Peripheral nervous system involvement in lymphoproliferative diseases, often due to direct nerve infiltration (neurolymphomatosis, NL), is mostly seen in aggressive B-cell lymphoma. We report the case of an 88-year-old man with stage IVA DLBCL, who achieved the first complete response after six R-miniCHOP21 cycles. One year post-treatment, he developed severe neurological symptoms, and PET-CT revealed widespread relapse with extensive neural involvement. Treatment with tafasitamab and lenalidomide led to a complete morpho-metabolic remission and full neurological recovery, with minimal side effects. This case underscores for the very first time the efficacy and tolerability of this regimen in treating NL, highlighting its potential for frail patients unfit for more intensive therapies.
