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.
Patient-, disease-, and transplant-related characteristics.
| 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 |
| 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 |
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 |
| 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 |
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.
Author notes
Asterisk with author names denotes non-ASH members.
