AUTHOR]