Cyclosporine dose Intensity Is a Critical Determinant of Outcome after a T Cell Depleted Reduced Intensity Allograft.
Authors: Craddock Charles F. , Nagra Sandeep , Brookes Cassandra , Duncan Nick , Thomson Alison H , Mahendra Prem , Ward Janice , Clark Fiona , Moss Paul , Cook Mark 
Published: April 2020

Abstract
The ability of reduced intensity conditioned (RIC) allografts to deliver long term disease free survival is dependent on the genesis of an immunologically mediated graftversus tumor (GVT) effect. Post-transplant immunosuppression plays an important role in limiting graft-versus-host disease (GVHD) but also modulates a GVT effect. Although cyclosporine A (CsA) is the most commonly utilised immunosuppressive agent in patients allografted using a RIC regimen the impact of CsA dose intensity on disease relapse and overall survival (OS) has not been studied. We have therefore measured CsA exposure in the first 21 days post-transplant and correlated individualised CsA area under the curve (AUC) values with OS and disease relapse in patients undergoing a RIC allograft. 132 patients with a diagnosis of acute myeloid leukemia (AML) (n=41), myelodysplasia (MDS) (n=17), Non-Hodgkin’s lymphoma (NHL)(n=51) or Hodgkin’s disease (n=23) were transplanted using an alemtuzumab containing RIC regimen. All patients with a myeloid malignancy (AML or MDS) were transplanted using a regimen consisting of fludarabine, melphalan and alemtuzumab (FMA). Patients with an underlying lymphoid disease (NHL or HD) were transplanted using FMA (n=31) or a regimen consisting of BCNU, etoposide, cytosine arabinoside, melphalan and alemtuzumab (BEAMA) (n=43). 39 patients had chemoresistant disease at the time of transplant. All patients received intravenous CsA at a loading dose of 5 mg/kg on day -1 followed by 2.5 mg/kg b.i.d. Patients were switched to oral CsA prior to discharge. Trough CsA levels were measured thrice weekly for the first three weeks after stem cell infusion and the dose of CsA adjusted to achieve levels in the region of 200–300 mg/l during this period. Trough levels obtained during the first 21 days post-transplant were used to calculate the CsA AUC for each patient. The median age of patients studied was 48 years (range 17–68). 71 patients were transplanted from HLA identical siblings and 61 from volunteer unrelated donors. The incidence of acute GVHD (Grades 2–4) was 34%. The median CsA AUC was 3682 mg.hr/l (range 2162- 8084 mg.hr/l). In univariate analysis the presence of chemoresistant disease at the time of transplant and a high CsA AUC were both associated with a decreased OS. In multivariate analyses chemoresistant disease (HR=2.60, 95% CI 1.44–4.65, p=0.002), increased age (HR=1.04, 95% CI 1.01–1.07, p=0.002) and linearly increasing CsA AUC were associated with an increased hazard of death (HR=1.1, 95%CI 1.02–1.24, p=0.02). The two year OS for patients with a CsA AUC less than 3682 mg.hr/l was 77% compared to 30% for patients with CsA of 3682 mg.hr/l and over (p&lt;0.0001). Increased CsA AUC and the presence of chemorefractory disease at the time of transplant were associated with an increased risk of relapse in univariate analysis. In multivariate analyses only increased CsA AUC was significantly associated with a higher risk of relapse (OR=4.1, 95% CI 2.50–6.81, p&lt;0.0001). Decreased CsA AUC and the use of an unrelated donor were associated with an increased risk of acute GVHD in univariate analysis. Multivariate analyses demonstrated that the use of an unrelated donor (HR=2.9, 9%% CI 1.36–6.36, p=0.006) and linearly decreasing CsA AUC were significantly associated with an increased risk of acute GVHD (HR=1.2, 95% CI 1.05–1.43, p=0.01). These data demonstrate the central importance of the intensity of post-transplant immunosuppression in determining outcome after a T cell depleted RIC allograft and support a randomised trial comparing CsA dose regimens in this population of patients. It will be important to determine whether post-transplant CsA exposure plays a similar role in determining outcome after a T replete RIC allograft.