News Hub

From the Editors - Another Piece of the Puzzle: Updated Look at the Development of Secondary Malignancies Within Patients Treated with CAR T-Cell Therapies

  
by Travis Byrd, Ph.D

Process Development
The James Cancer Hospital Cell Therapy Laboratory 
The Ohio State University Wexner Medical Center

In November 2023, the U.S. Food and Drug Administration (FDA) released a statement regarding the observed development of secondary malignancies in patients after receiving CAR T-cell therapy treatments. The release of this statement caused some of the pioneers in the field such as Dr. Bruce Levine and others to take an in depth look at the data (1,2,3). Ultimately, the observation resulted in a decision by the FDA that all CAR T-cell therapies must include a black box warning about the possible risk of secondary malignancies. This warning led to a cascade of studies by researchers in conjunction with an increasing number of questions from patients. 

In a recent systematic review and meta-analysis published in the journal Clinical Cancer Research(4), researchers examined data from 18 clinical trials and 7 real-world studies (published prior to May 17th, 2024), encompassing data from 5,517 patients treated with CAR T-cell therapy for lymphoma and myeloma. The review identified 326 cases of secondary malignancies, with an overall incidence rate of 5.8%, and the most common were hematologic malignancies (37%), followed by solid tumors (27%), non-melanoma skin cancers (16%), and T-cell malignancies (1.5%). Within the meta-analysis, it was found that the risk of secondary malignancies was influenced by the following three independent factors: the treatment setting (clinical trials vs. real-world studies), durations of follow-up (greater than the median of 21.7 months), and the number of prior treatment lines (exposure to more than 3 previous therapy lines). It is also important to note, the analysis showed no significant influence of a specific commercial CAR T-cell product on the subsequent development of secondary malignancies.

Interestingly, a subgroup analysis within four of the studies, of 1,253 patients including a control group of patients treated with standard of care, revealed that the rate of secondary malignancies was 5% in patients receiving CAR T-cell therapy and 4.9% in patients receiving standard of care. This suggests that the risk of developing secondary malignancies is no greater in those treated with CAR T-cell therapies as opposed to those treated with standard of care regimens.

This study highlights that while CAR T-cell therapy provides a potent treatment for hematologic cancers, it does carry a risk of secondary malignancies. However, the risk is comparable to that following standard of care treatments. The results also shed more light onto the importance of the number of prior lines of treatment the patient has received in association to the development of secondary malignances. Further research and continuous patient monitoring will be essential for a better understanding of long-term adverse events and possible identification of preventative strategies.

References

  1. Levine BL, Pasquini MC, Connolly JE, Porter DL, Gustafson MP, Boelens JJ et al. Unanswered questions following reports of secondary malignancies after CAR-T cell therapy. Nature Medicine. 2024 Feb;30(2):338-341.
  2. Hamilton MP, Sugio T, Noordenbos T, Shi S, Bulterys PL, Liu CL, Kang X, Olsen MN, Good Z, Dahiya S, Frank MJ, Sahaf B, Mackall CL, Gratzinger D, Diehn M, Alizadeh AA, Miklos DB. Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. N Engl J Med. 2024 Jun 13;390(22):2047-2060.
  3. Elsallab, M., Ellithi, M., Lunning, M. A., D'Angelo, C., Ma, J., Perales, M. A., Frigault, M., & Maus, M. V. (2024). Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA Adverse Events Reporting System. Blood, 143(20), 2099–2105.
  4. Tix, T., Alhomoud, M., Shouval, R., Cliff, E. R. S., Perales, M. A., Cordas Dos Santos, D. M., & Rejeski, K. (2024). Second primary malignancies after CAR T-cell therapy: A systematic review and meta-analysis of 5,517 lymphoma and myeloma patients. Clinical cancer research : an official journal of the American Association for Cancer Research, 10.1158/1078-0432.CCR-24-1798.


#CommunityFeature

0 comments
9 views

Permalink