Optimizing Cyclosporine Dosing Regimen to Achieve Therapeutic Levels At the Time of Allogeneic Bone Marrow Transplantation: A Pediatric Quality Improvement Intervention

Several studies have demonstrated that a therapeutic Cyclosporine (CsA) concentration within one week following graft infusion correlates with a reduced risk of grade III-IV acute graft versus host disease (aGVHD). Therefore, to begin a quality improvement (QI) project we performed a retrospective chart analysis to determine when, using our standard approach to initial CsA dosing, our allogeneic bone marrow transplant patients first achieved therapeutic CsA levels (Trough=150-250ng/ml). Fifty three allogeneic transplants were performed during the period assessed, of which 47 were eligible for evaluation. Patients were excluded from analysis due to alternate GVH prophylaxis or major drug interactions. In this historical cohort, CsA prophylaxis was initiated as follows: loading with Cyclosporine, 2mg/kg/dose IV Q 12 hrs for two days (day -2 and day-1) then decreasing to 1.5mg/kg/dose IV Q 12 hrs. Using this approach, 34% of patients had therapeutic levels within the first 3 days following transplant. Following this baseline analysis, we initiated a QI intervention aimed at achieving a therapeutic trough CsA level in at least 80% of patients by Day +3. To accomplish this, the following new CsA regimen was instituted.  Patients 5 years or older received Cyclosporine at 2.5mg/kg/dose IV Q 12 hrs beginning on day -3, and patients less than 5 years of age  received Cyclosporine at 2.5mg/kg/dose IV Q 8 beginning on day -3. If the trough level was subtherapeutic (below 100 NG/ML) on day 0, we gave an extra 2mg/kg/loading dose IV, then increased the basal dose by20%.  If the level was between 100 and 149, we increased the basal dose by 20% without an additional loading dose. The impact of this intervention on the percentage of patients achieving therapeutic CsA levels between Day 0 and Day + 3 was then assessed.   To date, we have performed 28 transplants under the new CsA regimen. Of these, 23 patients were evaluable. Five patients were excluded per the previous criteria. Using the new dosing guidelines, 87% of patients achieved therapeutic CsA levels in the Day 0 to Day +3 window. This represent a statiscally significant improvement over our previous dosing regimen in which 34% of patients achieved therapeutic CsA levels by Day +3 (p<.0003).  No patients had supratherapeutic CsA levels, defined as greater than 400 ng/ml within the first 3 days post transplant. One patient did exhibit nephrotoxicity, defined as a persistent doubling of the serum creatinine by Day +10. This patient also had Adeno and BK viruria at Day 0 which confounds assessment of causation. Overall,  the revised dosing regimen is both well tolerated and more effective in achieving the targeted CsA level in ≥ 80% of cases (95% confidence interval, 68-95%). Following  completion of this project, we plan further analyses to determine whether this practice change has impacted rates of aGVHD in our patient population.