To the Editor: Blinatumomab, a bispecific T-cell engager targeting CD19 B cells and CD3 T cells, has transformed the management of B-cell acute lymphoblastic leukemia (B-ALL) and is now approved for frontline therapy 1-3. Neurotoxicity, most commonly manifesting as immune effector cell-associated neurotoxicity syndrome (ICANS), is a recognized complication, occurring in up to 65% of treated patients, with 13%–17% experiencing grade ≥ 3 events 4-6. Clinical manifestations typically include encephalopathy, confusion, aphasia, tremors, and seizures 4. Although most episodes are resolved within days, prolonged symptoms such as language disturbance, tremor, or cognitive dysfunction have been described 7. Psychiatric sequelae, including new-onset of mood disorders or worsening of preexisting depression and anxiety, have been reported 8, 9, but persistent psychosis is exceedingly rare. Previously described cases typically involve transient affective or anxiety symptoms occurring in the context of delirium or encephalopathy, resolving with corticosteroids or treatment interruption 8-10. Here, we report a case distinguished by a psychiatric-predominant presentation with frank psychosis and catatonic features, with symptom persistence for 6 months following encephalopathy resolution and blinatumomab discontinuation, ultimately leading to a diagnosis of schizophrenia (Table 1). Rapid response to steroids Usually, complete recovery A 16-year-old Hispanic male with B-ALL, central nervous system (CNS)-1 with ETV6::RUNX1 fusion and TBXLR1 loss was treated according to the St. Jude Total 17 protocol 11. Measurable residual disease was negative after induction therapy (prednisone, vincristine, daunorubicin, calaspargase, cyclophosphamide, cytarabine, and 6-mercaptopurine). His first blinatumomab course, after consolidation therapy (four cycles of high-dose methotrexate 2 g/m2, 6-mercaptopurine, and triple methotrexate, hydrocortisone, and cytarabine intrathecal therapy), was uneventful. He had no history of neurologic or psychiatric disease or substance abuse, but did have a history of childhood trauma. He tolerated early maintenance therapy with vincristine, dexamethasone, methotrexate, and 6-mercaptopurine. On Day 8 of his second blinatumomab cycle, given after the second reinduction that included vincristine, dexamethasone, and calaspargase, he presented with acute agitation, insomnia, and disorganized thoughts. His mother reported new-onset auditory hallucinations and delusions, including beliefs that his siblings were dead and that his mother and roommate were the devil. On examination, he was fatigued, restless, intermittently disoriented, internally preoccupied, and exhibited mild catatonic features including resistance to passive movement, echopraxia, and right–left disorientation. No seizures were observed. He was hospitalized, blinatumomab was discontinued, and he was treated with dexamethasone, risperidone, clonidine, and a lorazepam challenge for suspected catatonia. Brain magnetic resonance imaging and cerebrospinal fluid studies were unremarkable. He was diagnosed with ICANS Grade 2. He was discharged on Day 8 of symptoms with close outpatient follow-up. Although agitation and disorganization gradually improved with risperidone titration, persecutory delusions, hyper-religiosity, and paranoia remained. Over subsequent months, psychotic symptoms demonstrated partial attenuation while adherent to antipsychotic therapy but reliably recurred with medication tapering or missed doses. He was followed for 6 months after discharge, during which he exhibited persistent psychotic features, including delusions, hallucinations, disorganized behavior, and negative symptoms, meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) duration criteria for schizophrenia and culminating in a formal diagnosis. Blinatumomab-related neurotoxicity is thought to arise from cytokine-mediated inflammation and endothelial activation, leading to blood–brain barrier disruption (Figure 1) 12. Proinflammatory cytokines, including interleukin (IL)-6, interferon-γ, and tumor necrosis factor-α, can cross into the CNS, alter excitatory-inhibitory balance, and produce neuropsychiatric symptoms 6, 13, 14. Neurotoxicity may occur in the absence of CNS leukemia, supporting an immune-driven mechanism rather than leukemic infiltration 15. The serial associations of blinatumomab exposure, immune-mediated neurotoxicity, secondary psychiatric symptoms that are resolved with antipsychotics, and the absence of similar reactions to prior chemotherapy that included glucocorticoids support a causal relationship. Given the short half-life of blinatumomab and inflammatory cytokines, the persistence of psychiatric symptoms for weeks after drug discontinuation is unexpected. The patient's protracted symptoms raise the possibility that blinatumomab unmasked an underlying psychiatric vulnerability. His early childhood history—including significant early-life psychosocial adversity, trauma exposure, chronic environmental stressors, and limited formal education—may have lowered the threshold for sustained psychotic symptoms following immune-mediated neuroinflammatory stress. Cytokine-driven limbic activation and stress reactivity could precipitate psychosis in predisposed individuals 16, 17. Emerging evidence links systemic inflammation with schizophrenia pathogenesis, with elevated IL-6 being implicated in dopaminergic and glutamatergic dysregulation 16, 17. In an open-label pilot clinical trial, IL-6 blockade with tocilizumab improved psychotic symptoms, a relevant observation given that tocilizumab is also used to treat cytokine release syndrome and ICANS 18. This suggests that cytokine-mediated neuroinflammation may not only underlie acute neurotoxicity but also unmask latent psychiatric disease in susceptible individuals. Distinguishing transient immune-mediated psychosis from a new-onset primary psychiatric disorder remains clinically relevant for risk stratification and long-term management. Evidence indicates that individuals with preexisting psychosocial stressors, cognitive impairment, or diminished cognitive reserve are more susceptible to medication-induced delirium, psychosis, or other mental status changes 19. Clinicians should maintain vigilance for psychiatric-predominant ICANS presentations, as prompt corticosteroid administration and blinatumomab cessation can prevent severe escalation. Multidisciplinary collaboration among oncology, neurology, psychiatry, and allied teams facilitates accurate diagnosis and supportive management. This case expands the recognized neuropsychiatric spectrum of blinatumomab-related toxicity, which can require long-term medical treatment, and underscores the need to consider psychosocial background and prior trauma when evaluating behavioral changes in patients receiving immune-engaging therapies. In summary, blinatumomab-associated neurotoxicity can manifest as isolated psychosis and may unmask an unrecognized psychiatric disorder. Early recognition and intervention can enable recovery while enabling continuation of chemotherapy once the patient is stabilized. Awareness of these atypical presentations may improve patient safety and help guide monitoring strategies in the era of targeted immunotherapy. The authors thank Keith A. Laycock, PhD, ELS, for scientific editing of the manuscript. This work was supported by the National Cancer Institute (Cancer Center Support CORE Grant CA021765) and by the American Lebanese Syrian Associated Charities (ALSAC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Hiroto Inaba receives consulting fees from Jazz Pharmaceuticals and Amgen. The other authors declare no conflicts of interest.
Zaheer et al. (Sun,) studied this question.