Transdifferentiation of high-grade B-cell lymphoma into monocytic/histiocytic neoplasm following CD19 CAR-T Therapy: A Case Report
Introduction/Background/Significance: Follicular lymphoma (FL) is classically indolent but may transform into aggressive disease such as high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-MYC/BCL2). While CD19-directed CAR-T therapy has shown significant promise in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), rare cases of post-CAR-T lineage transdifferentiation into histiocytic/dendritic or monocytic neoplasms have emerged, with limited therapeutic options and poor prognosis.
Results/Description/Main Outcome Measures: A 78-year-old woman initially diagnosed with stage III FL (grade 1-2) in 2016 experienced transformation in 2024 to HGBCL-MYC/BCL2. She received six cycles of dose-adjusted R-EPOCH and intrathecal methotrexate, achieving a complete metabolic response. Four months later, she developed leptomeningeal relapse confirmed by MRI brain and total spine and CSF cytology. Treatment included high-dose methotrexate (MTR regimen), intrathecal cytarabine, and CD19-directed CAR-T (lisocabtagene maraleucel) in March 2025, resulting in a near complete response.
However, within two weeks in May 2025, she developed rapidly enlarging cutaneous and subcutaneous tumors on the right breast and left chest/back. Two 6 mm punch biopsies revealed a diffuse dermal infiltrate of large atypical cells with abundant cytoplasm, which expressed monocytic/histiocytic markers (CD33, CD11c, CD68 [partial], CD163 [focal]), did not express MPO, CD13, CD34, CD117, or B-cell lineage markers, and showed evidence of clonal relatedness to the prior HGBCL, including MYC and BCL2 rearrangements and an identical clonal immunoglobulin gene rearrangement pattern. Next-generation sequencing showed multiple alterations, including KRAS, BRAF, CREBBP and subclonal MAP2K1(MEK) P124A, as well as CDKN2A loss. Bone marrow biopsy showed no evidence of malignancy. The findings were most consistent with histiocytic sarcoma transdifferentiated from HGBCL-MYC/BCL2. The pathologic diagnosis was made nearly a month after lesion onset due to its unusual features, by which time the disease had significantly progressed. PET/CT in June 2025 showed new FDG-avid skin and nodal lesions. CSF flow cytometry also revealed residual lambda-restricted B-cells resembling prior lymphoma, raising concern for persistent CNS involvement.
She received palliative radiation therapy (2000 cGy in 5 fractions) to her multifocal skin and nodal lesions with excellent response. Further cytotoxic therapy was initially deferred to preserve CAR-T function and avoid potential recurrence of leptomeningeal disease. Intralesional pegylated interferon-alpha (IFN-α) was offered as a non-cytotoxic alternative, extrapolating from basal cell carcinoma and myeloid sarcoma data. Remarkably, after only one treatment with intralesional IFN-α, she experienced a near complete resolution of her skin lesions. Research flow cytometry of her CSF and peripheral blood revealed no detectable circulating CD19 CAR-T cells, prompting discontinuation of IFN-α and transition to MEK inhibitor (cobimetinib) given NGS results. She declined an allogeneic stem cell transplant.
Conclusions: This case illustrates a rare but clinically important trajectory: FL transforming to HGBCL, relapsing in the CNS, responding to CAR-T therapy, and subsequently undergoing lineage transdifferentiation into a histiocytic sarcoma. The aggressive progression, diagnostic delay, and therapeutic complexity underscore the challenges of managing post-CAR-T relapses and secondary malignancies. As survival improves with CAR-T, unusual patterns of relapse such as this may become more apparent. There is a critical unmet need for diagnostic vigilance and development of tailored therapies that balance tumor control with preservation of CAR-T efficacy.
