An International Multicenter Comparative Analysis of Tacrolimus Plus Sirolimus with or without Antithymocyte Globulin As Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation
Authors: Kharfan-Dabaja Mohamed A. , Parody Rocio , Perkins Janelle , Lopez-Godino Oriana , Lopez-Corral Lucia , Vazquez Lourdes , Caballero Dolores , Falantes Jose , Shapiro Jamie , Orti Guillermo , Barba Pere , Valcárcel David , Esquirol Alber , Martino Rodrigo , Piñana Jose Luis , Solano Carlos , Pidala Joseph A , Anasetti Claudio , Perez-Simon Jose A. 
Published: October 2019

Abstract
Background: There is lack of consensus in regards to the optimal regimen for graft-versus-host disease (GVHD) prophylaxis in patients undergoing HLA-mismatched unrelated donor (MMUD) allografting. A regimen combining tacrolimus plus sirolimus (TAC-SIR) has been shown to be effective as GVHD prophylaxis in HLA-matched related (MRD) or matched-unrelated donor (MUD) allogeneic hematopoietic cell transplantation (HCT). Addition of antithymocyte globulin (ATG) has been shown to reduce incidence of acute GVHD but it is associated with a high rate of infectious complications. Here, we retrospectively compare post-transplant outcomes using TAC-SIR or TAC-SIR-ATG in 104 patients who underwent a MMUD allogeneic HCT between June 2008 and December 2014 at 5 Spanish and 1 transplant center (MCC) in the United States.
Patients and methods: Forty-three (MCC=5, Spanish Centers=38) patients received TAC-SIR whereas 61(MCC=41, Spanish Centers=20) received TAC-SIR-ATG as GVHD prophylaxis for MMUD allogeneic HCT. Patient-, disease-, and transplant characteristics are summarized in Table 1.
Results: The median follow-up (months) for all, TAC-SIR, and TAC-SIR-ATG patients were 29 (5-83), 27 (5-64), and 30 (6-83) months, respectively. Patients receiving TAC-SIR had faster platelets (12 vs. 15 days, p=0.005) but slightly slower neutrophil engraftment (16 vs. 15 days, p=0.037). Addition of ATG resulted in a lower incidence of acute GVHD (grade 2-4) (44% (95%CI=33-59%) vs. 67% (95%CI=55-83%), p=0.055) and over two-fold lower incidence, albeit not statistically significant, of moderate/severe chronic GVHD (17% (95%CI=10-30%) vs. 38% (95%CI=25-60%), p=0.086). Non-relapse mortality (NRM) (2-year) was two-fold higher, but not statistically significant, in the TAC-SIR-ATG group (TAC-SIR-ATG=35% (95%CI=24-50%) vs. TAC-SIR=17% (95%CI=10-35%), p=0.078) mainly attributable to a 3-fold higher number of non-relapse deaths attributed to infections (9 vs. 3). There was no difference in cumulative incidence of relapse (2-year) (TAC-SIR=28% (95%CI=17-46%) vs. TAC-SIR-ATG=26% (95%CI=17-41%), p=0.858) or in 2-year OS (TAC-SIR=56% (95%CI=40-72%) vs. TAC-SIR-ATG=47% (95%CI=34-60%), p=0.244) between the groups. These and other outcomes are summarized in Table 2.
Conclusion: In MMUD allogeneic HCT, addition of ATG to TAC-SIR results in a lower incidence of grade 2-4 acute GVHD but does not improve OS. The two-fold higher 2-year NRM with addition of ATG is probably explained by a higher incidence of resulting infectious complications with in vivo T-cell depletion. While these results are intriguing, a prospective randomized study is certainly needed to confirm these findings.Table 1.Patient-, disease-, and transplant-related characteristics.VariablesCategoriesTAC-SIRTAC-SIR-ATGMCC (N=5)Spanish Centers (N=38)MCC (N=41)Spanish Centers (N=20)Median age (range), years53 (25-64)51 (17-69)52 (24-67)55 (30-68)Gender mismatch(Donor→recipient)F→M F→F M→M,F Missing1 1 3 07 5 25 110 13 18 02 0 10 8 HLA-mismatchA B C DRB1 Missing1 1 3 0 010 14 8 6 024 13 4 0 08 3 3 5 1DiagnosesALL AML CLL CML HL MDS MF MM NHL Other1 2 0 0 0 1 0 0 1 03 10 3 1 3 7 1 1 10 04 18 3 2 1 5 1 0 7 01 6 1 0 1 3 0 1 5 2Preparative regimenFLU-BU FLU-MEL3 218 2035 611 7CIBMTR riskNone Low Intermediate High0 2 1 20 24 2 121 13 15 120 18 2 0Cell sourceBM PBSC0 58 300 411 19Median CD34 cells (range) x106/recipient Kg body weight7.99 (4.08-10.0)6 (1.2-11.0)8.57 (2.81-23.01)6.08 (0.67-9.5)Recipient/donor CMV serologic status+/+ +/- -/- -/+ Missing1 2 2 0 018 16 2 2 018 14 7 2 07 6 0 0 7
Table 2. Post-transplant outcomes. Outcomes TAC-SIR TAC-SIR-ATG P-value Median days (range) to ANC>500/µL 16 (10-29) 15 (9-24) 0.037 Median days (range) to platelets engraftment 12 (6-26) 15 (0-50) 0.005 Cum incidence acute GVHD (grade 2-4) (at 100 day) 67% (55-83%) 44% (33-59%) 0.055 Cum incidence acute GVHD (grade 3-4) (at 100-day) 16% (8-32%) 10% (5-21%) 0.347 Chronic moderate or severe (at 2-year) 38% (25-60%) 17% (10-30%) 0.086 Cum incidence of NRM (at 100-day) 12% (5-27%) 13% (7-25%) 0.078 Cum incidence of NRM(2-year) 17% (10-35%) 35% (24-50%) 0.078 Cum Incidence of relapse (2-year) 28% (17-46%) 26% (17-41%) 0.858 EFS (2-year) 54% (38-69%) 38% (26-52%) 0.191 OS (2-year) 56% (40-72%) 47% (34-60%) 0.244

Disclosures
Off Label Use: Sirolimus for GVHD prophylaxis. Perkins:PDL Biopharma: Research Funding. Falantes:Celgene: Honoraria. Valcárcel:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.