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Chapter 109 Complications After Hematopoietic Cell Transplantation 1681

addition to the backbone of calcineurin inhibitors in multicenter TABLE Common Clinical Manifestations of Chronic
trials include posttransplant cyclophosphamide (to lyse proliferating 109.7 Graft-Versus-Host Disease
alloreactive donor T cells), bortezomib, and maraviroc (inhibits
lymphocyte chemotaxis, but not function). Organ System Clinical Manifestations
Cutaneous Poikiloderma, lichen planus, dermal sclerosis,
morphea-like features, hypopigmentation or
Treatment of Acute Graft-Versus-Host Disease hyperpigmentation, ichthyosis, nail
dystrophy, onycholysis
Therapy for acute GVHD requires both immunosuppression to
blunt the T-cell–induced tissue injury and appropriate supportive Ocular Keratoconjunctivitis sicca, conjunctivitis,
care. Corticosteroids are the mainstay of initial therapy for acute corneal ulcerations
GVHD. GVHD involving limited areas of the skin can be treated Oral Lichen planus, hyperkeratotic plaques,
with topical corticosteroids alone. Oral beclomethasone can be used xerostomia, mucosal atrophy, ulcers,
to treat early stage GVHD of the upper gastrointestinal tract. Corti- restriction of mouth opening from sclerosis
costeroids (2 mg/kg per day prednisone) are initial therapy for more Pulmonary Bronchiolitis obliterans, bronchiolitis
advanced GVHD and yield response rates of approximately 50%. No obliterans-organizing pneumonia
regimen has shown a consistent increase in response rates or improve- Gastrointestinal Esophageal web and strictures, malabsorption
ment in survival compared with corticosteroids alone. In a recent syndrome, exocrine pancreatic insufficiency
large randomized phase II trial comparing corticosteroids with MMF,
pentostatin, etanercept or denileukin diftitox, efficacy and toxicity Hepatic Cholestasis
data suggested the combination of MMF and corticosteroids to be Genitourinary Vaginal stenosis or scarring, lichen planus
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most promising. This combination was not superior to corticoste- Musculoskeletal Fasciitis, joint contractures from sclerosis,
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roids alone in the follow-up randomized phase III trial, however. myositis or polymyositis, arthritis
Other investigational therapies include inhibitors of lymphocyte
homing to intestinal tissues and infusion of mesenchymal stem cells. Hematopoietic Thrombocytopenia, eosinophilia, lymphopenia,
Prognosis is poor for patients with steroid-resistant disease, which is hemolytic anemia, hypogammaglobulinemia
GVHD that does not respond to initial therapy with corticosteroids.
Up to 10% to 40% of patients will respond to salvage therapy with
ATG or other drugs such as sirolimus, tacrolimus, MMF, pentostatin
or cyclosporine, either as single agents or in combination. Monoclonal treatment with donor lymphocyte infusion. Similar to acute GVHD,
antibodies and immunotoxins directed against T-cells or inflamma- in vitro or in vivo T-cell depletion of the graft can reduce the inci-
tory cytokines have been investigated, although their effectiveness has dence of chronic GVHD.
not been demonstrated outside of small case series. Specific agents Chronic GVHD can affect any organ system; however, certain
with reported activity in steroid-refractory acute GVHD include pathognomonic clinical signs and symptoms have to be present to
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pentostatin, etanercept and infliximab (TNF-α receptor blockers), establish the diagnosis (Table 109.7). Other clinical manifestations,
dacluzimab and denileukin diftitox (IL-2 receptor inhibitors), and though not diagnostic of chronic GVHD, can be characteristic,
visilizumab (anti-CD3 antibody). Extracorporeal photochemotherapy though may be seen in acute GVHD as well. Additional investiga-
has also been reported to have some efficacy in steroid-refractory tions including biopsies might be needed to verify the diagnosis and
acute GVHD. In addition to effective immunosuppression, success- to rule out other etiologies, such as infections, drug effects and
ful management of acute GVHD involves attention to supportive malignancies. The skin, mouth, eyes, and liver are the most com-
care, particularly skin care, nutrition and limitation of polypharmacy- monly involved sites of chronic GVHD. The cutaneous manifesta-
associated drug interactions. Infections are a leading cause of death tions resemble autoimmune disease and can include poikiloderma,
in patients with GVHD and attention should be paid to infection lichen planus-like eruptions or scleroderma (sclerosis). An inflamma-
surveillance and prophylaxis. tory dermatitis can progress to severe dermal and periarticular fibrosis
with loss of skin appendages (hair and sweat glands) as well as sig-
Chronic Graft-Versus-Host Disease nificant skin tightness, fasciitis and loss of joint flexibility. Additional
manifestations include dry eyes and dry mouth, which can resemble
Sjögren syndrome clinically and histologically; enteritis with anorexia,
Risk Factors and Clinical Features early satiety, malabsorption, weight loss and failure to thrive, or
esophageal dysmotility or stricture; and cholestatic (or sometimes
Chronic GVHD is a complex syndrome in recipients of allogeneic hepatitic jaundice. Pulmonary involvement in the form of bronchi-
HCT that occurs later, typically between 3–7 months posttransplant, olitis obliterans is an uncommon manifestation, but can be particu-
although it can also begin before 3 months and even beyond 2 years. larly debilitating and dangerous. In addition, the profound immune
Its incidence ranges from 30% to 50% in HLA-matched sibling dysfunction associated with chronic GVHD because of hypogam-
donor transplants to 50% to 70% in HLA-matched URD transplants maglobulinemia, impaired cellular immunity and functional asplenia,
and it is the leading cause of nonrelapse late mortality in allogeneic greatly increases the risk of secondary infections from bacteria, viruses
HCT survivors. Recipients of UCB grafts have lower risks compared and fungi. After the onset of chronic GVHD, 25% to 40% of
with matched adult URD HCT and comparable or even lower than patients die within 2 years, often of infections.
matched related donor HCT recipients. Chronic GVHD occurs most Chronic GVHD can be classified as mild, moderate, or severe
frequently in patients with preceding acute GVHD, but can also depending on the number of organs involved and the degree of
manifest de novo without any preceding acute GVHD. The distinc- individual organ involvement. In general, factors associated with an
tion between classic chronic GVHD and overlap syndrome requires adverse prognosis include thrombocytopenia, progressive onset from
attention to clinical symptoms and signs which are characteristic and acute GVHD, poor performance status, lack of response to initial
thus diagnostic of chronic GVHD. therapy and extensive skin or lung involvement.
Acute GVHD is the most important risk factor for development
of subsequent chronic GVHD. Use of mismatched or URDs and
transplantation using peripheral blood derived hematopoietic stem Treatment of Chronic Graft-Versus-Host Disease
cells instead of bone marrow also increases its risk. Other reported
risk factors for chronic GVHD include older recipient age, use of a Although acute GVHD is one of the strongest predictors for chronic
female donor, CMV seropositivity, high graft CD34+ cell count, and GVHD, strategies to limit acute GVHD such as prolonging or