Secondary Hematologic Malignancies in Patients Following Chimeric Antigen Receptor T-Cell Therapy: Aggregated Clinical Trial Data from 1542 Patients
Authors: Cliff Edward R Scheffer , Lafeuille Penelope , Diamond Sheila , Aptekar Jacob , Russler-Germain David A , Rejeski Kai , Kesselheim Aaron S 
Published: December 2024

Overview
Chimeric Antigen Receptor (CAR) T-cells are an effective treatment for a variety of hematologic malignancies, received by &gt;30,000 patients to date. Autologous T-cells are genetically modified ex-vivo using lenti- or retro-viral transduction to express a CAR receptor, which confers T-cells with HLA-independent tumor antigen recognition and thus tumor specificity.
Recently, the FDA announced an investigation into 22 patients who developed T-cell malignancies following receipt of CD19- or BCMA-directed CAR T-cells and worked with manufacturers to add boxed warnings to approved CAR T-cell products used in patients with secondary myeloid malignancies and T-cell lymphomas. Patients with hematologic malignancies are already at higher risk of developing second primary malignancies, in large part due to prior exposure to cytotoxic chemotherapy.
We sought to quantify the incidence of second primary malignancies in a large cohort of patients who have received CAR T-cells while enrolled in clinical trials. These data offer the high quality, granularity and accuracy of clinical trial data but the aggregation offers a larger denominator in which to evaluate incidence.
Methods
For this cohort study, we identified all patients who had received CD19-directed CAR T-cells in clinical trials from data stored in the Medidata Clinical Cloud®. The Medidata Clinical Cloud® stores aggregated and anonymized study data from trials run on Medidata's platform.
We assessed the incidence of second primary hematologic malignancies. Second B-cell lymphomas were excluded as likely relapses of patients' original disease. Incidence over time was estimated using the Kaplan Meier method.
Results
All 1542 patients in this anonymized cohort had lymphoma and received CD19-directed CAR T-cells, with a median follow-up of 24 months, representing 3133 patient-years of total follow-up. Patients had a median age of 61, an initial diagnosis of predominantly diffuse large B-cell lymphoma (971, 63%), mantle cell lymphoma (184, 12%) or follicular lymphoma (260, 17%) and had received a median of two lines of treatment prior to CAR T-cells, excluding bridging therapy.
Secondary hematologic malignancies occurred in 53 (3.4%) patients at a median of 18 months post CAR T-cell infusion, of which 14 (26%) developed AML, 40 (75%) had MDS (4 patients had both), 2 (3.8%) had multiple myeloma (MM) and 1 patient developed peripheral T-cell lymphoma not otherwise specified. This represents an incidence of secondary hematologic malignancy of 2.45% per patient-year.
The patient who developed T-cell lymphoma post-CAR T-cells had had an initial diagnosis of DLBCL, had received 3 prior lines of treatment including prior autologous stem cell transplant, developed the T-cell lymphoma 1 month after CAR T-cell infusion, and died following diagnosis of T-cell lymphoma. Information regarding whether the T-cell lymphoma contained the CAR construct was not available in this database.
Discussion
The observed rate of secondary hematologic malignancies of 2.45% per patient-year is similar to previous literature of heavily pretreated lymphoma patients receiving other cellular therapies like autologous or allogeneic SCT.
T-cell malignancy was exceedingly rare and was reported in only a single patient (&lt;0.01%). These data corroborate a recent meta-analysis which evaluated 7604 patients for causes of non-relapse mortality (Dos Santos et al., Nat Med 2024), finding zero deaths secondary to T-cell lymphoma.
While it is essential to remain vigilant for T-cell lymphomas that may relate to CAR-mediated insertional mutagenesis - and to investigate the reported cases in greater detail to at least determine how many contain the CAR - this risk must be put into context of the overall positive outcomes post CAR-T.
It remains unclear to what extent CAR T-cells propagate clonal expansion (CHiP) and/or how CAR-T induced immunosuppression contributes to malignancy risk.
CAR T-cells continue to offer an effective treatment option for certain patients, and clinicians and patients must appropriately contextualize the risk of second hematologic malignancies post CAR-T.