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

Koning, Coco de; Gabelich, Julie-Anne; Langenhorst, Jurgen; Admiraal, Rick; Kuball, Jürgen; Boelens, Jaap Jan; Nierkens, Stefan

doi:10.1182/bloodadvances.2017015487

Cited by 26 publications

(21 citation statements)

References 41 publications

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“…This difference in innate recovery between BMT and CBT diminished by day 200 after transplantation. Interestingly, in our pediatric cohort CBT was also related to a higher chance of having successful CD4 + T cell reconstitution compared with BMT (P = .018) when residual ATG exposure after transplantation was low (<10 active ATG £ day/mL) or absent [16]. Nevertheless, the higher innate recovery after CBT only increases the chance of having successful CD4 + T cell reconstitution (>50 £ 10 6 cells/L blood within 100 days after transplantation) by 3.0%, compared with BMT, when correcting for all relevant covariates (age at transplantation, year of transplantation, and post-transplantation ATG exposure).…”

Section: Innate Immune Cell Recovery According To Cell Sourcementioning

confidence: 75%

“…Grafts containing more proliferating cells resulted in more robust innate recovery, which might indicate a more optimal graft condition. The generally higher CB graft cell proliferation capacity could also explain why CD4 + T cell reconstitution is faster after CBT compared with BMT in patients with no/low serotherapy exposure after transplantation [16]. Innate cell recovery might thus represent a healthy niche for homeostatic peripheral expansion mediated T cell reconstitution.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we found a relation between the proliferation potential in both CB and BM graft cells and innate recovery after transplantation in the respective individual patients. Of note, all CBT patients in our cohort were treated with G-CSF (from day +7 until neutrophils reach >2000/mL) as standard of care to enhance neutrophil levels, whereas BMT recipients were not [16]. This might also affect the recovery of both A B neutrophils and monocytes, because monocytes have functional G-CSF receptors as well [22].…”

Section: Discussionmentioning

confidence: 99%

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Innate Immune Recovery Predicts CD4+ T Cell Reconstitution after Hematopoietic Cell Transplantation

Koning

Langenhorst

Kesteren

et al. 2019

Biology of Blood and Marrow Transplantation

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A B S T R A C T Innate immune cells are the first to recover after allogeneic hematopoietic cell transplantation (HCT). Nevertheless, reports of innate immune cell recovery and their relation to adaptive recovery after HCT are largely lacking. Especially predicting CD4 + T cell reconstitution is of clinical interest, because this parameter directly associates with survival chances after HCT. We evaluated whether innate recovery relates to CD4 + T cell reconstitution probability and investigated differences between innate recovery after cord blood transplantation (CBT) and bone marrow transplantation (BMT). We developed a multivariate, combined nonlinear mixed-effects model for monocytes, neutrophils, and natural killer (NK) cell recovery after transplantation. A total of 205 patients undergoing a first HCT (76 BMT, 129 CBT) between 2007 and 2016 were included. The median age was 7.3 years (range, .16 to 23). Innate recovery was highly associated with CD4 + T cell reconstitution probability (P < .001) in multivariate analysis correcting for covariates. Monocyte (P < .001), neutrophil (P < .001), and NK cell (P < .001) recovery reached higher levels during the first 200 days after CBT compared with BMT. The higher innate recovery after CBT may be explained by increased proliferation capacity (measured by Ki-67 expression) of innate cells in CB grafts compared with BM grafts (P = .041) and of innate cells in vivo after CBT compared with BMT (P = .048). At an individual level, patients with increased innate recovery after either CBT or BMT had received grafts with higher proliferating innate cells (CB; P = .004, BM; P = .01, respectively). Our findings implicate the use of early innate immune monitoring to predict the chance of CD4 + T cell reconstitution after HCT, with respect to higher innate recovery after CBT compared with BMT.

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Section: Innate Immune Cell Recovery According To Cell Sourcementioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Innate Immune Recovery Predicts CD4+ T Cell Reconstitution after Hematopoietic Cell Transplantation

Koning

Langenhorst

Kesteren

et al. 2019

Biology of Blood and Marrow Transplantation

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“…Of the 59 CMV-seropositive patients, 44 reactivated CMV by day 60 for a cumulative incidence of 75% (95% CI, 61-84). The cumulative incidence of grade II to IV and III to IV aGVHD by day 100 was 77% (95% CI, 68-84) and 17% (95% CI, [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], respectively. Of the 64 patients with grade II day 100 aGVHD, 22 (34%) were treated with systemic corticosteroids by day 100; remaining patients were treated with nonabsorbable oral or topical corticosteroids.…”

Section: Transplant Outcomesmentioning

confidence: 99%

“…[17][18][19][20][21][22] Notably, low ATG exposure or omission of ATG has been associated with rapid thymusindependent T-cell expansion and robust immune reconstitution in pediatric CBT recipients. 19,[22][23][24][25] In contrast to children, however, relatively little is known about immune reconstitution after ATG-free CBT in adults. 12,[26][27][28][29][30] Herein, we report the kinetics of immune reconstitution in a large cohort of adult CBT recipients transplanted for hematologic malignancies at a single center without ATG.…”

Section: Introductionmentioning

confidence: 99%

Robust CD4+ T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin

et al. 2020

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Quality of immune reconstitution after cord blood transplantation (CBT) without antithymocyte globulin (ATG) in adults is not established. We analyzed immune recovery in 106 engrafted adult CBT recipients (median age 50 years [range 22-70]) transplanted for hematologic malignancies with cyclosporine/mycophenolate mofetil immunoprophylaxis and no ATG. Patients were treated predominantly for acute leukemia (66%), and almost all (96%) underwent myeloablation. Recovery of CD4+ T cells was faster than CD8+ T cells with median CD4+ T-cell counts exceeding 200/mm3 at 4 months. Early post-CBT, effector memory (EM), and central memory cells were the most common CD4+ subsets, whereas effector and EM were the most common CD8+ T-cell subsets. Naive T-cell subsets increased gradually after 6 to 9 months post-CBT. A higher engrafting CB unit infused viable CD3+ cell dose was associated with improved CD4+ and CD4+CD45RA+ T-cell recovery. Cytomegalovirus reactivation by day 60 was associated with an expansion of total, EM, and effector CD8+ T cells, but lower CD4+ T-cell counts. Acute graft-versus-host disease (aGVHD) did not significantly compromise T-cell reconstitution. In serial landmark analyses, higher CD4+ T-cell counts and phytohemagglutinin responses were associated with reduced overall mortality. In contrast, CD8+ T-cell counts were not significant. Recovery of natural killer and B cells was prompt, reaching medians of 252/mm3 and 150/mm3 by 4 months, respectively, although B-cell recovery was delayed by aGVHD. Neither subset was significantly associated with mortality. ATG-free adult CBT is associated with robust thymus-independent CD4+ T-cell recovery, and CD4+ recovery reduced mortality risk.

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Allogeneic haematopoietic cell transplants as dynamical systems: influence of early‐term immune milieu on long‐term T‐cell recovery

et al. 2023

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Objectives Immune recovery following haematopoietic cell transplantation (HCT) functions as a dynamical system. Reducing the duration of intense immune suppression and augmenting antigen presentation has the potential to optimise T‐cell reconstitution, potentially influencing long‐term outcomes. Methods Based on donor‐derived T‐cell recovery, 26 patients were adaptively randomised between mycophenolate mofetil (MMF) administered for 30‐day post‐transplant with filgrastim for cytokine support (MMF30 arm, N = 11), or MMF given for 15 days with sargramostim (MMF15 arm, N = 15). All patients underwent in vivo T‐cell depletion with 5.1 mg kg−1 antithymocyte globulin (administered over 3 days, Day −9 through to Day −7) and received reduced intensity 450 cGy total body irradiation (3 fractions on Day −1 and Day 0). Patients underwent HLA‐matched related and unrelated donor haematopoietic cell transplantation (HCT). Results Clinical outcomes were equivalent between the two groups. The MMF15 arm demonstrated superior T‐cell, as well as T‐cell subset recovery and a trend towards superior T‐cell receptor (TCR) diversity in the first month with this difference persisting through the first year. T‐cell repertoire recovery was more rapid and sustained, as well as more diverse in the MMF15 arm. Conclusion The long‐term superior immune recovery in the MMF15 arm, administered GMCSF, is consistent with a disproportionate impact of early interventions in HCT. Modifying the ‘immune‐milieu’ following allogeneic HCT is feasible and may influence long‐term T‐cell recovery.

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

Cited by 26 publications

References 41 publications

Innate Immune Recovery Predicts CD4+ T Cell Reconstitution after Hematopoietic Cell Transplantation

Innate Immune Recovery Predicts CD4+ T Cell Reconstitution after Hematopoietic Cell Transplantation

Robust CD4+ T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin

Allogeneic haematopoietic cell transplants as dynamical systems: influence of early‐term immune milieu on long‐term T‐cell recovery

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