Therapeutic Cyclosporine Exposure Measured As Area Under the Curve (AUC) Significantly Influences the Outcome after Allogeneic Hematopoetic Stem Cell Transplant (alloHSCT)
Authors: Kulkarni Samar , Murray John , Dennis Michael , Cavet Jim , Castleton Anna Z , Somervaille Tim , Wiseman Daniel , Tomlins Joanna , Bloor Adrian 
Published: October 2019

Abstract
Introduction: Prevention of Graft versus host disease (GVHD) forms the mainstay of obstacle in the successful outcome of alloHSCT. Various strategies are employed but combination of calcineurin inhibitors with methotrexate or mycophenolate is the commonest preventative measure used. Cyclosporine is dosed according to trough (C0) levels and the optimum level is defined as between 200 and 300 ng/ml. Daily doses are adjusted to achieve the therapeutic levels. As there can be fluctuations in the daily levels, it was postulated that area under the curve (AUC) extrapolated from daily levels may be more useful to define the optimum cyclosporine exposure for prevention of GVHD. Hence this retrospective analysis was carried out to evaluate if cyclosporine AUC for first 14 days has correlation with the incidence of GVHD.
Methods: 549 patients who received allograft and had cyclosporine C0 levels available for first 14 days were included in the analysis. The patient population included 353 males (64.3%) and 196 females (35.7%) with a median age of 44 yr. (range: 16-71). Underlying diagnosis included Ac. Leukaemia (n=319, 58.1%), Chr. Leukaemia (n=42, 7.7%), lymphoma (n=119, 21.7%), myeloma (n=57, 10.4%) or other (n=12, 2.2%).Donor was matched unrelated (n=330, 60.1%), sibling (n=204, 37.2%) or cord (n=15, 2.7%). Stem cell source was PBSC (n=454, 82.7%), BM (n=78, 14.2%), both (n=2, 0.4%) or cord blood (n=15, 2.7%). 415 patients had RIC (75.6%) and 134 had full intensity SCT (24.4%). Alemtuzumab or ATG was used in conditioning in 311 cases (56.6%). The target Cyclosporine AUC with a daily level of 200 was predicted as 2600, 2470 for cyclosporine level of 190 and 2730 for levels of 210.
Results: The median AUC for the entire cohort was 3338 (range: 370-6390). Only 56 cases (10.2%) had AUC below 2600. Incidence of AGVHD was significantly higher with use of PBSC (53.7% vs. 21.7%, p<0.001), NHL (66.3% vs. 44.8%, p=0.002) and Alemtuzumab/ATG use (55.9% vs. 40.8%, p<0.001), non-TBI conditioning (57.3% vs. 38.7%, p<0.001) but there was no difference with gender, gender mis-match, intensity of conditioning, CMV match or underlying malignancy. Risk of GVHD was not related to cyclosporine AUC below 2600 (41.2% vs. 50.3%, p=0.2), below 2470 (38.6% vs. 50.3%, p=0.14) or below 2730 (49.4% vs. 49.4%, p=0.99). Similarly incidence of CGVHD was higher with use of PBSC (66.7% vs. 36.6%, p<0.001), Alemtuzumab/ATG (66.2% vs. 53.8%, p=0.003), RIC (64.1% vs. 50.7%, p=0.013) and prior AGVHD (100% vs. 22%, p<0.0001). There was no effect of gender, gender mis-match, underlying malignancy and cyclosporine AUC. AUC did not influence the incidence of AGVHD or CGVHD when the analysis was done separately for full and reduced intensity transplants. The median OS from HSCT was 4.9 yr. (0.01-23.8 yr.). Even though incidence of AGVHD or CGVHD was not influenced by cyclosporine AUC, OS was significantly lower for AUC below 2470 (2.2 vs. 4.9 yr., p=0.0002), below 2600 (2.5 vs. 5.0 yr., p=0.0001) and below 2730 (2.1 vs. 4.6 yr., p<0.0001). By multi-variate analysis, Alemtuzumab/ATG (RR: 1.55, 95% CI: 1.04-2.3, p=0.031) and AUC below 2600 (RR: 1.9, 95% CI: 1.3-2.8, p<0.001) were independently associated with inferior OS. Patients with both the factors had lowest OS (none: 7.5 yr.; one: 5yr., both: 1.1 yr.; p<0.0001).
Conclusion: This retrospective analysis had high proportion of cases receiving Alemtuzumab/ATG based GVHD prophylaxis and shows that even though there is no effect of cyclosporine AUC on the incidence of either AGVHD or CGVHD, patients receiving Alemtuzumab/ATG with sub-therapeutic cyclosporine AUC have poor OS. This raises the possibility that in this group of patients it is imperative to have target cyclosporine levels in first 14 days. The duration of target cyclosporine levels before tapering the doses needs to be established to improve OS without increasing the toxicity.

Disclosures
Somervaille: Imago Biosciences: Consultancy; Novartis: Consultancy, Honoraria. Bloor:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria; GSK: Consultancy, Speakers Bureau.