Study: Suggested Cyclosporine Levels Posttransplant May Be Too Low to Prevent GVHD

Preventing graft-versus-host disease (GVHD) after allogeneic stem cell transplant is a key aspect of patient management, but current cyclosporine concentration guidelines may not be sufficient, according to a recent study.

Cyclosporine (CsA) is a common option for acute graft-versus-host disease (aGVHD) prophylaxis after allogeneic stem cell transplant, but the optimal CsA trough target to prevent aGVHD is controversial due to a lack of high-quality evidence. A study published in Clinical Transplantation aimed to identify an optimal CsA trough target and provide clarity on critical post-transplant time points for prophylaxis to prevent aGVHD.

Appropriate immunosuppression to prevent aGVHD, particularly following allogeneic stem cell transplant, is key in minimizing post-transplant toxicity. While aGVHD is rare, moderate to severe aGVHD is associated with lower overall survival (OS) post-transplant. Current CsA trough concentration recommendations vary between 200-400 mcg/L and narrower windows, with a typical minimum trough concentration of 200 mcg/L. But authors of the current study note that some past research suggests 200 mcg/L might be too low and could potentially lead to suboptimal outcomes.

The current study reviewed 565 consecutive adult patients undergoing their first peripheral blood allogeneic stem cell transplant after myeloablative conditioning in the Alberta Bone Marrow Transplant Program between January 2009 and December 2018. After 166 patients were excluded due to either death before engraftment or deviation from the standard conditioning or prophylaxis regimens, the final analysis included 399 patients, and the median follow-up was 1209 days.

All patients had hematological malignancies and received anti-thymocyte globulin, methotrexate, and CsA for aGVHD prophylaxis. On average, the CsA trough concentrations were 273 mcg/L on days 0-14 after transplant, 315 mcg/L on days 15-28, and 241 mcg/L on days 29-56.

Overall, 250 mcg/L was the CsA cut-off value with the highest sensitivity and specificity for predicting grade 2-4 aGVHD in this cohort. Those with an average CsA trough concentration lower than 250 mcg/L during days 15-28 post-transplant had a 31.5% rate of grade 2-4 aGVHD, versus 18.8% of patients with an average CsA trough concentration of 250 mcg/L or greater in the same time period (OR, 1.97; 95% CI, 1.04-3.71). During days 0-14 and 29-56, there were no significant associations with aGVHD.

There were no significant associations between average CsA trough levels in days 15-28 and relapse, nor were there associations between CsA trough levels and OS, relapse-related mortality, or non-relapse mortality. Regarding safety, 71.4% of patients developed grade 2 creatinine increases, and 5.5% experienced grade 3 creatinine increases. These changes were not significantly associated with CsA trough levels in days 0-28 after transplant.

Overall, the study suggests that average CsA trough levels below 250 mcg/L may produce higher rates of aGVHD compared with levels of 250 mcg/L or greater. The findings also suggest that immunosuppression prophylaxis should be well within the suggested therapeutic range in the short-term after transplant, not at the lower end of the spectrum. The current range of CsA trough levels may also be too wide, potentially leading to suboptimal outcomes. More studies are warranted to refine the appropriate range of prophylactic CsA trough levels.

The study was limited by its retrospective and single-center nature, as well as the exclusion of patients who discontinued CsA before day 56 post-transplantation. Still, it suggests that CsA trough levels below 250 mcg/L are associated with higher aGVHD rates. Therefore, the authors conclude that maintaining CsA trough concentrations of at least 250 mcg/L in the early days after transplant may help mitigate the risk of aGVHD.

Reference

Kwan ACF, Blosser N, Ghosh S, et al. Toward optimization of cyclosporine concentration target to prevent acute graft-versus-host disease following myeloablative allogeneic stem cell transplant. Clin Transplant. Published online May 23, 2022. doi:10.1111/ctr.14732