Background: Extranodal natural killer/T-cell lymphoma (ENKL) is a rare subtype of mature T and natural killer cell lymphomas associated with Epstein-Barr virus. Case: A 20-year-old presented with severe neurological symptoms and was diagnosed with stage IV ENKL, nasal type, with CNS involvement. Overall, the patient received nine treatment lines, including chemotherapy, craniospinal irradiation, allogeneic stem cell transplant (alloSCT), donor lymphocyte infusions, and novel agents (Nivolumab, Daratumumab, Thalidomide, Lenalidomide, virus-specific T cells) combined with intrathecal chemotherapy. The treatment effect was evaluated in both blood and CSF (cerebrospinal fluid). First-line SMILE chemotherapy resulted in systemic and CNS remission. Later Cytarabine-based chemotherapy and Daratumumab combination helped to reinduce remission before alloSCT. Conclusion: We show that efficacy monitoring should include both blood and CSF analysis. High-dose Cytarabine-based chemotherapy in combination with Daratumumab and intrathecal chemotherapy may be considered as salvage CNS-directed therapies. We add to existing limited data that Daratumumab penetrates the blood-brain barrier.