Commercial CAR T-cell Therapy and Secondary Malignancy

There is a known risk of secondary primary malignancy following treatment of hematologic malignancy,^1,2  with the risk amplified in patients following autologous or allogeneic hematopoietic cell transplantation.^3,4  Secondary primary malignancies (including solid and hematologic cancers) have also been reported in patients following BCMA- and CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies.⁵  In late 2023, the U.S. Food and Drug Administration (FDA) issued a warning regarding risk of T-cell malignancy following BCMA- or CD19-directed autologous CAR T-cell therapy based on reports from clinical trials and/or postmarketing adverse event data.⁶ 

The article by Guido Ghilardi, MD, and colleagues contains two parts. First, the authors present a single case of T-cell lymphoma arising in a patient after infusion of a retrovirally transduced, CD28–co-stimulated anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel) for B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma. The T-cell lymphoma was identified three months after axi-cel infusion and concurrently with diagnosis of a poorly differentiated squamous non-small cell lung cancer (NSCLC). The T-cell lymphoma was categorized as a CD8+ peripheral T-cell lymphoma, not otherwise specified, with a cytotoxic phenotype. The T-cell lymphoma contained a JAK3 variant of uncertain significance (p.D640Efs*30, variant allele frequency [VAF] of 11%) and a clonal T-cell receptor gamma gene rearrangement.

The authors performed quantitative polymerase chain reaction (qPCR) testing on DNA obtained from the tumor biopsy and identified very low levels of CAR transgene copies (corresponding to approximately 0.005% of cells). This finding was interpreted as representative of infiltrating CAR T cells rather than the neoplastic T cells (that is, a CAR-negative T-cell lymphoma). The authors interrogated peripheral blood from before axi-cel infusion (pre-lymphodepletion) for the specific T-cell receptor clonotype sequence. The sequence was identified reproducibly but at very low copy number. They suggested T-cell activation during CAR T-cell manufacturing and NSCLC-related inflammation may have led to stimulation of a pre-existent T-cell clone.

In the second part of the report, the authors analyzed a large cohort of patients treated with commercial CAR T-cell immunotherapy at the University of Pennsylvania. CAR T-cell therapies included axi-cel (n=69), tisagenlecleucel (n=189), lisocabtagene maraleucel (n=32), brexucabtagene autoleucel (n=34), idecabtagene vicleucel (n=67), and ciltacabtagene autoleucel (n=58). They studied 449 adult patients treated for Non-Hodgkin lymphoma (n=317, majority large B-cell lymphoma), multiple myeloma (n=125), and acute lymphoblastic leukemia (n=7).

By retrospective review of the electronic medical records, the authors identified 16 patients (3.6%) diagnosed with secondary primary malignancies.

Hematologic malignancies occurred in five patients (1.1%) and included:

• Myelodysplastic syndromes/neoplasm (2)

• Acute myeloid leukemia (1)

• Smoldering multiple myeloma (1)

• T-cell lymphoma (1)

Solid malignancies included:

• Non-melanoma skin cancers (5)

• Prostate cancer (3)

• NSCLC (3)

• Melanoma (1)

The predicted five-year incidence rate was 15.2% for secondary solid malignancies and 2.3% for secondary hematologic neoplasms. On multivariable analysis (including gender, age, number of previous lines of therapies, CAR T-cell product, co-stimulatory domain, and previous autologous hematopoietic cell transplantation), only age 65 years or older at the time of CAR T-cell infusion independently correlated with the incidence of secondary primary malignancy. The authors noted that their review may underestimate the incidence of secondary primary malignancy, as they relied on chart review for diagnosis and did not reach out to patients directly.