Impact of Cyclosporine Exposure Levels on Outcomes in Allogeneic Hematopoietic Cell Transplantation: A Retrospective Analysis
Authors: Alnughmush Ahmed , Remberger Mats , Kulasingam Vathany , Pasic Ivan , Novitzky-Basso Igor , Law Arjun , Lam Wilson , Kim Dennis Dong Hwan , Gerbitz Armin , Viswabandya Auro , Kumar Rajat , Mattsson Jonas , Michelis Fotios 
Published: December 2024

Background:
Allogeneic hematopoietic cell transplantation (HCT) remains a pivotal therapeutic intervention for numerous hematological malignancies and disorders. Calcineurin inhibitors (CNIs), particularly cyclosporine (CsA), are integral components of graft-versus-host disease (GVHD) prophylaxis regimens. Despite their widespread use, comprehensive data correlating specific CNI levels with transplant outcomes are sparse. This study aimed to investigate the relationship between CsA area under the curve (AUC) and various transplant outcomes in a cohort of patients undergoing allogeneic HCT.
Method:
We performed a retrospective analysis of 373 patients who underwent allogeneic HCT from January 1, 2019, to July 31, 2021, at Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. As part of routine post-transplant care, CsA trough levels were measured at defined intervals. We calculated CsA AUC over the first 90 days post-transplant and analyzed its association with multiple transplant outcomes, including relapse, graft failure (GF), acute and chronic GVHD (aGVHD, cGVHD), cytomegalovirus (CMV) reactivation, Epstein-Barr virus (EBV) reactivation, and bloodstream infections (BSI). For aGVHD correlation with CsA AUC, we calculated the CsA AUC up to the onset of aGVHD.
Results:
Our cohort predominantly comprised individuals with acute leukemia (65%), followed by MDS/MPN (25.9%), lymphoma (5.1%), and chronic leukemia (4%). The median age was 58 years (range 18-76). Peripheral blood stem cells (PBSC) were the main graft source in our cohort, with matched unrelated donors (MUD) constituting 48.5% of the donor pool. The GVHD prophylaxis regimen frequently included a combination of post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) (69.4%). The mean CsA AUC over the initial 90 days was 18,381 with a median of 18,363 (range 3,554 - 31,869). Among different GVHD prophylaxis regimens, there were no significant differences observed in the level of CSA exposure (p=0.42).
In our cohort, the 1-year OS was 77.5% (95% CI: 72.9-81.4) and the 3-year OS was 63.9% (95% CI: 58.8-68.6). The 100-day and 1-year NRM was 6.2% (95% CI: 4.2-9.2) and 13.9% (95% CI: 10.6-17.9), respectively. Higher CsA AUC levels were significantly associated with lower grades of aGVHD, with the highest AUC observed in patients with no GVHD and the lowest in those with grade 3-4 GVHD (p&lt;0.001). Higher CSA exposure correlated with a significantly reduced risk of graft failure, with the mean CsA AUC in patients without graft failure being approximately 18,500 compared to 14,000 in those with graft failure (p&lt;0.001).
No significant associations were observed between CsA AUC and the risk of relapse (p=0.56) or cGVHD (p=0.38). Additionally, the risk of EBV reactivation or the development of BSI was not correlated with different CsA exposure levels. However, higher CsA exposure was significantly associated with increased risks of CMV reactivation (p=0.03) and recurrence (p=0.027). By analyzing a subset of patients who were on letermovir prophylaxis, the level of CsA exposure did not seem to increase the risk of reactivation or recurrence (p=0.44).
Conclusion:
This study emphasizes the crucial importance of monitoring cyclosporine levels in allogeneic HCT. Higher cyclosporine exposure is linked to a reduced risk of graft failure and aGVHD without increasing the risk of relapse. However, while maintaining higher cyclosporine levels does not negatively impact relapse rates, it does raise the likelihood of CMV reactivation and recurrence, which can be mitigated by the use of letermovir. These findings underscore the need for meticulous management of immunosuppression to optimize transplant outcomes.