Abstract
Introduction
Cyclosporin (CSA) is commonly used as graft vs host disease (GvHD) prophylaxis in allogeneic haematopoietic stem cell transplant (alloHSCT) recipients. The usual IV dose is 3mg/kg and the recommended oral dose at switching is 3mg/kg BD in the pre-posaconazole era (Inoue et al. 2014). Posaconazole is now commonly used as antifungal prophylaxis in this context; it increases CSA levels through inhibition of the cytochrome involved in CSA metabolism (Sánchez-Ortega et al. 2012). We evaluated CSA-related toxicity after switch from IV to oral CSA in alloHSCT recipients receiving posaconazole with the aim of defining the optimal weight based oral dose.
Methods
A retrospective audit was performed of adult alloHSCT patients between October 2015 and October 2017 who received IV and then oral CSA together with posaconazole prophylaxis. Posaconazole was commenced during conditioning and continued at 300mg IV or oral daily according to gastrointestinal tolerance; patients with levels below 0.5mg/L received 200mg orally BD. Despite being protocolised, in practice the starting oral CSA dose in mg/kg, based on actual body weight, was at consultant discretion based on comorbidities at the time, predominantly renal dysfunction. Two groups were analysed: those with starting oral CSA doses ≥ 2.8mg/kg BD ('higher dose') and < 2.8mg/kg BD ('lower dose'). Exclusion criteria included continuation of IV CSA beyond day 30 or CSA taper before day 40 due to relapsed or persistent disease. Data collected included CSA doses in mg/kg at 3 time points: transition from IV to oral CSA, day 40 and day 60, and CSA dose reductions due to the following toxicities: renal impairment (fall in eGFR >15 ml/min/1.73m2 from transition eGFR), new/worsening hypertension, hypomagnesaemia (<0.60 mmol/L on 2 consecutive blood tests despite IV replacement), nausea and/or headache not attributable to other causes, and miscellaneous (thrombotic microangiopathy and EBV driven PTLD). The primary endpoints were the incidence and magnitude of dose adjustment at days 40 and 60.
Results
Twenty eight of 44 patients allografted during this period were eligible with a median age of 43 (19-68) years. All received CSA/methotrexate as GvHD prophylaxis with T cell depletion in 20 (71%). The majority continued posaconazole at day 40 (71%) and day 60 (68%); reasons for discontinuation were heterogenous. Details of CSA doses in each group at each time point are summarised in the Table.
Toxicities requiring adjustment were: renal impairment (51%), nausea (43%), hypomagnesemia (43%), hypertension (14%), headache (11%), and miscellaneous (6%). Four patients were admitted to hospital due to toxicity. By day 60, one patient had ceased CSA due to toxicity. Acute GvHD (grade 3-4) occurred in one patient.
Conclusion
The switch to oral CSA in alloHSCT patients on concomitant posaconazole is associated with frequent early toxicity, particularly at (but not isolated to) doses above 2.8mg/kg BD. Substantial renal dysfunction is common. We are prospectively evaluating whether a starting dose of 2.25mg/kg BD reduces toxicity without compromising the risk of GvHD, particularly in patients receiving T cell depletion.
Robinson:The University of Melbourne: Employment. Grigg:Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.
