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Only one of 724 patients treated with chimeric antigen receptor (CAR) T-cell therapy for B-cell lymphoma subsequently developed a T-cell lymphoma, according to a large clinical series.

The T-cell lymphoma occurred in a patient who received CAR T-cell therapy for a diffuse large B-cell lymphoma (DLBCL). Molecular, genetic, and cellular analyses showed the two lymphomas had distinct immunophenotypes and genomic profiles but had a common association with Epstein-Barr virus (EBV) and two mutations affecting clonal hematopoiesis.

The findings highlighted the rarity of second malignancies after CAR T-cell therapy but also provided a framework for defining clonal relationships and viral vector monitoring in patients treated with CAR T-cell therapy, reported Ash Alizadeh, MD, PhD, of Stanford University in California, and coauthors in the (NEJM).

"We found that T-cell lymphoma was rare, accounting for only a single case," the authors wrote of their findings. "No evidence was found to implicate a direct contribution from the engineered retroviral vector in the index T-cell lymphoma at the DNA, messenger RNA, or protein level and on interrogation of circulating, tissue-resident, and cell-free anatomical compartments."

They continued: "Supporting a priori susceptibility to T-cell lymphoma transformation, the presence of a pre-existing heterozygous DNMT3A R882C and hemizygous TET2 L1212Vfs*15 co-mutant clone in the patient described in the current study suggests that underlying lymphoid clonal hematopoiesis was probably a modifying factor in this malignant condition, even if its presence alone is insufficient to drive the T-cell neoplasm. Given the underlying multilineage DNMT3A and TET2 mutations, we postulate that this tumor was derived from a DNMT3A and TET2 co-mutant lymphoid progenitor."

As for the viral link between the two lymphomas, the authors noted that "EBV tends to infect mature B cells, but it is also known to occasionally infect hematopoietic stem cells and progenitor cells."

"However, it is not possible to conclude at what level of differentiation EBV infection occurred in the present case," they added. "This study highlights the critical potential of lymphoid clonal hematopoiesis mutations to transform into lymphoid malignant conditions as previously reported and further suggests pre-existing susceptibility to T-cell lymphoma."

A published simultaneously in NEJM described a case of indolent CD4+ CAR T-cell lymphoma after B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy for multiple myeloma. The T-cell lymphoma was discovered following a biopsy of the patient's small intestine. Targeted messenger RNA sequencing revealed the presence of CAR gene product in tumor cells, reported Metin Ozdemirli, MD, PhD, of MedStar Georgetown University Hospital in Washington, D.C., and coauthors.

Whole-genomic sequencing of tumor tissue and peripheral blood identified a single lentiviral insertion site in the SSU72 gene. Investigators identified numerous other genetic alterations that might have contributed to malignant transformation.

Context and Interpretation

The discovery of shared identical mutations in DNMT3A and TET2 by Alizadeh and colleagues suggests "independent derivation from pre-existing clonal hematopoiesis," noted Emily Mitchell, MD, PhD, and George S. Vassiliou, MD, PhD, of the University of Cambridge in England, in an .

"The authors found no evidence of CAR vector integration in the T-cell lymphoma and reasonably conclude that it was not directly related to CAR therapy," the editorialists wrote.

In contrast, Ozdemirli and colleagues found that a T-cell lymphoma that harbored CAR-vector integration in the second intron of SSU72, which has a role in T-cell homeostasis, Mitchell and Vassiliou continued. This team found no evidence that the insertion affected SSU72 mRNA expression and identified other genetic aberrations that plausibly might drive the neoplasm.

"Overall, the evidence of viral vector integration and the development of T-cell lymphoma 5 months after CAR T-cell infusion are suggestive of a causal link to CAR therapy," stated Mitchell and Vassiliou.

"Despite the lack of a clear etiologic path, the case reported by Ozdemirli et al shows that CAR T cells themselves can occasionally progress to T-cell lymphoma, which may be higher when premalignant T-cell clones are present before harvest," the editorialists continued.

"Similarly, the findings by [Alizadeh] suggest the possibility that EBV-positive lymphoid cancer may be more likely to arise from premalignant or clonal hematopoiesis clones after CAR T-cell therapy," Mitchell and Vassiliou added.

Interest in second malignancies after CAR T-cell therapy intensified late last year after the FDA announced an investigation into a "serious risk of T-cell malignancy" after BCMA- or CD19-targeted CAR T-cell therapy. At the time the agency had received information about 19 cases of T-cell malignancies. The investigation pertained to all currently approved CAR-T therapies.

The FDA acknowledged that "the overall benefits of these products continue to outweigh their potential risks," but earlier this year requested that drugmakers add a boxed warning about the risks on the labeling of all CAR T-cell therapies on the market.

In their editorial, Mitchell and Vassiliou pointed out that as of early 2024, more than 34,000 patients had received autologous CAR T-cell therapy in the U.S. Available data suggest the with CAR T-cell therapy is not higher than expected in patients with substantial exposure to chemotherapy.

"However, the 20 to 25 reported cases of T-cell cancer are attracting particular attention owing to the possibility of a direct causal link to CAR therapy that would mirror cancer arising from genetically modified hematopoietic stem cells that were used to treat inherited immunodeficiencies," Mitchell and Vassiliou noted.

Key Findings, Conclusions

In an effort to inform investigations into second malignancy after CAR T-cell therapy, Alizadeh and colleagues reviewed their experience with the therapy since 2016. The one case of T-cell lymphoma in 587 B-cell lymphoma patients treated with CAR T-cell therapy represented an incidence of 0.17%.

"A bidirectional risk between B-cell lymphoma and T-cell lymphoma is known, with a standardized incidence of T-cell lymphoma after B-cell lymphoma that was described in a to be approximately five times as high as that in the general population," the authors noted.

The previous report identified 354 cases of T-cell lymphoma in 288,478 patients with B-cell lymphoma, an incidence of 0.12%.

Alizadeh and coauthors said their findings suggest that development of T-cell lymphoma after CAR T-cell therapy is rare and may occur through various mechanisms in susceptible individuals.

"Given the known increased baseline risk of second T-cell malignant tumors in patients with previous B-cell lymphomas, even in the absence of CAR therapies, the observed T-cell tumors after CAR T-cell therapies, in a sufficiently large population of patients, may reflect a bystander instead of a direct effect," they suggested.

"In this context, emerging data suggest that an inflammatory memory characterizes a special subset of hematopoietic stem cells that expands with age and is enriched for somatic mutations associated with clonal hematopoiesis," the authors continued. "Although this remains to be definitively determined, we speculate that such mutant progenitors could be especially prone to CAR-associated inflammation and corresponding selection pressures."

Ozdemirli and coauthors stated that their findings suggest "the addition of switch or on-off mechanisms to CAR T-cell products could possibly prevent such an unexpected, severe complication" as the unusual indolent CD4+ intestinal CAR T-cell lymphoma they described.