Twice-daily intravenous bolus tacrolimus infusion for acute graft-vs-host disease prophylaxis

Abstract

Background: Tacrolimus (FK) is usually given as a continuous 24-hour infusion for acute graft-vs-host disease (GVH) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). Often, this schedule becomes logistically difficult and requires dedicated line and monitoring. We report our experience with the use of twice-daily intravenous (IV) bolus injection. Patients and Methods: Between 01/00–06/04, 59 patients (pts) with hematologic indication for allogeneic HSCT received twice-daily FK for GVH prophylaxis. Patients were given FK at initial dose of 0.015 mg/kg IV bolus over 3 hours on day T −1 then every 12 hours. First trough level was drawn before the seventh dose on day T +2 and then twice weekly unless clinically indicated otherwise. Doses were adjusted for a target level of 10 ng/ml (range 5–20 ng/ml). Patients were switched to oral form when were clinically able to tolerate it. Results: Median age was 49 years (range 19–64 y). Donors were transplanted for hematologic disorder indications. Donor compatibility status was as follows: matched-related 38 (64.4%), matched-unrelated 10 (17%), and mismatched-related 11 (18.6%). FK was used in 2 GVH prophylaxis protocols: with methotrexate or in combination with mycophenolate mofetil and daclizumab. Median first trough level was 9 ng/ml (range 2.6–22.5). Rate of grade I or II acute GVH was 16.9%. Only one pt developed grade III (1.7%) and no pt had grade IV. Significant nephrotoxicity (peak creatinine level ≥2× baseline or ≥2 mg/dl) occurred in 16 patients (27.1%). Five of these pts (31.25%) had at least 1 FK trough level ≥20 ng/ml whereas 15 of 44 patients with normal renal function (34.1%) had such elevated levels. Severe nephrotoxicity requiring dialysis occurred in 4 pts and only 1 of these had elevated FK level. One pt developed HUS/TTP and had all FK trough levels <20 ng/ml. There were no grade 3 or 4 seizures or tremors. Median discharge day was T +19 (range 12–34). Two pts relapsed, but were alive, by day 100. Day-100 relapse-free mortality was 18.6%. Conclusion: Results of twice-daily bolus tacrolimus compare favorably to historical safety and efficacy data of continuous infusion of FK in allogeneic HSCT. Bolus infusion was easy to administer and adjust and did not correlate with increased risk of nephrotoxicity. These results should be further investigated in a prospective clinical trial. Background: Tacrolimus (FK) is usually given as a continuous 24-hour infusion for acute graft-vs-host disease (GVH) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). Often, this schedule becomes logistically difficult and requires dedicated line and monitoring. We report our experience with the use of twice-daily intravenous (IV) bolus injection. Patients and Methods: Between 01/00–06/04, 59 patients (pts) with hematologic indication for allogeneic HSCT received twice-daily FK for GVH prophylaxis. Patients were given FK at initial dose of 0.015 mg/kg IV bolus over 3 hours on day T −1 then every 12 hours. First trough level was drawn before the seventh dose on day T +2 and then twice weekly unless clinically indicated otherwise. Doses were adjusted for a target level of 10 ng/ml (range 5–20 ng/ml). Patients were switched to oral form when were clinically able to tolerate it. Results: Median age was 49 years (range 19–64 y). Donors were transplanted for hematologic disorder indications. Donor compatibility status was as follows: matched-related 38 (64.4%), matched-unrelated 10 (17%), and mismatched-related 11 (18.6%). FK was used in 2 GVH prophylaxis protocols: with methotrexate or in combination with mycophenolate mofetil and daclizumab. Median first trough level was 9 ng/ml (range 2.6–22.5). Rate of grade I or II acute GVH was 16.9%. Only one pt developed grade III (1.7%) and no pt had grade IV. Significant nephrotoxicity (peak creatinine level ≥2× baseline or ≥2 mg/dl) occurred in 16 patients (27.1%). Five of these pts (31.25%) had at least 1 FK trough level ≥20 ng/ml whereas 15 of 44 patients with normal renal function (34.1%) had such elevated levels. Severe nephrotoxicity requiring dialysis occurred in 4 pts and only 1 of these had elevated FK level. One pt developed HUS/TTP and had all FK trough levels <20 ng/ml. There were no grade 3 or 4 seizures or tremors. Median discharge day was T +19 (range 12–34). Two pts relapsed, but were alive, by day 100. Day-100 relapse-free mortality was 18.6%. Conclusion: Results of twice-daily bolus tacrolimus compare favorably to historical safety and efficacy data of continuous infusion of FK in allogeneic HSCT. Bolus infusion was easy to administer and adjust and did not correlate with increased risk of nephrotoxicity. These results should be further investigated in a prospective clinical trial.