Evaluating Secondary Primary Malignancy Risk After CAR T-cell Therapy

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In 2023, the FDA issued a warning on secondary primary malignancies after treatment with CAR T-cell therapy.

In November 2023, the FDA published a warning to patients who had previously received B-cell maturation antigens or CD19-directed CAR T-cell therapy who were reported to have T-cell malignancies and CAR-positive lymphoma.

In November 2023, the FDA published a warning to patients who had previously received B-cell maturation antigens or CD19-directed CAR T-cell therapy who were reported to have T-cell malignancies and CAR-positive lymphoma.

The FDA Adverse Event Reporting System (FEARS) reported secondary primary malignancies in 4.3% of patients who received CAR T-cell therapies, according to a recently published study in Blood.1

The study authors analyzed 12,394 unique CAR T adverse effect (AE) reports, and after exclusion criteria were applied, 536 (4.3%) identified secondary primary malignancies. The most common treatments that resulted in AEs included axicabtagene ciloleucel (axi-cel; Yescarta) in 51.7% of patients and tisagenlecleucel (tisa-cel; Kymriah) in 33.0%.

"It is crucial to recognize that these are rare reports of second primary malignancies within the broader context of the transformative benefits that CAR T cell therapies offer to patients. The continuous monitoring is critical to understand the safety profile of these therapies. That being said, the benefits of CAR T cell therapies continue to outweigh the risks for the approved indications," Magdi Elsallab, MD, PhD, from Harvard Medical School, said in a written statement to CancerNetwork®.

The most common secondary primary malignancies included leukemias (62.1%), which made up 2.7% of the CAR T report. Of the leukemia reported, the report included myelodysplastic syndromes (MDS; 38.8%), acute myeloid leukemia (AML; 19.8%), and 2 cases of T-cell large granular lymphocytic leukemia.

Following leukemia, skin neoplasms were the second most common secondary primary malignancy occurring in 10.1% of patients and 0.4% of all CAR T reports. These neoplasms included non-melanoma skin neoplasms (7.8%), and skin melanomas (2.2%).

Other secondary primary malignancies included hematopoietic neoplasms that excluded leukemias and lymphomas (4.9%) but included lymphoproliferative disorder (n = 15), myeloproliferative neoplasms (n = 7), and histiocytosis (n = 4). Additionally, nervous system tumors were noted in 3.9% of patients, and respiratory neoplasms were noted in 3.7%. which comprised 0.2% each of CAR T reports.

In 3.2% of reports, T-cell non-Hodgkin lymphomas were identified and included 12 cases of large T-cell lymphomas with 7 occurring on treatment with tisa-cel, 3 with axi-cel, and 2 with ciltacabtagene autoleucel (cilta-cel; Carvykti); 3 peripheral T-cell lymphoma occurring with 1 in tisa-cel, 1 in cilta-cel, and 1 in lisocabtagene maraleucel (liso-cel; Breyanzi); 1 in angioimmunoblastic T-cell lymphoma occurring with axi-cel; and 1 case of enteropathy-associated T-cell lymphoma occurring with cilta-cel. Of these 17 cases, 8 patients died, 4 had hypogammaglobulinemia, 3 had cytokine release syndrome, 2 had hemophagocytic lymphohistiocytosis, and 2 had neurotoxicity.

Of the available CAR T-cell therapy treatments, the reporting odds ratio (ROR) was highest for those with MDS treated with axi-cel (ROR, 3.5; 95% CI, 2.9-4.2), tisa-cel (ROR, 1.3; 95% CI, 1.0-1.8), liso-cel (ROR, 4.6; 95% CI, 2.4-8.5), ide-cel (ROR, 2,8; 95% CI, 1.2-6.7), and cilta-cel (ROR, 6.7; 95% CI, 3.3-13.5). For AML, tisa-cel (ROR, 1.5; 95% CI, 1.2-2.0) and cilta-cel (ROR, 4.1; 95% CI, 1.3-2.8) were associated with higher ROR. Those treated with tisa-cel had disproportionately more cases of anaplastic large T-cell lymphoma (ROR, 7.4; 95% CI, 3.1-17.4).

The report also highlighted a number of trials conducted using CAR T-cell therapies, with 6 of 8 trials reporting secondary primary malignancies.

  • Tisa-cel
    • Phase 2 ELIANA NCT02435849) and phase 2 ENSIGN (NCT02228096): 2.2% for those with acute lymphoblastic leukemia
    • Phase 2 JULIET (NCT02445248): no secondary primary malignancies
  • Axi-cel
    • Phase 1/2 ZUMA-1 (NCT02348216) and phase 3 ZUMA-7 (NCT03391466): secondary primary malignancies were reported in less than 1% and 4.7%, respectively
  • Brexucabtagene autoleucel (Brexu-cel; Tecartus)
    • Phase 1/2 ZUMA-3 (NCT02614066): no secondary primary malignancies
  • Liso-cel
    • Phase 1 TRANSCEND NHL-001 (NCT02631044) and phase 3 TRANSFORM (NCT03575351): secondary primary malignancy rates of 8.1% and 3.3%
  • Cilta-cel
    • Phase 1/2 CARTITUDE-1 (NCT03548207): secondary primary malignancies in 25.8%
  • Ide-cel
    • Phase 2 KarMMa-1 (NCT03361748): no secondary primary malignancies

The authors noted that while 4.3% of secondary primary malignancies were reported to FAERS, this only reflects the likelihood of those reporting to the FDA. It was also highlighted the FAERS has several limitations including duplicate report submissions, missing information, inability to establish causal relationships, and underreporting, or overreporting, of AE severity.

While secondary primary malignancies were a small fraction of reported AEs after CAR T-cell therapy, there is a suggested increase in risk associated with certain therapies, the report noted. There is no conclusive evidence associated with these low numbers, but additional dedicated registries to these events can provide insights into patient care.

In November 2023, the FDA published a warning to patients who had previously received B-cell maturation antigens or CD19-directed CAR T-cell therapy who were reported to have T-cell malignancies and CAR-positive lymphoma.2 The FDA noted an investigation was underway, but currently, the benefits of the treatment outweighed the risks.

"We will continue to analyze the data released by the FDA. We hope to update this analysis periodically to keep the scientific community and the public updated," Elsallab concluded.

References

  1. Elsallab M, Ellithi M, Lunning M, et al. Second primary malignancies after commercial CAR T cell therapy: analysis of FDA Adverse Events Reporting System (FAERS). Blood. 2024. doi.10.1182/blood.2024024166
  2. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. News release. FDA. November 28, 2023. Accessed November 29, 2023. https://bit.ly/47CkPYY
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