Impact of Serotherapy on Immune Reconstitution and Survival Outcomes after Stem Cell Transplantations in Children: Thymoglobulin Versus Alemtuzumab

Abstract

The administration of antibodies targeting T cells and other immune cells ("serotherapy" or "in vivo T cell depletion") to prevent graft-versus-host disease (GVHD) appears beneficial. For rabbit polyclonal "antieT cell globulin" (ATG), five randomized and multiple nonrandomized studies have shown that, in the setting of adult marrow or mobilized blood stem cell transplantation using myeloablative conditioning, ATG given with conditioning prevents GVHD without compromising relapse incidence or survival [1]. This leads to improved immunosuppression-free survival [2] and improved quality of life [3][4][5]. This is true in spite of the fact that ATG appears to increase viral infections, particularly Epstein-Barr virus (EBV)e driven post-transplantation lymphoproliferative disorder [1].Alemtuzumab (humanized rat monoclonal antibody targeting CD52) may reduce GVHD to a greater degree than ATG [6,7]. The incidence of relapse has been reported to be not higher with alemtuzumab than it is with ATG [6,7]. Viral infections may occur more frequently with alemtuzumab than with ATG [8], except for EBV post-transplantation lymphoproliferative disorder, which may be more frequent with ATG. However, whether alemtuzumab can be substituted for ATG as GVHD prophylaxis is not known because only a few studies comparing ATG with alemtuzumab are available, and all are retrospective.The study of Willemsen et al.[9] is a welcome addition to the group of retrospective studies. It showed that, compared with w10 mg/kg ATG (Thymoglobulin, Sanofi, Paris, France), w.8 mg/kg alemtuzumab resulted in a trend toward less acute GVHD, as expected. Also as expected, adenoviral reactivation was more frequent in the alemtuzumab group, whereas EBV reactivation was more frequent in the ATG group. Surprisingly, relapse incidence was higher in the alemtuzumab group, which resulted in lower overall and relapse-free survival. This could not be attributed to the longer half-life of alemtuzumab (compared with ATG), as when patients with short alemtuzumab exposure (low area under the time-concentration curve) were compared with patients with long ATG exposure, the relapse incidence and survival were still significantly worse in the short exposure alemtuzumab group. This was true despite the similar relative exposure to antibodies for both groups. It should not be assumed that the increased relapse incidence and mortality with alemtuzumab applies to adults, who are more prone to develop GVHD than children (without serotherapy) and, thus, could theoretically derive a greater benefit (less GVHDassociated mortality and morbidity) from alemtuzumab.The strength of the study is in its mechanistic componentsdimmune reconstitution and pharmacokinetics. Reconstitution of virtually all immune cell subsets (neutrophils, monocytes, total and memory/effector CD4 T cells, total and memory/effector CD8 T cells, and NK cells, but not B cells) was delayed in the alemtuzumab group, compared with the ATG group. This was caused, at least in part, by the longer halflife of alemtuzuma...

Differential Elimination of Anti-Thymocyte Globulin of Fresenius and Genzyme Impacts T-Cell Reconstitution After Hematopoietic Stem Cell Transplantation

“…It is intriguing that active ATG from the two products is cleared at different rates. It can be assumed that this is due to differences in manufacturing, since ATG-FRES is absorbed to human placental cells and erythrocytes, while ATG-GENZ is absorbed to erythrocytes only (39). Another explanation might be the differences in antigens recognized by the polyclonal antibodies in both products.…”

Features of Epstein–Barr Virus and Cytomegalovirus Reactivation in Acute Leukemia Patients After Haplo-HCT With Myeloablative ATG-Containing Conditioning Regimen

“…Furthermore, the pattern of immunoreconstitution was not analyzed due to insufficient data on the dynamic monitoring of lymphocyte subsets. Because our retrospective study focused on recipients after haplo-HCT with an ATG-contained regimen, the impact of serotherapy should be taken into account in further studies ( Lindemans et al., 2015 ; Storek, 2015 ; Willemsen et al., 2015 ; Gergely et al., 2021 ; Keogh et al., 2021 ). Hence, our findings need to be validated by large-scale real-world studies and laboratory investigations in the future.…”

The Role of Anti-Thymocyte Globulin or Alemtuzumab-Based Serotherapy in the Prophylaxis and Management of Graft-Versus-Host Disease

“…GVHD, however, still remains a pronounced issue, especially with the advent of reduced intensity conditioning (RIC), which capitalizes on graft-versus-tumor (GVT) effect to optimize responses [ 10 ]. The conditioning regimens usually involve chemotherapy, irradiation, and/or serotherapy, also referred to as “in vivo T cell depletion” [ 11 , 12 ]. It usually involves administration of either a polyclonal immunoglobulin, anti-thymocyte globulin (ATG), or alemtuzumab, a monoclonal antibody (mAb) specific for CD52 [ 13 , 14 ].…”