Optimizing anti-T-lymphocyte globulin dosing to improve long-term outcome after unrelated hematopoietic cell transplantation for hematologic malignancies

Abstract

Prophylaxis of graft‐versus‐host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT) remains challenging. Because prospective randomized trials of in‐vivo T cell depletion using anti‐T‐lymphocyte globulin (ATLG) in addition to a calcineurin inhibitor and methotrexate (MTX) led to conflicting outcome results, we evaluated the impact of ATLG on clinical outcome, lymphocyte‐ and immune reconstitution survival models. In total, 1500 consecutive patients with hematologic malignancies received matched unrelated donor (MUD) HCT with cyclosporin and MTX (N = 723, 48%) or with additional ATLG (N = 777, 52%). In the ATLG cohort, grades III‐IV acute (12% vs 23%) and extensive chronic GVHD (18% vs 34%) incidences were significantly reduced (P < .0001). Nonrelapse mortality (27% vs 45%) and relapse (30% vs 22%) differed also significantly. Event‐free and overall survival estimates at 10 years were 44% and 51% with ATLG and 33% and 35% without ATLG (P < .002 and <.0001). A dose‐dependent ATLG effect on lymphocyte‐ and neutrophil reconstitution was observed. At ATLG exposure, lymphocyte counts and survival associated through a logarithmically increasing function. In this survival model, the lymphocyte count optimum range at exposure was between 0.4 and 1.45/nL (P = .001). This study supports additional ATLG immune prophylaxis and is the first study to associate optimal lymphocyte counts with survival after MUD‐HCT.

Cytomegalovirus kinetics after hematopoietic cell transplantation reveal peak titers with differential impact on mortality, relapse and immune reconstitution

“…It is likely that in some patients, ATG-mediated low T cell numbers early after HCT favored the presence of CMV viremia. Dosage optimizing strategies of ATG39,40 may prevent excessive depletion and subsequent CMV reactivation. Other risk models have associated CMV area under the curve (AUC)25 or cumulative infections of differentF I G U R E 3 Patients with CMV reactivation ≤d + 30 are characterized by a delayed reconstitution of naïve and memory helper T cells.…”

Impact of CMV reactivation on relapse of acute myeloid leukemia after HCT is dependent on disease stage and ATG

“…ATG exposure modulates how CMV replication affects the incidence of relapse after HCT, 20 and a recent study 31 highlighted the role of CMV kinetics and T cell subpopulations in this interaction. Indeed, the immune reconstitution of T helper cells and naïve T helper cells is impaired after ATG prophylaxis, 32 and also lower CD8+ T cell receptor (TCR) repertoire diversity has been reported compared with MUD patients without ATG exposure. 33,34 Poor T cell reconstitution may favor relapse.…”

“…43 With or without CMV reactivation, ATG exposed patients had more late relapse events without reaching a plateau. Novel ATG dose optimization strategies 32,44,45 may improve relapse incidence and modify CMV-dependent effects. While previous reports associated CMV reactivation both with reduced early (<12 months) 7 and later relapse, 9,18 our data highlight that a late-relapse (>18 months)-protective impact of CMV is only detected in patients without ATG.…”

Combined Analysis of Early CD4+ T Cell Counts and CMV Serostatus May Improve CMV Risk Assessment after Allogeneic Hematopoietic Cell Transplantation

“…The latter might either relate to rapid peripheral expansion of CD4 + T cells due to aGVHD or viral reactivation events triggering CD4 + cell recovery [ 36 , 37 ], which has not been evaluated in this study. Furthermore, a very delayed early reconstitution of helper T cells (0–39 cells/µL) at d+ 30 after HCT was previously related to in vivo T cell depletion protocols with, e.g., ATG [ 38 ]. Although our cohort included a high proportion of patients with ATG ( n = 189, 71%), this was not considered in the final CMV risk model.…”