Central Nervous System-Directed Therapy

The introduction of therapy to eradicate leukaemic cells in the central nervous system (CNS) represented a breakthrough in the treatment of childhood acute lymphoblastic leukaemia (ALL). Early CNS-directed therapy employed craniospinal and cranial irradiation alongside systemic chemotherapeutics to generate substantial improvements to overall survival (OS) and event free survival (EFS) among paediatric patients. However, radiotherapy causes significant short- and long-term neurotoxic side effects prompting a switch to intrathecal chemotherapy and systemic agents with good CNS penetration in most modern protocols. Diagnosis of CNS ALL is established through analysis of patient cerebrospinal fluid (CSF) samples obtained via lumbar puncture. Results from conventional cytology classifies patients based on the number of leukocytes, the presence of leukaemic blasts in the CSF and the presence or absence of red cells, denoted as CNS 1, 2, 3, or traumatic lumbar puncture (>10 red cells/μL) (TLP) with or without blasts (TLP+/−). CNS 3 status and/or TLP+ at diagnosis is associated with a poorer prognosis and increased risk of CNS relapse. However, cytospin classification is unsatisfactory as the majority of CNS relapses occur in CNS 1 patients. New approaches such as CSF flow cytometry may provide more sensitive detection of CNS leukaemia, but response biomarkers, akin to bone marrow minimal residual disease assays, are still lacking in the CNS. Modern treatment for standard risk patients encompasses intrathecal (IT) and/or systemic chemotherapeutics, namely methotrexate (MTX), glucocorticoids and cytarabine. High- and very high-risk ALL patients may receive more intensive chemotherapy regimens and/or cranial radiation. In cases of T-cell ALL and ALL cells harbouring BCR-ABL fusion gene (Philadelphia positive) there may be additional benefit of including nelarabine and tyrosine kinase inhibitors (TKIs), respectively. The curtailment of radiation in modern CNS directed protocols has reduced the neurotoxicity associated with treatment. However, there are still significant short and long-term neurological sequelae associated with chemotherapy-only regimens. Short-term neurotoxicity includes seizures, cerebral sinus venous thrombosis, stroke-like syndrome (SLS) and posterior reversible encephalopathy syndrome (PRES). Long-term neurotoxicities include impairments to executive function, memory and processing speeds. The incidence of CNS relapse is less than 5%, however the CNS is involved in over 30% of all relapse cases. Standard treatment for relapse involves cranial irradiation and chemotherapy, with some evidence to suggest that haematopoietic stem cell transplant (HSCT) may provide an effective treatment strategy for some patients. However, the optimal therapeutic regimen for children with isolated CNS relapse, following modern intensive upfront protocols, remains undetermined. Finally, the neurotoxic burden associated with standard-of-care CNS prophylaxis has stimulated significant interest into the potential of novel, less-toxic targeted therapeutics and response biomarkers to risk-stratify patients. A better understanding of the unique biological features of CNS-ALL has resulted in several possible new treatments although few have entered phase1/2 trials to date. Immunotherapies such as CAR T cells or bispecific antibodies also show early promise in treating CNS-ALL although some unique challenges related to possible enhanced neurotoxicity, antibody penetration and T cell exhaustion in the CNS remain.