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Volume: 20 Issue: 7 July 2022

FULL TEXT

ARTICLE
Therapeutic Plasma Exchange in Pediatric Patients With Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease After Hematopoietic Stem Cell Transplantation: A Single-Center Experience

Objectives: Sinusoidal obstruction syndrome/veno-occlusive disease is a significant complication of hematopoietic stem cell transplantation. Due to high mortality rates, new treatment strategies have been investigated. Here, we have presented outcomes of therapeutic plasma exchange performed on patients with sinusoidal obstruction syndrome/veno-occlusive disease.
Material and Methods: Our study included 70 pediatric patients diagnosed with sinusoidal obstruction syndrome/veno-occlusive disease. Therapeutic plasma exchange procedures in patients were evaluated retrospectively.
Results: There were 9 mild (12.9%), 9 moderate (12.9%), 21 severe (30%), and 31 very severe (44.2%) cases of sinusoidal obstruction syndrome/veno-occlusive disease. Therapeutic plasma exchange was performed in 31 of the 70 study patients (59.6%). Moreover, 10/21 patients with severe (47.6%) and 21/31 patients with very severe (67.7%) disease underwent plasma exchange. Mean time from diagnosis of sinusoidal obstruction syndrome/veno-occlusive disease to therapeutic plasma exchange initiation was 2.3 days. The 31 patients who received therapeutic plasma exchange had a total of 146 sessions. Overall survival rates at 100 days were 87.1% and 92.3% for patients who did and did not undergo therapeutic plasma exchange, respectively. When patients with mild and moderate disease who were not expected to undergo plasma exchange were excluded (n = 52), 100-day overall survival rates were 87.1% and 90.5% for those who did and did not undergo plasma exchange, respectively. When we compared severe versus very severe groups, no significant difference was found.
Conclusions: Plasmapheresis had no positive effect on survival. However, overall survival in all groups was higher than that in the literature, despite the high number of patients with severe and very severe disease. Interpretation of the results is limited by the retrospective nature of the study. Thus, prospective, randomized controlled trials with larger numbers of patients are necessary to investigate the role of therapeutic plasma exchange in patients with sinusoidal obstruction syndrome/veno-occlusive disease.


Key words : Hematopoietic stem cell transplantation, Therapeutic plasma exchange

Introduction

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a serious complication of hematopoietic stem cell transplantation (HSCT), which is characterized by excessive weight gain, painful hepatomegaly, jaundice, and ascites. Because SOS/VOD may result in multiorgan failure and death, presence of this disease is defined as an emergency. The development of SOS/VOD has generally been associated with endothelial damage caused by the toxic effects of conditioning regimens in the presence of a previously damaged liver.1,2 Defibrotide, diuretics, and ursodeoxycholic acid are used for treatment. However, in response to high mortality rates, new treatment strategies have been investigated.3,4

Interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) are major cytokines produced by endothelial cells in SOS/VOD. Interleukin 1β and TNF-α induce the expression of various leukocyte adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. Also, the coagulation system is triggered by the release of proinflammatory cytokines, leading to increased circulating levels of von Willebrand factor, factor VIII, fibrin, fibrinogen, and thrombomo-dulin. Of note, TNF-α can induce a procoagulant environment with increased levels of plasminogen activator inhibitor-1, which is one of the most important antifibrinolytic proteins.5,6

Therapeutic plasma exchange (TPE) is a treatment modality that enables the removal of toxic metabolites, proinflammatory molecules, cytokines, coagulation factors, immune complexes, antibodies, and complement components from the circulation. Therapeutic plasma exchange is used as a supportive and even curative treatment option for many diseases.7,8 Because TPE can be used to extract circulatory components that trigger SOS/VOD, this treatment may be valuable to reduce the severity of disease or prevent progression. To our knowledge, there is no comprehensive study on the use of TPE in the treatment of SOS/VOD. Thus, we aimed to analyze the outcomes of TPE procedures performed on pediatric patients with SOS/VOD after HSCT.

Materials and Methods

Study design and data source
This was a single-center, retrospective study. From August 2014 to July 2020 in our transplant center, 680 patients underwent HSCT. A single investigator performed data collection from medical records, with data control performed by a second investigator. Local ethics approval was obtained. In total, 70 pediatric patients met the SOS/VOD criteria for study inclusion. Among these patients, we investigated those who underwent TPE due to SOS/VOD.

Criteria for diagnosis of sinusoidal obstruction syndrome/veno-occlusive disease
Before 2018, we had used the Baltimore and modified Seattle criteria for the diagnosis of SOS/VOD. After the new European Society for Blood and Marrow Transplantation (EBMT) criteria were defined, we started using these criteria. We separated medical records of patients who received treatment for SOS/VOD based on old versus new criteria according to the aforementioned dates. We subsequently applied the EBMT criteria to patients who had been diagnosed according to the Baltimore and modified Seattle criteria to confirm the diagnosis. Only patients who fulfilled the EBMT criteria were included in the study. All other patients or patients with missing information in their files were excluded from the study.

According to the EBMT, patients were diagnosed with SOS/VOD based on the presence of 2 or more of the following criteria: (1) unexplained consumptive and transfusion-refractory thrombocytopenia, (2) otherwise unexplained weight gain on 3 consecutive days despite the use of diuretics or weight gain exceeding 5% of the baseline value, (3) hepatomegaly exceeding baseline status, (4) ascites exceeding baseline status, or (5) bilirubin elevation from baseline value for 3 consecutive days or bilirubin ≥2 mg/dL within 72 hours. The severity of SOS/VOD (mild, moderate, severe, and very severe) was defined with respect to the following characteristics: liver function tests (LFTs), bilirubin levels, coagulation tests, duration of persistent refractory thrombocytopenia, ascites, and impairment of renal, pulmonary, and cognitive functions.1 Patients with severe or very severe disease had 1 of the following features: increase in LFT of >5 days, refractory thrombocytopenia lasting >7 days, bilirubin level ≥2 mg/dL, need for paracentesis, presence of impaired coagulation, and need for invasive pulmonary ventilation. Patients with severe SOS/VOD had glomerular filtration rate between 15 and 30 mL/min, and those with very severe disease had lower glomerular filtration rate values (<15 mL/min). Patients with very severe SOS/VOD also demonstrated new-onset cognitive impairment and required coagulation factor replacement in addition to all the aforementioned factors.

Prophylaxis and treatment approach
All patients received ursodeoxycholic acid for SOS/VOD prophylaxis. The decision of which patients should use defibrotide prophylaxis was given according to the patient’s diagnosis, transplant-related factors, conditioning regimen, and hepatic factors.4,9 If the patient had a diagnosis of thalassemia, neuroblastoma, or hemophagocytic lymphohistiocytosis, if the patient had haploidentical or a second transplant, if patients had used a busulfan-based regimen, and if patients had possible hepatic damage (ie, high transaminase level, iron overload, and biopsy-proven hepatic fibrosis), patients used defibrotide prophylactically at a dose of 16 mg/kg/day. Close control and management of fluid and sodium balance were applied to all patients. Patients used diuretics (furosemide and/or spironolactone) as a part of fluid control. Once patients were diagnosed with SOS/VOD, defibrotide was started at 25 mg/kg/day for those who did not receive prophylaxis, with a greater amount for patients who already received it.4,9 Oxygen support was provided according to respiratory parameters, and, if there was pleural effusion disrupting oxygenation, thoracentesis was performed. All patients who had massive ascites received paracentesis. Patients with renal failure received hemofiltration. Critically ill patients were hospitalized in the intensive care unit.

Plasmapheresis procedure
Therapeutic plasma exchange was given to all patients classified as SOS/VOD severe and very severe who were admitted to the intensive care unit because of clinical instability, who needed oxygen support, who had a very rapid increase in LFTs and bilirubin levels, who developed renal failure, and who had ≥2 criteria in the SOS/VOD grading. Table 1 presents criteria used for selecting patients for TPE. Centrifugation was used in the TPE procedure, and fresh frozen plasma was used as replacement fluid. Because of the high bleeding risk in patients with SOS/VOD because of impaired LFTs, prolonged coagulation tests, and low platelet levels, we preferred to use acid-citrate-dextrose as anticoagulant. To prevent citrate toxicity, patients were given sup-plementary calcium in the form of calcium gluconate. A 1-to-1.5 plasma volume exchange was applied.

Assessment of treatment response
A complete clinical response was defined as regression of edema, weight gain, hepatomegaly, disappearance of oxygen need, and relief of all signs and symptoms. A complete laboratory response was defined as normalization of bilirubin, LFTs, kidney function tests, and coagulation parameters (return to reference values for age). A complete response was defined as patients whose clinical and laboratory findings demonstrated complete improvement after treatment.

Statistical analyses
All clinical data were analyzed using IBM SPSS for Windows version 22. We used numbers and percentages to describe categorical variables. We used chi-square tests to compare distributions of discrete variables. P < .05 indicated significance. We defined transplant-related mortality (TRM) as death from causes unrelated to underlying disease (like relapse). We calculated survival rates using the Kaplan-Meier method.

Results

Patient characteristics
Seventy children diagnosed with SOS/VOD were included in the study. The mean age of the patients was 88 months (range, 7-220 months), and the girl-to-boy ratio was 1:2. The most common diagnosis was malignancy (including acute lymphoblastic leukemia, acute myeloblastic leukemia, and neuroblastoma) in 24 patients (34.3%). Hemoglobinopathies (n = 17, 24.3%), hemophagocytic lymphohistiocytosis (n = 10, 14.2%), immunodeficiencies (n = 6, 8.6%), and bone marrow deficiencies (n = 4, 5.7%) were also noted.

Diagnosis and severity grading of sinusoidal obstruction syndrome/veno-occlusive disease
The average time from HSCT to diagnosis of SOS/VOD was 13.5 days (range, 3-41 days). There were 9 mild (12.9%), 9 moderate (12.9%), 21 severe (30%), and 31 very severe (44.2%) cases of SOS/VOD.

Characteristics of patients who underwent therapeutic plasma exchange
Therapeutic plasma exchange was just administered only to patients diagnosed with severe or very severe SOS/VOD (ie, not to those with mild or moderate forms). Of 70 patients, 31 (59.6%) received TPE: 10 of 21 patients (47.6%) in the severe group and 21 of 31 patients (67.7%) in the very severe group. The median age of the patients who underwent TPE was 104 months (range, 19-220 months). There were a total of 146 TPE sessions in these 31 patients, with mean and median numbers of TPE procedures per patient of 4.7 and 3, respectively (range, 1-10). After diagnosis of SOS/VOD, plasmapheresis was performed in most patients (23/31) within the first 72 hours. The remaining patients (8/31) underwent TPE after 3 days. The average time to start of TPE for all patients was 2.3 days. When patients were compared according to the onset of TPE, the recovery period was 9.3 days for those who started treatment before 72 hours and 11.8 days for those who started treatment after 72 hours (not significant; P = .104). No adverse reactions related to the TPE procedure were encountered in any of the patients.

Survival analysis and comparison of groups according to plasmapheresis status
When we divided patients between groups who underwent TPE (TPE group; n = 31) and those who did not (non-TPE group; n = 39), we observed no difference in terms of age and sex (Table 2). Moreover, 29 of 31 patients who underwent TPE and 37 of 39 patients who did not had been using defibrotide prophylaxis before the diagnosis. There were no significant differences in terms of defibrotide prophylaxis between the TPE group and the non-TPE group. The 100-day overall survival (OS) rates were 87.1% and 92.3% in the TPE group and non-TPE group, respectively. In addition, the 1-year OS rates were 69.6% and 76.7% for the TPE group and the non-TPE group, respectively (P = .17). Transplant-related mortality rates at day 100 were 19.3% (5/31 died) for the TPE group and 10.2% (4/39 died) for the non-TPE group. The 1-year TRM rates were 38.7% (9/31 died) and 20.5% (8/39 died) for the TPE group and the non-TPE group, respectively (P = .094). The mean recovery time in the TPE group and non-TPE group was the same (9 days).

When we excluded the mild and moderate group of patients, there were 52 patients with severe (n = 21) and very severe (n = 31) disease. The 100-days OS rates were 87.1% (5/31 patients died) for patients who underwent TPE and 90.5% (2 of 21 patients died) for patients who did not. The 1-year OS rates were 69.6% (9/31 patients died) and 72.9% (5/21 patients died) for the TPE group and the non-TPE group, respectively (P = .15).

Because all patients who underwent TPE were in the severe and very severe groups, we compared these 2 groups in terms of survival according to their TPE status (Table 3). In the severe patient group, none of the patients who underwent TPE died within the first 100 days (OS of 100%). However, the 1-year survival rate was 88.9% (1/10 patients died). In the remaining patients in the severe group, the 100-day and 1-year OS rates were 81.8% (2/11 patients died) and 70.1% (3/11 patients died), respectively. There was no statistically significant difference between patients who received TPE or not in the severe group (P = .31). The Kaplan-Meier curve of the severe group is shown in Figure 1. The 100-day TRM rates were 0% in the TPE group and 18% (2/11 died) in the non-TPE group. The 1-year TRM rates were 10% (1/10 died) and 27.2% (3/11 died) in the TPE and non-TPE groups, respectively. There was no statistically significant difference in the severe group in terms of TRM (P = .07). In the severe group, complete remission was achieved in all patients in the TPE and non-TPE groups, and no patient died of SOS/VOD. When we excluded deaths other than from SOS/VOD, the OS at 100 days was 100%. In the severe group, the recovery times of patients with and without TPE were 9 and 9.8 days, respectively (P = .49).

In the very severe group, the 100-day OS rates were 81% (4/21 patients died) and 100% in the TPE and non-TPE groups, respectively. Figure 2 shows the Kaplan Meier curve of the very severe group. The 1-year OS rates were 60.7% (8/21 patients died) in the TPE group and 72.9% (2/10 patients died) in the non-TPE group. There was also no statistically significant difference in OS of the very severe group of patients (P = .27). In the same group, the 100-day TRM rates were 23.8% (4/21 died) and 0% in the TPE and non-TPE groups, respectively, and the 1-year TRM rates were 42.8% (8/21 died) and 20% (2/10 died) in the TPE and non-TPE groups, respectively (P = .09). In patients with very severe disease, 3 who underwent TPE died, whereas all patients who did not undergo TPE were alive. Thus, when we excluded deaths other than from SOS/VOD, the 100-day OS rates were 85.4% and 100% in the TPE and non-TPE groups, respectively. In patients with very severe disease, the recovery times with and without TPE were 8.2 and 8.9 days, respectively.

Discussion

The treatment of SOS/VOD includes supportive measures and intensive care in addition to specific therapy with defibrotide.10-12 Apart from these standard regimens, many treatment methods have been investigated. Corticosteroids, tissue plas-minogen activator, and N-acetylcysteine are not yet presently standard.13 Still, the mortality rate of patients who develop severe/very severe SOS/VOD after HSCT is very high. In a retrospective study published by the Italian Hematology-Oncology Association in 2019, the mortality rate at day 100 was 22%.14 In another study that included 1000 pediatric patients with allogeneic HSCT, Kernan and colleagues reported 100-day survival rate of 67.9%. This rate was noted to have decreased to 49.5% in patients with multiorgan insufficiency.15 With these results and because of the high incidence of SOS/VOD in patients using defibrotide prophylaxis as shown in our study, new treatment approaches are still needed.

The incidence of severe and very severe SOS/VOD in our study was higher than in other pediatric studies.14,16 This may have been because of the use of the revised EBMT criteria instead of traditional ones. Yoon and associates validated the EBMT criteria and found that most of their patients were categorized into the very severe group, and these patients were found to have significantly shorter OS than the others.17 Therefore, evidently, different treatment options are required for SOS/VOD, especially for patients with severe and very severe disease.

Therapeutic plasma exchange is a treatment modality with a continuously expanding list of indications.18 It has been reported to reduce the levels of inflammatory cytokines including IL-1α, IL-6, IL-8, TNF-β, and interferon gamma,19-21 adhesion molecules such as intercellular adhesion molecule 1,22 and procoagulant factors such as von Willebrand factor antigen in the plasma.23 The liver has a critical role in the clearance of bilirubin and ammonia, and accumulation of toxic metabolites may ultimately lead to hepatic failure in the SOS/VOD process.24 The theoretical concept of TPE in SOS/VOD combines 2 major aspects in 1 intervention: (1) removal of harmful circulating cytokines, bilirubin, and ammonia and (2) replacement of protective plasma proteins that compensate for the loss of factors important for fibrinolysis. This treatment approach saves time in all patient groups, in which cytokine release is thought to be effective in pathogenesis. Reports investigating the use of TPE for SOS/VOD in the literature are limited. We could find just a single case report in which the patient benefited from TPE.25 In this retrospective study, we tried to clarify this issue.

Therapeutic plasma exchange can be performed through 2 methods: centrifugal and membrane filtration type. In centrifugal TPE, whole blood is extracted from the body and centrifuged to separate cellular components from the plasma. The supernatant is then removed, and a replacement fluid mixed with the remaining blood is given back to the patient. During membrane filtration TPE, the patient’s blood is pumped through a fiber filter. The pores of the filter allow passage of plasma but not the cells in the blood. Therefore, the plasma is removed.26 We preferred to use centrifugal TPE because it is less selective in separating plasma, thereby enabling better removal of cytokines, adhesion molecules, and fibrinolytic agents, which are at the center of SOS/VOD pathogenesis. Our analysis of severe and very severe groups showed that TPE recipients had shorter recovery times than those without TPE; however, no statistically significant difference was found. In addition, we found no differences between groups with and without TPE in terms of TRM and OS in severe and very severe SOS/VOD. However, although most of our cases were classified as severe and very severe, OS was higher and TRM was found to be lower in the entire group of patients compared with results in previously published studies.14,15 Furthermore, TPE was performed in patients who had ≥2 criteria for severity grading or in patients in the severe and very severe groups who were clinically unstable. All of these criteria have led us to think that these patients could rapidly progress to multiorgan failure and that early intervention with TPE may be an advantage for this critical group of patients. However, this prediction requires extensive studies and supportive data before any conclusions can be drawn, particularly with respect to the overall efficacy of TPE in SOS/VOD. Future studies may benefit from assessing TPE as an additive treatment, with a view to determine whether it can be effective in alleviating the deleterious endothelial reaction in the liver.

Our study has some limitations. We retros-pectively evaluated all of our patients according to the modified EBMT criteria. Before the EBMT criteria were published, we had been using the Baltimore and modified Seattle criteria for the diagnosis of SOS/VOD. In addition, because of our retrospective study design, patients with severe and very severe disease could not be randomized for TPE treatment. Thus, it is not known how the prognosis would have been if plasmapheresis had not been applied to these patients, whose conditions were predicted to worsen quickly and progress to multiorgan failure. Therefore, various factors and differences (conditioning regimen, donor type, and other accompanying complications such as sepsis, viral infections, and drug toxicities) among patients with and without TPE may have altered the results.

Conclusions

Severe/very severe SOS/VOD is a clinical situation that is difficult to treat and still has a high mortality rate. In our study, we observed a lack of difference between the severe and very severe groups of patients and plasmapheresis had no significant effect on survival. We do not know what the prognosis would be in the absence of plasmapheresis. However, our OS rate was higher than that in the literature, despite the high number of patients with severe and very severe disease. Thus, prospective, randomized controlled trials with a larger number of patients are needed on this topic.


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Volume : 20
Issue : 7
Pages : 680 - 686
DOI : 10.6002/ect.2021.0475


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From the Department of Pediatric Hematology/Oncology & Bone Marrow Transplantation Unit, School of Medicine, Altunizade Hospital, Acıbadem University, Istanbul, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Burcu Akıncı, Department of Pediatric Hematology/Oncology & Bone Marrow Transplantation Unit, School of Medicine, Altunizade Hospital, Acıbadem University, Istanbul, Turkey
Phone: +90 505 8296116
E-mail: bdeveci@windowslive.com