Screening for CHIP Mutations to Guide CAR T Cell Candidacy in Lymphoma

In an interview with CancerNetwork® at the 2026 Society of Hematologic Oncology (SOHO) Annual Meeting, Jasmine Zain, MD, attending physician in the Lymphoma Division of Memorial Sloan Kettering Cancer Center, discussed how baseline genomic profiling for clonal hematopoiesis of indeterminate potential (CHIP) mutations should factor into pre-infusion evaluation for CAR T-cell therapy.

Zain described a mechanistic model in which the CAR T lentiviral vector can integrate into a CHIP mutation–carrying hematopoietic cell; when those cells subsequently expand in response to antigenic stimulation, they do so while carrying the pre-existing mutation, creating the conditions for a secondary oncogenic event. She drew a direct parallel to current practice in autologous stem cell transplant, where the presence of CHIP mutations already prompts consideration of alternative or modified approaches to limit additional genotoxic exposure. She also addressed TP53 mutation as a distinct, clinically relevant predisposing factor, warranting explicit discussion with patients, though not classified in the same risk category as canonical CHIP mutations.

Transcript:

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

Zain: 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. 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.

It is possible 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 with that mutation. A secondary event could then lead to a secondary malignancy. If CHIP mutations are present, there is a 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 definitely 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.

Reference

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