Risk factors identified for secondary leukemia in patients who received CAR T cells
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Key takeaways:
- Older age, diminished platelet count could be factors associated with developing secondary leukemia after CAR-T.
- The mechanism for myeloid neoplasms in this patient population needs further examination.
Researchers at Mayo Clinic have identified clinical factors associated with increased risk for developing myeloid neoplasms following chimeric antigen receptor T-cell therapy, according to data published in JAMA Oncology.
The specific impact CAR-T has on the development of leukemia remains unknown, but results of a case-control analysis indicate individuals who received treatment for both lymphoma and multiple myeloma had equal risk.
“It’s almost impossible at this point to prove that CAR-T is the cause of this problem,” Mithun V. Shah, MD, PhD, hematologist at Mayo Clinic, told Healio. “It’s not going to be resolved soon. What we really hoped for, instead, was recognition of the phenomenon. To a patient, developing this leukemia is catastrophic. You take a survivor or somebody who is doing phenomenal — you’ve cured their lymphoma, you’ve controlled their myeloma like no other treatment; yet the patient may not see that benefit because once this leukemia develops, median survival is 9 months. That recognition is the first step.”
CAR-T has fast become a “miraculous treatment” for hematologic malignancies, Shah said, but between 2018-2021, 5.3% of 189 patients who received CAR T cells at Mayo Clinic developed therapy-related myeloid neoplasms, Shah and colleagues wrote in a 2022 article published in Blood Cancer Journal.
“In medical school, the dogma was 5 to 7 years after your treatment you might get leukemia. Here, we’re seeing patients developing leukemia within 3 to 5 months — median being about 10 months,” Shah said.
“It’s a minority, but still a little higher-than-expected proportion of patients,” he added. “It’s not something that we kick the can down the road and say we’ll talk about this in 5 years. This is more urgent.”
Researchers identified 20 individuals (median age 67 years, 60% women) who developed myeloid neoplasms following CAR-T between June 1, 2016, and Dec. 31, 2021. The median diagnosis occurred 10 months following treatment.
The investigators conducted pairwise multivariate analysis for 4 models using various clinical factors to determine any association with risk for developing a myeloid neoplasm after CAR-T.
They originally believed clonal hematopoiesis would be a determinant of leukemia.
“We did not follow-up on that for multiple reasons. One is approximately 50% of patients going through CAR-T will have clonal hematopoiesis,” Shah said, adding they are yet to understand which clones stay stable, disappear, or evolve into T-cell myeloproliferative neoplasms.
They also expected inflammatory markers to the differentiate patient populations, but “that did not turn out to be the case,” Shah said.
Rather, the model with the highest concordance index featured patients aged 65 years and older who had platelet counts below 140,000/µL.
Hemoglobin levels lower than 9 g/dL also showed a significant correlation with risk for myeloid neoplasms.
“Every single patient going through CAR-T, you will have their age and you will have their complete blood count available at the time you are sitting down with the patient,” Shah said. “What we really thought was valuable is that it divides the cohort asymmetrically. Forty-three percent of patients considered to be [low-risk] had no events noted. If this model gets validated, then you are reassured that a younger patient with adequate hematopoiesis and platelet counts would be somebody who is low risk and can be monitored in the standard fashion.”
Individuals considered immediate or high risk could be monitored more carefully before treatment even begins.
“We can start by making sure that, morphologically, they don’t have the typical features or the presence of leukemia,” Shah said. “Some patients have developed leukemia at 1, 2 or 3 months. That means there is a small chance they may have had a leukemia present even before CAR-T and the [treatment] just unmasked it. I would make sure that we have their cytogenetics and [next-generation sequencing], if not performed already, at least I would have the sample saved so I can go back and take a look.
“I would proceed with CAR-T as long as there are no other concerns,” he continued, “but if the counts were not to come back as expected or the counts were to dip down, I would have a very low threshold to do a bone marrow biopsy.”
The small sample size limits the applicability of the study’s results, according to Shah. He wants to validate the model across CAR-T products, phenotypes and independent cohorts.
He also hopes to investigate the mechanism that causes leukemia.
Many with whom Shah as spoken believe that previous cytotoxic treatments are the cause of these myeloid neoplasms.
“CAR-T just happens to be a bystander” for those who express this opinion, he said.
“There are people who are more skeptical and say it is the inflammation that’s causing it or contemplate whether there is some other mechanism that [they] haven’t even thought about,” Shah added. “Our approach is to try and understand and isolate each of these cytotoxic treatments and inflammation, and see whether we can recapitulate the milieu in patients undergoing CAR-T.”
References:
- Alkhateeb HB, et al. Blood Cancer J. 2022;doi:10.1038/s41408-022-00707-4.
- Gurney M, et al. JAMA Oncol. 2024;doi:10.1001/jamaoncol.2023.7182.
For more information:
Mithun V. Shah, MD, PhD, can be reached at shah.mithun@mayo.edu.
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