Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Sinusoidal obstruction syndrome
Introduction
Sinusoidal obstruction syndrome (SOS) is a well-described complication of the high-dose conditioning regimens used in hematopoietic stem cell transplantation (HSCT), as well as certain hepatotoxic chemotherapies or radiation therapy used in other settings, and is a well-recognized cause of HSCT patient mortality. It was previously known as hepatic veno-occlusive disease based on the pathologic features, but the term was changed to SOS when it became clear that the initial injury is caused by changes in the hepatic sinusoidal cells. , The epidemiology of SOS is difficult to define because of differences in definitions and patient populations, and the clinical presentation ranges from mild, self-limited disease to severe SOS with multiorgan failure and mortality rates in excess of 80%. In recent years, there has been improvement in the understanding of the pathogenesis of SOS and new strategies for both prevention and treatment.
Epidemiology
Incidence
The incidence of SOS varies greatly in the literature, because of controversies in diagnosis, variable diagnostic criteria, and confounding factors, such as the patient population being studied. The published rates of SOS in all populations range from 0% to 60% of HSCT patients, but the mean incidence in a recent systematic review was 13.7%. The incidence of SOS clearly varies by type of transplant; rates in fully myeloablative allogeneic transplants are 10% to 60%, whereas in reduced-intensity conditioning regimens and autologous transplants, the incidence is much lower, ranging from 5% to 30%.
Adults
The average incidence of SOS in adults is 8% to 14% depending on the series and in a few studies is as high as 40%; this is much lower than observed in children. The incidence of SOS has steadied now that there is a greater emphasis on use of reduced intensity conditioning regimens.
Pediatrics
In contrast to adults, SOS is a common complication of HSCT in children, occurring in approximately 20% to 30% of patients overall and as many as two-thirds of those at high risk for this complication. One of the challenges of making this diagnosis in the pediatric population is the fact that one-third of children with SOS do not have hyperbilirubinemia; , therefore dependence on strict fulfillment of the Baltimore or modified Seattle criteria may miss the diagnosis, and children are more likely to present with late-onset SOS (20%). , , Pediatric patients who do develop hyperbilirubinemia usually do so late in their disease progression or as a manifestation of more severe SOS. An early diagnostic clue in the pediatric population is thrombocytopenia that is refractory to platelet transfusion; this usually precedes the diagnosis by 1 week. Children also can have more severe disease, with 30% to 60% developing multiorgan dysfunction. ,
Risk factors ( table 12.1 )
Patient related
Extremes of age increase the risk of SOS in both adults and children, , as does poor Karnofsky performance status (< 90%) , or dependence on parenteral nutrition before transplant. Advanced malignant disease, and the etiology of the underlying malignancy, are well-recognized risk factors. , In children, a diagnosis of osteopetrosis, familial hemophagocytic lymphohistiocytosis, juvenile myelomonocytic leukemia, thalassemia major, sickle cell disease, neuroblastoma, Wilms tumor, or rhabdomyosarcoma have all been associated with a higher risk of SOS. Laboratory abnormalities indicative of liver injury or inflammation, such as elevated transaminases, ferritin, or bilirubin, also are associated with a higher SOS risk. Several genetic mutations predisposing to the condition have been identified, including GSTM1-null, C282Y allele, and the MTHFR 677CC/1298CC haplotype. Patients with preexisting liver disease caused by viral hepatitis or iron overload are also at elevated risk for this complication. Although it had been suggested in the past that there may be a gender difference in SOS, the increased risk for SOS development seems to be limited to women maintained on norethisterone to prevent gynecologic bleeding.
Table 12.1
Risk factors for Development of Sinusoidal Obstruction Syndrome
| Pretransplant | Transplant |
|---|---|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
CML, chronic myeloid leukemia; CMV, cytomegalovirus; GSTM1, glutathione transferase mu- 1; GVHD, graft-versus-host disease; Gy, units of gray; HCT, hematopoietic cell transplantation, MDS , myelodysplastic syndrome.
Pretransplant treatment related
There are several pretransplant treatment characteristics associated with an elevated risk of SOS, including prior abdominal or liver radiation and baseline abnormalities in transaminases or bilirubin. , , Certain salvage chemotherapies used in leukemia to control disease and allow patients to proceed to HSCT deserve special mention. There are two antibody-drug conjugates that contain the same toxin, ozogamicin, that have been associated with SOS. Gemtuzumab ozogamicin (anti-CD33) was previously used in acute myeloma leukemia patients and was associated with SOS. , In patients exposed to gemtuzumab ozogamicin before HSCT, the risk of SOS was increased and fatalities resulting from SOS noted. However, the use of the lower dose regimen may be associated with an acceptable SOS risk of around 8%. This agent was taken off the market because of lack of use and toxicity concerns, but has recently been reapproved at a new dose. Inotuzumab (anti-CD22) ozogamicin has been approved for the salvage treatment of acute lymphoblastic leukemia and is associated with a 17% risk of SOS after HSCT.
Transplantation related
In general, more intensive consolidating regimens and less well-matched transplants increase the risk of SOS. SOS is more common in fully myeloablative regimens than in reduced-intensity regimens, but has been described as a complication of autologous transplants. Use of fludarabine, cyclophosphamide, high-dose melphalan, and busulfan for consolidation have all been associated with SOS; intravenous administration of busulfan may decrease the risk because of improved pharmacokinetic profiling of the dose. High-dose or unfractionated total body irradiation increase SOS risk. Second HSCT transplant recipients are also at increased risk for SOS because of their larger cumulative chemotherapeutic and radiation burden.
Although SOS can occur in autologous SCT, it is much more common in allogeneic transplants. Unrelated donors, donors with a greater degree of human leukocyte antigen (HLA) mismatch, non-T cell depleted grafts, and peripheral blood stem cell transplants are all associated with an increased risk for development of SOS. , Posttransplant factors, such as choice of graft-versus-host disease (GVHD) prophylaxis, can also have an effect, with patients maintained on a calcineurin inhibitor, especially if given in combination with sirolimus and methotrexate, being at higher risk.
Clinical presentation
Patients present with volume overload, with ascites, and weight gain greater than 5% of baseline. They often have jaundice and painful hepatomegaly. Acute kidney injury is frequently a component and mimics the hepatorenal syndrome with hypotension, hyponatremia, and a low fractional excretion of sodium. Although most patients with SOS present with symptoms within the first 30 days of transplant, a subset of patients will develop late-onset disease. ,
Diagnostic criteria
There are two established clinical criteria for the diagnosis of SOS, the Baltimore and modified Seattle criteria ( Table 12.2 ). Recently, the European Society for Blood and Marrow Transplantation (EBMT) proposed updated criteria for adults and pediatrics to address the limitations of the Baltimore and modified Seattle criteria ( Table 12.3 ). The rationale for this update was multiple—there are now effective therapies for SOS, making prompt diagnosis critical, and advances in our understanding of risk factors and imaging techniques to aid in diagnosis. In addition, there is a growing recognition that “late” SOS is a more common presentation than previously thought and that pediatric manifestations of the disease differ significantly from those seen in adults.
Table 12.2
Clinical Diagnostic Criteria for Sinusoidal Obstruction Syndrome
| Modified Seattle criteria | Baltimore criteria |
|---|---|
| In the first 20 days after HCT, ≥ 2 of the following: | In the first 21 days after HCT, bilirubin ≥ 2 mg/dL plus ≥ 2 of the following |
| Bilirubin > 2 mg/dL | Painful hepatomegaly |
| Hepatomegaly or pain in right upper quadrant | Ascites |
| Weight gain (> 2% basal weight) | Weight gain |
HCT , Hematopoietic cell transplantation.
Table 12.3
Summary of British Committee for Standards in Haematology and British Society for Blood and Marrow Transplantation for the Diagnosis and Management of Sinusoidal Obstruction Syndrome
| Diagnosis | Should be based on clinical criteria (modified Seattle or Baltimore) |
| Ultrasound may be helpful | |
| Liver biopsy only in patients where SOS diagnosis unclear | |
| If performed, liver biopsy should be transjugular | |
| Risk factors | Patients should be assessed pretransplant for risk factors, and managed when possible |
| Prophylaxis | Defibrotide is recommended in children with risk factors |
| Defibrotide is suggested in adults with risk factors | |
| Prostaglandin E1, pentoxifylline, heparin, and antithrombin are not recommended | |
| Ursodeoxycholic acid is suggested | |
| Treatment | Defibrotide is recommended in children and adults |
| TPA and N-acetylcysteine are not recommended | |
| Methylprednisone may be considered with caveat for infectious risk | |
| Careful fluid management | |
| Early involvement of critical care specialists |
SOS , Sinusoidal obstruction syndrome; TPA , tissue plasminogen activator.
The modified Seattle criteria specify that within the first 20 days after transplant, a patient must have two or more of the following: bilirubin greater than 2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain (> 2% of baseline weight). The Baltimore criteria specify that within the first 21 days after transplant, a patient must have a bilirubin greater than 2 mg/dL plus two or more of the following: painful hepatomegaly, ascites, or weight gain (> 5% of baseline weight).
The new EBMT criteria for diagnosis of SOS in adults recognize two clinical entities: “classic” SOS and “late onset” SOS. Classic SOS by EBMT criteria presents within the first 21 days after transplant. Patients must have an elevated bilirubin level (≥ 2 mg/dL) and two of the following: painful hepatomegaly, weight gain more than 5% of baseline, or ascites. Late onset SOS is any patient with the classic presentation beyond day +21 or those with biopsy proven SOS; alternatively, any patient beyond day 21 after transplant with two or more of the following: bilirubin of 2 mg/dL or more, painful hepatomegaly, weight gain more than 5% of baseline, ascites, and hemodynamic or ultrasound findings suggestive of SOS (decrease in velocity or reversal of portal venous flow). Thrombocytopenia, although common in patients with SOS, is not an official part of the new diagnostic criteria.
The EMBT has also established new diagnostic criteria for children. In these criteria, there is no longer a time limitation for the onset of symptoms. Patients require any two or more of the following: unexplained and transfusion refractory thrombocytopenia, unexplained weight gain for 3 days despite diuretics or weight gain more than 5% of baseline, hepatomegaly, ascites, and rising bilirubin for 3 consecutive days or an absolute bilirubin of 2 mg/dL or more.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here