Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation

Williams, Louis; Cirrone, Frank; Cole, Kelli; Abdul-Hay, Maher; Luznik, Leo; Al-Homsi, Ahmad Samer

doi:10.3389/fimmu.2020.00636

Cited by 32 publications

(18 citation statements)

References 47 publications

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“…The pathophysiology of GVHD involves activated donor T cells that function as alloreactive effector cells and activate other cells, such as B cells and macrophages, leading to an inflammatory cascade that damages host tissue [ 18 ]. In order to counter the effects of activated and alloreactive T cells, PTCy demonstrated the ability to either reduce or impair the function of alloreactive T cells of donor origin, while sparing precursors to stem cell memory T cells, allowing immune reconstitution and engraftment following aHSCT [ 19 , 20 ]. It is also believed that myeloid-derived suppressor cells (MDSCs), a form of immature myeloid cells that do not complete differentiation, are stimulated following exposure to cyclophosphamide and along with suppressing the immune system, MDSCs, in turn, stimulate regulatory T cells (Treg), which provides protection from GVHD [ 21 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Post-Transplant Cyclophosphamide after Matched Sibling and Unrelated Donor Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia

Sheikh

Alqahtani

Ragoonanan

et al. 2022

IJMS

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Non-relapse mortality due to GVHD and infections represents a major source of morbidity and mortality in pediatric HSCT recipients. Post-transplant cyclophosphamide (PTCy) has emerged as an effective and safe GVHD prophylaxis strategy, with improved GVHD and relapse-free survival in matched (related and unrelated) and mismatched haploidentical HSCT adult recipients. However, there are no published data in pediatric patients with acute myeloid leukemia who received matched-donor HSCT with PTCy. We demonstrate, in this case series, that the use of PTCy in this population is potentially safe, effective in preventing acute GVHD, does not impair engraftment, is associated with reduced non-relapse mortality, and does not hinder immune reconstitution post HSCT.

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Section: Discussionmentioning

confidence: 99%

Post-Transplant Cyclophosphamide after Matched Sibling and Unrelated Donor Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia

Sheikh

Alqahtani

Ragoonanan

et al. 2022

IJMS

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“…Post-transplantation treatment has been unexplored in this setting. Post-transplantation cyclophosphamide (Cy) is used in haploidentical HSCT to suppress graft versus host disease (Williams et al, 2020 ). The use of Cy on days +3 and +4 enables the efficient elimination of activated autoreactive lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Post Transplantation Cyclophosphamide Improves Outcome of Autologous Hematopoietic Stem Cell Transplantation in Animal Model of Multiple Sclerosis

Kasarełło

Snarski

Sulejczak

et al. 2021

Arch. Immunol. Ther. Exp.

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Experimental allergic encephalomyelitis (EAE) is the animal model of multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (AHSCT) has recently been recognized as the standard treatment for MS. The aim of our experiment was to investigate the effect of AHSCT with the addition of low-dose post-transplantation cyclophosphamide (Cy) on EAE in rats. Low dose post-transplantation Cy is used in haploidentical HSCT to reduce the risk of graft versus host disease. We hypothesized that it could bring additional benefit in autologous HSCT in autoimmune diseases. Rats with evoked EAE were treated with high dose (125 mg/kg) Cy, followed by AHSCT or high dose (125 mg/kg) Cy followed by AHSCT followed by low dose (20 mg/kg) Cy in two-time schedules—with the therapy applied during the pre-symptomatic or symptomatic phase of the disease. Both AHSCT and AHSCT with post-transplantation Cy in accordance with both time schedules reduce the intensity of the inflammatory response in the CNS, in comparison with non-treated EAE rats. The reduction of clinical symptoms was present in all AHSCT treatment protocols, however, it was significantly stronger when post-transplantation Cy was given during the symptomatic phase of the disease. AHSCT with the addition of post HSCT low dose Cy improved the results of AHSCT by not only reducing the intensity of inflammation in the CNS but also by significantly reducing the clinical symptoms in treated animals when compared to AHSCT alone. We provide an experimental rationale that the addition of post-transplantation Cy may improve the outcome of HSCT in MS. Graphic Abstract

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“…Post-transplant cyclophosphamide (PT-CY) is becoming widely adopted for GVHD prophylaxis following HLA matched 22 and haploidentical transplantation 23 24 . This modality is associated with significant immune modulation, with different mechanisms of GVHD control proposed 25 .…”

Section: Discussionmentioning

confidence: 99%

Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Anti-Thymocyte Globulin (ATG) Administration Schedules in Allogeneic Stem Cell Transplantation

Zelikson

Toor

Simmons

et al. 2021

Preprint

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Alloreactivity forms the basis of allogeneic hematopoietic cell transplantation (HCT), with donor derived T cell response to recipient antigens mediating clinical responses either in part or entirely. These encompass the different manifestations of graft vs. host disease (GVHD), infection risk as well as disease response. Whilst the latter is contingent upon disease biology and thus may be less predictable, the former two are more likely to be directly proportional to the magnitude of donor derived T cell recovery. Herein we explore the quantitative aspects of immune cell recovery following allogeneic HCT and clinical outcomes in two cohorts of HLA matched allograft recipients who received rabbit anti-thymocyte globulin (ATG) on different schedules (days -9 to -7 vs. -3 to -1). Monocyte as well as donor derived T cell (ddCD3) recovery was superior in those given ATG early in their course (days -9/-7). This difference was related to a more rapid rate of ddCD3 recovery, largely driven by CD3+/8+ cells in the first month following transplantation. Early monocyte recovery was associated with later T cell recovery, improved survival, and less chronic GVHD. In contrast rapid and early ddCD3 expansion out of proportion to monocyte recovery was associated with a high likelihood of acute GVHD and poor survival. This analytic methodology demonstrates that modeling 'early-term immune reconstitution' following HCT yields insights that may be useful in management of post-transplant immunosuppression and adaptive cellular therapy to optimize clinical outcomes.

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Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation

Cited by 32 publications

References 47 publications

Post-Transplant Cyclophosphamide after Matched Sibling and Unrelated Donor Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia

Post-Transplant Cyclophosphamide after Matched Sibling and Unrelated Donor Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia

Post Transplantation Cyclophosphamide Improves Outcome of Autologous Hematopoietic Stem Cell Transplantation in Animal Model of Multiple Sclerosis

Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Anti-Thymocyte Globulin (ATG) Administration Schedules in Allogeneic Stem Cell Transplantation

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