Upfront Calcineurin Inhibitor Dose Reduction of 40% in Pediatric Haematopoietic Stem Cell Transplant Does Not Result in Increased Graft Versus Host Disease in Patients Receiving Voriconazole Maintenance Therapy

The treatment of choice for proven or probable fungal infection prior to haematopoetic stem cell transplant (HSCT) is often a mould active azole. The decision to continue these agents through the transplant period has resulted in debate in managing drug interactions and dosing of cyclosporin (CSA) as hepatic microenzyme inhibition predicts decreased metabolism and subsequent clearance of CSA. In 2008 following a number of supratherapeutic levels in patients treated with voriconazole and standard dose CSA our center reduced up front CSA doses by 40% for patients receiving voriconazole prior to and during HSCT.

Aim: To determine if upfront CSA dose reduction when used in combination with voriconazole resulted in similar graft versus host disease (GVHD) incidence compared to patients treated with no mould active azole and standard dose CSA.

Method: An analysis of allogeneic HCST activity performed between mid 2008 and 2012 identified 78 pediatric patients undergoing HSCT for malignant disease and immunodeficiencies.   

The patients were grouped according to fungal prophylaxis and starting CSA dose. Patients without previous fungal infection received IV CSA 5mg/kg/day with fluconazole or liposomal amphotericin. Patients with previous fungal infection who received voriconazole prior to HSCT were prescribed a 40% reduced dose of CSA at 3mg/kg/day. To account for drug interactions with the preparative regimen patients received liposomal amphotericin from the start of conditioning and re-commenced voriconazole on day 0.

CSA levels were evaluated from Day 0 to 8. The incidence of grade II-IV GVHD was compared in the two groups.

Results: The groups were equal for donor source, remission status and mean day to engraftment (17.6 vs 18). 61 patients (78.3%) received full dose CSA with no mould active azole and 17 (21.7%) patients received voriconazole and an initial 40% dose reduction in CSA.

Day 0 CSA levels in the reduced dose were lower (71.3 vs 134.3 p=0.04) however by day 8 there was no difference in the mean CSA levels. CSA doses were adjusted according to levels and there were equal numbers of dose adjustments in both groups. Despite early low CSA levels, there was no difference in the incidence of grade II-IV GVHD, 47.05% in patients receiving upfront dose reduction and 41% in full dose (p=0.358).

It was difficult to assess toxicity as patients may have also received voriconazole later in the transplant course. There were similar rates of acute kidney injury however GGT was elevated in patients who received voriconazole at any time point. There were no other distinguishing toxicity features between the groups. 

Conclusion: An initial 40% dose reduction of CSA for patients receiving voriconazole results in lower initial CSA levels but does not translate into an increased incidence of grade II-IV GVHD. Future transplant patients requiring voriconazole prophylaxis should receive initial dose reduction in CSA