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

Abstract

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.

Controversies and expectations for the prevention of GVHD: A biological and clinical perspective

“…Because aßTB depletion removes the T cells most closely linked to acute and chronic GVHD and depletes the B cells that can contribute to chronic GVHD, the rates of these complications were anticipated to be lower than that observed after matched donor HCTs despite the increased HLAmismatch. Overall, this has been observed with median rates of grade II-IV aGVHD of 18% (ranging from 11-28%), and cGVHD of 8% (range 0-30%), with 0-21% experiencing extensive cGVHD (129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144). Notably, most of these studies utilized ATG, which has reduced aGVHD (see above), and not surprisingly, in one study in which ATG was removed, the observed rates of aGVHD were increased (136).…”

“…Thus, most but not all the studies use this graft engineering approach with related HLA-mismatched donors. This newer therapy has largely been studied in children, comprising 95% of the nearly 700 total patients reported in the literature, and a still small cohort compared to other alternative donor approaches (129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141). More data is needed to evaluate the success of this approach in adult HCT recipients and would be beneficial in pediatric cohorts as well.…”

A great disturbance in the force: IL-2 receptor defects disrupt immune homeostasis

“…Matched related transplants were associated with the best survival in most studies, while Human Leukocyte Antigen (HLA)-mismatched transplants were associated with worse outcomes [30,35]. Mismatched and even haplo-identical transplants can be performed with lower rates of graft-versus-host disease (GVHD) graft rejection, and survival if the graft is TCRαβ and/or CD19 depleted [31 ▪ ,36 ▪ ,37].…”

“…Over the last decade, conditioning regimens have become an increasingly recognized factor in determining long-term immune reconstitution. Myeloablative conditioning or reduced intensity conditioning resulted in higher T-cell counts [19,30] and independence from immunoglobulin [20 ▪ ,30,36 ▪ ]. Poor B-cell reconstitution with lack of memory B cells and persistent humoral dysfunction may be particularly problematic in patients with X-SCID transplanted without conditioning as recipient B cells are unable to respond to IL-21, class switch or differentiate to plasmablasts [15,16,38] (Fig.…”

Delayed but Successful T Cell Immune Reconstitution Following Umbilical Cord Blood Transplantation Conditioned with Thymoglobulin alone in IL-7Rα-mutated SCID

“…One of the advantages of using UCB in the treatment was higher likelihood of B cell engraftment and decreased need for long term IVIG [9] [3], also in contrast to T cell depleted haploidentical and matched unrelated bone marrow transplants [10] [11]. Other advantage of using UCBT in SCID is lower risk of transmitting infections and viral reactivation following engraftment [12], which has been a problem with unrelated donor or TCRαβ-depleted haploidentical HSCT as well as with alemtuzumab conditioning [3,5,13].…”