HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders

Bertaina, Alice; Merli, Pietro; Rutella, Sergio; Pagliara, Daria; Bernardo, Maria Ester; Masetti, Riccardo; Pende, Daniela; Falco, Michela; Handgretinger, Rupert; Moretta, Francesca; Lucarelli, Barbarella; Brescia, Letizia Pomponia; Pira, Giuseppina Li; Testi, Manuela; Cancrini, Caterina; Kabbara, Nabil; Carsetti, Rita; Finocchi, Andrea; Moretta, Alessandro; Moretta, Lorenzo; Locatelli, Franco

doi:10.1182/blood-2014-03-563817

Cited by 401 publications

(360 citation statements)

References 29 publications

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“…[56][57][58] In this scenario, Schumm et al 59 recently introduced an innovative approach of graft manipulation, which consist in depleting the leukapheresis product of only TCR αβ + T cells and CD19 + B cells, thus retaining large numbers of crucial immune effectors such as TCR γδ + T cells, NK cells and DCs; this method has been safely tested in a cohort of children by Locatelli and colleagues. 60 Although G-CSF mobilization is known to alter phenotype and cytokine polarization of transplanted immune cells, very few data are available on the impact of plerixafor on allogeneic graft cell subsets, as it is not approved for administration in healthy donors yet. Two recent studies in mice compared the effect of G-CSF and plerixafor on T-cell alloreactivity, showing that alterations in the T-cell phenotype and cytokine gene expression profile characteristic of G-CSF mobilization do not occur with plerixafor.…”

Section: Mobilized Pbsc: the Immunological Perspective F Saraceni Et Almentioning

confidence: 99%

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

Saraceni

Shem‐Tov

Olivieri

et al. 2015

Bone Marrow Transplant

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Although stem cell mobilization has been performed for more than 20 years, little is known about the effects of mobilizing agents on apheresis composition and the impact of graft cell subsets on patients' outcome. With the increasing use of plerixafor and the inclusion of poor mobilizers in autologous transplant procedures, new parameters other than CD34 + stem cell dose are emerging; plerixafor seems to mobilize more primitive CD34 + /CD38 − stem cells compared with G-CSF, but their correlation with stable hematopoietic engraftment is still obscure. Immune recovery is as crucial as hematopoietic reconstitution, and higher T and natural killer cells infused within the graft have been correlated with better outcome in autologous transplant; recent studies showed increased mobilization of immune effectors with plerixafor compared with G-CSF, but further data are needed to clarify the clinical impact of these findings. In the allogeneic setting, much evidence suggests that mobilized T-cell alloreactivity is tempered by G-CSF, probably with the mediation of dendritic cells, even though no clear correlation with GVL and GVHD has been found. Plerixafor is not approved in healthy donors yet; early data suggest it might mobilize a GVHD protective balance of immune effectors, but further studies are needed to define its role in allogeneic transplant.

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Section: Mobilized Pbsc: the Immunological Perspective F Saraceni Et Almentioning

confidence: 99%

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

Saraceni

Shem‐Tov

Olivieri

et al. 2015

Bone Marrow Transplant

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“…Two recent studies on αβ-depleted HHCT reported CIs of acute ⩾ grade 3GvHD as 0 and 15%, respectively. 5,16 In our present study, the incidences of acute and chronic GvHD were acceptable; notably, no patient died of GvHD.…”

Section: Discussionmentioning

confidence: 74%

“…Recent reports on αβ-depleted HHCT in children with malignant or nonmalignant disease revealed low TRM rates of less than 10%. 5,16 Relapse was the major treatment failure in our present series. In studies of HHCT using αβ-or CD3-depleted grafts for pediatric patients with malignant disease, the major cause of death was relapse, especially in patients with advanced disease.…”

Section: Discussionmentioning

confidence: 93%

“…6,[10][11][12][13][14][15] There have been several reports on HHCT in pediatric patients. 4,5,7,[16][17][18] In our current study, all 42 patients achieved stable engraftment early post transplant at a median of 10 days. No patient experienced graft failure (GF), including late GF.…”

Section: Discussionmentioning

confidence: 95%

“…Recent studies reported that a GF rate after αβ-depleted HHCT for pediatric patients ranged from 12 to 16.2%. 5,16 GvHD is one of the major limitations in HHCT and a major cause of NRM. Two recent studies on αβ-depleted HHCT reported CIs of acute ⩾ grade 3GvHD as 0 and 15%, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ+ cells by add-back after a reduced intensity preparative regimen containing low-dose TBI

Koh

et al. 2016

Bone Marrow Transplant

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Between 2012 and 2015, 42 pediatric patients underwent haploidentical hematopoietic cell transplantation using an αβ + T-cell-depleted graft with targeted αβ cells at 1-5 × 10 5 /kg by add-back; 31 had hematologic malignancy (HM), 8 had non-malignant disease (NM) and 3 had solid tumors. All patients received uniform reduced-intensity conditioning with fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin and low-dose TBI. All 42 patients achieved neutrophil engraftment at a median of 10 days. The cumulative incidences (CIs) of ⩾ grade II and ⩾ grade III acute GvHD were 31 ± 7.1% (SE) and 12 ± 5.0%, respectively, and 1-year CI of chronic GvHD was 15 ± 5.8%. One patient died of CMV pneumonia, leading to transplant-related mortality (TRM) of 2.6 ± 2.5%. Sixteen patients relapsed and 11 died of disease. At a median follow-up of 19 months (range, 5-43 months), the estimated 2-year event-free survival for NM and HM were 88 ± 11.7 and 50 ± 10.1%, respectively. Our study demonstrated that haploidentical hematopoietic cell transplantation after ex vivo depletion of αβ + T cells with targeted dose noticeably reduced the graft failure rate and TRM in pediatric patients and could be applied to patients lacking a suitable related or unrelated donor. While αβ + T cells are known to be associated with the initiation of GvHD, γδ + T cells can enhance immune reconstitution and are not implicated in GvHD. 6 Recently, we reported our experience with HHCT using a CD3-depleted graft. 7 Since 2012, we have initiated HHCT using ex vivo depletion of αβ + T cells with targeted αβ cells at 1-5 × 10 5 /kg after add-back. Here, we report our prospective results using αβ-depleted grafts in HHCT for children and adolescents with malignant or non-malignant disease.

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Hematopoietic cell transplant in thalassemia

Angelucci

Pilo

2017

Clinical Manual of Blood and Bone Marrow Transplantation

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HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders

Abstract: Key Points Removal of αβ+ T and CD19+ B cells is an effective strategy for successful HLA-haploidentical hematopoietic stem cell transplantation. The high probability of disease-free survival renders this transplant option attractive for any child with a nonmalignant disorder.

Cited by 401 publications

References 29 publications

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ+ cells by add-back after a reduced intensity preparative regimen containing low-dose TBI

Hematopoietic cell transplant in thalassemia

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