Case Report Highlights Case of Distinct DLBCLs in a Single Patient

A rare case of a single patient with 2 mutationally distinct diffuse large B-cell lymphomas (DLBCLs) may help physicians identify and treat complex cases of the disease.

Medical team reviewing case | Image Credit: © mrmohock - stock.adobe.com

The case was described in the journal Cold Spring Harbor Molecular Case Studies. The authors noted that mutational burden, microsatellite instability (MSI), mismatch repair (MMR), pathway deficiency, and PD-L1 expression have in recent years become important factors for consideration when characterizing a range of malignancies, both for establishing a prognosis and determining whether immune checkpoint inhibitors (ICIs) might be a treatment option.

“Their utility in hematopoietic neoplasms, however, largely remains under investigation,” they wrote. “This is particularly the case for [DLBCL], the most common lymphoma, despite its diverse mutational landscape arising in the mutation-permissive setting of B-cell maturation, often involving DNA repair genes.”

In the report, authors described the case of a 56-year-old man who had a family history of B-cell lymphoma. He presented with adenopathy both above and below the diaphragm, along with spleen involvement. He was treated with EPOCH-R chemotherapy (etoposide phosphate, prednisone, vincristine sulfate [Oncovin], cyclophosphamide, doxorubicin hydrochloride, and rituximab [Rituxan]), and had an initially robust response, the authors said.

However, after 5 months, PET revealed residual disease in the spleen. Physicians performed a splenectomy.

They found that this lymphoma had “an exceptionally high mutational burden (8 disease-associated variants [DAVs] and 41 variants of undetermined significance [VUSs]), along with MSI and an acquired PMS2 mutation with the loss of PMS2 protein expression.”

This prompted his care team to further investigate the initial lymph node DLBCL. It had only 3 DAVs and 14 VUDs, none of which had been detected in the spleen, the authors said. A PD-L1 immunostain was positive, but expression of all 4 MMR proteins was retained.

With a fuller understanding of the case, the patient’s physicians turned to additional therapies. He progressed with salvage therapy of rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAC) and was then given the anti–PD-1 ICI pembrolizumab (Keytruda), which only achieved stable disease status.

Next came CD19-directed chimeric antigen receptor (CAR) T-cell therapy along with mosunetuzumab (Lunsumio), a T-cell engaging anti-CD3/CD20-bispecific monoclonal antibody. That combination yielded a significant partial response at 1 year, but progression had resumed by month 19.

“The patient went on to complete targeted radiation and 6 cycles of monthly obinutuzumab (anti-CD20; sold under the brand name Gazyva),” they wrote. “At month 23, PET/CT imaging revealed a complete metabolic response, and at month 28, no evidence of lymphoma was detected by follow-up thoracic and abdominal/pelvic CT scans.”

The authors said they suspect these 2 DLBCLs were of distinct B-cell clones, noting that the 2 specimens had entirely distinct mutational profiles. They said the case “raises the question of whether more patients might present in this manner, with divergent mutational landscapes (and potentially equally divergent prognostic and therapeutic implication) detectable only by comparative studies performed on spatially and temporally separate samples.”

The investigators noted that the case shows that PD-L1 expression and associative states that allow high mutational burden should be more routinely considered in cases of DLBCL.

“Appropriate testing may be predictive of outcome and inform the utility of targeted therapy in these genetically diverse and historically treatment-refractory malignancies,” they concluded.

Reference

Allbee AW, Gerson J, Yang G, Bagg A. PD-L1+ diffuse large B-cell lymphoma with extremely high mutational burden and microsatellite instability due to acquired PMS2 mutation. Cold Spring Harb Mol Case Stud. 2024;9(4):a006318. doi:10.1101/mcs.a006318