Sirolimus, Tacrolimus and Antithymocyte Globulin Are Associated with Improved Overall Survival When Compared to Methotrexate, Tacrolimus and Antithymocyte Globulin in Mismatched Unrelated Allogeneic Hematopoietic Cell Transplantation
Authors: Nelson Rebecca , Perkins Janelle , Shapiro Jamie , Kim Jongphil , Yue Binglin , Anasetti Claudio , Kharfan-Dabaja Mohamed A 
Published: November 2019

Abstract
Background: Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is used in combination with tacrolimus as prophylaxis for acute graft-versus-host-disease (GVHD). Two published randomized trials (one single institution and a multicenter one) failed to demonstrate a survival advantage of sirolimus plus tacrolimus (SIR-TAC) vis-à-vis methotrexate plus tacrolimus (MTX-TAC) when used for acute GVHD prophylaxis in HLA-matched related or unrelated allogeneic hematopoietic cell transplantation. No data exists comparing these two regimens when combined with antithymocyte globulin (ATG) in mismatched unrelated donor (MMUD) allografting. This study aims at comparing the efficacy of SIR-TAC-ATG vs. MTX-TAC-ATG in MMUD allografting.
Patients and methods: We retrospectively analyzed 122 patients allografted between 01/2006 and 08/2013 after acute GVHD prophylaxis using SIR-TAC-ATG (n=28) or MTX-TAC-ATG (n=94). All patients received 7.5 mg/kg of rabbit ATG. Conditioning regimens were myeloablative (n=94) or reduced-intensity (n=28). Patient-, disease-, and treatment-related characteristics are summarized in Table 1.
Results: Patients receiving SIR-TAC-ATG were older (54 vs. 47 years, p=0.015). The median follow-up from day of cell infusion for all patients was 11.2 (0.5-84.4) months; and for patients in the sirolimus-group or methotrexate-group were 11.5 (1.8-54.9) months and 10.4 (0.5-84.4) months, respectively. The 1-year survival was superior in patients who received SIR-TAC-ATG (83% vs. 57%, p=0.012). The 100-day cumulative incidences of grade 2-4 acute GVHD were 57% in the sirolimus- and 71% in the methotrexate-group, p=0.14. Patients who received methotrexate had over two-fold higher cumulative incidence of NRM (3-year), albeit not statistically significant (37% vs. 16%, p=0.1). There were no difference in median relapse-free survival (RFS) (MTX-TAC-ATG=17.8 months vs. SIR-TAC-ATG=not reached, p=0.21) or cumulative incidence of relapse at 1-year (MTX-TAC-ATG =19% vs. 19%, p= 0.94). Use of rituximab for preemptive treatment of EBV reactivation was higher in the group treated with sirolimus (79% vs. 51%, p= 0.01). Multivariate analyses using Cox proportional-hazard model identified use of sirolimus (HR=0.28 (95%CI=0.10, 0.78), p=0.015) and low CIBMTR disease risk (Hazard ratio (HR) =0.49 (95%CI=0.27, 0.88), p=0.018) as favorable predictors of overall survival (OS); but only low CIBMTR disease risk (HR=0.47 (95%CI=0.22, 0.98), p=0.045) as predictor for lower NRM.
Conclusion: This study suggests that combining SIR-TAC-ATG results in improved OS in MMUD allogeneic hematopoietic cell transplantation when compared to MTX-TAC-ATG. These findings need to be confirmed in a prospective randomized controlled trial.
Table 1. Variables Sirolimus-based Methotrexate-based p-value Recipient median (range) age (years) 54 (24-67) 47(20-69) 0.015 Recipient gender Male (M) Female (F) M=46% F=54% M=63% F=37% 0.13 Conditioning regimen MAC RIC MAC=75% RIC=25% MAC=78% RIC=22% 0.80 Recipient CMVserology seropositive 75% 70% 0.81 Primary disease Myeloid Lymphoid Others 68% 11% 21% 55% 17% 28% 0.55 CIBMTR disease risk High=18% Int=36% Low=47% High=23% Int=33% Low=44% 0.78 Median CD34 cell dose (x106/kg) 8.5 (3.2-23) 8.6 (1.8-25) 0.53 Rituximab Yes 79% 51% 0.01
MAC regimens: FLU-BU (AUC5300); RIC regimens: FLU-BU (AUC3500), FLU-CY, FLU-MEL, FLU-2GyTBI; Myeloid: AML, CML, MDS; Lymphoid: ALL, CLL

Disclosures
Off Label Use: sirolimus for prophylaxis for acute Graft-versus-host disease; Antithymocyte globulin for prophylaxis for acute Graft-versus-host disease.