Introduction

The most frequent serious complications of allogeneic hematopoietic cell transplant (HCT) are leukemia relapse and graft-vs-host disease (GVHD). Rabbit anti-T cell globulin (ATG, Thymoglobulin) reduces GVHD without increasing relapse, as shown in 3 randomized studies (Chang et al. Cancer 2017, Walker et al. Lancet Oncol 2016, Bacigalupo et al. BBMT 2006). ATG has a direct anti-leukemic effect in vitro (Dabas et al. BBMT 2016, Dabas et al. BMT 2018 in press). In spite of that, in the randomized studies ATG did not reduce relapse. We hypothesized that this could be due to differential effects of ATG pre- vs post-HCT on relapse. Specifically, post-HCT (but not pre-HCT), the anti-leukemic effect of ATG could be countered by ATG impairing graft-vs-leukemia effect (GVL). Here we set out to determine whether pre- vs post-HCT ATG area-under-the-curve (AUC) is associated with relapse and GVHD, the latter possibly being a surrogate for GVL.

Methods

A total of 153 patients were studied. All received first allogeneic HCT using conditioning with fludarabine (250 mg/m2), busulfan (~12.8 mg/kg) + TBI (4 Gy) and GVHD prophylaxis with rabbit ATG (0.5 mg/kg on day -2, 2 mg/kg on day -1 and 2 mg/kg on day 0 before graft infusion), methotrexate and cyclosporine. Serum was collected at the end of the last ATG infusion, immediately pre-graft infusion, 30 minutes after the end of graft infusion and days 7 and 28.

Serum levels of ATG capable of binding to total mononuclear cells (MNCs) were determined using a flow cytometry-based assay (similar to Podgorny et al. BBMT 2010). Pre-HCT ATG AUC was estimated from ATG levels at the end of the last ATG infusion and pre-graft infusion. Post-HCT ATG AUC was estimated from the ATG levels 30 minutes post graft infusion and on days 7 and 28. AUCs were split into above and below median for analysis.

Multivariate competing risks regression (according to Fine and Gray) was used to determine whether high ATG AUC was associated with the cumulative incidence of relapse. Multivariate Cox regression was used to determine if high ATG AUC was associated with relapse-free survival (RFS).

Results

High (above median) pre-HCT AUC was associated with a lower incidence of relapse (SHR=0.430, P=0.029) (Fig. 1, top). It was also associated with improved RFS (HR=0.534, P=0.040). For post-HCT AUC, there appeared to be a trend toward an opposite association - high (above median) post-HCT AUC associated with a higher incidence of relapse (SHR=1.470, P=0.302) (Fig. 1, bottom). There was no association between high post-HCT AUC and RFS.

Regarding GVHD, there appeared to be a trend toward an association between high pre-HCT AUC and a lower incidence of significant GVHD (grade 2-4 aGVHD or moderate-severe cGVHD) (SHR=0.667, P=0.128) (Fig. 2, top). A strong and significant association was observed between high post-HCT AUC and a lower incidence of significant GVHD (SHR=0.462, P=0.005) (Fig. 2, bottom).

Conclusion

High pre-HCT ATG AUC appears to result in less relapse and improved RFS. This may be the in vivo reflection of the known anti-leukemic activity of ATG in vitro. In contrast, high post-HCT AUC appears to have a neutral or deleterious impact on relapse. As high post-HCT AUC is strongly associated with a low incidence of GVHD, which may be a surrogate for weak GVL, it is possible that after HCT, the anti-leukemic effect of ATG is overshadowed by its anti-GVL effect.

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Disclosures

No relevant conflicts of interest to declare.

Topics:
thymoglobulin, graft-versus-host disease, infusion procedures, tissue transplants, allogeneic hematopoietic stem cell transplant, busulfan, cancer, cyclosporine, fludarabine, globulins

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2018 by The American Society of Hematology
2018
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