Page 1156 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 82 Immune Reconstitution Therapy for Immunodeficiency 1121

such as infections and GvHD. In particular, according to the Factors that may contribute to such poor outcome may include
1
European study, the current survival rate after HSCT from the presence of autologous NK cells that may mediate graft
HLA-identical related donors is 90%, whereas 3-year survival rejection. Consistent with this, in a UK series of 77 infants with
after HSCT from related HLA-mismatched donors has improved SCID who received HSCT, survival rate was higher among patients
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−
from 49% in transplantations performed up to 1994 to 69% in with NK SCID than among recipients with NK SCID (see Fig.
17
those performed between 1995 and 1999. However, no further 82.1). Furthermore, RAG and Artemis deficiencies cause a later
improvement in survival has been observed since that time. block in T-cell development compared with the majority of
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Several factors influence survival after HSCT for SCID. In genetic defects associated with B SCID. This may lead to a
particular, younger age at transplantation leads to superior stronger competition between donor-derived and autologous
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survival. In the North American study, among 68 infants who T-cell progenitors in patients with B SCID who receive uncon-
2
were treated before 3.5 months of life, 64 (94%) survived. ditioned HSCT.
Similarly high survival rates were observed also among infants Finally, in a series of 106 patients with SCID caused by adenos-
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older than 3.5 months with no history of infections or whose ine deaminase deficiency (ADA SCID), unconditioned trans-
infections had resolved before HSCT (90% and 84% 5-year plantation from MMRDs was associated with a high risk of graft
2
survival rates, respectively). Collectively, these data emphasize failure. 18
the importance of early diagnosis to prevent infections and
provide strong support to newborn screening for SCID. For CLINICaL PEarLS
patients of any age who do not have MSDs and have an active Outcome of Hematopoietic Stem Cell
infection at the time of HSCT, a higher survival rate (65%) is
observed with unconditioned transplantation from MMRDs. 2 Transplantation (HSCT) for Primary
The SCID genotype and phenotype may also affect the outcome Immunodeficiencies
+
of HSCT. In the European series, infants with B SCID had For severe combined immunodeficiency (SCID), the 5-year survival rate
superior 10-year survival after HSCT compared with infants of patients transplanted between 2000 and 2009 is over 74% and is
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1
with B SCID (70% vs 51%, respectively; Fig. 82.3), although higher (97%) for patients who receive transplant from matched sibling
no significant difference in survival between these two groups donors.
2
of infants with SCID was observed in the North American study. Improvements in clinical care (both in critical care and in prevention and
Furthermore, haploidentical transplantation without conditioning treatment of infections) have also contributed to the improved outcome
of HSCT for SCID, including transplantation from matched unrelated
or with immunosuppression only in patients with recombinase donors (MUDs). However, the decision to attempt a MUD transplanta-
activating gene (RAG) or Artemis deficiency is associated with tion for SCID must be weighed against the risks associated with the
16
a high risk of graft failure or of incomplete T-cell reconstitution. time interval required to identify such a donor.
Factors influencing survival after transplantation for SCID include younger
age at transplant and lack of active infections at the time of
1.0 transplantation.
The decline of T-cell function that is observed at 10 years or more after
transplantation remains a concern and may cause clinical problems.
0.8 Therefore there is a need for improvements in the procedures used
to facilitate and sustain stem cell engraftment and/or to boost donor-
Other For primary immunodeficiencies other than SCID, there has been a
derived immunity.
Proportion surviving 0.6 B– progressive improvement in the outcome following stem cell trans-
B+
plantation. In particular, results are good both for human leukocyte
antigen–identical transplants (with a survival rate of 70% or more,
0.4
depending on the disease) and for MUD or cord blood transplantations.
Reduced-intensity conditioning regimens have been often used in
these patients, in the attempt to reduce the risks of drug-related
0.2 P <.0001
toxicity.
0
Complications Following HSCT for SCID
0 12 24 36 60 120 Despite advances in prophylaxis and treatment, infections
Time after transplantation (months) (especially those caused by viruses) remain a significant cause
of death after HSCT for SCID. In a report of 166 transplantations
Months 0 6 12 24 36 60 120 performed at their center, Buckley et al. indicated that viral
18a
Number at risk infections accounted for 30 of the 40 deaths observed. CMV
B+ 345 247 195 168 147 111 55 and adenovirus were responsible for nine deaths each, and 18
B– 300 184 135 109 91 69 33 additional deaths resulted from infections caused by EBV,
Other 54 38 26 22 20 15 3 enteroviruses, parainfluenza virus type 3, varicella virus, herpes
FIG 82.3 Cumulative probability of survival in patients with T B or simplex virus, and respiratory syncytial virus. In a series of 240
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T B severe combined immunodeficiency (SCID) after hemato- patients with SCID who received HSCT in North America between
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poietic stem cell transplantation (HSCT). (With permission from 2000 and 2009, infections accounted for 24 of 62 deaths. 2
Gennery AR, Slatter MA, Grandin L, et al. Transplantation of Viral and opportunistic infections are more common early
hematopoietic stem cells and long-term survival for primary after HSCT, especially in recipients of T cell–depleted haploidenti-
immunodeficiencies in Europe: entering a new century, do we cal HSCT, because of the delay in achieving immune reconstitu-
do better? J Allergy Clin Immunol 2010;126:602-10.e1–11.) tion. Incomplete recovery of immune function at 1 year after