ASH 2025 | The effect of pre-existing CHIP on toxicity, outcomes, and inflammatory profiles in CAR-T recipients

Today I’m going to talk about clonal hematopoiesis of intermediate potential, also known as CHIP, which relates to a myeloid precursor lesion characterized by the presence of clonal hematopoiesis without signs of neoplasia and cytopenia. Previous studies have highlighted its high frequency in lymphoma and multiple myeloma patients treated with CAR T-cells. However, its immunologic impact and potential influence on CAR T-mediated toxicities, inflammation, and inflammatory profiles was not really identified so far. So we performed an observational study analyzing 104 patients diagnosed with large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and multiple myeloma patients treated with either CD19 or BCMA-targeted CAR T-cells. And we identified the toxicity data and the outcome data of these patients and we performed all-in proteomic profiling in 83 patients collecting their serum samples, and targeted next-generation sequencing in 104 PBMC samples. 

The sequencing of PBMC samples showed 39 patients bearing CHIP mutations, and we identified the DNMT3A mutation as the most abundant one in the cohort, followed by TP53, ASXL1, TET2, SF3B1, and NRAS and BRAF. Looking at the inflammatory profile of these patients, we detected no differences between the CHIP and non CHIP cohorts. And this was also reflected in the progression-free survival and overall survival of these patients. And looking at CAR-T-mediated toxicities, and in particular, CRS, ICANS, early and late ICAHT we saw again no differences between the two groups. 

Next, we identified and analyzed the clonal expansion of CHIP mutations and we saw that 13 CHIP clones exhibited an increase in VAF over time, while 21 clones exhibited a decrease in VAF over time. And in particular, TP53 and ASXL1 showed an increase in VAF over time. Importantly, on subgroup analysis, we saw that TP53 CHIP patients exhibited a baseline inflammatory profile characterized by higher levels of CRP and ferritin compared to the non TP53 patients. And we also saw that there was a lower absolute count of platelets and hemoglobin in TP53 patients. Importantly, the O-link analysis also showed an inflammatory profile characterized by high expression, so high abundance of interleukin-18, HO1, MYC, and GAL9. Importantly, we also saw a trend towards a lower progression-free and overall survival in TP53 CHIP patients compared to the non TP53 CHIP patients. 

Finally, two patients in our cohort were identified to develop therapy-related myeloid neoplasms after CAR T-cells, and one patient developed MDS, and this patient exhibited a marked expansion of ASXL1, while the patient who developed AML exhibited a marked expansion of TP53 and occurrence of NRAS. Importantly, these patients also showed a distinctive inflammatory profile, which could be related to clonal occurrence and expansion. 

So in summary, we identified no differences between CHIP groups and non CHIP groups in terms of CAR T-mediated toxicities, survivals, and inflammation, which were instead linked to TP53 CHIP patients. And the two patients that developed therapy-related myeloid neoplasms were characterized with clonal expansion and a distinctive inflammatory profile.

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