To the Editor,
Severe combined immunodeficiency disorder (SCID) due to mutation in interleukin-7 receptor-alpha (IL-7Rα) gene resulting in B+NK+ phenotype can be successfully treated with hematopoietic stem cell transplantation (HSCT) [1, 2]. NK+ SCID cases have been challenging due to risk of graft rejection mediated by NK cells. We report an outcome of a baby with IL-7Rα-mutated SCID who underwent umbilical cord blood transplantation (UCBT) with anti-thymocyte globulin alone conditioning.
A male patient with B+NK+ SCID secondary to homozygous IL7R α exon 1 deletion underwent UCBT at 3 months of age. There was no evidence of maternal engraftment. Matched sibling or unrelated donors were not available, and parents opted UBCT over haploidentical SCT. The patient received molecularly HLA 7/8-matched (C allele mismatch) UCBT at a total nucleated cell dose of 15.6x108/kg and CD34+ dose of 2.43x106/kg conditioned with Thymoglobulin® (rabbit anti-thymocyte globulin) (rATG) at a total dose of 7.5mg/kg (days -4 thru -2). For graft versus host disease (GvHD) prophylaxis, he was given mycophenolate mofetil (days 0- thru +35) and tacrolimus day -3 through day +57 at which time he had no evidence of engraftment.
Due to lack of any T cell recovery at 4 months post-UCBT, keeping the possibility of UCB donor T cell depletion from rATG in mind, proceeding with a second transplant option was debated. However, he was noted to have evidence of T cell recovery (absolute CD3+ count of 98 cells/mcL with 6.6% CD4+ naïve T cells) five months post-UCBT, which continued to improve over time.
Engraftment and immune reconstitution were monitored by flow cytometric immune profiling and recent thymic emigrant population (RTE) determination characterized by CD31+/CD4+ naïve T cells, T cell receptor excision circles (TREC) analysis, short tandem repeat (STR) studies in myeloid and lymphoid populations, serum immunoglobulin levels and mitogen response assessments (Figure 1). Serum IgA and IgM levels were detected at 16 and 83 mg/dl, respectively on day +183. Absolute lymphocyte counts, T cell numbers, RTE percent and serum IgG, IgA, IgM levels all increased and reached normal levels by day +273; last intravenous immunoglobulin (IVIG) supplementation was on day +183. While myeloid chimerism was 0%, B-cell donor chimerism increased progressively to a maximum of 41% and NK cells at 21% donor chimerism on day +217 post UCBT. Following T-cell recovery, the patient maintained full donor chimerism in T cells (98% on day +518). Interestingly, higher CD5-dim T cell percent, seen during early days of RTE observation; however, had declined later. T cells have shown almost normal mitogen responses at day+248 (Figure 1). Subsequently, anti-microbial prophylaxis was discontinued. The patient is now 25 months post-UCBT and is doing well. He did not develop GvHD. He has been growing and developing age-appropriately and has started childhood immunizations.
This is the first reported case of a successful UCBT for IL-7Rα-mutated SCID conditioned with rATG alone. The patient achieved full donor T cell chimerism along with normal quantitative and qualitative T and B cell function. Our experience suggests that conditioning with rATG in the setting of UCBT may lead to delayed T cell recovery likely due toin-vivo presence of rATG at the time of UCBT infusion leading to depletion of T cells in the UCB graft. Admiraal et al. also showed that T cell reconstitution was dependent on ATG exposure in children undergoing UCBT [6, 7]. During the initial months following HSCT, T cell reconstitution is dependent on homeostatic peripheral expansion of graft T cells. In-vivo graft T cell depletion by ATG adversely impacts homeostatic peripheral expansion. Thymopoiesis is established around 4-6 months post-HSCT and subsequently contributes to T cell reconstitution. In our patient, T cell recovery along with presence of RTE was noted at 5 months post-UCBT, which is consistent with recovery through thymopoiesis. Based on our experience, it may be prudent to consider a lower dose or earlier administration of rATG in the setting of UCBT for SCID to deplete host rather than non-primed cord blood T and NK cells.
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].
In a T cell–depleted graft, circulating T cells may not be detected for several months after transplantation [14]; which might increase the risk of infection. However, our patient did relatively well with anti-microbial prophylaxis. As reported previously, T cell-depleted UCBT may have a superior B cell engraftment in IL-7Rα-mutated SCID [9] paralleling our experience as mixed chimerism was observed in the B-cell lineage along with normal serum immunoglobulin levels without supplementation. In conclusion, UCBT with modified ATG conditioning can be an acceptable alternative in IL-7Rα-mutated SCID cases when HLA-matched sibling donor or newly advanced graft T cell depletion strategies are not available [6, 7].