Page 524 - Clinical Immunology_ Principles and Practice ( PDFDrive )

504 ParT fOur Immunological Deficiencies

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prevention and successful treatment of infections are strong (VOD). Alternative conditioning agents include treosulfan
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determinants of HSCT outcome and is associated with decreased (1-treitol-1,4-bis-methanesulfonate), which has both myeloabla-
frequency of GvHD. In particular, infection prevention is critical tive and immunosuppressive properties, as well as an improved
in patients with SCID receiving matched unrelated HSCT, where patient safety profile.
the risk of GvHD has been reported to be >70% (the main cause Reduced intensity conditioning (RIC) involving incomplete
of morbidity and mortality). 68 ablation of the bone marrow may also be beneficial in permitting
engraftment and immune reconstitution. However, where such
Hematopoietic Stem Cell Transplantation regimens may offer improved survival and reduced toxicity, there
HSCT is the only potentially curative therapeutic approach for have also been reports of increased incidences of mixed donor
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patients SCID and various forms of CID. The replacement of chimerism and graft failure. In these instances, repeat HSCT or
defective HSCs with cells from a healthy donor, typically bone donor lymphocyte infusions may be necessary, which may pose
marrow, allows T-cell precursors to repopulate the native thymus further risk to patients. 77
and permits reconstitution of a functional immune system. As HSCT without conditioning has been attempted in patients
a result of advancements made in preparing the host, donor who are too sick to tolerate pre-transplant chemoablation,
cells, conditioning regimens, and supportive therapy, HSCT however, this is associated with a high frequency of complications
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survival rates have markedly improved since the early 1980s and mortality. In such circumstances, it is recommended that
(Chapter 82). the patient be stabilized until a full protocol can be implemented.
Donor Source Prophylaxis and Treatment of Graft versus Host Disease
Transplantation involving related HLA-identical donors (RID), GvHD is caused by T cell mediated attack of the host tissue by
usually a sibling, carry the most favorable prognosis, with survival the graft, and is a significant cause of morbidity and mortality
rates of 90 to 100%. Complete immune reconstitution occurs to allogeneic HSCT recipients. The principal affected organs are
rapidly and carries a low risk of GvHD. However, since such skin, gastrointestinal tract and liver, with the current grading
donors are available in less than 20% of cases, donor sources system (grades I-IV) based upon the extent of organ involve-
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including HLA-matched unrelated donors (MUD) or HLA- ment. Risk factors for GvHD include donor-host incompatibility
mismatched related donors (MMRD) can be considered. as well as the source of stem cells, and can be significantly reduced
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The survival rates for MUD HSCT are greater than 70%, by introducing prophylactic immunosuppression and depletion
with some centers reporting rates of up to 83% 68,71 and low of donor T cells before infusion. The primary response to such
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incidences of GvHD. This modality has proven especially first-line treatment is the most important predictor of long term
effective in cases with CID. Experience with MMRD HSCT in survival in patients with acute GvHD.
the past has been disappointing, 73,74 but recent reports suggest Options for pharmacologic prophylaxis include monotherapy
improved survival rates for these transplants, although follow-up with a calcineurin inhibitor (such as cyclosporine or tacrolimus),
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in many of the cases is still too short. Such transplants involving or in combination with steroids, methotrexate or mycopholate
haploidentical donors require the marrow to be depleted of T mofetil. The efficacy of steroids in improving the outcome and
cells, and immune reconstitution may be prolonged. Rates of probability of survival is well documented. 80,81
graft failure necessitating a second transplant have been high, T cell depletion is recommended for HSCT involving HLA-
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along with incomplete immune reconstituation. Complications mismatched donors. However, while depletion of donor T cells
include opportunistic infections, chronic GVHD, autoimmunity using physical separation techniques, monoclonal antibodies or
and late deaths. anti-thymocyte globulin can reduce GvHD, it is also associated
Nevertheless, regardless of donor source, HSCT prior to 3.5 with delayed immune reconstitution and an increased incidence of
months of age or before the onset of infection is associated with post-transplant lymphoproliferative disorders and life-threatening
high rates of survival (95% and 90% respectively) when compared infections. 79
to older children (76%). 2
Gene Therapy
Conditioning Gene therapy represents a therapeutic option for patients with
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Pre-transplant conditioning helps to prepare the recipient marrow primary immunodeficiency who lack a HLA-identical donor
for optimal engraftment of donor stem cells and T cell reconstitu- (Chapter 85). By using retroviruses to introduce a functional
tion, and plays an important role in the long-term outcome of copy of the defective gene into the patient’s own HSCs, this
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HSCT. Whether conditioning is necessary depends in part on technique negates the need for a donor and is not associated
the type of immunodeficiency. For example, whereas myeloabla- with complications normally arising from HLA-incompatibility.
tion is necessary for HSCT in patients with sufficient immune To date, gene therapy has been demonstrated to be extremely
cells to reject a graft (as in CID), it may not be indicated for effective in treating patients with ADA deficiency, resulting in a
patients with SCID receiving HLA-matched stem cells from a variable increase in T and B cell numbers as well as significant
sibling donor. However, it is worth noting that donor B cells improvement of immune function. Importantly, there have been
rarely engraft in the absence of conditioning regimens, and many no reports of serious adverse events or malignancy to this
patients remain on lifelong immunoglobulin replacement with indication. 23
increased risk of infective lung damage and T lymphocyte However, early attempts to utilize gene therapy in other forms
senescence. of primary immunodeficiency were met with mixed results, and
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Myeloablative conditioning with busulfan and cyclophospha- highlighted various pitfalls related to the first-generation vectors.
mide was once commonly used for HSCT in patients with SCID A number of serious adverse events, including leukemia, were
and CID, although a protocol including busulfan and fludarabine caused by preferential integration of retroviral vectors in the
is currently proposed due to risk of veno-occlusive disease proximity of transcription initiation sites, leading to increased