Impact of anti-thymocyte globulin on results of allogeneic peripheral blood stem cell transplantation for patients with Philadelphia-positive acute lymphoblastic leukaemia: An analysis by the Acute Leukemia Working Party of the EBMT

Highlights

• Decreased risk of chronic graft-versus-host disease for patients treated with anti-thymocyte globulin (ATG).

• Increased risk of relapse associated with the use of ATG.

• No impact on survival associated with the use of ATG.

Abstract

Background

Anti-thymocyte globulin (ATG) is widely used to prevent graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (alloPBSCT). The goal of this study was to retrospectively assess the effect of ATG on outcomes in the setting of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL).

Methods

In the analysis, 1170 adult patients undergoing alloPBSCT from human leucocyte antigen–matched sibling or unrelated donors in the first complete remission between 2007 and 2016 were included. ATG was used in 429/575 (75%) and 121/595 (20%) patients transplanted from unrelated or sibling donors, respectively.

Results

The incidence of chronic GVHD was 35% for patients treated with ATG compared with 52% in those not receiving ATG (p < 0.001), while the rate of extensive chronic GVHD was 16% and 36%, respectively (p < 0.001). The probability of survival free from GVHD and relapse (GRFS) was 42% and 32%, respectively (p = 0.002). In a multivariate model, the use of ATG was associated with reduced risk of overall chronic GVHD (hazard ratio [HR] = 0.52, p < 0.001) and extensive chronic GVHD (HR = 0.46, p < 0.001). It was also associated with better GRFS (HR = 0.77, p = 0.007), despite increased risk of relapse (HR = 1.41, p = 0.02). No significant effect was found with regard to the risk of non-relapse mortality and overall mortality.

Conclusions

The use of ATG for patients with Ph+ ALL undergoing alloPBSCT is associated with reduced risk of chronic GVHD without impact on survival and therefore, could be considered. However, increased risk of relapse suggests the need for strict monitoring of minimal residual diseases and appropriate interventions after transplantation.

Introduction

The prognosis of patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia (Ph+ ALL) improved markedly with the introduction of tyrosine kinase inhibitors (TKIs) [1], [2]. However, without allogeneic haematopoietic stem cell transplantation (alloHSCT), most of the patients relapse, and therefore, transplantation from either human leucocyte antigen (HLA)–matched sibling (MSD) or unrelated donor (MUD) is still considered a standard of care [3], [4], [5], [6]. Unfortunately, despite improvement over time, the procedure is still associated with significant mortality and morbidity [7]. Some complications, including chronic graft-versus-host disease (cGVHD), may negatively affect long-term quality of life [8]. Results of several randomised trials indicate an increased risk of cGVHD for transplantations using peripheral blood stem cell transplantation (PBSCT) compared with bone marrow, which is important in view of increasing proportion of PBSCTs among alloHSCT procedures [9], [10].

Attempts to decrease the risk of cGVHD include in vivo T-cell depletion using anti-thymocyte globulin (ATG) as a part of a conditioning regimen [11]. Several prospective, randomised studies documented its efficacy with regard to both overall and extensive cGVHD after transplantation from either MUD or MSD [12], [13], [14], [15], [16]. Although the use of ATG may be associated with delayed immune reconstitution, most studies did not report its detrimental effect on the risk of relapse or the overall mortality. It must be stressed, however, that those studies included mainly patients with myeloid malignancies. While the effect of ATG on the risk of GVHD seems independent of the baseline diagnosis, theoretically, there may be differences regarding its impact on relapse. In this regard, for malignancies such as ALL in which a strong association between cGVHD and relapse incidence has been demonstrated, suppression of cGVHD may result in increased risk of disease recurrence [17], [18]. The goal of the current analysis was to evaluate the impact of in vivo T-cell depletion using ATG on outcomes of patients with Ph+ ALL, treated with alloPBSCT. This population has been poorly represented in the recent prospective clinical trials, and therefore, no disease-specific conclusions are available so far.