ASH 2024 | The significance of increased clonal hematopoiesis mutation allele frequency after CAR-T therapy

Well, I’ve been blessed to work with the whole team at Stanford, and in particular, a fellow Mark Hamilton, who has really taken this on in conjunction with Dr Ash Alizadeh, who has really revolutionized cell-free DNA monitoring of disease burden as well as disease progression through something that we call Capture Sequence Analysis or CAP-SEQ. We’ve made some significant contributions. So what are they? Last year at ASH, we showed that if you monitored 200 or 300 genes that are thought to be involved in lymphoma progression, that you could distinguish those which are lymphoma progression from those that impact on non-relapse mortality through infection and cytopenia. So this year, Mark has come back and really analyzed what we will call clonal hematopoietic mutations or CHIP and looking at those before and then after CAR-T again showing that clonal hematopoiesis allele variant frequency across these 40 genes increases after a CAR-T therapy and that those elevated levels of allele frequency persist unlike what we see in short-term CHOP induction chemotherapy or even auto transplant so there’s an inflammatory cascade going on after CAR-T that is leading to this elevated level of clonal hematopoiesis. But the good news is that really only the DNA damage pathway, in particular P53 mutation allele frequency, is associating with second myeloid malignancies. And likewise, everybody asks, so I’ll just answer, does the allele frequency or detection of a P53 mutation before the patient goes to CHOP assure that they’re going to develop a secondary malignancy and should we avoid that therapy? And the answer is no, it’s still a minority of those patients that go on to develop second myeloid malignancies. So I think the understanding of the inflammatory cascade of the CAR T-cells being different than chemotherapy is being elucidated. I think that data from prospective analyses of 500 or more patients who’ve received these therapies, but again, monitoring before, during, and at late time points is giving us more confidence that while cytopenias may occur, those patients who are cytopenic due to, again, CAR persistence in the bone marrow causing inflammatory cascades with cytotoxic molecules do not result the majority of the time in a second myeloid malignancies. And we have to be cautious before we tell those patients at three or six months after CAR, oh, you’ve developed myelodysplastic syndrome. we need to, again, investigate with bone marrow biopsies, but more importantly, a tincture of time to allow most of those patients’ blood counts to improve.

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