Universal donor strategy for primary immunodeficiency

Arguably, the most difficult transplants are those of patients with primary immune deficiencies with persistent viral infection and no matched donor. In this issue of Blood, Laberko et al report an approach to this problem using T-cell receptor (TCR)αβ−depleted donors.¹ 

For many years, the outcomes of transplant for patients with primary immune deficiencies have been improving, although outcomes remain worse for patients with no matched family or unrelated donor.²  With increasingly sophisticated methods of graft engineering, T-lymphocyte–depleted graft outcomes have been improving, particularly for patients with primary immunodeficiency,³  so that today, survival outcomes for patients receiving T-lymphocyte–depleted grafts are similar to those receiving replete HLA-matched grafts.^4,5  Although overall survival may be similar, there are other risks associated with fully matched, and with T-lymphocyte–depleted transplants. The risk of significant acute graft-versus-host disease (aGvHD) remains for patients receiving matched stem cell sources,⁶  an unwanted consequence with no survival advantage in patients with primary immune deficiencies. The risk of viral reactivation continues to complicate outcomes following T-lymphocyte–depleted transplants.⁵  Laberko and colleagues, in the biggest reported primary immune deficiency series to date transplanted using the TCRαβ/CD19–depleted grafts, describe outcomes on 2 groups of patients: those receiving matched unrelated donor and those receiving related parental haploidentical stem cells. Ninety-eight patients with combined or other non-T-lymphocyte–related immune deficiencies are reported. Two significant patient groups are omitted from the report: those patients with severe combined immune deficiency and those with Nijmegen breakage syndrome, because of unique problems of transplant pertaining to these groups; the results of these transplants will be important to consider in the future. In an attempt to avoid sequelae of significant aGvHD, the largest group of patients received T-lymphocyte–depleted peripheral blood stem cells from matched or slightly mismatched unrelated donors, whereas the rest received haploidentical parental grafts. Outcomes between the 2 groups were identical in terms of overall survival, which was excellent at 86%, primary graft failure, aGvHD, immune recovery kinetics, and importantly, incidence of viral reactivation, particularly in those with combined immune deficiency, which was high with significant clinical consequences in both groups, and the coequal cause of death with bacterial infection.

Several lessons can be synthesized from this study. First, it is confirmed that survival outcomes of T-lymphocyte–depleted transplants for primary immune deficiency patients are equivalent to outcomes using other donors. Second, as the authors state, the outcomes are equivalent in all examined parameters for T-lymphocyte–depleted unrelated donor or haploidentical related donor transplants. In the pediatric setting, given the ready availability of medically fit parental donors, these are to be preferred, because they are more likely to harbor viral-specific T lymphocytes active against viruses carried by the patient; the cost of sourcing and manipulating the graft is less than for unrelated donors, and there are more quickly available. However, given that the results are equivalent, for older patients, or other situations where medically fit related donors may not be available, transplant physicians may be confident that the use of T-lymphocyte–depleted mismatched unrelated donors, although more costly, leads to extremely good outcomes. The use of haploidentical donors is increasing in the field of hematopoietic stem cell transplantation.⁷  This report, with others,⁵  highlights the ongoing risk of significant or fatal viral reactivation, even when parental donors are used, despite the infusion of NK cells and TCRγδ T lymphocytes within the graft. Despite the excellent overall survival results, further strategies to reduce the risk of viral reactivation are required. The use of donor or third-party viral-specific T lymphocytes,⁸  CD4/CD45RA⁺–depleted donor lymphocyte infusions,⁹  or the infusion of icaspase 9 genetically modified “suicide” T lymphocytes¹⁰  have all been reported. Randomized controlled trials are now required to determine which, if any, of these strategies will improve outcomes of T-lymphocyte–depleted transplants still further, reducing the risk of viral infection, which, along with preexisting autoimmunity remains a leading cause of adverse outcomes.