Cytomegalovirus Lymphadenitis After Anti-CD19 Chimeric Antigen Receptor T-cell (CAR-T): An Underappreciated Etiology of Hypermetabolic Lymphadenopathy in the Post-CAR-T Setting

Chimeric antigen receptor T-cell (CAR-T) is a revolutionary type of immunotherapy that genetically engineers a patient's own immune T-cells to recognize and attack cancer cells. This type of therapy has transformed the treatment of relapsed/refractory large B-cell lymphoma (LBCL). However, profound immunosuppression may lead to opportunistic infections that could resemble relapse in rare situations. Cytomegalovirus (CMV) reactivation and clinical infection are well recognized after hematopoietic stem cell transplantation but are less studied in the post-CAR-T setting. We describe a 56-year-old woman with primary refractory stage IV diffuse LBCL, not otherwise specified, treated with axicabtagene ciloleucel. She initially achieved a complete remission (CR), but at six months s/p CAR-T, she developed constitutional symptoms and non-tender palpable lymphadenopathy. Positron emission tomography (PET) and computed tomography (CT) demonstrated hypermetabolic cervical and axillary lymph nodes, as well as focal uptake in the appendix. A biopsy did not show relapsed lymphoma but did reveal classic CMV inclusions, positive CMV immunohistochemistry, and high-level tissue CMV DNA despite negative plasma PCR, with a final diagnosis of CMV lymphadenitis. Symptoms resolved with a three-week course of valganciclovir, and follow-up imaging showed near-complete resolution of the disease. CMV lymphadenitis is a rare but important differential diagnosis of hypermetabolic lymphadenopathy in the post-CAR-T setting, which can mimic lymphoma relapse. Tissue biopsy remains essential for accurate diagnosis and to prevent unnecessary oncologic therapy. Clinicians should maintain vigilance for infectious etiologies in this setting, and future studies may clarify whether targeted CMV monitoring is warranted in high-risk patients.