Second Primary Cancers & CAR-T Therapy: Risks, Insights & Mitigation

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, offering new hope to patients, but a growing body of evidence raises concerns about an emerging complication: the risk of second primary cancers (SPCs). This issue is explored in depth in a recent review published in JAMA Oncology (2025; https://doi.org/10.1001/jamaoncol.2024.5412). CAR-T therapy has revolutionized the treatment of hematologic malignancies, offering hope to patients with conditions such as aggressive lymphomas, multiple myeloma, and acute lymphoblastic leukemia. While its efficacy in achieving durable remissions is well-documented, emerging evidence highlights a concerning complication: the development of SPCs. This article explores the pathobiology, epidemiology, and mitigation strategies for SPCs in CAR-T recipients, aiming to provide clinicians with a comprehensive understanding of this evolving challenge. Pathobiology of SPCs in CAR-T Recipients CAR-T therapy relies on the genetic modification of autologous T cells via viral transduction, typically using lentiviral vectors. While effective, this process introduces the theoretical risk of insertional mutagenesis—the integration of the transgene into genomic loci prone to oncogenic transformation. Although rare, documented cases of transgene-positive SPCs, such as T-cell lymphomas, have underscored this risk. For example, integration of the CAR construct into oncogenes like PBX2 and SSU72 has been implicated in malignant transformation. Most SPCs, however, are transgene-negative and arise from alternative mechanisms, including impaired immune surveillance and genotoxic stress from prior therapies. The lymphodepletion and chemotherapy required for CAR-T administration can perturb the immune system, fostering an environment conducive to neoplastic growth. Epidemiology of SPCs Post-CAR-T Therapy Data from large-scale studies provide insights into the incidence and nature of SPCs among CAR-T recipients. A 2023 analysis reported approximately 20 cases of T-cell lymphoma in a cohort of 30,000 CAR-T recipients. Furthermore, multicenter studies estimate SPC rates ranging from 1.7 percent to 4.3 percent, with diagnoses including solid tumors, myeloid neoplasms, and rare T-cell malignancies. The timeline of SPC development varies. Many cases manifest within 2 years of CAR-T infusion, highlighting the importance of vigilant post-therapy monitoring. Interestingly, the overall incidence of SPCs in CAR-T recipients does not appear significantly higher than in patients treated with conventional therapies, although longer follow-up periods are needed to validate this observation. Risk Mitigation Strategies Addressing the risk of SPCs requires a multifaceted approach encompassing primary, secondary, and tertiary prevention strategies. Primary Prevention: Informed Consent: Comprehensive discussions with patients regarding the small but definitive risk of SPCs are essential. Consent processes should explicitly outline these risks, empowering patients to make informed decisions. Genomic Safety in Manufacturing: Advances in gene-editing technologies, such as CRISPR-Cas9, offer the potential for targeted integration of transgenes into genomic “safe harbors,” minimizing the risk of insertional mutagenesis. Routine genomic screening of modified T cells post-transduction may further enhance safety. Secondary Prevention: Baseline Screening: Testing for clonal hematopoiesis (CH) and other predispositions can identify patients at elevated risk for myeloid neoplasms. While current guidelines do not mandate exclusion of patients with CH, detailed genomic profiling may aid in personalized risk assessment. Monitoring Inflammation: Chronic inflammation is a known driver of carcinogenesis. Evaluating markers such as C-reactive protein and erythrocyte sedimentation rate pre- and post-CAR-T therapy may help identify patients at heightened risk. Tertiary Prevention: Active Surveillance: Post-infusion monitoring should include regular physical exams, biomarker testing, and imaging studies to detect SPCs early. Proposed guidelines suggest integrating surveillance into standard follow-up protocols. Transparent Reporting: Establishing centralized registries for SPCs, such as through the Center for International Blood and Marrow Transplant Research (CIBMTR), will facilitate data collection and improve our understanding of long-term risks. To delve deeper into the topic of second primary malignancies following CAR-T therapies, Oncology Times spoke with the study authors, Shyam A. Patel, MD, PhD, and Saurabh Dahiya, MD. Patel serves as Assistant Professor of Hematology/Oncology at UMass Chan Medical School and UMass Memorial Medical Center, while Dahiya is Associate Professor at Stanford University School of Medicine and the Clinical Director of Cancer Cell Therapy in the Stanford BMT and Cell Therapy Division. Both authors played an equal role in providing insightful responses. Oncology Times: What are the primary mechanisms implicated in the development of SPCs after CAR-T therapy? How do they differ between transgene-positive and transgene-negative cases? Patel & Dahiya: “We reviewed the evidence basis for primary mechanisms that govern the development of SPCs following administration of CAR-T therapy, and we noted three overarching mechanisms. First, the most direct (yet most infrequent) mechanism is insertional mutagenesis involving the CAR transgene, leading to transgene-positive lymphoma. “Specifically, there have been rare reports of these CAR-T lymphomas following inadvertent insertion into the 3' UTR of PBX2 and the intronic region of SSU72. This mechanism likely accounts for only a fraction of a percent of SPCs in the post-CAR-T setting. Secondly, with regard to myeloid malignancies, the process of CAR-T administration can lead to clonal hematopoietic expansion within the myeloid compartment. Pre-existing clonal hematopoiesis has been noted in some recipients of CAR-T infusion, and this might place patients at risk for progression to overt myeloid neoplasm, given that lymphodepleting chemotherapy (fludarabine/cyclophosphamide) can contribute to genotoxic stress within the hematopoietic stem/progenitor cell pool. Thirdly, solid tumors can develop in the post-CAR-T setting given the disruption of immune surveillance by the CAR-T process. Impaired anti-tumor immunity can facilitate solid tumorigenesis.” Oncology Times: How does baseline CH influence the likelihood of SPCs? What are the current recommendations for CH screening in CAR-T candidates? Patel & Dahiya: “Baseline CH places patients at risk for development of overt myeloid neoplasm in the setting of the correct inciting factors. Given that CH is largely an age-related phenomenon, older adults are more likely to experience adverse effects of CAR-T therapy compared to younger adults. Canonical mutations in DNMT3A and TET2 are often found within a subset of hematopoietic cells of seemingly healthy individuals, and such CHIP clones can emerge after lymphodepleting chemotherapy or long-standing immunosuppression imparted by the CAR-T process. “At the 2023 ASH Annual Meeting, the Stanford group reported clonal selection and expansion of DNMT3A and PPM1D mutations after CD19-directed CAR-T therapy (Blood 2023; https://doi.org/10.1182/blood-2023-182522). Such phenomena might explain why some patients have prolonged cytopenias after CAR-T therapy, and these patients appear to be at risk for myeloid neoplasm. “There are currently no consensus guidelines for CH screening prior to CAR-T therapy. In the stem cell transplant literature, this remains a matter of debate also. CH screening decisions may depend partly on the risk-benefit ratio on an individual basis (Br J Haematol 2025; https://doi.org/10.1111/bjh.19948). The field is now gaining insight into the effects of pre-existing CH in cell therapy recipients. Our teams have studied such aspects of CH in larger primary datasets of cell therapy recipients and have noted an increased risk for therapy-related myeloid neoplasm for patients with baseline CH (Bone Marrow Transplant 2024; https://doi.org/10.1038/s41409-024-02403-2). Further studies will need to be performed to either validate or refute the utility of baseline CH screening prior to administration of CAR-T therapy. In the absence of guidelines stemming from expert panels, we recommend that the presence of baseline CH should not preclude the administration of life-saving CAR-T therapy for the primary malignancy, as the risk for SPC is relatively small.” Oncology Times: What strategies, including pre-treatment discussions and post-infusion monitoring, are proposed to enhance patient safety and early detection of SPCs following CAR-T therapy? Patel & Dahiya: “Mitigation strategies that may enhance patient safety and early detection of SPCs following CAR-T therapy can be broadly divided into primary, secondary, and tertiary prevention measures. Primary prevention includes pretreatment discussions with open, two-way communication between physicians and patients with full disclosures of risks involved. “Primary prevention strategies may also include identification of genomic safe harbors such that oncogene disruption is avoided during the CAR-T manufacturing process in the first place. Patient safety also can be enhanced by use of non-viral delivery systems, such as CRISPR/Cas9, which can more safely ‘knock in’ CAR cassettes into specific loci, without incurring the risk of insertional mutagenesis from semi-random integration of lentiviruses. Secondary prevention measures may include myeloid variant testing on bone marrow aspirates for patients with baseline cytopenias. Evaluation for germline predisposition in select patients can also be assessed prior to CAR-T administration such that clinicians can better gauge the risk for developing SPCs. Finally, tertiary prevention includes real-time and reliable reporting to agencies such as the CIBMTR in the event that SPCs occur in the post-CAR-T setting.” Oncology Times: What are the long-term research priorities identified for reducing SPC risks while optimizing the therapeutic potential of CAR-T therapies in both oncology and autoimmune disease settings? Patel & Dahiya: “Long-term research priorities include identification and validation of superior transgene delivery methods for cell therapy. Sequencing of T-cell genomes post-transduction may help identify the site of transgene integration, though this can be costly. The field might benefit from identifying genomic safe harbors within the T-cell genome or developing methods that allow for locus-specific integration of transgene. “On a more global scale, cellular therapists may benefit from identifying patient prototypes that are susceptible to eventual development of SPCs. Such prototypes include patients with chronic inflammatory states, multiple comorbidities, or baseline clonal hematopoiesis. “As for autoimmune disease settings, this field is quite young and we are just beginning to learn more details. Long-term research priorities in the autoimmune space may include laboratory studies aimed at resetting aberrant autoimmunity within specific disease subtypes. Such strategies might allow us to provide high-value personalized CAR-T therapeutics across global markets and across multiple disease indications.” Dibash Kumar Das is a contributing writer.