ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.

Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21(10%) with Hodgkin lymphoma and eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (p=.76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI 19.5-32.4). Germline ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n=110) were classified as having absent (n=81) or residual (n=29) ATM kinase activity. Four-year EFS was 39.4% (95% CI 29-53.3) vs 78.7% (95% CI 63.7-97.2), (p<.001), and TRM rates were 37.6% (95% CI 26.4-48.7) vs 4.0% (95% CI 0-11.8), (p=.017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR=0.362, 95% CI 0.16-0.82; p=.009) and increased TRM (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

A natural history study of nitrous oxide versus propofol-assisted intrathecal therapy in the treatment of acute lymphoblastic leukemia.

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) treatment requires numerous lumbar punctures (LPs) with intrathecal (IT) chemotherapy to prevent and treat central nervous system disease. Historically, LPs in this setting are performed using propofol sedation at most institutions. At our center, LPs are often alternatively performed under nitrous oxide (N2 O). To date, there have been no large-scale assessments comparing these sedation methods for this purpose. PROCEDURES: Retrospective cohort study of patients aged 0-31 years with ALL treated between January 1, 2013 and December 31, 2018 at the Children's Minnesota Cancer and Blood Disorders Center, including all therapeutic LPs performed in the clinic setting under either propofol or N2 O. RESULTS: Among 215 patients and 2677 therapeutic LPs, 56.6% (n = 1515) occurred under N2 O, with 43.3% (n = 93) of patients using exclusively N2 O with all LPs. The incidence of traumatic LPs (red blood cell [RBC] ≥10 cells/µl) was similar between both treatments (27.3% vs. 30.2%). Successful IT chemotherapy delivery (99.7% N2 O vs. 99.8% propofol) did not differ between sedation types. Experiencing a traumatic LP under N2 O was associated with a sedation switch for the subsequent LP (adjusted odds ratio [aOR] 2.40, p = .002), whereas older age (aOR 1.08, p < .0001) and higher body mass index (BMI) percentile (aOR 1.01, p = .009) were associated with increased likelihood for undergoing a traumatic LP. CONCLUSION: N2 O is an effective sedation option for therapeutic LPs in children with ALL with noninferiority to propofol in terms of IT chemotherapy administration and traumatic LP incidence. For many patients, N2 O can effectively replace propofol during LP procedures, which has important safety and quality-of-life implications.

Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib.

Activating variants of the MAPK pathway have been found in some Langerhans cell histiocytosis (LCH) lesions. Inhibition of the MAPK pathway with trametinib (MEK inhibitor) has been shown to induce responses in LCH patients. Two adolescent males with LCH driven by BRAF p.N486_P490del have received trametinib for >1 year with no reactivation in one and partial response in another (including stable lung disease). A third male with neonatal LCH and MAP2K1p.K57_G61del had a complete response to trametinib with no active disease after 22 months. All patients continue on trametinib monotherapy with tolerable skin and creatine phosphokinase toxicity.

Impact of fluid overload and infection on respiratory adverse event development during induction therapy for childhood acute myeloid leukemia.

BACKGROUND: Treatment-related morbidity and mortality occur frequently in childhood acute myeloid leukemia (AML) induction. Yet the contributions of respiratory adverse events (AEs) within this population are poorly understood. Furthermore, the roles of fluid overload (FO) and infection in AML pulmonary complications have been inadequately examined. OBJECTIVES: To describe the incidence, categories, and grades of respiratory AEs and to assess the associations of FO and infection on respiratory AE development in childhood AML induction. METHODS: We retrospectively examined the induction courses of a cohort of de novo pediatric AML patients for any NCI CTCAE grade 2 to 5 respiratory AE, FO, and systemic/pulmonary infection occurrence. Demographic, disease, and treatment-related data were abstracted. Descriptive, univariate, survival, and multivariable analyses were conducted. RESULTS: Among 105 eligible subjects from 2009 to 2016, 49.5% (n = 52) experienced 63 discrete respiratory AEs. FO occurred in 28.6% of subjects (n = 30), with half occurring within 24 hours of hospitalization. Positive FO status < 10 days (aHR 5.5, 95% CI 2.3-12.8), ≥ 10 days (aHR 13, 95% CI 4.1-41.8), and positive infection status ≥ 10 days into treatment (aHR 14.9, 5.4-41.6) were each independently associated with AE development. CONCLUSIONS: We describe a higher incidence of respiratory AEs during childhood AML induction than previously illustrated. FO occurs frequently and early in this course. Late infections and FO at any time frame were strongly associated with AE development. Interventions focused on the prevention and management of FO and infectious respiratory complications could be instrumental in reducing preventable treatment-related morbidity and mortality.

The role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia/lymphoma: challenges, opportunities, and future directions.

INTRODUCTION: Nelarabine is a guanine nucleoside analog and functions to terminate DNA synthesis in dividing cells. Pre-clinical and clinical studies have shown that it preferentially accumulates in T-cells where it exerts its cytotoxic effects. After generations of treatment protocol advances, it has been incorporated into numerous treatment regimens against T-lineage acute lymphoblastic leukemia/lymphoma (T-ALL/LLy). On 8 March 2023, the FDA approved the use of nelarabine for its use in T-ALL due to clear evidence of clinical benefits. This announcement concludes a nearly 6-decade period of evaluation for nelarabine and its role in the management of high-grade, aggressive T-cell malignancies. AREAS COVERED: We review the medicinal biology of nelarabine, its evaluation through decades of clinical studies, its dose-limited adverse effects, and its areas of highest impact in the treatment of T-ALL/LLy. EXPERT OPINION: We provide a context of when nelarabine might be considered in treatments against T-ALL/LLy, and also alternative strategies when it has or has not been used in therapies prior to relapse. We anticipate that an increasing number of treatment regimens will include nelarabine as a part of front-line therapy.

Clonal Evolution of B-Cell Acute Lymphoblastic Leukemia with del(9)(p13p21) into Mixed Phenotype Acute Leukemia Presenting as an Isolated Testicular Relapse.

Lineage switch in acute leukemias is a well-reported occurrence; however, most of these cases involve a switch from either lymphoid to myeloid or myeloid to lymphoid lineage. Here, we report a case of a 14-year-old male with B-cell acute lymphoblastic leukemia (B-ALL) who initially responded well to standard chemotherapy but then later developed mixed phenotype acute leukemia (MPAL) at relapse, likely reflecting a clonal evolution of the original leukemia with a partial phenotypic shift. The patient had a del(9)(p13p21) in his leukemia blasts at diagnosis, and the deletion persisted at relapse along with multiple additional cytogenetic aberrations. Interestingly, the patient presented with an isolated testicular lesion at relapse, which on further analysis revealed both a lymphoid and myeloid component. Unfortunately, the patient did not respond well to treatment at relapse and eventually succumbed to his disease. To our knowledge, an isolated extramedullary MPAL at relapse in a patient with previously diagnosed B-ALL has not been reported in the literature before.

Germline mutations in the bone marrow microenvironment and dysregulated hematopoiesis.

The relationship between the hematopoietic stem cell (HSC) population and its surrounding bone marrow microenvironment is a rapidly evolving area of research. Normal HSC processes rely heavily on a complex communication network involving various marrow niches. Although leukemogenesis largely results from abnormal genetic activity within the leukemia stem cell itself, mounting evidence indicates a significant contributory role played by marrow niche dysregulation. Furthermore, numerous instances of activating or inactivating germline mutations within marrow microenvironment cells have been shown to be sufficient for development of myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia, even in the context of wild-type HSCs. Recent evidence suggests that targeting aberrant chemokine production from germline-mutated marrow stromal cells can potentially reverse the process of leukemogenesis. This elaborate interplay between the HSC population and the marrow microenvironment allows for a number of unique clinical possibilities in efforts to induce remission, enhance chemosensitivity, manage relapsed disease, and prevent leukemia development, both in de novo and germline mutation-associated leukemias, including the use of targeted cytokine/chemokine inhibitors, immune checkpoint blockade, CXCR4/CXCL12 axis antagonists, and combined allogeneic HSC and mesenchymal stem cell transplantation. In this review, we discuss the pathways underlying normal and abnormal bone marrow niche functioning, the relationship between germline mutations in the stem cell microenvironment and dysregulated hematopoiesis, and future clinical perspectives that may be particularly applicable to prevention and treatment of germline-associated leukemias.