Page 1168 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1132 PART NINE Transplantation

prime example of drug-induced immunological tolerance, a bortezomib, or high doses of potent glucocorticoids before
concept first demonstrated by Schwartz and Dameshek in their collection and storage of autologous HSCs, resulting in a period
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experiments using 6-mercaptopurine. Subsequently, in 1963, of immune dysregulation occurring early after autologous HSCT.
Berenbaum and Brown demonstrated immune tolerance to skin Patients with “engraftment syndrome” may require intensive
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allografts in adult mice by using cyclophosphamide. Post- treatment with corticosteroids and a calcineurin inhibitor, with
transplantation cyclophosphamide given on days 3 and 4 after courses more similar to those experienced by patients undergoing
transplantation is now a standard regimen used in haploidentical allo-HSCT.
allogeneic transplantations in combination with other immu-
nosuppressive drugs and as a single agent in matched unrelated Clinical Aspects of cGvHD
and related transplantations, reducing the complications of graft cGvHD is the leading cause of late transplant-related mortality
failure and life-threatening aGvHD associated with transplantation (TRM) among those undergoing allo-HSCT and resembles
of HLA disparate grafts. 12 autoimmune disorders, such as scleroderma, Sjögren syndrome,
Glucocorticoids with a calcineurin inhibitor remain the and primary biliary cirrhosis. Diagnosis is, as with aGvHD, based
standard approach to initial systemic management of clinically on clinical observations and secondary confirmation with labora-
significant aGvHD. About 30–50% of patients will respond to tory or pathology tests (Table 83.2). A falling performance status,
initial therapy, and patients who fail to respond have a poor progressive weight loss, or recurrent infections are usually signs
prognosis, as additional agents added for control greatly increase of severe cGvHD. About 50% of long-term survivors will develop
the risk of opportunistic infections and other treatment-related cGvHD at a median of 9 months after transplantation, and
complications. The use of higher doses of corticosteroids, or the patients must be monitored closely for this complication for at
addition of ATG, for example, in the initial treatment of aGvHD least 3 years so that appropriate treatment can be initiated before
do not improve patient outcomes and should be reserved for extensive end-organ damage ensues. Permanent ocular or oral
patients who fail initial therapy. A number of drugs, including sicca syndrome and pulmonary dysfunction can result if cGvHD
ATG, pentostatin, switching to tacrolimus from cyclosporine, and is not appropriately treated, leading to a marked deterioration
newer monoclonal antibodies (mAbs) have shown limited activity in quality of life.
in the salvage treatment of patients with steroid-refractory aGvHD. Factors predictive of the development of cGvHD include the
Extracorporeal exposure of peripheral blood mononuclear cells degree of HLA and miHA disparity, as well as prior aGvHD,
(PBMCs) to the photosensitizing agent 8-methoxypsoralen and older patient age, the source of HSCs (greater risk after peripheral
ultraviolet A (UVA) radiation (photopheresis) is effective in the blood stem cell [PBSC] transplantation than after bone marrow
treatment of selected diseases mediated by T cells, including transplantation), gender (female donor–male recipient), and
both aGvHD and cGvHD, although the mechanism of this effect donor lymphocyte infusion (DLI) after transplantation. Inflam-
remains to be elucidated. matory events, such as sunburn or surgical procedures, can
precipitate cGvHD. Patients who develop cGvHD have a higher
Autologous GvHD risk of TRM but a lower risk of relapse as a result of the immu-
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A form of aGvHD can also occur after auto-HSCT, probably as a nological GvT effect. T-cell depletion of the graft or treatment
manifestation of immune system dysregulation during reconstitu- with ATG may decrease the risk of cGvHD, although this has
tion of the immune system after dose-intensive therapy. Initially not been demonstrated in all studies. Most patients require at
studied in murine models of auto-HSCT, it was demonstrated least two drugs for effective treatment of cGvHD, with the
that the abrupt withdrawal of cyclosporine could induce clinical standard initial treatment being glucocorticoids and a calcineurin
features nondistinguishable from that observed after allo-HSCT. inhibitor. About half the patients do not achieve a complete
A mechanism that involves the depletion of central memory cells remission with first-line therapy, although the manifold signs
has been proposed, although depletion of Tregs with inhibition and symptoms of cGvHD complicate the definition of response
of peripheral tolerance may also be involved. Autologous GvHD to treatment. There are no clear recommendations regarding
is also reported in patients not receiving posttransplantation second-line treatments and various pharmacological and immu-
immunomanipulations (spontaneous GvHD). Based on the clini- nological techniques have been used. Photopheresis has an overall
cal benefits of GvT observed in allo-HSCT, several clinical trials response rate of 50–60%, with many patients achieving complete
with administration of cyclosporine with or without interferon remission. At least transient responses can be achieved with
(IFN) were performed in patients undergoing auto-HSCT without rituximab treatment, an anti-CD20 chimeric antibody, which
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obvious GvT effect. Both induced and spontaneous autologous illustrates the humoral immunity contribution to cGvHD. The
aGvHD are usually self-limiting complications, and are usually demonstration of activation of the Janus kinase (JAK) pathways
easily managed with a course of corticosteroids in patients with in activated T lymphocytes has led to studies demonstrating a
more extensive involvement, in contrast to the more extensive potential benefit of Jak2 inhibitors in the management of steroid-
and difficult-to-manage aGvHD that occurs after allo-HSCT. refractory cGvHD.
Furthermore, cGvHD does not occur after auto-HSCT.
A spontaneously occurring severe, and sometimes fatal, reac- GvT Responses
tion involving the gastrointestinal (GI) system with severe diarrhea Although recognized in mouse models of transplantation in the
during the periengraftment period is reported in patients 1950s, the first clinical report of a relationship between GvHD
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undergoing auto-HSCT for MM and other malignancies (“engraft- and GvT was published in 1979. This relationship between the
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ment syndrome”). The presentation is clearly distinct from the incidence (but not the severity) of aGvHD or cGvHD and the
spontaneous or induced GvHD previously observed in patients relapse rate of chronic myeloid leukemia (CML) and, to a lesser
undergoing auto-HSCT. “Engraftment syndrome” may be a extent, acute myeloid leukemia (AML), acute lymphocytic
consequence of prior treatments with immunomodulatory drugs, leukemia (ALL), and MM has been observed in patients who
such as lenalidomide or thalidomide, the proteasome inhibitor received allo-HSCT. Relapses after HSCT are thought to occur