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368 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 369

Mucositis porcine oligodeoxyribonucleotides which induces antithrombotic and
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Mucositis occurs in more than 90 percent of patients receiving high- fibrinolytic effects in preclinical models. Its mechanism of action
dose regimens and is often regarded as the most difficult issue from the against SOS remains unknown. A randomized phase II dose-finding
patient’s perspective. Current management is supportive and includes trial involving 149 patients with severe SOS reported day +100 survival
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frequent rinsing with saline solutions and antimicrobials, cryotherapy, of 42 percent with few adverse events, and a dose of 25 mg/kg/day was
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pain control (often with continuous intravenous infusions of opioids), selected for ongoing randomized phase III trials. However, defib-
and parenteral nutrition when needed. Improvement typically occurs rotide is not yet approved by the FDA and remains available only on an
within 10 to 21 days of transplantation, around the time of engraftment. investigational or compassionate-use basis in the United States.
Fully ablative regimens, TBI-based conditioning, and the administra-
tion of posttransplantation methotrexate (MTX) for GVHD preven- Pulmonary Complications
tion are associated with more severe mucositis. Severe mucositis may Noncardiogenic and noninfectious diffuse lung injury, also referred to
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result in significant tissue edema, upper airway obstruction, and/or as idiopathic pneumonia syndrome (IPS), remains a significant prob-
aspiration pneumonitis, although fortunately these complications are lem following autologous or allogeneic HCT, occurring in 10 to 15
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rare. Regimen-related gastroenteritis results in nausea, vomiting, and percent of transplant recipients. Risk factors for idiopathic IPS
diarrhea, which may persist for weeks after the transplant. Breaches in include high-dose conditioning, TBI, GVHD, older recipient age, prior
the mucosal lining predispose to bacterial translocation from the gastro- history of cigarette smoking, prior thoracic/mediastinal irradiation,
intestinal tract, with increased risk of bacteremia and sepsis. Palifermin and abnormal gas exchange as measured by pretransplant pulmonary
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(keratinocyte growth factor) can reduce patient-controlled anesthesia function testing. Preclinical models suggest that donor T cells play a
(PCA) and total parenteral nutrition (TPN) usage because of mucositis, key role in the development of IPS, indicating that it may be a form of
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predominantly in patients receiving TBI-based conditioning, but at a graft-versus-host reaction. In a small subset of patients, diffuse alve-
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cost of $5500 to $14,000 per day. Initial hopes that this agent would olar hemorrhage (DAH) develops, characterized by progressive short-
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prevent GVHD after allogeneic HCT have not been realized, 303,304 and ness of breath, cough, and hypoxemia. Classically, DAH is defined by
the benefits of palifermin appear limited to ameliorating mucositis. the demonstration of progressively bloodier aliquots in bronchoalveolar
lavage fluid. Mortality from this complication is high (often >75 per-
Sinusoidal Obstructive Syndrome cent) despite aggressive treatment. Another subset of patients with IPS
Sinusoidal obstructive syndrome (SOS) is a clinical syndrome of develop periengraftment respiratory distress without a bloody bron-
regimen-related hepatotoxicity characterized by tender hepatomeg- choalveolar lavage. In the autologous setting, the IPS often responds
aly, fluid retention, weight gain, and elevated serum bilirubin follow- promptly to glucocorticoids, whereas in the allogeneic setting response
ing autologous or allogeneic HCT. This syndrome was formerly called rates are lower, indicating that perhaps some cases may be complicated
venoocclusive disease (VOD), but this term is no longer used as it inac- by GVHD.
curately describes the underlying pathobiology: the liver injury is ini- The management of suspected IPS begins with bronchoscopy to
tiated by damage to hepatic sinusoidal epithelium, and obstruction of rule out infectious etiologies and to evaluate for DAH. Care is sup-
hepatic venules is not essential to the development of the syndrome. portive and aimed at maximizing respiratory function and preventing
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The incidence of SOS varies significantly with the intensity of condi- volume overload or multiorgan failure. Patients are typically treated
tioning and with the stringency of diagnostic criteria, from less than 10 with high-dose glucocorticoids (methylprednisolone at 2 mg/kg/day or
percent to as high as 30 to 40 percent. CY is a key culprit in the develop- higher), along with broad-spectrum antimicrobials and intensive sup-
ment of SOS, and large interpatient variability in CY metabolism may portive care. Retrospective studies have suggested that tumor necrosis
account for the syndrome’s unpredictability. 306,307 Other contributing factor (TNF) blockade with etanercept may be effective as an adjunct to
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factors include the preadministration of BU in the BU/CY regimen, high-dose glucocorticoids, but a prospective randomized study failed
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which potentiates CY hepatotoxicity ; preexisting hepatic fibrosis, as to find an additive benefit, and thus etanercept cannot be routinely
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in patients with cirrhosis or with hepatic extramedullary hematopoie- recommended at this time. Patients with IPS who progress to require
sis as in myelofibrosis ; and pretreatment with higher doses of gemtu- mechanical ventilation have a very poor prognosis, and a frank discus-
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zumab ozogamicin. 309,310 The incidence of SOS appears to be decreasing sion of the goals of care is indicated in this setting, particularly in the
over time, likely a result of the prevalence of RIC regimens and the presence of multiorgan failure. 323
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prophylactic use of ursodiol, which prevents SOS and other forms of Lung inflammation following the administration of BCNU is
hepatic injury during allogeneic HCT. 312,313 a separate form of noninfectious lung injury seen in HCT recipients
SOS is generally is classified as mild (clinically apparent yet resolves who receive this agent as part of their conditioning regimens. BCNU-
without treatment), moderate (requiring diuretics and pain medication induced pneumonitis is often characterized by a nonproductive cough
for abdominal discomfort yet completely resolves before day +100), or with increasing dyspnea and bilateral pulmonary infiltrates on chest
severe (not resolving before day +100 or death). Severe SOS has a ten- radiography, with or without fevers, and often occurs 1 to 2 months after
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dency to progress to multiorgan failure and is associated with a mor- transplantation. Pulmonary function tests reveal a restrictive pattern
tality rate of greater than 80 percent. Therapy for SOS is supportive of lung injury and a decrease in diffusing capacity compared to pre-
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and includes management of sodium and water balance with diuretics, transplant values. Prompt treatment with glucocorticoids reduces mor-
preservation of renal blood flow, and paracentesis for ascites associated tality and morbidity and is crucial to a successful outcome. If untreated
with significant discomfort or pulmonary compromise. Patients with a or recognized late, significant pulmonary fibrosis may develop.
poor prognosis can be recognized early after SOS onset by steep rises in
serum bilirubin, body weight, and other liver enzymes; hepatic venous INFECTIONS
pressure measurement greater than 20 torr; development of portal vein Susceptibility to infection is a significant challenge in the clinical man-
thrombosis; and multiorgan failure requiring mechanical ventilation or agement of transplant recipients. The essential principles are preven-
renal dialysis. 316 tion, judicious monitoring, and expeditious treatment of all bacterial,
There are few satisfactory therapies for severe SOS; the most com- fungal, and viral infections. These basic principles are widely accepted,
monly used is intravenous defibrotide, a mixture of single-stranded yet the day-to-day strategy for implementing them varies widely among

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