Immune Reconstitution Following TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for Hematologic Malignancy in Pediatric Patients

Arnold, Danielle E.; MacMath, Derek; Seif, Alix E.; Heimall, Jennifer; Wang, Yongping; Monos, Dimitri; Grupp, Stephan A.; Bunin, Nancy

doi:10.1016/j.jtct.2020.10.006

Cited by 11 publications

(11 citation statements)

References 36 publications

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“…Figure 5 reports details on immune reconstitution of the study population. As previously described in this transplant setting, 9,29 the early posttransplant period is characterized by prompt recovery of TCRgd 1 and NK cells, followed by the progressive emergence of TCRab 1 lymphocytes. Although CD3 1 cell recovery was fast, CD3 1 CD4 1 cell counts approached 500/ml only at 6 months after HSCT.…”

Section: Immune Reconstitutionmentioning

confidence: 62%

“…43 We recently tested the use of genetically modified donor lymphocytes (transduced with the safety switch inducible Caspase-9, which can be activated in case of uncontrolled GVHD), showing feasibility and encouraging results in terms of survival, 44 although specific analyses on viral infections are ongoing. Recovery of adaptive immunity after ab T cell and B cell depleted haplo-HSCT is still suboptimal, 29,45 once more calling for the implementation of new strategies aimed at accelerating immune reconstitution. Two of the 6 patients included in this study who did not reach independence from IgG replacement therapy had experienced acute GVHD, a well-known risk factor for this complication.…”

Section: Discussionmentioning

confidence: 99%

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TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

et al. 2022

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Several non-malignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders or metabolic diseases, lacking a fully-matched donor or requiring urgent transplantation, underwent TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study (#NCT01810120). Median age at transplant was 3.5 years (range 0.3-16.1); median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (e.g., aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade I-II acute GvHD was 14.4% (no patient developed grade III-IV acute GVHD). Only one patient at risk developed mild chronic GvHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment for children with NMDs. Prompt donor availability, low incidence of GvHD and TRM make this strategy an attractive option in NMDs patients.

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Section: Immune Reconstitutionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

et al. 2022

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“…Importantly, this cannot be extrapolated to in vivo or ex vivo TCD HCT platforms [81À83]. In fact, new approaches to ex vivo graft engineering such as a/b T cell and CD3/CD19 depletion allow optimization of the T cell and CD34 graft composition for recipients of ex vivo TCD HCT [84,85] resulting in reports of improved T cell IR compared to historical approaches to ex vivo TCD relying on CD34+ selection [86,87].…”

Section: Transplant Platformmentioning

confidence: 99%

An ISCT Stem Cell Engineering Committee Position Statement on Immune Reconstitution: the importance of predictable and modifiable milestones of immune reconstitution to transplant outcomes

et al. 2022

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“…With respect to engraftment, ex vivo TCD transplants have a significantly shorter interval to neutrophil engraftment than do PTCy transplants (>500/µL: 10 vs. 15 days, respectively) and a trend towards faster thrombocyte engraftment (>20,000/µL: 16 vs. 20 days, respectively) but lower rates of primary engraftment (88 vs. 100%, respectively) (79). However, in recent studies using TCRAb/CD19-depletion, hHSCT resulted in 96-98% primary engraftment rates after sufficiently intense immunosuppressive conditioning (35,41,80), indicating that both techniques yield comparable and safe engraftment with a faster neutrophil recovery after TCRAb/CD19-depletion.…”

Section: Engraftment and Immune Reconstitutionmentioning

confidence: 99%

T-Cell-Replete Versus ex vivo T-Cell-Depleted Haploidentical Haematopoietic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukaemia and Other Haematological Malignancies

Kleinschmidt

Yanir

et al. 2021

Front. Pediatr.

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Allogeneic haematopoietic stem cell transplantation (HSCT) represents a potentially curative option for children with high-risk or refractory/relapsed leukaemias. Traditional donor hierarchy favours a human leukocyte antigen (HLA)-matched sibling donor (MSD) over an HLA-matched unrelated donor (MUD), followed by alternative donors such as haploidentical donors or unrelated cord blood. However, haploidentical HSCT (hHSCT) may be entailed with significant advantages: besides a potentially increased graft-vs.-leukaemia effect, the immediate availability of a relative as well as the possibility of a second donation for additional cellular therapies may impact on outcome. The key question in hHSCT is how, and how deeply, to deplete donor T-cells. More T cells in the graft confer faster immune reconstitution with consecutively lower infection rates, however, greater numbers of T-cells might be associated with higher rates of graft-vs.-host disease (GvHD). Two different methods for reduction of alloreactivity have been established: in vivo T-cell suppression and ex vivo T-cell depletion (TCD). Ex vivo TCD of the graft uses either positive selection or negative depletion of graft cells before infusion. In contrast, T-cell-repleted grafts consisting of non-manipulated bone marrow or peripheral blood grafts require intense in vivo GvHD prophylaxis. There are two major T-cell replete protocols: one is based on post-transplantation cyclophosphamide (PTCy), while the other is based on anti-thymocyte globulin (ATG; Beijing protocol). Published data do not show an unequivocal benefit for one of these three platforms in terms of overall survival, non-relapse mortality or disease recurrence. In this review, we discuss the pros and cons of these three different approaches to hHSCT with an emphasis on the significance of the existing data for children with acute lymphoblastic leukaemia.

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Immune Reconstitution Following TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for Hematologic Malignancy in Pediatric Patients

Cited by 11 publications

References 36 publications

TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

An ISCT Stem Cell Engineering Committee Position Statement on Immune Reconstitution: the importance of predictable and modifiable milestones of immune reconstitution to transplant outcomes

T-Cell-Replete Versus ex vivo T-Cell-Depleted Haploidentical Haematopoietic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukaemia and Other Haematological Malignancies

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