Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can involve the bone marrow, peripheral blood, skin, lymph nodes, and the central nervous system. Though more common in older adults, BPDCN has been reported across all age groups, including infants and children. The incidence of pediatric BPDCN is extremely low and little is known about the disease. Pediatric BPDCN is believed to be clinically less aggressive but often with more dissemination at presentation than adult cases. Unlike adults who almost always proceed to a hematopoietic stem cell transplantation in first complete remission if transplant-eligible, the majority of children can be cured with a high-risk acute lymphoblastic leukemia-like regimen. Hematopoietic stem cell transplantation is recommended for children with high-risk disease, the definition of which continues to evolve, or those in relapse and refractory settings where outcomes continue to be dismal. Novel agents used in other hematologic malignancies and CD123 targeted agents, including chimeric antigen receptor T-cells and monoclonal/bispecific antibodies, are being brought into research and practice. Our goal is to provide a comprehensive review of presentation, diagnosis, and treatment by review of pediatric cases reported for the last 20 years, and a review of novel targeted therapies and therapies under investigation for adult and pediatric patients.

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.

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.

Acute myeloid leukemia (AML) resides in an immune-rich microenvironment, yet, immune-based therapies have faltered in eliciting durable responses. Bridging this paradox requires a comprehensive understanding of leukemic interactions within the bone marrow microenvironment. We optimized a high-throughput tissue-microarray-based pipeline for high-plex spatial immunofluorescence and mass cytometry imaging on a single slide, capturing immune, tumor, and structural components. Using unbiased clustering on the spatial K function, we unveiled the presence of tertiary lymphoid-like aggregates in bone marrow, which we validated using spatial transcriptomics and an independent proteomics approach. We then found validated TLS signatures predictive of outcomes in AML using an integrated public 480-patient transcriptomic dataset. By harnessing high-plex spatial proteomics, we open the possibility of discovering novel structures and interactions that underpin leukemic immune response. Further, our study's methodologies and resources can be adapted for other bone marrow diseases where decalcification and autofluorescence present challenges.

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.

Background: Advances in care have led to improvements in survival for adolescents and young adults (AYAs) diagnosed with cancer; however, the risk of early death remains high for certain cancers, particularly acute leukemias. Risk factors for early death in AYAs diagnosed with acute leukemia have not been well studied. Methods: The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death (within 2 months of diagnosis) in AYAs diagnosed with acute leukemia (n = 16 153). Early death proportion, by year, for AYAs diagnosed between 2006 and 2020 was described. Associations between incidence of early death and age at diagnosis, sex, race and ethnicity, socioeconomic status, rurality, acute leukemia type, and year of diagnosis were evaluated with logistic regression. Results: Overall, 6.0% of AYAs experienced early death and there was a significant annual decrease in the odds of early death (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.95 to 0.98, P < .0001) across the study period. Over the entire study period, AYAs diagnosed with acute promyelocytic leukemia (9.6%, 95% CI = 8.4 to 11.1) or other acute leukemias (13.3%, 95% CI = 10.5 to 16.7) had the highest proportion of early death and AYAs diagnosed with T lymphoblastic leukemia/lymphoma had the lowest (2.6%, 95% CI = 1.9 to 3.7). Older age at diagnosis, male sex, and Hispanic ethnicity were all associated with increased risk of early death. Conclusions: A high proportion of AYAs with acute leukemia experience early death and risk varies by leukemia type and sociodemographic factors. A better understanding of the complex interplay between disease biology and sociodemographic factors is needed to guide risk prediction and prevention.