ASH 2023 | The impact of CHIP on clinical outcomes in older patients with lymphoma undergoing chemotherapy

So I presented an interim analysis of a prospective study that we’re conducting in older lymphoma patients who are scheduled to receive first- or second-line chemotherapy. We’re evaluating whether or not there is clonal hematopoiesis detectable in their peripheral blood at baseline, prior to receiving chemotherapy, that leads to an increased incidence of chemotherapy-related complications. As well as whether or not it explains why some patients never recover their blood counts to normal or have persistent abnormal morphology like macrocytosis and anisocytosis, even months to years after they finish the chemotherapy. So was there clonal selection for CHIP?

We measure them at baseline after three cycles of chemotherapy at 6 and 12 months after chemotherapy, and we correlate that with blood counts as well as complications, infections, and so forth. The complications that we are interested in during chemotherapy include admissions to hospital, ED visits, needing to increase your G-CSF dose because of neutropenia or start G-CSF, any major toxicities.

The bottom line is we found a very high prevalence of CHIP in a largely untreated patient population, 27% at baseline. That expanded largely due to an expansion of mutations in the DDR genes, PPM1D, in addition to presence of TP53 and SRCAP at the 6-month mark, that starts to contract a little bit at the 12-month mark. So at any point on our study, 47% so far that we’ve evaluated have detectable CHIP and of the DDR mutations, when we went back to their baseline samples, when they were called negative, when we used a lower VAF cutoff of less than 2%, we found the majority of them had the DDR mutation there, which is called negative because it didn’t meet the 2% cut point.

With regards to complications, there was a trend to more ED visits and infections in those with DDR CHIP, not yet statistically significant because of sample size. Intriguingly, there was a higher rate of respiratory complications in those with CHIP than those who don’t have CHIP, dominated by infectious pneumonitis as well as rituximab-induced pneumonitis, but a lower rate of neuropathy and syncope in those who have CHIP versus those who don’t have CHIP, which is intriguing because there’s a lower rate of Alzheimer’s dementia in patients that have CHIP. Also, a higher percentage of patients with CHIP or DDR CHIP had elevated monocyte counts at 6 and 12 months post-chemotherapy, and many of them exceeded their baseline monocyte count. So the question is, is the monocyte perhaps in delayed fashion, a biomarker of somebody who has got clonal hematopoiesis? Results are preliminary. We’re still enrolling another 80 patients on the study, and we hope to also pool our data with other groups to sort of get better power to evaluate these questions.