Secondary T-Cell Malignancies: Identifying and Counseling After CAR T-Cell Therapy

CAR T-cell therapy has transformed outcomes for patients with B-cell malignancies and multiple myeloma, but the FDA’s November 2023 safety communication, followed by class-wide boxed warnings formally mandated in April 2024 across all 6 approved CAR T-cell products, has raised important questions about T-cell malignancies that may arise as secondary complications after CAR T-cell infusion.

CancerNetwork® spoke with Jasmine Zain, MD, about the risk, mechanisms, and clinical implications of these rare but clinically significant secondary T-cell malignancies. Drawing on her presentation at the 2026 Society of Hematologic Oncology (SOHO) Annual Meeting , Zain explained how to distinguish insertional mutagenesis from background genotoxic risk, outlined the role of pre-existing clonal hematopoiesis of indeterminate potential (CHIP) mutations in predisposing patients to secondary malignancy, and offered guidance on how multidisciplinary teams should counsel patients navigating FDA boxed warning concerns. She also addressed how moving CAR T-cell therapies into earlier lines of treatment may affect the background rate of these complications, what pharmacovigilance infrastructure community oncology teams should establish for long-term monitoring, and what emerging CAR T-cell platforms may mean for the field going forward.

Zain is an attending physician in the Lymphoma Service at Memorial Sloan Kettering Cancer Center.

CancerNetwork: What were the key takeaways from your presentation on secondary CAR T-cell malignancies at SOHO 2026?

Zain: My presentation focused on the risk of secondary CAR T-cell malignancies, specifically the T-cell cancers that may be arising from the CAR T-cell vector itself. There is not a lot of data on this, but I discussed the incidence, some of the mechanisms and possible risk factors, and touched on what may be becoming a separate category of these lymphomas and how they would be classified.

Given the FDA’s class-wide boxed warnings regarding second primary malignancies post-CAR T-cell therapy, how do you clinically differentiate between malignancies directly driven by retroviral or lentiviral insertional mutagenesis vs those resulting from cumulative genotoxic stress?

That is the key to determining the causation of these secondary lymphomas. First, I want to clarify that it is very rare to develop T-cell malignancies [resulting from] what we think may be CAR T-cell–related mutagenesis. There are secondary malignancies that can arise in the setting of CAR T-cell therapy or other anti-cancer and anti-lymphoma therapies that are not directly related to the CAR T-cell vector itself.

In terms of how we determine causation: you have to dig very deep into the malignant tissue — into the malignant T cell. You must first establish that it is a T-cell malignancy through clonality, flow cytometry, and the usual methods of diagnosing T-cell lymphoma. After that, you have to look for the presence of the CAR vector in the tumor genome, and for that you need molecular biology techniques such as PCR [polymerase chain reaction]. You need to know the sequence of the CAR T product so you can search for it in the tumor and then perform further molecular studies to determine where the insertion site is in relation to oncogenes or tumor suppressor genes, to assess whether it is directly causing mutagenesis and malignancy.

The prevailing theory is that the insertion site should be within 300 base pairs of the initiation or promoter region of the proto-oncogene or tumor suppressor gene, or involve a direct insertion into the promoter site, which can either activate or deactivate the relevant gene and drive mutagenesis. However, there is thought that this may not be the only event. Secondary events may occur as a result of the rapid cell division stimulated by these CAR T cells, and something called mutational burden may develop, leading to additional pathways toward malignancy.

What baseline patient features, such as pre-existing mutations including TET2 or DNMT3A, should prompt heightened surveillance or alter the pre-infusion conditioning strategy?

Some patients have a baseline or underlying CHIP mutation. These could be TET2 or DNMT3A mutations, and they predispose patients to malignancies that may represent the original predisposition to the disease being treated, or lead to an independent T-cell lymphoma that is independent of the CAR T-cell therapy entirely. It is important to establish that genetic profile before the patient undergoes therapy, or, if the patient has already developed a second malignancy, to go back and look at blood samples from before the infusion to see whether this was present.

The concern is that the CAR vector may get inserted into one of these cells that already carries the CHIP mutation, and when these CAR T cells expand in response to antigenic stimulation, they will expand carrying that mutation. A secondary event could then lead to a secondary malignancy. If CHIP mutations are present, there is a definite predisposition to developing a secondary malignancy, which may or may not be related to the CAR T-cell therapy. It is important to screen patients for this, counsel them carefully, and possibly offer alternative therapies. We do the same in the context of autologous stem cell transplant: if patients have a CHIP mutation, we try to avoid further genotoxic stress from high-dose therapy and transplant. Patients who nonetheless need to receive CAR T-cell therapy should be counseled very clearly and in detail, so they fully understand the risks. Fortunately, the overall risk remains small, but it is present.

A TP53 mutation is another consideration. Patients with TP53 mutations are typically very difficult to treat to begin with, and the mutation does predispose them to other malignancies; this is something to discuss with the patient, though it is not in the same category as a CHIP mutation.

How should multidisciplinary oncology teams communicate the risk-benefit ratio of these secondary primary malignancies to patients who may express anxiety over the FDA warnings when considering cellular therapy, given that these rates are similar between CAR T-cell therapy and standard-of-care salvage?

Patients should be made aware. It is a boxed warning on all 6 products approved for B-cell and multiple myeloma malignancies, and the risk is higher with certain subtypes of CAR T cells, particularly the BCMA [B-cell maturation antigen]-directed CAR T cells. Patients should be informed of this risk, but they should also be told that the risk is very low: it is approximately 1.5%, based on what we have seen so far, and the FDA registry is in place to collect this information and ensure we do not miss it.

The other important thing to understand is that the presentations of these lymphomas vary considerably, from what is called a lymphoproliferative disorder or a mildly abnormal clone in the peripheral blood, which can happen with any kind of inflammatory situation and sometimes resolves on its own, to skin lesions or small collections of abnormal or malignant T cells that can be easily treated. How any individual patient will present, if they develop this, is unclear. It is possible that some patients may decline therapy based on this risk, because these second malignancies can be very difficult to treat and may result in a negative outcome. That unpredictability is something that should also be communicated to the patient. The bottom line is very careful, thorough counseling, making sure patients understand the risks and the outcomes, and what can be done about these situations.

As CAR T-cell therapies move into earlier lines of oncologic treatment and non-malignant autoimmune indications, how might the reduced burden of prior cytotoxic exposure change the observed background rate and etiology of second primary malignancies in these populations?

That remains to be seen, that is the short answer. We know from prior experience that patients exposed to genotoxic stress from cytotoxic chemotherapy have a higher risk of secondary malignancies, with or without CAR T-cell therapy, and in some cases that risk is very well defined. As we move these agents into upfront therapies and away from chemotherapy toward chemo-free regimens, we expect—though it remains to be seen—whether this will result in a further reduction in the risk of these malignancies, including the myeloid malignancies that patients may develop over time. We hope that these treatments will not only improve outcomes, but also decrease the risk of these secondary complications.

What operational workflow or registry mechanisms should community oncologists, surgical teams, and cellular therapy centers establish to ensure long-term, multi-year pharmacovigilance and prompt bidirectional reporting when a secondary malignancy is detected post-CAR T?

These patients need to be followed very carefully. The FDA has a registry and is actively following this information, so if a second malignancy develops, it must be reported, both by the pharmaceutical company and by the treating facility and treating physicians. As part of the education forums for these products, pharmaceutical companies as well as cancer centers of excellence should ensure that community physicians are aware of this risk. If a secondary malignancy occurs, the patient should be referred for the proper workup, which is detailed and nuanced and may require specialized expertise. The reporting should happen so that we can continue to follow these patients, better understand the risk, and generate more robust information about these issues.

Reference

Zain JM. Understanding the risk of second malignancies after CAR T therapies. Presented at: Society of Hematologic Oncology Annual Meeting; September 9–12, 2026; Houston, TX.