Page 1868 - Hematology_ Basic Principles and Practice ( PDFDrive )

1660 Part X Transplantation

commonly given for acute GVHD. Various dosing regimens have immunity include decreases in the production of antibodies against
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been used, none of which is clearly superior. High-bolus doses specific antigens, defects in the number and function of CD4 T
2
(10–20 mg/kg or 500 mg/m ) have higher initial response rates, but cells, and increases in the number of nonspecific suppressor cells,
flares on tapering and opportunistic infections are common. Both the which further diminish lymphocyte responses. Skin changes resem-
Seattle and Minnesota transplant groups have found that treatment bling widespread lichen planus with papulosquamous dermatitis,
with steroids was as effective as, or more effective than, other therapies plaques, desquamation, dyspigmentation, and vitiligo occur in 80%
or combination of therapies, with 20% to 40% of patients having of patients. 309,336 Destruction of dermal appendages leads to alopecia
durable long-term responses. 325,326 Long-term salvage rates for patients and onychodysplasia. Severe chronic GVHD of the skin can
who did not respond to steroids were 20% or less; most patients resemble scleroderma, with induration, joint contractures, atrophy,
eventually died from infection, acute GVHD, and/or chronic and chronic skin ulcers. Chronic cholestatic liver disease occurs in
GVHD. More recently, a randomized trial demonstrated that topical 80% of patients and often resembles acute GVHD; it rarely pro-
therapy with oral budesonide can have prednisone sparing effects and gresses to cirrhosis. Severe mucositis of the mouth and esophagus
327
is efficacious in treatment of GI GVHD. Clinically, two types of can result in weight loss and malnutrition. Intestinal involvement,
failure of corticosteroid treatment of acute GVHD can be distin- however, is infrequent. 309,336 Chronic GVHD also produces a sicca
guished: true steroid resistance (i.e., progression of GVHD symptoms syndrome, with atrophy and dryness of mucosal surfaces caused by
and manifestations while patients are receiving full-dose corticoste- lymphocytic destruction of exocrine glands, usually affecting the
roid treatment) and steroid dependence (i.e., reoccurrence [or flare] eyes, mouth, airways, skin, and esophagus. 24,336,337 The hematopoi-
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of GVHD during or after tapering of steroid treatment). In general, etic system may also be affected, and thrombocytopenia is an
309
the prognosis with true steroid-resistant GVHD is worse than the unfavorable prognostic factor in patients with chronic GVHD.
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prognosis of steroid-dependent patients. A comparison of trials Important predictors of unfavorable outcome are progressive onset,
dealing with steroid-resistant GVHD is hampered by variable inclu- lichenoid skin changes, elevated serum bilirubin level, continued
sion of both patient groups in many of these trials. A number of thrombocytopenia, and failure to respond to 9 months of
agents have been tested, including chemical immunosuppressants therapy. 309,338–340 Among patients with none of these risk factors,
such as MMF, antithymocyte globulin (ATG), anti-CD3, anti-T-cell 70% are expected to survive, compared with less than 20% with
antibodies, and more specific agents directed against activation or two or more of these risk factors. 340
adhesion molecules anti-CD25, anti-CD147, or cytokines or extra- Histologic examination of the immune system reveals involution
corporeal photopheresis. 328,329 To date, there are no randomized trials of thymic epithelium, disappearance of Hassall corpuscles, depletion
testing one agent versus the other in this clinical situation. Recent of lymphocytes, and absence of secondary germinal centers in lymph
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data suggested a role for TNF inhibition when added to steroids in nodes. Pathologic skin findings include epidermal atrophy with
treating GVHD, although a randomized trial failed to demonstrate changes characteristic of lichen planus and striking inflammation
any difference when compared with the addition of pentostatin or around eccrine units. Sclerosis of the dermis and fibrosis of the
anti-IL2 to steroids and was inferior to the addition of MMF. 319,330 hypodermis subsequently develop. GI lesions include localized
Targeted elimination of alloreactive T cells has recently been inflammation of the mucosa and stricture formation in the esophagus
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demonstrated to be a safe and efficacious method to mitigate GVHD. and small intestine. Histologic findings in the liver are often similar
Fusion of human caspase 9 to a modified human FK-binding protein to those that occur in acute GVHD but are more intense, with
that allowed for dimerization when exposed to a synthetic dimerizing chronic changes such as fibrosis and hyalinization of portal triads,
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drug led to the rapid death of 90% of alloreactive T cells expressing obliteration of bile ducts, and hepatocellular cholestasis. The
this construct and mitigated acute GVHD in a pilot trial of five endocrine glands of the eyes, mouth, esophagus, and bronchi show
patients following haploidentical BMT. 331 destruction focused on centrally draining ducts, with secondary
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involvement of alveolar components. Findings of bronchiolitis
obliterans, similar to those that occur in rejection of lung transplants,
Other Supportive Approaches are now generally considered a pulmonary manifestation of chronic
GVHD, although the pathogenesis of this process remains
Infections are the main cause of death in patients with steroid- unclear. 337
refractory acute GVHD, and careful surveillance and control of
infections is mandatory in patients with acute GVHD. Fungal infec-
tions, especially aspergillosis, are the leading complication. Prophy- Clinical Manifestations of Chronic
laxis and early aggressive treatment should be facilitated by the Graft-Versus-Host Disease
introduction of new azoles (voriconazole, posiconazole) or echino-
candins (caspofungin, micafungin), which broaden therapeutic effi- Chronic GVHD can present with a plethora of clinical manifesta-
cacy with acceptable toxicity. Other supplementary approaches have tions. Because of its unpredictable pattern and the late onset, when
332
been suggested, such as the use of octreotide and oral beclometha- patients are no longer receiving care at their transplant center, the
sone (or budesonide) to control large volumes of diarrhea. 327 diagnosis is often delayed or not recognized. The staging of chronic
GVHD is summarized in Table 108.4. However, consensus criteria
recently developed by the National Institutes of Health (NIH) might
CHRONIC GRAFT-VERSUS-HOST DISEASE soon become the standard for diagnosing and evaluating responses
for chronic GVHD. 341,342
Chronic GVHD was initially defined as a GVHD syndrome present-
ing more than 100 days after transplantation; its onset occurred either
as an extension of acute GVHD (progressive), after a disease-free Dermatologic
interval (quiescent), or with no precedent (de novo). 333,334 Chronic
GVHD may be limited or extensive (see Table 108.3). Any grade of Skin involvement in chronic GVHD presents with varied features.
acute GVHD increases the probability of chronic GVHD, although Lichenoid chronic GVHD presents as an erythematous, papular rash
24
no singular pathologic feature of the former predicts the development that resembles lichen planus with no typical distribution pattern.
of the latter. Its incidence ranges from 30% to 60% after transplanta- Sclerodermatous GVHD may involve the dermis and/or the muscular
tion with the bone marrow, although it may be higher after peripheral fascia and clinically resembles systemic sclerosis. The skin is thick-
blood progenitor transplants. 335 ened, tight, and fragile, with very poor wound healing. Either hypo
As with acute GVHD, the immune system appears to be affected or hyperpigmentation may occur. In severe cases the skin may become
in all patients, who are highly susceptible to bacterial, viral, fungal, blistered and ulcerate. Hair changes can include increased brittleness,
and opportunistic infections. Specific abnormalities of cellular premature graying, and alopecia. Fingernails and toenails may also be