Dr Dahiya on the Pathobiology of Second Primary Cancers After CAR T-Cell Therapy

“In the next few years, [we will] have a lot more data about the incidence of these SPCs as we move CAR T-cell therapy into earlier lines and as we [use and investigate] CAR T-cell therapy for autoimmune [diseases]. A lot of things in terms of the risk of developing these second myeloid neoplasms or myeloid neoplasms will be demystified.”

Saurabh Dahiya, MD, FACP, associate professor, medicine (blood and marrow transplantation and cellular therapy), Stanford University School of Medicine, clinical director, Cancer Cell Therapy, Stanford BMT and Cell Therapy Division, details the pathobiology of second primary cancers (SPCs) following receipt of CAR T-cell therapy and ongoing efforts to better elucidate SPC incidence and risk for patients with hematologic cancers.

In 2023, the FDA issued draft guidance regarding the oncogenic potential of CAR T-cell therapy following reports of 20 cases of T-cell lymphoma among approximately 30,000 treated patients. The report reflected growing concerns about the incidence of SPCs following CAR T-cell administration and the long-term safety profile of this drug class, Dahiya begins.

At the time of the FDA’s warnings in November 2023 and again in January 2024, the primary concern centered on the increased observation of T-cell lymphomas in patients post-CAR T-cell therapy, he says. From the inception of CAR T-cell therapies, insertional mutagenesis has been a theoretical risk, Dahiya states. He explains that insertional mutagenesis is a process by which the CAR transgene integrates into the T-cell genome, potentially activating an oncogene and driving malignant transformation. This risk was initially discussed in the FDA’s perspective article in the 

, which reported 3 such cases following CAR T-cell therapy, Dahiya notes.

Additional concerns have emerged regarding T-cell malignancies that are transgene negative, Dahiya continues. These malignancies do not appear to be caused directly by insertional mutagenesis, indicating that CAR T-cell therapy could lead to oncogenic events via other mechanisms, such as immune dysregulation or genomic instability induced by the therapy’s effects on the host immune system, Dahiya suggests.

Further research is needed to clarify the incidence and causality of SPCs associated with CAR T-cell therapy, particularly as its use expands into earlier lines of treatment and autoimmune indications, he emphasizes. As more data become available, the understanding of CAR T-cell–related oncogenic risks will be refined, particularly concerning secondary myeloid neoplasms, Dahiya notes. Future studies comparing CAR T-cell therapy across oncology and autoimmune diseases may help delineate therapy-related risks and inform mitigation strategies, he concludes.

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Saurabh Dahiya, MD, FACP, details the pathobiology of second primary cancers following receipt of CAR T-cell therapy for hematologic malignancies.

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In today’s episode, we had the pleasure of speaking with Saurabh Dahiya, MD, FACP, and Shyam A. Patel, MD, PhD, about their research into the risk of developing second primary cancers (SPCs) following CAR T-cell therapy and how this risk, though low, may be mitigated. Dr 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. Dr Patel is an associate professor in the Department of Medicine at the UMass Chan Medical School, as well as a hematologist/oncologist at UMass Memorial Medical Center in Worcester, Massachusetts.

In our exclusive interview, Drs Dahiya and Patel discussed the pathobiology of SPCs that develop after CAR T-cell therapy, potential SPC prevention strategies, and how SPC research may help optimize CAR T-cell product development in the future.

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Podcasts

Drs Dahiya and Patel discuss how SPC research may help optimize CAR T-cell product development in the future.

How Second Primary Cancer Risk Factors Into CAR T-Cell Therapy Considerations: With Saurabh Dahiya, MD, FACP; and Shyam A. Patel, MD, PhD

Dr Dahiya on the FDA Approval of Liso-Cel for Relapsed/Refractory Follicular Lymphoma

Saurabh Dahiya, MD, FACP, associate professor, medicine (blood and marrow transplantation and cellular therapy), Stanford University School of Medicine, clinical director, Cancer Cell Therapy, Stanford BMT and Cell Therapy Division, discusses the significance of the FDA approval of lisocabtagene maraleucel (liso-cel; Breyanzi) for patients with relapsed/refractory follicular lymphoma (FL).

the FDA granted accelerated approval to liso-cel

 for the treatment of patients with relapsed/refractory FL who have received at least 2 prior lines of systemic therapy. This regulatory decision was based on findings from the single-arm, phase 2 TRANSCEND-FL trial (NCT04245839), in which liso-cel generated an overall response rate of 95.7% (95% CI, 89.5%-98.8%) in the population of patients with relapsed/refractory FL who had received at least 2 prior lines of systemic therapy, including an alkylating agent and an anti-CD20 antibody. After a median follow-up of 16.8 months (95% CI, 16.3-17.0), the median duration of response was not yet reached (NR; 95% CI, 18.04-NR).

In TRANSCEND-FL, patients received a single dose of liso-cel 2 to 7 days after completing lymphodepletion. The recommended dose of liso-cel is 90 x 10

The most common nonlaboratory adverse effects observed in the study included cytokine release syndrome (CRS), headache, fatigue, musculoskeletal pain, fever, and constipation. Notably, the FDA approved liso-cel with a Risk Evaluation and Mitigation Strategy because of its associated risk of life-threatening or fatal neurologic toxicities and CRS.

Liso-cel is the third CAR T-cell therapy to receive FDA approval for patients with relapsed/refractory FL, Dahiya says. Liso-cel is an autologous, CD19-directed CAR T-cell therapy containing a 1:1 ratio of CD8-positive and CD4-positive CAR T cells, Dahiya explains. Liso-cel was previously shown to elicit deep and durable responses in patients with relapsed/refractory large B-cell lymphoma (LBCL), Dahiya notes. This regulatory decision confirms the agent’s efficacy in relapsed/refractory FL as well as LBCL, Dahiya concludes.

Saurabh Dahiya, MD, FACP, discusses the FDA approval of lisocabtagene maraleucel for patients with relapsed/refractory follicular lymphoma.

Saurabh Dahiya, MD, FACP

Articles

Dr Dahiya on the Pathobiology of Second Primary Cancers After CAR T-Cell Therapy

How Second Primary Cancer Risk Factors Into CAR T-Cell Therapy Considerations: With Saurabh Dahiya, MD, FACP; and Shyam A. Patel, MD, PhD

Dr Dahiya on the FDA Approval of Liso-Cel for Relapsed/Refractory Follicular Lymphoma