Page 1894 - Hematology_ Basic Principles and Practice ( PDFDrive )

1676 Part X Transplantation

host immunosuppression by the conditioning regimen and peritrans- BOX 109.2 Sinusoidal Obstruction Syndrome
plant immunoprophylaxis. T-lymphocyte depletion of donor marrow
performed as GVHD prophylaxis can also adversely affect engraft- Diagnostic Criteria for Sinusoidal Obstruction Syndrome (SOS)
ment, even from matched sibling donors. Ex vivo marrow manipula- Bilirubin ≥2 mg/dL before day 21 post-HCT and at least two of the
tion can deplete stem cells. T-cell depletion can also render the graft following: (1) hepatomegaly or right upper quadrant pain, (2) ascites,
immunoincompetent and functionally less capable of preventing or (3) weight gain >5% over baseline.
graft rejection. SOS is a clinical diagnosis; liver ultrasound with Doppler studies or
Compared with related or URD allografts, time to neutrophil liver biopsy can support or confirm the diagnosis.
recovery is significantly delayed in patients receiving UCB grafts. In Risk Factors
addition, the overall incidence of graft failure is somewhat greater, Pretransplant Factors
currently 5% to 15% with present selection strategies. The most
critical determinants of engraftment following UCB transplantation Prior hepatic inflammatory disease (e.g., chronic hepatitis B or C,
nonalcoholic steatohepatitis, alcoholic hepatitis)
are both HLA matching and cell dose, and units with a total nucle- Prior hepatic fibrotic disease (e.g., cirrhosis)
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ated cell dose of at least 2.5 × 10 cells/kg or more have a greater Extensive pre-HCT chemotherapy
probability of successful engraftment. Since each UCB unit has a Prior exposure to gemtuzumab ozogamicin
limited number of hematopoietic stem and progenitor cells, methods Prior liver irradiation
to overcome this limitation of cell dose are being investigated. These Transplant-Related Factors
include transplantation using multiple UCB units, ex vivo expansion
to increase the number of progenitor cells, and approaches to improve Conditioning regimen (e.g., myeloablative total body irradiation or
busulfan-based regimens)
homing including intrabone marrow injection of the graft or prein- Exposure to other agents (e.g., sirolimus, itraconazole)
cubation with prostaglandins. Increasing overall cell dose and the
added antihost immunologic response with transplantation of two Prognostic Factors
UCB units has increased the chances of successful engraftment, Adverse prognostic factors include: development of multiorgan failure,
especially in adults. rapid increase in weight, rapid increase in bilirubin.
The use of recombinant G-CSF or GM-CSF, which stimulate Treatment
myelopoiesis, has improved the treatment of graft failure. Improve- For >70% of patients, SOS will recover spontaneously with supportive
ment in myelopoiesis can be seen in 50% to 60% patients with poor care. However, mortality rates are >80% for patients with severe SOS.
graft function within 14–21 days after initiation of growth factor Treatment options, especially for patients with more severe SOS,
therapy. Myeloid growth factor therapy can increase peripheral blood includes:
leukocyte recovery, but has little effect on platelet reconstitution. Pharmacologic
Recombinant human thrombopoietin receptor agonists are now Ursodeoxycholic acid (prophylaxis)
available, although their efficacy and safety profile in HCT recipients Defibrotide (investigational—prophylaxis and treatment)
is currently being studied. Limited experience suggests the value of Low-dose heparin and low-molecular-weight heparin (prophylaxis)
recombinant erythropoietin in reducing red blood cell transfusion Tissue plasminogen activator (investigational – prophylaxis and
needs. treatment)
A second stem cell infusion can be useful if graft failure occurs. Antithrombin III (investigational—prophylaxis and treatment)
In the case of a failed autograft, infusion of previously harvested and Nonpharmacologic
frozen marrow or blood cells frequently reestablishes functional Supportive care with management of multiorgan failure
hematopoiesis and hematologic improvement. In the case of graft Transjugular intrahepatic portosystemic shunt
failure after related-donor transplantation, a second infusion of donor Liver transplantation
marrow or cytokine-mobilized PBSC may allow successful engraft-
ment. Sometimes, because of the presumption of immune-mediated
rejection, reconditioning with reduced doses of cytotoxic agents or
further immunosuppression with ATG, corticosteroids, or cyclospo-
rine is used to prepare the recipient for a second infusion.
The treatment of graft failure after URD transplantation poses (TBI) used in pretransplant conditioning regimens produce sinusoidal
special problems. URDs may not be available for a second marrow endothelial injury. Subsequent deposition of fibronectin and factor
harvest or blood stem cell apheresis. In experimental settings where VIII/von Willebrand factor at the site of damaged endothelium can
graft failure risks are high, it may be prudent to store autologous lead to activation of the coagulation system and subsequent sinusoidal
stem cells from patients undergoing URD transplantation, although obstruction. Such changes are often associated with depressed plasma
this is rarely done. The original donor is not available in recipients of protein C levels and other signs of procoagulant activity, including
unrelated UCB grafts and the only treatment option for graft failure lower antithrombin III levels and elevated factor VIII and fibrinogen
in this setting is a second transplant using cells from a different UCB levels. Cytokines such as tumor necrosis factor (TNF)-α and altera-
or volunteer adult donor (related or unrelated) second allograft, or tions in the levels of nitric oxide and matrix metalloproteinases may
reinfusion of autologous backup cells, if available. Because of vari- also have a role in its pathogenesis.
ability in the circumstances and donor options available, there are few Risk factors associated with the development of SOS include
clear data on the outcomes of second allografts in these situations. 24 history of pretransplant hepatitis or liver injury, intensive preparative
regimens, increased TBI dose and dose rate and increased busulfan
dose. SOS may also be more frequent after mismatched related or
Sinusoidal Obstruction Syndrome URD transplantation. Prior therapy with gemtuzumab ozogamicin
also increases the risk of posttransplant SOS. Sirolimus has also been
Sinusoidal obstruction syndrome (SOS), also known as hepatic shown to increase the risks of SOS after myeloablative allogeneic
venoocclusive disease, is a serious liver disorder characterized by HCT, particularly using busulfan-based regimens.
jaundice, ascites, fluid retention, and hepatomegaly that complicates Signs of SOS usually occur within 2–4 weeks after hematopoietic
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up to 5% to 50% of HCT’s. The varying reported incidence is based graft infusion, but may be recognized much sooner, even during
upon stringency of the definition of the clinical diagnosis (Box 109.2). administration of an intensive preparative regimen. Clinical evidence
The primary initiating event is thought to be portal hypertension of venoocclusive disease includes hyperbilirubinemia, tender hepato-
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caused by inflammatory and edematous obstruction of hepatic sinu- megaly, ascites, and weight gain. More advanced stages can be
soids and venules, which secondarily leads to damage to surrounding associated with encephalopathy along with renal, pulmonary, and
centrilobular hepatocytes. Chemotherapy and total body irradiation multiorgan failure. The diagnosis of SOS is primarily based on