CAR T-Cell Therapy Results in Secondary Primary Cancers in Approximately 4% of Patients

The rare development of second primary cancers (SPCs) following CAR T-cell therapy may be influenced by disease control and bridging therapy, especially if genotoxic therapy is administered for multiple cycles before receipt of CAR T-cell therapy, according to Shyam A. Patel, MD, PhD, and Saurabh Dahiya, MD, FACP.1 However, data are limited regarding the suggestion that inadvertent transgene insertion is associated with SPCs in the post–CAR-T setting.

“We performed an objective evidence-based appraisal of the existing primary literature on the risk of SPCs following CAR T-cell therapies. We found that the overall incidence of SPCs is approximately 4% or less across most studies, and there is no causal association between CAR T-cell therapy administration and the development of transgene-positive SPCs,” Patel said in an interview with Dahiya and OncLive®. “In conjunction with this small risk, there’s an even smaller risk for the development of CAR-positive T-cell lymphomas after CAR T-cell therapy administration. Overall, we favor proceeding with CAR T-cell therapy in most cases, as the benefits of CAR T-cell therapy outweigh that minimal risk of SPCs, and we look forward to additional investigations in this field to help further minimize these risks.”

The review examined reported cases of SPCs to date, and noted an analysis of the FDA Adverse Events Reporting System concluded the incidence of SPCs was 4.3%. Patel et al highlighted that as the risk of developing SPCs following CAR T-cell therapy is relatively low compared with the opportunity cost of forgoing CAR T-cell therapy, next steps should include implementing primary and secondary prevention/mitigation strategies. In a concurrent interview, Patel and Dahiya discussed such steps including the optimization of T-cell manufacturing and implementation of high-fidelity genomic testing, notably with baseline screening for clonal hematopoiesis.

In this interview, Patel and Dahiya highlighted aspects of the pathobiology of SPCs after CAR T-cell therapy and findings from their review as well as other studies examining these cancers. Patel is a hematologist/oncologist at UMass Memorial Medical Center, and an associate professor at the UMass Chan Medical School in Worcester, Massachusetts, and Dahiya is an associate professor of medicine at Stanford University School of Medicine and clinical director of Cancer Cell Therapy in the Stanford BMT and Cell Therapy division in Palo Alto, California.

OncLive: What was your inspiration for writing this review article?

Patel: CAR T-cell therapies have provided transformative benefits for patients with leukemia, lymphoma, and multiple myeloma. Over the past few years, we’ve seen significant data that attest to the high value of CAR T-cell therapies, including the curative potential these therapies [have for patients with] a variety of different hematologic malignancies. However, the recent news of post–CAR T-cell therapy SPCs created significant distress amongst the public, physicians, and scientists. There have been scattered reports of T-cell lymphomas diagnosed after CAR T-cell therapy administration, but the details of these reports were somewhat unclear. Our inspiration for this manuscript was to better educate physicians, scientists, and the public about the risk for SPCs in the post–CAR T-cell therapy setting. Our main goal was to assess the epidemiology of SPCs and to provide information on risk mitigation strategies based on the best available evidence. We also aimed to provide practical recommendations for the management of these risks.

Dahiya: We wanted to define these secondary primary cancers that patients are experiencing after getting CAR T-cell therapy and further provide insights into the pathobiology of these SPCs. As we learned in our research, the incidence of these SPCs is fairly low. The concern was T-cell malignancies, specifically insertional mutagenesis and transgene-positive T-cell malignancies. [Notably], transgene-positive T-cell lymphoma [occurred very] rarely in our analysis.

What is the pathobiology of SPCs after CAR T-cell therapy?

Dahiya: Originally, when the FDA issued this warning in November 2023 and later in January 2024, the main concern was increased observation of T-cell lymphomas after [patients received] CAR T-cell therapy. Even at the advent of CAR T-cell therapy, there [has] always been concern about insertional mutagenesis, where the CAR transgene inserts itself into the T-cell genome, potentially into an oncogene, resulting in an oncogenic event that results in T-cell proliferation and a T-cell malignancy. Insertional mutagenesis was a concern that the FDA had in their original perspective article written in the New England Journal of Medicine, with 3 cases seen in their original observation. The additional concern they had was [an] increased incidence of T-cell malignancies that are transgene negative for these patients. We tried to further elaborate and expand on [those worries] in our analysis and review research paper.

Patel: In addition to those aspects of the pathobiology, there’s also a risk for therapy-related myeloid neoplasms and solid tumors. For therapy-related myeloid neoplasms, there can be clonal hematopoietic expansion of mutated hematopoietic stem cells or progenitors as a direct result of cytotoxic chemotherapy exposure in the setting of CAR [T-cell therapy] lymphoid depleting chemotherapy. Genotoxic stress within the myeloid compartment can contribute to the development of therapy-related myeloid neoplasms and TP53 mutations are often found in these therapy-related myeloid neoplasms, leading to high-risk SPCs. There have [also] been reports of the development of solid tumors post–CAR T-cell therapy, though the frequency is relatively low. The pathobiology of the development of solid tumors may involve impaired immune surveillance after CAR T-cell therapy administration.

What can be learned from studies examining the epidemiology of SPCs after CAR T-cell therapy?

Patel: One of the first reports of SPC risk came [in 2022] from a multicenter study at the University of Washington, in which it was found that approximately 2% of CAR T-[cell therapy] recipients developed SPCs. Around the same time, a number of single institutional studies came out showing a small but defined risk for SPCs, typically in the range of 3%. Then, in November 2023, the FDA was notified of 20 cases of T-cell lymphomas amongst approximately 30,000 CAR T-cell therapy recipients; most of these lymphomas occurred within approximately 24 months of CAR T-cell therapy infusion.

In 2024, the Center for International Blood and Marrow Transplant Research [CIBMTR] issued a report documenting an approximate 4% incidence of SPCs, [and] very few of these SPCs were T-cell lymphomas. There have been occasional, rare reports of transgene-positive T-cell lymphomas from single institutional experiences. Dr Dahiya, I’m curious to hear about your thoughts based on the study that your team at Stanford did on SPC risk.

Dahiya: This was an example of the field getting together and putting out institutional experiences as well as registry data at a very fast pace. In 2024, we saw close to approximately a dozen reports from institutions including single institution and registry data from organizations like CIBMTR—there was an amazing response to this new safety risk that emerged.

At Stanford, we looked at our experience [with more than] 700 patients who had received a gene-modified T-cell treatment or CAR T-cell therapy—we excluded patients who received non-gene modified T-cell therapies. For those patients who received CAR T-cell therapy, our data was in line with [what] the other institutions had reported [as approximately 6.5% of patients experienced a secondary cancer in the 3 years after therapy]. We only saw a single case of transgene-negative T-cell lymphoma, and we did deep genomic sequencing to elucidate the pathobiology of that T-cell lymphoma and showed that there was no transgene that was detectable in that case.

Additionally, we showed that the incidence of SPCs, including therapy-related myeloid neoplasms and solid tumors, were comparable with what other institutions and registry data have shown with incidence [rates of approximately] less than 3% for secondary myeloid neoplasms and less than 5% for solid tumors. [These are] rather low-risk and extremely rare events that we observed in our single institution experience, in line with other large centers putting out their data and registry-based data.

Reference

1. Patel SA, Spiegel JY, Dahiya S. Second primary cancer after chimeric antigen receptor-T-cell therapy: a review. JAMA Oncol. Published online December 12, 2024. doi:10.1001/jamaoncol.2024.5412