Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation

Admiraal, Rick; Lindemans, Caroline A.; Kesteren, Charlotte van; Bierings, Marc; Versluijs, A. Birgitta; Nierkens, Stefan; Boelens, Jaap Jan

doi:10.1182/blood-2016-06-721936

Cited by 142 publications

(132 citation statements)

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“…T‐cell immune reconstitution has been associated with the use of ATG shortly before or after infusion of CB as ATG will increase the depletion of T cells and prohibit the proliferation of CB 30. The reduction of ATG after CBT could achieve an early CD4+ T‐cell immune reconstitution and no exposure to ATG results in even exceptional immune reconstitution potential, as recently shown 31. NK cells typically recover within the first month after transplant and are therefore one of the first lymphocytes to recover after transplant, regardless of stem‐cell source 32.…”

Section: Discussionmentioning

confidence: 99%

Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study

Sun

Liu

Luo

et al. 2018

Intl Journal of Cancer

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Cord blood transplantation (CBT) is an effective option for treating hematological malignancies, but graft failure (GF) remains the primary cause of therapy failure. Thus, based on myeloablative conditioning (MAC) of busulfan with cyclophosphamide (Bu/Cy) or total body irradiation with Cy (TBI/Cy), fludarabine (Flu) was added to Bu/Cy and cytarabine (CA) to TBI/Cy for a modified myeloablative conditioning (MMAC). To compare the prognosis of MMAC with MAC, we conducted a retrospective study including 58 patients who underwent CBT with MAC or MMAC from 2000 to 2011. Neutrophil and platelet engraftment rate, overall survival (OS) and disease free survival (DFS) were significantly higher in the MMAC group (adjusted hazard ratio [HR], 2.58, 2.43, 0.36 and 0.37; p < 0.01, p = 0.01, p = 0.02 and p = 0.02, separately). Nonrelapse mortality (NRM) was comparable (p = 0.183). To validate the outcomes noted in the MMAC group, we conducted a prospective single‐arm clinical trial including 188 patients who underwent CBT with MMAC from 2011 to 2015. Engraftment rate, survival and NRM of the MMAC group in the prospective trail (MMAC‐P) were similar to the MMAC group in the retrospective study (MMAC‐R). This study is the first to demonstrate the superiority of MMAC to MAC in CBT for hematological malignancies.

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Section: Discussionmentioning

confidence: 99%

Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study

Sun

Liu

Luo

et al. 2018

Intl Journal of Cancer

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“…11 Furthermore, it is possible that the effect and outcomes with ATG are dependent on lymphocyte count at the time of infusion, and it is likely that an individualized approach to ATG dosing and timing could be beneficial to avoiding significant impairment in post-HSCT immune reconstitution. [12][13][14] In one interesting study, the serum from patients who underwent HSCT with ATG showed that subpopulations of T lymphocytes (CD4, CD8) and natural killer cells (CD56) are selected that lose epitopes recognized by ATG, whereas B lymphocytes (CD20) and monocytes (CD14) maintain a homogeneity with respect to epitopes recognized by ATG. 15 How the antisera select for specific subpopulations of lymphocytes is unknown and further complicates our understanding of the mechanism of action as well as the variability of activity of ATG.…”

Section: Not All Atg Formulations Are the Samementioning

confidence: 99%

ATG in allogeneic stem cell transplantation: standard of care in 2017? Counterpoint

Kekre

Antin

2017

Blood Advances

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This article has a companion Point by Bacigalupo.Despite improvements in HLA matching, quality control measures, and supportive care used in hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) remains a common cause of morbidity and mortality in transplant recipients. 1 The primary goal of HSCT is to cure the underlying hematological disorder with as little residual disability as possible. Achieving this goal requires supporting the patient through a conditioning regimen and its associated toxicity, opportunistic infections, and GVHD while avoiding relapse. Despite recognizing that donor T cells are critical in the establishment of both acute and chronic GVHD, it is important to remember that these cells also help in preventing opportunistic infections and providing a graft-versus-leukemia (GVL) effect when necessary. It was not surprising then that early on we discovered that ex vivo T-cell depletion could prevent or minimize GVHD, but at the cost of increases in mortality from rejection, relapse, and opportunistic infection.It is generally accepted that preventing GVHD is more effective than treating it once it has been established. The use of antithymocyte globulin (ATG) reflects a form of in vivo T-cell depletion, which concomitantly depletes host T cells that have survived the conditioning regimen. This reduces the risk of rejection, while similarly depleting newly infused donor T cells, thus potentially reducing GVHD, GVL, and the passive transfer of memory T cells that reconstitute early immunity. An analysis of ATG's value is complicated by considerations of ATG formulation, sensitivity of the underlying disease to GVL, intensity of conditioning regimen, donor source, and other medications used for GVHD prophylaxis. The decision to use ATG must balance the circumstances in which ATG may be beneficial by reducing the incidence of GVHD with the situations in which ATG may be either neutral or harmful by increasing the risk of Epstein-Barr virus (EBV) posttransplant lymphoproliferative disease and other infections as well as relapse. Not all ATG formulations are the sameAlthough randomized controlled trials have demonstrated that ATG can reduce the risk of GVHD, 2,3 the differences in dosage and formulation of ATG make it difficult to generalize these results. For example, rabbit ATG (Thymoglobulin) is associated with more effective depletion of lymphocytes than horse ATG (ATGAM). 4 In addition to lymphocyte depletion, rabbit but not horse ATG enhances the number and function of regulatory T cells, 5,6 which are important in suppressing immune response and maintaining tolerance. The preservation or permissive expansion of regulatory T cells may limit GVHD after HSCT because these cells are needed for tolerance, controlling alloreactive donor lymphocytes involved in GVHD as well as innate and adaptive immune responses. These mechanistic differences between rabbit and horse ATG result in different outcomes in patients receiving immunosuppressive therapy or bone marrow transplantat...

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“…9,13 Another way would be to adjust (or delay) timing of G-CSF treatment to prevent coexposure with ATG. G-CSF treatment might even be abandoned in some patients with residual ATG exposure.…”

Section: Org Frommentioning

confidence: 99%

“…All patients received gut decontamination and Pneumocystis jiroveci prophylaxis according to local protocol as previously described. 13 Patients were treated in highefficiency, positive-pressure, particle-free isolation rooms. All CBT patients received 10 mg/kg granulocyte colony-stimulating factor (G-CSF; Neupogen) from day 17 after HCT until neutrophils were .2000 cells/mL.…”

Section: Patients and Treatmentmentioning

confidence: 99%

“…10 Nevertheless, in patients undergoing a CBT without ATG in the conditioning, very rapid T-cell reconstitution associated with very low incidences of viral reactivations and relapse was observed. 13,14 Although the lower T-cell dose in cord blood (CB) grafts does not explain the higher effect of ATG on IR, 15 other possible covariates that may influence T-cell reconstitution, such as steroid-treated acute GVHD (aGVHD) after HCT, have not yet been evaluated in these analyses. Therefore, the underlying mechanism for the suggested higher impact of ATG on CD4…”

Section: Introductionmentioning

confidence: 99%

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Filgrastim enhances T-cell clearance by antithymocyte globulin exposure after unrelated cord blood transplantation

et al. 2018

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Key Points• Residual ATG exposure delays CD4 1 T-cell reconstitution more severely after CBT than after BMT.• Filgrastim (G-CSF), given early after CBT, enhances ATGmediated T-cell clearance in patients with residual ATG exposure.Residual antithymocyte globulin (ATG; Thymoglobulin) exposure after allogeneic hemato-subsequently increasing morbidity and mortality. This effect seems particularly present after cord blood transplantation (CBT) compared to bone marrow transplantation (BMT).The reason for this is currently unknown. We investigated the effect of active-ATG exposure on CD4 1 IR after BMT and CBT in 275 patients (CBT n 5 155, BMT n 5 120; median age, 7.8 years; range, 0.16-19.2 years) receiving their first allogeneic HCT between January 2008 and September 2016. Multivariate log-rank tests (with correction for covariates) revealed that CD4 1 IR was faster after CBT than after BMT with ,10 active-ATG 3 day/mL (P 5 .018) residual exposure. In contrast, .10 active-ATG 3 day/mL exposure severely impaired CD4 1 IR after CBT (P , .001), but not after BMT (P 5 .74). To decipher these differences, we performed ATG-binding and ATG-cytotoxicity experiments using cord blood-and bone marrow graft-derived T-cell subsets, B cells, natural killer cells, and monocytes. No differences were observed. Nevertheless, a major covariate in our cohort was Filgrastim treatment (only given after CBT). We found that Filgrastim (granulocyte colony-stimulating factor [G-CSF]) exposure highly increased neutrophil-mediated ATG cytotoxicity (by 40-fold [0.5 vs 20%; P 5 .002]), which explained the enhanced T-cell clearance after CBT. These findings imply revision of the use (and/or timing) of G-CSF in patients with residual ATG exposure.

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Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation

Abstract: Key Points Immune reconstitution after CBT is excellent provided ATG exposure is low or absent. Individualized dosing, or omission of ATG in selected patients, may increase the chance of survival after CBT.

Cited by 142 publications

References 40 publications

Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study

Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study

ATG in allogeneic stem cell transplantation: standard of care in 2017? Counterpoint

Filgrastim enhances T-cell clearance by antithymocyte globulin exposure after unrelated cord blood transplantation

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