A phase II study of post-transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA-matched related/unrelated allogeneic hematopoietic stem cell transplantation

Nakamae, Hirohisa; Nakane, Takahiko; Okamura, Hiroshi; Koh, Hideo; Nakashima, Yasuhiro; Hirose, Asao; Nakamae, Mika; Nishimoto, Mitsutaka; Kuno, Masatomo; Makuuchi, Yosuke; Harada, Naonori; Takakuwa, Teruhito; Hino, Masayuki

doi:10.1007/s12185-021-03228-1

Cited by 9 publications

(5 citation statements)

References 27 publications

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“…23 Further studies confirming the high efficacy of PTCy after matched allo-HSCT in adults continue to emerge. [24][25][26][27][28] To our knowledge, the present study is the first to demonstrate high efficacy of PTCy-based GVHD prophylaxis in a large cohort of pediatric patients with acute leukemia after MUD allo-HSCT. In general, study and control groups were balanced, except for conditioning regimens, the year of transplantation, and the number of infused CD34+ cells.…”

Section: Ptcy Group Control Group P-valuementioning

confidence: 64%

“…Another prospective randomized HOVON‐96 trial confirmed higher efficacy of PTCy‐based GVHD prophylaxis (grade III‐IV acute GVHD, 6%; chronic GVHD, 19%) over conventional immunosuppression (grade III‐IV acute GVHD, 12%; chronic GVHD, 50%) in matched allo‐HSCT 23 . Further studies confirming the high efficacy of PTCy after matched allo‐HSCT in adults continue to emerge 24–28 …”

Section: Discussionmentioning

confidence: 94%

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Post‐transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia

Borovkova,

Paina,

Semenova

et al. 2023

Clinical Transplantation

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IntroductionThe data on post‐transplant cyclophosphamide (PTCy) in pediatric acute leukemia after matched allo‐HSCT are limited to case series. The present study aimed to assess the results of PTCy‐based GVHD prophylaxis in a large cohort of children with acute leukemia after matched allo‐HSCT.MethodsA retrospective analysis of 190 pediatric patients with acute leukemia who had a first allograft between 2008 and 2020 from a matched sibling donor (MSD) or matched unrelated donor (MUD) was carried out. In the MSD setting, GVHD prophylaxis consisted of PTCy alone (n = 28) for the study group, and calcineurin inhibitor (CNI) ± antimetabolite (n = 30) for the control group. In MUD setting, most patients in the study group received GVHD prophylaxis with PTCy+CNI+mycophenolate mofetil (n = 42, 66.7%) or PTCy+CNI+sirolimus (n = 12, 19%). All patients (n = 69) in the control group received ATG+CNI+antimetabolite.ResultsAfter MUD allo‐HSCT, the incidences of acute GVHD grade III‐IV and moderate/severe chronic GVHD were significantly lower in the PTCy group compared to control (6.6% vs. 35.0% and 12.7% vs. 47.1%, respectively, p < .0001). Five‐year GVHD‐free, relapse‐free survival (GRFS) after MUD allo‐HSCT was higher in the PTCy group compared to control (35.1% vs. 7.3%, p < .0001). At the same time, there was no significant difference between both groups after MSD allo‐HSCT.ConclusionsIn pediatric acute leukemia, PTCy‐based GVHD prophylaxis for MUD allo‐HSCT is a feasible and effective option that results in a low incidence of GVHD. Compared to the ATG‐based approach, PTCy provides better control of GVHD in children. In pediatric allo‐HSCT from MSD, PTCy demonstrates comparable effectiveness to conventional GVHD prophylaxis.

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Section: Ptcy Group Control Group P-valuementioning

confidence: 64%

Section: Discussionmentioning

confidence: 94%

Post‐transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia

Borovkova,

Paina,

Semenova

et al. 2023

Clinical Transplantation

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“…A parallel series of studies examining transplant donor‐recipient whole exomes using NGS identified nonsynonymous polymorphisms in the recipients, which were then used to simulate a donor T‐cell response in silico and reproduced the power law distribution observed in the clinical studies 15,16 . Further evidence of dynamical behaviour comes from the observation that early interventions have a lasting impact on transplant outcomes, for example the use of post‐transplant cyclophosphamide given on Days 3 and 4 post‐transplant, which mitigates chronic GVHD many months later 17–19 . Chronic GVHD risk is also mitigated using antithymocyte globulin (ATG), particularly following HLA‐matched unrelated donor HCT 20–22 .…”

Section: Introductionmentioning

confidence: 97%

“…15,16 Further evidence of dynamical behaviour comes from the observation that early interventions have a lasting impact on transplant outcomes, for example the use of post-transplant cyclophosphamide given on Days 3 and 4 posttransplant, which mitigates chronic GVHD many months later. [17][18][19] Chronic GVHD risk is also mitigated using antithymocyte globulin (ATG), particularly following HLA-matched unrelated donor HCT. [20][21][22] However, ATG administration delays T-cell recovery, especially CD4 + helper T-cell reconstitution [23][24][25] and may impact relapse and viral infection risk.…”

Section: Introductionmentioning

confidence: 99%

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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“…10 11 Further evidence of dynamical behavior comes from the observation that early interventions have a lasting impact on transplant outcomes, for example the use of post-transplant cyclophosphamide which mitigates chronic GVHD. 12 13 14 Chronic GVHD risk is also mitigated using anti-thymocyte globulin (ATG), particularly following HLA matched unrelated donor HCT. 15 16 However, ATG administration delays T cell recovery, especially CD4+ helper T cell reconstitution 17 18 19 and may impact relapse and viral infection risk.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic Hematopoietic Cell Transplants as Dynamical Systems: Effect of Early-Term Immune Suppression Intensity on Long-Term T Cell Recovery

Zelikson

Sabo

Serrano

et al. 2022

Preprint

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Reduced intensity conditioning (RIC) is fraught with risk for disease relapse. This may be overcome by donor T cell alloreactivity. Reducing the duration of intense immune suppression in the early term following transplantation may create an immunologic environment favoring rapid T cell reconstitution to influence longer term transplant outcomes. Twenty-six patients were adaptively randomized based on donor-derived T cell recovery, between 2 different dosing schedules of mycophenolate mofetil (MMF): MMF for 30 days post-transplant, with filgrastim for cytokine support (MMF30 arm, 11 patients), or MMF for 15 days post-transplant, with sargramostim (MMF15 arm, 15 patients). All patients were treated with anti-thymocyte globulin at a dose of 1.7 mg/kg/day from day - 9 through day -7 and total body irradiation, 450 cGy given in 3 fractions. Patients were well matched between the study arms and underwent HLA matched related and unrelated donor hematopoietic cell transplantation (HCT). The MMF15 arm demonstrated superior T cell recovery in the first month. This difference persisted through the first year for total T cells, T cell subsets and NK cells. T cell repertoire tended to be more diverse in the MMF15 arm. The long term superior immune recovery in the MMF15 arm is consistent with a disproportionate impact of early interventions in HCT. Clinically, shorter course MMF post-transplant was not associated with increased risk of acute or chronic graft vs. host disease (GVHD), and relapse and there was a trend toward improved overall survival in the MMF15 arm. Reducing the duration of intense immunosuppression in the early term and the use of sargramostim following allogeneic HCT is feasible and leads to superior long-term T cell recovery. This regimen should be studied to improve immune recovery in large cohorts of patients undergoing HCT with RIC.

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A phase II study of post-transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA-matched related/unrelated allogeneic hematopoietic stem cell transplantation

Cited by 9 publications

References 27 publications

Post‐transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia

Post‐transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia

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

Allogeneic Hematopoietic Cell Transplants as Dynamical Systems: Effect of Early-Term Immune Suppression Intensity on Long-Term T Cell Recovery

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