Association of AL with neurological effects in the pediatric population

A retrospective study on a pediatric population has shown that neurologic manifestations (NMs) in patients with acute leukemia (AL), relating to a greater mortality rate.1 AL is the most prevalent childhood cancer, which accounts for one-third of all cancers within the age range.1 Although the survival rate is approximately 90%, AL is still the most common cause of death by a single disease in childhood.1

The 2 main types of AL include acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).2 ALL constitutes approximately three-quarters of leukemia and is defined as an overproduction of immature lymphocytes, which is characterized by the hematopoietic tissue in the bone marrow, peaking at the age of 2-6 years.2 AML accounts for most of the remaining AL cases and is characterized as cancer of the myeloid white blood cell line, with a poorer prognosis than ALL and a 5-year survival rate of 41%.2 The infiltration of AL cells into the central nervous system (CNS), due to the expression of adhesion molecules by AL cells to endothelial cells, may cause brain tumor formation.3 In addition, hypoxia along with vascular endothelial growth factor-A (VEGF-A) secretion by AL causing vascular permeability in the bone marrow also causes blood-brain barrier disruption.3 Most of the deaths in childhood from AL are due to infections and cerebrovascular events.4 Therapies for treating AL, such as high-dose systemic chemotherapy, intrathecal radiotherapy, cranial irradiation, and other side effects of AL, including infection, hemorrhage, cerebrovascular lesions, metabolic/hydroelectrolytic imbalance, syndromes of the inappropriate secretion of antidiuretic hormone or nutritional deficiencies, are further associated with significant acute and long-term toxicity to the CNS.1,5 The study by Cruz-Chávez DA et al. aimed to evaluate NMs in the pediatric population with AL and related demographic, clinical characteristics, risk factors, and clinical outcomes.1

The retrospective, longitudinal, analytical study included 607 pediatric patients diagnosed with AL at the Hematology Department from Centro Médico Nacional “20 de Noviembre” between  January 1, 2015 and December 31, 2020.1 NMs were referred to as any NS symptom, sign or laboratory finding within the study period, established by a board-certified pediatric neurologist.1 ALL chemotherapy schemes were based on the St. Jude XV protocol, Intermediate and High-Risk Relapsed Acute Lymphoblastic Leukemia (LALRA) scheme and Isolated Relapse to CNS [Pediatric Oncology Group (POG)], while that of AML was based on mercaptopurine, cytarabine, steroid, dexrazoxane, idarubicin, etoposide, and mitoxantrone.1 Participants were split into 2 groups regarding the presence of NM.1

NM was the first clinical symptom in about 17.4% of the study population, and the age was 9.7 ± 4.5 years in this group, with NM patients being significantly older (p=0.01) and the most prevalent age range being 6-12 years.1 ALL was the most common lineage, followed by AML and mixed phenotype acute leukemia (MPAL), and ALL were diagnosed at a significantly younger age than AML (6.3 ± 3.9 vs. 12.3 ± 4.3 years; p<0.0001).1 AL was also significantly more prevalent in boys than girls (54.8% vs. 44.1%; p<0.01).1

CNS infiltration was present in 26.4% of NM patients and discovered during the re-induction phase, while 73.6% presented neurological deficits or other NM symptoms, including seizures (26.4%), headache (18.9%), neuropathy (11.3%), which were mostly discovered during the induction and re-induction phases (p≤0.0001).1 CNS infiltration (55.7%) was also the most common final neurological diagnosis through different chemotherapy phases, followed by epilepsy (15.9%) and primary headache (13.6%).1 The mean time from NM to death was 13.0 ± 19.5 months and in particular, the mean time from NM to death for ALL and other lineages were 14.2 ± 20.9 months and 8.8 ± 13.3 months, respectively (p=0.525).1 The mortality rates were 18.7% in AML patients, 11.8% in ALL patients, and 50% in MPAL patients (p≤0.002).1 The NM group had a greater mortality rate than the non-NM group during the follow-up (44.4% vs. 8.9%; HR=3.83; 95% CI: 2.50-5.96; p≤0.0001), whereas 36.7% and 42.6% died within the first and second years of follow-up among the NM group.1

To conclude, the most common type of leukemia is ALL, and the most common NM being infiltration to the CNS, seizures, headache and neuropathy.1 Therapy-induced neurotoxicity may be associated with NM, as shown by the higher mortality rate and symptoms developed especially during the induction and re-induction of therapy.1

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