Abstract
Objectives
Determine the effectiveness and cost of defibrotide in patients with severe hepatic sinusoidal obstruction syndrome following haematopoietic stem cell transplantation in a tertiary hospital.
Methods
A retrospective observational study. Adults or children treated with defibrotide at a mean dose of 6.8 mg/kg every 6 hours, until the total bilirubin levels are normalised, were included. Main endpoint was complete response, defined as normalised total serum bilirubin levels and resolution of multiple organ failure. Secondary endpoints were survival by 100 days post-transplant, influence of risks factors in effectiveness and cost of treatment.
Results
51 patients (36 adults and 15 children) received defibrotide; median dose of defibrotide administered was 25.19 mg/kg/day (10.0–100.3). Complete response was achieved in 19 (37.3%) patients. By 100 days post-transplant complete response was achieved in 18 (35.3%) patients and the survival rate was 29 (56.9%) patients. There were no significant differences in effectiveness between adults versus paediatrics and between patients who presented risk factors. The mean cost of treatment per patient was €32 916, mean costs in adults was €104 292 and €17 394 in children.
Conclusion
Regarding the results of our study, it is convenient to identify the patients who will be able to benefit from this treatment according to clinical conditions, medical history and prognosis. Given the great economic impact of defibrotide, we consider that more cost-effectiveness studies are required.
Trial registration number
EPA-OD, number LBM-DEF-2016-01
Keywords: sinusoidal obstruction syndrome, defibrotide, veno-occlusive disease, hematopoietic stem cell transplant, cyclophosphamide, busulfan
Introduction
Sinusoidal obstruction syndrome (SOS) of hepatic veno-oclusive disease is a pathology caused by toxic damage to sinusoidal endothelial cells and hepatocytes, caused mainly after exposure to high doses of conditioning chemotherapy used for the transplantation of haematopoietic progenitor cells. As a consequence of this process, obstruction occurs at the level of venules and hepatic sinusoids due to increased coagulability and decreased fibrinolytic activity.1–3
The current diagnosis is held according to established clinical criteria (Baltimore criteria, more restrictive, and Seattle) that are based on the onset of certain clinical manifestations during the first 21 days of the transplant: painful hepatomegaly, jaundice, fluid retention, increase of weight, oedema and ascites. This condition could present with multiorgan failure characterised by liver failure, renal failure with elevated creatinine, hepatic encephalopathy and respiratory failure.4–6
The incidence fluctuates depending on the type of transplant (autologous/allogeneic), the criteria used for the diagnosis, the conditioning chemotherapy regimen received and its intensity and the patient’s clinical condition. Generally, the average of the estimated prevalence is 14% and ranges between 5% and 60%.3 7 It is estimated that in patients with severe SOS, mortality can reach 90% on the day+100 of the transplant.8
Certain characteristics of the patient and factors related to the transplant procedure could lead to the development of SOS: liver disease prior to transplantation (elevation of transaminases, viral hepatitis), conditioning chemotherapy regimen (based on cyclophosphamide and/or busulfan and/or total body irradiation), type of transplant (allogeneic greater than autologous, myeloablative greater than reduced intensity), patient’s concurrent conditions, treatment with vancomycin, acyclovir, enzyme inhibitors (voriconazole) and in general hepatotoxic drugs may also increase the risk of SOS.9–11
Prognosis of SOS will depend on the severity of the pathology, according to elevation of bilirubin, elevation of transaminases, weight gain with respect to baseline, serum creatinine and clinical evolution. For its management, the patient will undergo support therapy based on liquid restriction, use of diuretics, analgesics, haemodialysis and paracentesis. Patients with mild or moderate SOS progress satisfactorily with supportive therapy. However, in patients with severe prognosis, the use of defibrotide is considered as an additional and safe measure, since the use of alteplase is related to the risk of haemorrhage.2
Defibrotide is an orphan drug authorised in October 2013 by the European Medicines Agency (EMA) and approved in March 2016 by the Food and Drug Administration (FDA) for the treatment of SOS in adults, children and infants over 1 month; it should be remarked that defibrotide has not yet been commercialised in Spain and it is ordered as foreign drug.12 13 According to the published multicentre studies, the benefit–risk ratio seems favourable.14 15 Its mechanism of action is unknown but it has been shown to have selective and protective effects on the endothelium of small vessels, with antithrombotic, anti-inflammatory and anti-ischaemic activity. It is administered intravenously and dosed at 6.25 mg/kg every 6 hours, until the total bilirubin levels are normalised.16
The objectives of the present study were to (1) determine the effectiveness of defibrotide in patients who developed SOS in a tertiary hospital, (2) analyse the association of risk factors of SOS with the effectiveness of defibrotide, (3) evaluate the effectiveness in different population groups (adults vs paediatrics) and (4) evaluate the cost of treatment per patient.
Methods
A retrospective observational study was designed in which adults and paediatric patients with SOS who had received defibrotide at a mean dose of 6.8 mg/kg every 6 hours, from January 2010 to March 2016 were included.
Table 1 defines the measurement of the results. The main endpoint of effectiveness analysed was the complete response (CR) defined as the decrease in total serum bilirubin at baseline values and the resolution of multiple organ failure associated with SOS. Complete response was measured after defibrotide withdrawal (CR1) and at 100 days post-transplant (CR2). The resolution of multiorgan failure is defined as the decrease in creatinine at baseline values and/or dialysis withdrawal, resolution of oxygen requirement dependency and the absence of encephalopathy. Baseline levels were considered as serum bilirubin less than 2 mg/dL and creatinine less than 1 mg/dL.
Table 1.
Endpoints
| Definition | |
| CR1 | Decrease in total serum bilirubin at baseline values and the resolution of multiple organ failure after defibrotide treatment. |
| CR2 | Decrease in total serum bilirubin at baseline values and the resolution of multiple organ failure at 100 days post-transplant. |
| Day-100 survival | Survival at 100 days post-transplant. |
| Risk factors | Elevation of transaminases before receiving chemotherapy and chemotherapy based on busulfan and/or cyclophosphamide. |
| Cost | Defibrotide cost of treatment per patient |
CR, complete response.
Secondary endpoints included: percentage of survival at 100 days post-transplant, influence of risk factors on the effectiveness of the treatment (elevation of transaminases before receiving chemotherapy and chemotherapy based on busulfan and/or cyclophosphamide) and cost of treatment per patient.
Endpoints were obtained from the clinical history of the patients; vital signs during admission were consulted in Gacela-HIS programme; chemotherapy regimen was obtained from Oncofarm-farmis database; treatment with defibrotide was collected from the historical electronic prescriptions of the single dose management programme of Farmatools.
Cost per patient was estimated from the administered doses. The doses prescribed were captured from the historical electronic prescriptions; the mean administered dose was 361.5 mg/daily (30–800). Each vial contains 200 mg and the cost pervial in Spain was €443.
A descriptive statistical analysis was carried out through the statistical data processor SPSS V.13.0; quantitative variables are shown as mean±SD or median and 25–75 percentiles according to their distribution; qualitative variables are shown as percentage. For the comparative analysis of the qualitative variables, the Χ2 test and Fisher’s test were used.
Results
A total of 51 patients were treated with defibrotide after clinical evidence of SOS: 36 adults (five women and 31 men) and 15 paediatric patients (eight women and seven men). The average age of the adult population was 47.64±13.25 years, and the average age of the paediatric population was 6.69±5.78 years (table 2).
Table 2.
Characteristics of patients
| N | Value* | |
| Patients included in the study | ||
| Mean age (years) | 51 | |
| Adults | 36 | 47.64±13.25 years |
| Children | 15 | 6.69±5.78 years |
| Gender (%) | ||
| Male | 38 | 74.5% |
| Female | 13 | 25.5% |
| Graft (%) | ||
| Autologous | 8 | 16% |
| Allogeneic | 40 | 78% |
| UCB | 3 | 6% |
| Diagnosis (%) | ||
| LMA | 14 | 27.45% |
| LLA | 7 | 13.72% |
| Non-Hodgkin’s lymphoma | 11 | 21.56% |
| Hodgkin’s lymphoma | 4 | 7.84% |
| Other leukaemia | 7 | 13.72% |
| Other syndromes | 8 | 15.68% |
| Patients with sinusoidal obstruction syndrome before defibrotide administration | ||
| Bilirubin (mg/dL) | 51 | 3.2 (1.85–5.26) |
| Creatinine (mg/dL) | 51 | 0.9 (0.58–1.23) |
| Oxygen requirement (%) | 45 | 35.6% |
| AST and ALT >50 U/L (%) | 51 | 34% |
| Defibrotide onset (median- day) | 51 | 16 (13–19) |
| Median duration of defibrotide treatment (days) | 51 | 11 (4–14) |
| Median dose administered (mg/kg/day) | 51 | 25.19 (10.0–100.3) |
*Quantitative variables are shown as mean±SD or median and 25–75 percentiles according to their distribution; qualitative variables are shown as percentage.
AST, aspartate transaminase; ALT, alanine transaminase; LLA, acute lymphoid leukaemia; LMA, acute myeloid leukaemia; UCB, umbilical cord blood.
Median onset of defibrotide after receiving conditioning chemotherapy was 16 (13–19) days. Treatment was maintained until resolution of symptoms (resolution of ascites, normalisation of portal flow and total serum bilirubin). Median duration of defibrotide therapy was 11 (4–14) days. Median dose administered was 25.19 mg/kg/day.
Before receiving defibrotide, the average serum bilirubin was 3.2 (1.85–5.26) mg/dL, average serum creatinine was 0.9 (0.58–1.23) mg/dL and 45 patients (35.6%) required oxygen administration.
After ending treatment with defibrotide in 19 patients (37.3%), complete response was reached, CR1, with a mean bilirubin of 1.24 mg/dL (SD±0.44) and a mean creatinine of 0.89 mg/dL (SD±0.50). Twenty-six patients (51%) did not reach complete response with a mean bilirubin of 7.1 mg/dL (SD±4.51) and a mean creatinine of 1.43 mg/dL (SD±0.94). It was observed that six (11.8%) of the patients who received defibrotide did not present diagnostic criteria for SOS (ascites, weight gain, hepatomegaly, bilirubin >2 mg/dL, renal dysfunction, multiorgan failure) before initiating therapy with defibrotide (table 3).
Table 3.
Study results
| Complete response 1 | Complete response 2 | 100-day survival | P values | |
| Total patients, n=51 | 19 (37.3%) | 18 (35.3%) | 29 (56.9%) | |
| Adults, n=36 | 14 (38.9%) | 12 (33.3%) | 18 (50%) | >0.05 |
| Paediatrics, n=15 | 5 (33.3%) | 5 (33.3%) | 11 (73.3%) | > 0.05 |
| Chemotherapy based on busulfan and/or cyclophosphamide, n=30 | 13 (43.3%) | 12 (40%) | 17 (56.7%) | > 0.05 |
| No chemotherapy based on busulfan and/or cyclophosphamide, n=21 | 6 (28.61%) | 6 (28.61%) | 12 (57.14%) | > 0.05 |
| Previous elevation of transaminases, n=17 | 5 (29.41%) | 5 (29.41%) | 10 (58.8%) | > 0.05 |
| No previous elevation of transaminases, n=34 | 14 (41.2%) | 13 (38.23%) | 19 (54.5%) | > 0.05 |
At 100 days posthematopoietic transplant, 18 patients (35.3%) reached CR2, with a mean bilirubin of 0.73 mg/dL (SD±0.32) and a creatinine of 0.87 mg/dL (SD±0.47). Twenty-six patients (51%) did not respond with an average of bilirubin of 3.26 mg/dL (SD±1.66) and creatinine of 0.94 mg/dL (SD±0.52).
At 100 days posthematopoietic transplantation, 29 patients (56.9%) of the total number of patients evaluated were alive.
According to published studies, exposure to busulfan and/or cyclophosphamide is related to the development of SOS.9–11 In our study, 30 patients (58.8%) received conditioning chemotherapy regimen with busulfan or/and cyclophosphamide. Of these 30 patients, after ending treatment with defibrotide, 13 patients (43.3%) reached CR1. At 100 days posthematopoietic transplant, 12 of these patients (40%) reached CR2 and 17 patients survived (56.7%). Of the 21 (41.2%) patients not exposed to busulfan or/and cyclophosphamide, six (28.61%) reached the CR1 after treatment with defibrotide and six (28.61%) reached the CR2 at 100 days of posthematopoietic transplantation and 12 patients (57.14%) survived. There were no significant differences (p>0.05) for the variables analysed between the group exposed to risk chemotherapy and the one not exposed.
Elevated levels of transaminases prior to conditioning chemotherapy is another risk factor associated with the development of SOS.9 10 In our study, 17 (34%) patients showed elevated transaminase levels previously. Of these 17, after ending treatment with defibrotide, five patients (29.41%) reached CR1. At 100 days posthematopoietic transplantation, five (29.41%) patients reached CR2 and 10 patients survived (58.8%). According to the blood tests, 34 patients did not present high levels of transaminases previously. In this subgroup, 14 patients (41.2%) achieved CR after ending treatment. Of these 34 patients, after 100 days posthematopoietic transplantation, CR2 was achieved in 13 patients (38.23%) and 19 patients survived (54.5%). There were no significant differences (p>0.05) for the variables analysed between the groups with and without transaminase elevation prior to the chemotherapy treatment.
From the 15 paediatric patients, CR1 was reached after defibrotide treatment in five of the paediatric patients (33.3%), the CR2 at 100 days posthematopoietic transplantation was achieved in five patients (33.3%) and 11 patients survived (73.3%). Of the 36 adult patients, 14 adults (38.9%) reached the CR1 after defibrotide treatment; at 100 days posthematopoietic transplantation, 12 adult patients (33.3%) reached the CR2 and 18 adults survived (50%). No significant differences were found (p>0.05) comparing both population groups for the variables analysed.
The average cost of treatment per patient was €32 916 (95% CI 24 293 to 41 539), mean costs in adults was €104 292 and in children was €17 394. Of the total number of patients treated, CR1 37.3% and CR2 35.3%. Therefore, to achieve a CR1 and a CR2, it was necessary to treat three patients; according to the average cost per patient, it would represent a cost of €98 747 for each complete response achieved in both 100 days post-transplant.
Discussion
According to the published clinical trials, the efficacy of defibrotide patients reach the complete response between 30% and 60% and survive between 35% and 65% at 100 days post-transplant.17–19 In our study, similar results were achieved: complete response was reached in 37.3% patients after ending defibrotide treatment and in 35.3% patients at 100 days posthaematopoietic transplant; survival at 100 days post-transplant was 56.9%. According to a multicenter observational study of 710 patients, survival at 100 days post-transplant was 54% and showed that the optimal dose with the highest survival rate (58%) was 25 mg/kg/day.15
Defibrotide, in paediatric population, is more effective in reaching complete response and the percentage of patients who survive 100 days post-transplant is higher compared with the adult population.17 19 20 However, a multicenter phase II study, which included 101 adults and 48 paediatrics, showed significant differences in the paediatric population in the 100 day post-transplant survival rate (70% vs 36%; p=0.02).21 In our study, the percentage of paediatric patients who achieved the complete response was similar, and the percentage of paediatric patients who survived was higher than adults. However, the sample size between both population groups was small and the distribution was not homogeneous; thus, no significant differences were reached.
Risk factors of SOS might impair the patient’s prognosis.9–11 In our study, as the sample size was small, no significant statistical differences were obtained when analysing the effectiveness of defibrotide according to the risk factors that the patients gathered. At this time, there are no published studies that have analysed the effectiveness of defibrotide according to the characteristics and prognosis of patients; more studies are needed to identify the patients who would benefit most from this therapy.
The limitations of our study are mainly characterised because the sample collected from the population is small; as it is an orphan drug, the incidence of patients candidates to receive defibrotide is low; the study population is not homogeneous due to the difference in the number of adult patients compared with the paediatric population; it is a retrospective study. The aforementioned justifies why no significant differences were found among the population groups analysed.
In our study from 2010 to 2016, there were 51 patients with SOS who received defibrotide, mean seven patients per year. However, considering the great economic impact of this treatment, some studies have shown that defibrotide is not cost-effective on prophylaxis or on treatment of SOS.22–25 However, a recently published study, which included 134 patients, shows that defibrotide is cost-effective, since the total cost of haematopoietic transplantation is much higher compared with the cost of defibrotide, considers that defibrotide provides an important survival advantage and the quality adjusted life years gained lead to defibrotide being profitable with respect to the total cost of the transplant.22 In our hospital, the average annual cost is €260 344. According to the consumption data provided by the Spanish Agency of Medicines and Products from 2010 to 2014, the consumption of defibrotide in Spain remained constant, the average of packages dispensed was 1094 (95% CI 1046 to 1142) and the average of the expenditure was €4 846 420 (95% CI 4 633 703 to 5 059 136). However, in 2015, the consumption of defibrotide increased by 70.2% compared with the previous years assuming an increase in expenditure of €3 402 240.26
Conclusion
Regarding the results of our study, we consider that it is convenient to identify the patients who will be able to benefit from this treatment according to clinical conditions, medical history and prognosis.
It should be outlined that this drug has not yet been commercialised in Spain despite having received the authorisation by the EMA in 2013 and by the FDA in 2016. Given the great economic impact of defibrotide, we consider that more cost-effectiveness studies are required.
What this paper adds.
What is already known on this subject
According to clinical trials, the efficacy of defibrotide patients reach the complete response between 30% and 60% and survive between 35% and 65% at 100 days post-transplant.
In a multicenter non-interventional study, the 54% of the patients survive at 100 days post-transplant.
At this time, there are no published studies that have analysed the effectiveness of defibrotide according to the characteristics and prognosis of patients.
There are few cost-effectiveness studies despite the great economic impact of defibrotide.
What this study adds
A non-interventional study that analyses the effectiveness of defibrotide in a tertiary hospital; one of the endpoints is to assess the influence of risks factors.
This study provides a vision of the great economic impact in the Spanish health system due to the procedure of authorisation as an orphan drug.
Acknowledgments
Compasionate Drugs Clinical department of AEMPS and stadistic department of Hospital Universitario La Paz.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent: Not required.
Ethics approval: This study was approved by the Clinical Research Ethics Committee of the University Hospital La Paz on 10 November 2016, by the Research Commission of the Health Research Institute of the University Hospital La Paz-IdiPAZ on 26 April 2016 and by the department of Pharmacoepidemiology of the Spanish Agency of Medicines and Health Products on 19 April 2016.
Provenance and peer review: Not commissioned; externally peer reviewed.
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