Drops in Serum Phosphate Levels May Help Predict Severe CRS After CAR T

Researchers have identified a serum biomarker they say may be able to predict the occurrence and severity of cytokine release syndrome (CRS) in patients receiving chimeric antigen receptor (CAR) T-cell therapy.

In their retrospective study, published in British Journal of Haematology, the group found that a drop in serum inorganic phosphate (iP) was an early predictor of severe CRS occurrence, suggesting that monitoring serum iP levels could help promote safer management of the most common toxicity associated with CAR T-cell therapy.

“This is the first report of the importance of serum iP level monitoring in relation to subsequent CRS. Compared to conventional pre–CAR-T phase risk factors for CRS, including systemic tumour volumes, serum iP is a novel biomarker that reflects the in vivo dynamic response to CAR T infusion and can be clinically closely associated with initiation of CRS,” explained the researchers. “A drop in serum iP precedes CRS occurrence by a median of just 1 day, but in clinical settings, this lead time is valuable to prepare physical and human resources for forthcoming severe CRS.”

The researchers observed CRS in 96% of the 48 patients receiving either tisagenlecleucel or isocabtagene maraleucel for diffuse large B-cell lymphoma. CRS occurred a median of 3 (range, 1-6) days following infusion.

According to the researchers, significant drops in serum iP levels among patients were seen as early as the day following CAR T-cell infusion (median, 0.97 [range, 0.42–1.36] mmol/L; P = .021) for these patients. These reductions in iP levels were independent of other patient characteristics. Normal levels returned approximately 21 days after infusion, after CRS. Results indicated that having a serum iP level of below 0.81mmol/L 3 days following infusion could also put a patient at risk of CRS.

Notably, serum calcium (Ca) level corrected by albumin was stable throughout the course of treatment. Typically, serum Ca level corrected by albumin is coupled with that of iP.

“Due to the discrepancy in the trends of serum iP and Ca levels after CAR T injection, we sought a renal abnormality to explain the significant decrease in serum iP levels,” detailed the researchers. “We first checked the urine analyses and found that at the time of the serum iP decrease, renal tubular reabsorption of phosphate (TRP) was as low as 56.2% (median; range, 27.2%-71.0%), and the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 5.65mmol/L (median; range, 3.33-6.62mmol/lL. TRP < 80% and TmP/GFR < 7.10 mmol/L indicated that the decrease of renal reabsorption and a concomitant increase of renal excretion can explain the iP decrease in serum.”

The group also assessed hormones prior to and following CAR T-cell infusions among 10 of the patients, finding significant changes in vitamin D3 and fibroblast growth factor 23 (FGF23). However, increases in vitamin D3 and decreases in FGF23 are typically associated with increases in serum iP levels, rather than decreases, suggesting that the reductions in iP levels seen among the patients were independent of the hormones or that changes in the hormones were not sufficient enough compared with the significant decreases in iP.

Reference

Nakamura N, Arai Y, Kotawaki T, et al. Decreased serum phosphate levels are a useful biomarker to predict occurrence and severity of cytokine release syndrome in chimeric antigen receptor T-cell therapy. Published online October 11, 2022. Br J Haematol. doi:10.1111/bjh.18504