Sirolimus exposure and the occurrence of cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation

Abstract

Sirolimus appears to protect against cytomegalovirus (CMV) in organ transplant recipients. The effect of this drug in allogeneic hematopoietic stem cell transplantation recipients remains unexplored. By means of multivariate continuous-time Markov model analyses, we identified 3 independent covariates that significantly impacted the risk of CMV DNAemia: recipient/donor CMV serostatus, tacrolimus exposure, and sirolimus exposure. CMV-seropositive recipients with CMV-seronegative donors had a significantly higher probability of having detectable CMV DNAemia. Increasing the tacrolimus trough concentration from 0 to 16 ng/mL increased the probability of patients having detectable CMV DNAemia by 40% (from 40% to 80%), whereas this probability decreased by 25% (from 40% to 15%) when trough concentrations of sirolimus increased from 0 to 16 ng/mL. Sensitivity analysis showed that sirolimus exposure between 0 and 6 ng/mL has no or negligible effect on CMV DNAemia, but levels >8 ng/mL significantly decreased the number of detectable CMV DNAemia cases (the risk ratios decreased from 0.68 to 0.21 when whole blood sirolimus concentrations changed from 8 to 18 ng/mL, P < .01). In conclusion, we used a pharmacometric statistical tool to provide the first clinical evidence that fewer CMV DNAemia events become detectable as sirolimus exposure increases.

Effect of Sirolimus Exposure on the Need for Preemptive Antiviral Therapy for Cytomeglovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

“…We previously observed that higher sirolimus concentrations had an inhibitory effect on CMV replication by reducing the probability of detectable CMV DNAemia at any level after RIC-allo-HSCT [11]. The present study confirms that higher sirolimus exposure also translates into a clinical benefit by reducing the probability of preemptive anti-CMV therapy in a larger multicenter cohort of RIC-allo-HSCT recipients.…”

“…We previously demonstrated that higher sirolimus exposure significantly reduced the risk of detectable CMV DNAemia at any level after allo-HSCT [11]. Our next step was to explore whether higher sirolimus concentrations could also have the clinical benefit of reducing the number of CMV DNAemia events necessitating preemptive antiviral therapy in allo-HSCT recipients.…”

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution

“…In comparing CNI-based GVHD prophylaxis with CNI +mTORi-based approaches, the latter was associated with less CMV infection. There are data to suggest that mTORi may protect against CMV infection [21], although 2 randomized trials of CNI/methotrexate versus CNI/mTORi reported no differences in CMV infection incidence between treatment arms, with similar rates of GVHD between the arms [22,23]. However, the relationship between GVHD onset/ treatment and CMV infection was not examined for differences between arms in either trial [22,23].…”

Ex vivo T‐cell depletion vs post‐transplant cyclophosphamide, sirolimus, and mycophenolate mofetil as graft‐vs‐host disease prophylaxis for allogeneic hematopoietic stem cell transplantation

“…2,3 Cyclosporine and tacrolimus, with or without methotrexate or mycophenolate mofetil (MMF), are by far the most common agents given in association with PTCy in different allo-HSCT scenarios. 2,4,5 However, sirolimus (Sir) with MMF has recently emerged as an alternative option to calcineurin inhibitor (CNI)-containing approaches, since it has an apparently more favorable toxicity profile [6][7][8] with encouraging results. 9,10 The aim of the present study was to retrospectively compare the clinical outcomes of adults with acute leukemia or myelodysplastic syndrome (MDS) undergoing myeloablative allo-HSCT from matched sibling donors (MSD) or unrelated donors at three institutions with two different strategies for GVHD prophylaxis, ex vivo TCD by CD34+ selection and unmanipulated grafts with PTCy-Sir-MMF.…”