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].