Improved survival and graft function in ex vivo T-cell depleted haploidentical hematopoietic cell transplantation for primary immunodeficiency

Lum, Su Han; Sobh, Ali; Carruthers, K. J. M.; Nademi, Zohreh; Watson, H. J. C.; McNaughton, Peter; Selvarajah, Sabeena; Deyà‐Martínez, Àngela; Abinun, Mario; Flood, Terry; Cant, Andrew J.; Hambleton, Sophie; Gennery, Andrew R.; Slatter, Mary

doi:10.1038/s41409-020-01152-2

Cited by 13 publications

(12 citation statements)

References 8 publications

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“…TCRab 1 /CD19 1 depleted haploHSCT compares favorably with other types of transplants from related 58 and unrelated donors in the pediatric NMD setting. 33,59 Moreover, despite being characterized by high initial costs, mainly related to the process and consumables to perform TCRab 1 /CD19 1 depletion, a pharmacoeconomic analysis suggests that this approach may be cost-effective as compared with HSCT from MUD. 60 Obviously, in cases of GF requiring a second HSCT, the pharmacoeconomic profile becomes less favorable.…”

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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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: 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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“…Across patients undergoing HSCT for IEI, previous data from our center demonstrate improved overall and event-free survival with the advent of TCRαβ-HaploSCT compared to other methods of ex vivo T-lymphocyte depletion such as CD34 + selection, but with increased rates of viremia [ 11 ], which remain a concern due to associated morbidity and mortality [ 3 , 9 , 11 ]. While options for enhancing viral immunity in these patients include CD45RA + -depleted lymphocyte infusions [ 14 ], our study of SCID patients demonstrated similar cumulative incidence of any viremia post-HSCT between TCRαβ-HaploSCT and other donor types.…”

Section: Discussionmentioning

confidence: 99%

“…An alternative is using a mismatched family donor, with ex vivo T-lymphocyte depletion to reduce alloreactivity; while prompt availability of a parental donor may favor their use, this must be balanced against the risks of acute GvHD and delayed T-lymphocyte reconstitution, particularly in the context of viremia [ 7 ]. CD3 + TCRαβ/CD19-lymphocyte depletion is increasingly used in SCID and non-SCID inborn errors of immunity (IEI) HSCT [ 8 – 10 ] due to increased overall survival and reduced rates of GvHD compared to previous strategies such as CD34 + selection [ 11 ], though data on its use in SCID are sparse.…”

Section: Introductionmentioning

confidence: 99%

TCRαβ-Depleted Haploidentical Grafts Are a Safe Alternative to HLA-Matched Unrelated Donor Stem Cell Transplants for Infants with Severe Combined Immunodeficiency

et al. 2022

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Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8–16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52–99%) for TCRαβ-HaploSCT, 80% (41–98%) for MFD, 87% (36–98%) for MUD, and 89% (43–98%) for CB (p = 0.89). Cumulative incidence of grade II–IV acute graft-versus-host disease was 11% (2–79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7–100%) after MUD, and 11% (2–79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0–100%) versus unconditioned transplant (median 3%, 0–9%) (p < 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p < 0.001). TCRαβ-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.

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“…Thirty-four patients received CAMPATH-1M depleted bone marrow, 34 had CD34+ selected products, 7 CD3+/CD19+ PBSC and 40 CD3+ TCR alpha beta/CD19+ depleted PBSC. The 5-year OS was 58% (95% CI, 40–77%) for CAMPATH-1M, 68% (95% CI, 49–81%) for CD34+ selection, 69% (95% CI,23–92%) for CD3+/CD19+ depletion and 84% (95% CI, 67–93%, p=0.01) for CD3+ TCR alpha beta/CD19+ depletion ( 137 ). Conditioning changed from busulfan-based to reduced toxicity treosulfan-based and supportive care also improved with time.…”

Section: Cd3+tcr Alpha Beta/cd19+depletionmentioning

confidence: 99%

Personalized hematopoietic stem cell transplantation for inborn errors of immunity

Slatter

Lum

2023

Front. Immunol.

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Patients with inborn errors of immunity (IEI) have been transplanted for more than 50 years. Many long-term survivors have ongoing medical issues showing the need for further improvements in how hematopoietic stem cell transplantation (HSCT) is performed if patients in the future are to have a normal quality of life. Precise genetic diagnosis enables early treatment before recurrent infection, autoimmunity and organ impairment occur. Newborn screening for severe combined immunodeficiency (SCID) is established in many countries. For newly described disorders the decision to transplant is not straight-forward. Specific biologic therapies are effective for some diseases and can be used as a bridge to HSCT to improve outcome. Developments in reduced toxicity conditioning and methods of T-cell depletion for mismatched donors have made transplant an option for all eligible patients. Further refinements in conditioning plus precise graft composition and additional cellular therapy are emerging as techniques to personalize the approach to HSCT for each patient

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Improved survival and graft function in ex vivo T-cell depleted haploidentical hematopoietic cell transplantation for primary immunodeficiency

Cited by 13 publications

References 8 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

TCRαβ-Depleted Haploidentical Grafts Are a Safe Alternative to HLA-Matched Unrelated Donor Stem Cell Transplants for Infants with Severe Combined Immunodeficiency

Personalized hematopoietic stem cell transplantation for inborn errors of immunity

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