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

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. 

Variables	Categories	TAC-SIR		TAC-SIR-ATG
		MCC (N=5)	Spanish Centers (N=38)	MCC (N=41)	Spanish Centers (N=20)
Median age (range), years		53 (25-64)	51 (17-69)	52 (24-67)	55 (30-68)
Gender mismatch (Donor→recipient)	F→M F→F M→M,F Missing	1 1 3 0	7 5 25 1	10 13 18 0	2 0 10 8
HLA-mismatch	A B C DRB1 Missing	1 1 3 0 0	10 14 8 6 0	24 13 4 0 0	8 3 3 5 1
Diagnoses	ALL AML CLL CML HL MDS MF MM NHL Other	1 2 0 0 0 1 0 0 1 0	3 10 3 1 3 7 1 1 10 0	4 18 3 2 1 5 1 0 7 0	1 6 1 0 1 3 0 1 5 2
Preparative regimen	FLU-BU FLU-MEL	3 2	18 20	35 6	11 7
CIBMTR risk	None Low Intermediate High	0 2 1 2	0 24 2 12	1 13 15 12	0 18 2 0
Cell source	BM PBSC	0 5	8 30	0 41	1 19
Median CD34 cells (range) x106/recipient Kg body weight		7.99 (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	+/+ +/- -/- -/+ Missing	1 2 2 0 0	18 16 2 2 0	18 14 7 2 0	7 6 0 0 7

                                                     Table 1.Patient-, disease-, and transplant-related characteristics.

 

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

Table 2. Post-transplant outcomes.