Transdifferentiation of diffuse large B-cell lymphoma to a poorly differentiated neoplasm following CAR T-cell therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy is a recent advancement in precision medicine with promising results for patients with relapsed or refractory B-cell malignancies. However, rare post-therapy morphologic, immunophenotypic, and genomic alterations can occur. This study is to present a case of a patient with diffuse large B-cell lymphoma (DLBCL) who underwent anti-CD19 CAR-T therapy with disease in the uterus that showed transdifferentiation to a poorly differentiated malignant neoplasm that failed to express any lineage specific markers. In immunohistochemistry, fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS) were utilized to fully characterize the diagnostic DLBCL sample in comparison to the poorly differentiated neoplasm of the uterus. Analysis of the diagnostic DLBCL and the poorly differentiated neoplasm demonstrated evidence of a clonal relationship as well as revealing acquisition of mutations associated with CAR-T resistance. Furthermore, downregulation of B-cell associated antigens was observed, underscoring a mechanistic link to CAR-T evasion as well as demonstrating diagnostic confusion. This case illustrates the utility of employing multiple diagnostic modalities in elucidating a pathologic link between a B-cell lymphoma and poorly differentiated neoplasm following targeted therapy.

Primary Central Nervous System Anaplastic Large Cell Lymphoma, ALK Positive.

OBJECTIVES: Primary central nervous system anaplastic large cell lymphoma, anaplastic lymphoma kinase positive (primary CNS ALCL, ALK+) is a rare CNS lymphoma whose description is limited to case reports. These tumors have a variable clinical course, and prognosis is primarily determined by age. We present the largest case series to date of primary CNS ALCL, ALK+, with observational data. METHODS: A retrospective search of multiple academic centers was performed to identify cases of primary CNS ALCL, ALK+. We also performed a review of published cases of primary CNS ALCL, ALK+. Clinical history, radiography, pathology, and genetic testing data were obtained to determine the prognostic implications in the context of clinical course. RESULTS: We identified three cases of primary CNS ALCL, ALK+ from our databases. A literature review identified 30 published reports of 31 individual cases. Clinical features for the combined 34 cases included a median age of 18.5 years, with a male to female ratio of 4.7:1, and the most common symptom was headache. Genetic studies demonstrated an ALK rearrangement by fluorescence in situ hybridization, and a gene fusion assay confirmed an NPM1-ALK gene fusion in one case. CONCLUSIONS: We present the largest case series to date of a rare primary CNS lymphoma with additional diagnostic and clinical information.