Long-Term Sequelae in Patients Treated for Recurrent CNS Relapses of Pediatric B-Cell Acute Lymphoblastic Leukemia: 20-Year Follow-Up, Neurological Consequences, and Survivorship Burden—A Case Report and Literature Review

Central nervous system (CNS) relapse remains a major cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL). Repeated isolated CNS relapse is particularly rare and associated with poor prognosis, while optimal therapeutic strategies remain insufficiently defined. Intensified CNS-directed therapy may improve disease control but is also associated with substantial long-term neurotoxicity and survivorship burden. We present the case of a boy with favorable-risk B-cell ALL who developed two isolated CNS relapses despite a good initial response to frontline therapy and absence of classical CNS relapse risk factors. The second relapse was associated with extensive meningeal involvement and optic nerve infiltration. The patient underwent intensive multimodal CNS-directed therapy, including repeated intrathecal chemotherapy, liposomal cytarabine administered according to the IntReALL 2010 protocol, cranial irradiation, and allogeneic hematopoietic stem cell transplantation (alloHSCT) from a matched sibling donor. Durable long-term remission was achieved despite the extremely unfavorable prognosis that is associated with a second isolated CNS relapse. A twenty-year follow-up extending into early adulthood revealed substantial late complications, including epilepsy, transient ischemic attack, optic nerve injury, endocrinopathies, obesity, secondary thyroid malignancy, neurocognitive difficulties, and depression requiring long-term psychiatric and psychological support. The present case illustrates the complex balance between effective CNS disease control and cumulative treatment-related neurotoxicity in pediatric ALL survivors. It also highlights the cumulative CNS injury and long-term survivorship burden that is associated with repeated CNS relapse and multimodal CNS-directed therapy.