Primary mediastinal large B-cell lymphoma (PMBCL) is a rare and aggressive subtype of large B-cell lymphoma that predominantly affects young adults and usually presents as a bulky anterior mediastinal mass. Although overall outcomes are favorable with modern chemoimmunotherapy, a minority of patients develop refractory disease or relapse. Central nervous system (CNS) involvement in PMBCL is uncommon but associated with a particularly poor prognosis.

We report the case of a 22-year-old male patient diagnosed with stage IV bulky PMBCL with multiple extranodal sites, including the lungs, chest wall, pancreas, pelvis, rib, and proximal humerus. The diagnosis followed a pathological humeral fracture that led to the detection of a large mediastinal mass. Initial treatment with CHOP14 was complicated by asymptomatic SARS-CoV-2 infection, which resulted in delayed administration of rituximab. Despite therapy and intrathecal prophylaxis, end-of-treatment PET-CT demonstrated only a partial metabolic response. Second-line treatment with the R-GDP regimen was initiated; however, the patient rapidly developed neurological symptoms. Neuroimaging revealed a parietal–occipital brain lesion, and biopsy confirmed CNS relapse of PMBCL.

Salvage treatment with the R-MIV regimen (rituximab, methotrexate, ifosfamide, and vincristine) resulted in marked clinical and radiological improvement. After five cycles of therapy, PET-CT demonstrated complete metabolic remission. Treatment was subsequently consolidated with radiotherapy to the brain and mediastinum followed by autologous hematopoietic cell transplantation after BEAM conditioning. Although the post-transplant period was complicated by severe mucositis, sepsis, and venous thrombosis, the patient achieved full hematologic recovery and remains in sustained complete remission more than three years after CNS relapse.

This case highlights the therapeutic challenges of PMBCL with secondary CNS involvement and suggests that the R-MIV regimen may represent a feasible salvage treatment option for CNS and systemic relapse. Further clinical studies are required to confirm its efficacy in this setting.