Page 828 - Hematology_ Basic Principles and Practice ( PDFDrive )

714 Part VI Non-Malignant Leukocytes

infants with SCID in North America confirm excellent survival of Therapeutic Approach to Severe Combined Immune Deficiency
90% and 94%, respectively, after matched sibling donor HCT.
Outcomes after mismatched related, unrelated adult volunteer, and • HSC transplantation is the mainstay of treatment. Optimal survival
umbilical cord blood HCT have improved, although a clear advantage is achieved when the transplant is performed early in life. This is
of one alternative donor versus another has not been demonstrated. now possible with newborn screening.
Mismatched related donor HCT performed without conditioning • Transplantation for SCID can be performed without conditioning,
may be associated with better survival than when conditioning is due to the profound absence of T cells and inability to reject.
given. Thus, the bone marrow of a fully HLA-matched sibling can
Respiratory infections and older age at the time of transplant have be infused without manipulation and without giving any
long been associated with poorer outcome. Infants older than 3.5 conditioning to the baby. GVHD prophylaxis is also not necessary.
months at the time of HCT who have never had infection or had Haploidentical bone marrow from a parent can also be infused
without conditioning but must first be T-cell depleted.
infections that were amenable to treatment prior to HCT interest- • Such transplants without conditioning can result in T-cell
ingly have similar survival to infants younger than 3.5 months at the reconstitution that lasts for decades. In the case of a matched
time of HCT. Among infants who were not actively infected at the sibling graft, initial T-cell reconstitution is rapid, generally within
time of HCT, survival was very good even for alternative donor the first 1–3 months, due to proliferation of mature T cells. In
recipients. These results suggest that early diagnosis and protection the case of a haploidentical graft, mature T cells are removed
of infection, i.e., through newborn screening, would improve survival and thus 4–6 months is required for HSC to develop and emerge
significantly. The specific type of SCID also affects outcome: survival from the thymus as mature T cells.
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after HCT is better in patients with B than B SCID. • Without conditioning, only a low number of donor-derived
In infants with SCID, long-term T-cell reconstitution may be long-lived HSCs engraft, and this may lead to lack of donor B-cell
achieved in the absence of conditioning and the absence of engraft- reconstitution and lack of humoral immunity. With conditioning,
donor HSCs are more likely to engraft and give rise to donor
ment of donor-derived stem cells, due to engraftment of committed B cells. Currently, matched unrelated donor transplants are
lymphoid progenitors that seed the thymus. Consistent with this, performed with conditioning.
donor T-cell chimerism and T-cell reconstitution after HCT are • Enzyme replacement may be used in patients with adenosine
achieved in >90% of infants with SCID and the majority have a deaminase deficiency. Gene therapy has offered promising
polyclonal repertoire. The durability of T-cell reconstitution in the results; however, it is also associated with increased risk of
absence of conditioning is variable, and some reports have indicated leukemic proliferation due to insertional mutagenesis.
a progressive decline of thymic function after HCT for SCID. Such
reports are supported by the finding that survivors after HCT per-
formed with conditioning have higher T-cell counts and higher naive vectors expressing the ADA complementary (c)DNA. All are alive,
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CD4 CD45RA T-cell counts than those after HCT performed with sustained production of gene marked T, B and myeloid cells,
without conditioning. Reconstitution of humoral immunity after and the majority of patients have been able to stop ERT. In all trials,
HCT for SCID is less uniform; for genetic subtypes that affect B-cell engraftment of gene-corrected stem cells has been facilitated by the
development or function, engraftment of donor B cells is typically use of a reduced-intensity chemotherapy regimen with low-dose
required for humoral immune reconstitution. For example, inadequate busulfan.
B-cell function (requiring immunoglobulin-replacement therapy) is Twenty patients with X-linked SCID were treated by gene
often observed in patients with γc and JAK3 deficiency who remain therapy using a gammaretroviral vector in Paris and London at the
with autologous B cells, due to intrinsic defects in the host B cells’ turn of the century, without chemotherapy conditioning. Eighteen
response to γc-dependent cytokines such as IL-4 and IL-21. The patients are alive, and 17 of them show normalization of T-cell
number of circulating NK lymphocytes often remains low in patients count and function, with sustained thymic output, diversified T-cell
with γc and JAK3 deficiency, and may contribute to the increased repertoire, and ability to mount antigen-specific T-cell responses.
risk of warts. In a few cases, improvement of humoral immunity has also been
Rates of acute GVHD (aGVHD) are generally low, ~20%, largely observed. However, leukemic T-cell proliferation due to insertional
limited to recipients of alternative donor HCT. Patients with poor mutagenesis was observed in 5 out of 20 patients. A modified
T-cell reconstitution are at risk for viral and opportunistic infections; self-inactivating gammaretroviral vector based on the previously
autoimmunity (especially cytopenias and hypothyroidism) has been mentioned parent vector has now been reported to be efficacious in
reported in 10% to 20% of these patients, particularly in those nine patients with X-linked SCID in a multicenter trial. Preliminary
with cGVHD. Other long-term complications include nutritional evidence from this trial suggests that deletion of viral enhancers has
problems, poor growth and development, and neurologic complica- decreased expansion of clones bearing insertion sites near lymphoid
tions (mental retardation, motor dysfunction, sensorineural hearing protooncogenes, suggesting an improved safety profile with regard
deficits). Some of these complications are more common in certain to leukemogenesis. Self-inactivating lentiviral vectors based on
subtypes, particularly growth in patients with Artemis-SCID and HIV are being developed and/or tested in both ADA and X-linked
neurologic problems in patients with ADA deficiency. SCID.

Gene Therapy for SCID OTHER COMBINED IMMUNODEFICIENCIES

Gene therapy, in which the gene of interest is introduced into the Defects of TCR Signaling
patient’s own cells, is an attractive therapeutic option for SCID, in
particular for infants who do not have an HLA-identical related Several forms of combined immune deficiency are caused by genetic
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donor. Expression of the normal copy of the gene in CD34 stem defects that affect molecules involved in TCR signaling. In particular,
cells confers a selective advantage to the gene-corrected cells during the T lymphocyte-specific protein tyrosine kinase (Lck) associates
T-cell differentiation. Furthermore, there is no risk of GVHD. Gene with CD4 and CD8 molecules and mediates phosphorylation of
therapy has been used successfully to correct SCID in patients with CD3 chains upon TCR engagement. The Zeta-associated protein of
ADA deficiency and with X-linked SCID. 70 kDa (ZAP-70) tyrosine kinase phosphorylates the CD3 chains,
Since the year 2000, more than 70 patients with ADA-deficient thus promoting downstream TCR signaling. RHOH is an atypical
SCID have been treated with gene therapy worldwide. Published Rho GTPase that participates in receptor-induced signaling in
reports from Milan (Italy), London (United Kingdom) and the hematopoietic cells. The IL-2-inducible tyrosine kinase (ITK) is a
United States have collectively described 26 patients who received member of the thymic epithelial cell (TEC) family of nonreceptor
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autologous CD34 progenitor cells transduced with gammaretroviral tyrosine kinases, and modulates the strength of the TCR-induced