1.
Evaluation of the pharmacokinetic interaction between letermovir and tacrolimus in allogeneic hematopoietic cell transplant recipients
Marciano, K. A., Seago, K., Dillaman, M., Ross, K. G., Veltri, L., Cumpston, A.
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Data describing the magnitude of the pharmacokinetic interaction between letermovir and tacrolimus in allogeneic hematopoietic cell transplant (allo-HCT) recipients are limited, and varying outcomes have been reported. The need for empiric dose adjustment of tacrolimus upon letermovir initiation has not been established; instead, it is suggested to closely monitor tacrolimus trough concentrations and adjust doses as needed. Further understanding of this interaction is imperative to accurately manage the narrow therapeutic window of tacrolimus post-transplant. OBJECTIVES The primary objective of this study was to determine the percent change in tacrolimus concentration-to-dose ratio over the 14-day period after initiation of letermovir. Secondary objectives were to describe the frequency of tacrolimus dose adjustments after initiation of letermovir, percent change in daily tacrolimus dose over the 14-day period after initiation of letermovir, and the incidence of both sub- and supratherapeutic tacrolimus trough concentrations. STUDY DESIGN This study was a retrospective chart review that included adult allo-HCT recipients at WVU Medicine who received tacrolimus in combination with oral letermovir and had been taking tacrolimus for at least five days prior to letermovir initiation. Patients receiving strong CYP3A4 inhibitors or intravenous tacrolimus were excluded. RESULTS Thirty-five patients were included in the analysis. The median percent increase in tacrolimus concentration-to-dose ratio over the 14-day period after initiation of letermovir was 22% (days 2 to 4), 47% (days 5 to 7), 66% (days 8 to 11), and 81% (days 12 to 14). The mean frequency of tacrolimus dose adjustments was 0.66 (days 2 to 4), 0.69 (days 5 to 7), 1.06 (days 8 to 11), and 0.57 (days 12 to 14). CONCLUSION The pharmacokinetic interaction between tacrolimus and letermovir is substantial based on results from this study and continued to affect tacrolimus concentrations over the 14-day period after letermovir initiation. Close monitoring of tacrolimus trough concentration upon initiation of letermovir should be considered.
PICO Summary
Population
Adults who underwent allogeneic transplant at a single centre in the USA (n=35)
Intervention
Oral letermovir initiated after at least five days of tacrolimus therapy
Comparison
None
Outcome
The median percent increase in tacrolimus concentration-to-dose ratio over the 14-day period after initiation of letermovir was 22% (days 2 to 4), 47% (days 5 to 7), 66% (days 8 to 11), and 81% (days 12 to 14). The mean frequency of tacrolimus dose adjustments was 0.66 (days 2 to 4), 0.69 (days 5 to 7), 1.06 (days 8 to 11), and 0.57 (days 12 to 14).
2.
Post-Transplant Cyclophosphamide (PTCy) is Associated with Increased Cytomegalovirus Infection: A CIBMTR Analysis
Goldsmith, S. R., Abid, M. B., Auletta, J. J., Bashey, A., Beitinjaneh, A., Castillo, P., Chemaly, R. F., Chen, M., Ciurea, S. O., Dandoy, C. E., et al
Blood. 2021
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Abstract
Prior studies suggest increased CMV infection following haploidentical donor transplantation with post-transplant cyclophosphamide (HaploCy). The role of allograft source and PTCy in CMV infection and disease is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection as well as transplant outcomes as it relates to CMV serostatus and occurrence of CMV infection by d180. We examined patients reported to CIBMTR between 2012-2017 who had received HaploCy (n = 757), Sib with PTCy (SibCy, n=403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605) for AML/ALL/MDS. Cumulative incidences of CMV infection by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26), respectively [p<0.001]. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3 (14.4 - 175.2); SibCy (n=279): HR 47.7 (13.3 - 171.4); SibCNI (n=1065): HR 24.4 (7.2 - 83.1); p<0.001]. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD (p=0.006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy. This study supports aggressive prevention strategies in all patients receiving PTCy.
PICO Summary
Population
Patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or myelodysplastic synrome (n=2765)
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (HaploCy, n=757),
Comparison
Sibling donor with post-transplant cyclophosphamide (SibCy, n=403), or Sibling donor with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605)
Outcome
Cumulative incidences of CMV infection by day 180 were 42% (HaploCy), 37% (SibCy), and 23% (SibCNI), respectively. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3; SibCy (n=279): HR 47.7; SibCNI (n=1065): HR 24.4. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD. PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy.