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The goal of this study was to evaluate the incidence, inpatient mortality, and economic burden of hepatic veno-occlusive disease (VOD) in adults with B-cell acute lymphoblastic leukemia (ALL) in the United States.
Methods
Using MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database, data for patients with B-cell ALL from April 1, 2009, to October 31, 2016, were extracted by using diagnosis codes. VOD was identified based on clinical criteria and expert opinions. Patients with VOD were followed up from diagnosis of VOD until the earliest occurrence of inpatient death, end of continuous enrollment, end of study period, or for a maximum of 100 days. The incidence of VOD and VOD-associated inpatient mortality were calculated. VOD-related health care costs based on paid adjudicated claims were calculated.
Findings
Of the 2571 adults with B-cell ALL, the overall incidence of VOD was low at 3.4% (88 of 2571). Of these patients with VOD, 52% (46 of 88) experienced multiorgan failure and were identified as having severe VOD. VOD was only identified in patients having undergone hematopoietic stem cell transplantation (5.4% [88 of 1624]). The inpatient mortality rate of those with any VOD over the 100-day postindex period was 26.1%, and the inpatient mortality was even higher for patients with severe VOD (37.0%). Total mean (SD) medical costs per patient during the 100 days’ post-VOD diagnosis were $55,975 ($160,335); mean (SD) costs per patient were ∼4-fold higher for severe ($86,953 [$206,906]) versus nonsevere ($22,047 [$72,847]) VOD.
Implications
Clinical criteria were used to identify VOD events and thus VOD might be underdiagnosed. The mortality of VOD also might be underestimated because only inpatient deaths are captured in the data. The incidence and mortality of VOD could also be underestimated because we focused on adult patients who might receive reduced-intensity treatment. The economic burden of VOD may be underestimated because the Healthcare Common Procedure Coding System code specific for defibrotide was not available, and thus the cost for defibrotide might not be included. Finally, as the study population consisted of patients with commercial or Medicare supplemental insurance, results may not be generalizable to all patients with VOD in the United States. Although VOD occurred infrequently in adults with B-cell ALL, it was associated with high inpatient mortality and substantial costs. Patients with severe VOD were associated with highest mortality and highest costs. Given the clinical and economic burden associated with VOD, it is important that patients at high risk for VOD be identified and treated to minimize this risk.
Acute lymphoblastic leukemia (ALL) is a rare disease that affects lymphoblasts derived from lymphoid stem cells. Because of its acute nature, ALL is rapidly fatal without treatment.
Based on an American Cancer Society report, ∼5970 new cases (3350 male subjects and 2620 female subjects) and 1440 deaths are estimated in the United States in 2017.
Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol.
However, the prognosis for relapsed and refractory adult ALL is very poor. More than 90% of patients eventually die, with a median overall survival of 3 to 6 months and 5-year overall survival of ∼7%.
Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration.
Before newer antibody–drug conjugates and immunotherapies became available, treatments for ALL included multiagent chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) in suitable candidates.
Patients undergoing HSCT are at risk for potential life-threatening complications, including hepatic veno-occlusive disease (VOD). The reported incidence of VOD after HSCT varies widely among patient populations and ranges from 0% to >60%.
The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade.
Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen.
Severe VOD, often characterized by multiorgan failure (MOF), has a reported mortality rate of ≥60% by day 100. Known risk factors for VOD may broadly be grouped as transplant related, patient and disease related, and hepatic related.
Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives—a position statement from the European Society for Blood and Marrow Transplantation (EBMT).
VOD reportedly develops in patients receiving chemotherapy and monoclonal antibody therapy in the absence of HSCT, particularly after treatment with antibody–ozogamicin conjugates.
Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study.
Idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) for untreated patients with high-risk MDS or AML evolved from MDS: a phase II study from the EORTC and GIMEMA Leukemia Groups (protocol 06013).
However, the risk for VOD with agents such as inotuzumab ozogamicin (inotuzumab) and gemtuzumab ozogamicin seems to be greatest when these agents are used before or after HSCT.
In a randomized, Phase III trial that compared inotuzumab versus standard of care in adults with relapsed or refractory B-cell ALL, VOD occurred in 11% of the patients who received inotuzumab and in 1% of the patients who received standard of care.
was approved by the US Food and Drug Administration in 2016 but was available in the United States through the expanded-access protocol starting in 2007.
Previous studies reported a wide range of incidence of VOD using literature review and single institution chart review, but to the best of our knowledge, no peer-reviewed papers have investigated the incidence of VOD in the real-world setting using large-scale claims databases. In addition, the economic burden of VOD in patients with B-cell ALL has not been reported in the published literature. Quantifying the impact of VOD provides insights into VOD risk management and the value of new treatment options for B-cell ALL. The goal of the present study therefore was to investigate the incidence, inpatient mortality, and economic burden of VOD among adults with B-cell ALL in the United States.
Materials and Methods
Data were derived from the 2008 to 2016 MarketScan Commercial Claims and Encounters (Commercial) Database and MarketScan Medicare Supplemental and Coordination of Benefits (Medicare) Database (Truven Health Analytics, an IBM Company, Ann Arbor, Michigan). The MarketScan commercial database contains the inpatient, outpatient, and outpatient prescription drug experience of ∼132.0 million employees and their dependents, covered under a variety of fee-for-service and managed care health plans, including exclusive provider organizations, preferred provider organizations, point of service plans, indemnity plans, and health maintenance organizations. The MarketScan Medicare database contains the health care experience (both medical and pharmacy) of ∼9.9 million retirees with Medicare supplemental insurance paid for by employers. Both the Medicare-covered portion of payment (represented as coordination of benefit amount) and the employer-paid portion are included in this database. Both the MarketScan commercial and Medicare databases provide detailed cost, use, and outcomes data for health care services performed in inpatient and outpatient settings. The medical claims are linked to outpatient prescription drug claims and person-level enrollment data through the use of unique enrollee identifiers.
The identification of adults with B-cell ALL and VOD events in the MarketScan databases is detailed in Figure 1. From April 1, 2009, to October 31, 2016, data were extracted for patients with at least 1 inpatient claim or 2 nondiagnostic outpatient claims ≥30 days apart of any ALL diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification codes 204.00/204.01/204.02; International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes C91.00/C91.01/C91.02). All patients were required to have at least 1 hospitalization with Diagnosis Related Group in 834 to 839 on or after the first ALL diagnosis, be aged ≥18 years, and have at least 6 months of continuous enrollment before the first ALL diagnosis date. Patients with claims for medications (ie, nelarabine) for T-cell ALL during the study period were excluded.
Figure 1Identification of adults with B-cell acute lymphoblastic leukemia (ALL) and veno-occlusive disease (VOD) events in the MarketScan databases. Data were extracted based on inpatient and outpatient claims. *International Classification of Diseases, Ninth Revision, Clinical Modification codes 204.00 to 204.02 and International Classification of Diseases, Tenth Revision, Clinical Modification codes C91.00 to C91.02 from April 1, 2009, to October 31, 2016 (ALL index date = first observed ALL diagnosis date). †Diagnosis Related Group codes 834 to 839. ‡VOD index date = first observed VOD diagnosis or defibrotide) prescription date or hematopoietic stem cell transplantation (HSCT) admission date for patients undergoing HSCT. §One or more nondiagnostic claims for at least 2 different symptoms in any position during the HSCT inpatient stay or within 60 days (VOD symptoms include ascites, abnormal weight gain, hyperbilirubinemia, or hepatomegaly) (n = 132) or ≥1 multiorgan failure (MOF) and liver failure nondiagnostic claims in any position during the HSCT inpatient stay or within 60 days (n = 34). GVHD = graft-versus-host disease; TPN = total parenteral nutrition.
and expert opinions. The diagnosis of VOD was established based on one of the following criteria: (1) a ICD-10-CM code specifically for VOD diagnosis (K76.5); (2) a prescription for defibrotide sodium, which is indicated in the United States for the treatment of VOD; (3) at least 2 VOD symptoms from either the Baltimore or Seattle criteria
The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade.
for VOD (ie, ascites, abnormal weight gain, hyperbilirubinemia, or hepatomegaly) within 60 days’ post-HSCT admission; or (4) MOF with liver failure within 60 days’ post-HSCT admission. The VOD index date was the first observed VOD diagnosis date, defibrotide prescription date, or HSCT admission date. Patients receiving HSCT were excluded if they had evidence of chronic graft-versus-host disease at any time before or 100 days after the VOD index date, or if they had acute graft-versus-host disease or total parenteral nutrition cholestasis during 60 days before or 100 days after the VOD index date. Patients with severe VOD were defined as those with MOF.
The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade.
Patients with VOD were followed up until the earliest occurrence of inpatient death, end of continuous enrollment, end of the study period (October 31, 2016), or for a maximum of 100 days’ postindex date. The International Classification of Diseases, Ninth Revision, Clinical Modification/ICD-10-CM diagnosis and Current Procedural Terminology codes used to identify VOD are summarized in the Supplemental Table (see in the online version at doi:https://doi.org/10.1016/j.clinthera.2018.08.005).
Analyses were conducted to examine the incidence of VOD in patients with B-cell ALL, the incidence of VOD in patients with B-cell ALL after HSCT, VOD-related inpatient mortality during 100 days’ post-VOD diagnosis in patients with B-cell ALL, and the VOD-related costs incurred during the 100 days’ post-VOD diagnosis. Health care costs were based on paid amounts of adjudicated claims, including health plan payments and patient cost-sharing in the form of copayment, deductible, and coinsurance. All cost measures were adjusted for inflation by using the medical component of the Consumer Price Index and standardized to 2016 dollars. Health care costs were calculated over the 100-day postindex period for all patients with VOD and separated according to VOD severity status. The VOD-related costs were identified by using medical claims with diagnosis codes for VOD, VOD symptoms (ie, hyperbilirubinemia, hepatomegaly, ascites, abnormal weight gain), VOD-related medication (ie, defibrotide sodium), and MOF codes (for severe VOD). VOD-related diagnosis can be in any position (ie, primary or secondary diagnoses) in the inpatient and outpatient setting. For VOD-related hospitalizations, the following approach was used: if VOD was the primary diagnosis, then the total inpatient cost was attributed to the VOD event; if VOD was the secondary diagnosis, then the inpatient cost associated with the VOD-related claims was attributed to the VOD event. In addition, VOD-related length of stay (LOS) during 100 days’ post-VOD diagnosis was also calculated.
Descriptive statistics were used to summarize patient demographic and clinical characteristics, and all outcomes, including costs. Continuous measures are presented as mean (SD) and median. Categorical measures are presented as counts and percentages.
Results
A total of 2571 patients with B-cell ALL were identified. Of these patients, 88 (3.4%) had VOD; 46 (52%) experienced MOF and were classified as severe VOD. Of the B-cell ALL population, 1624 (63.2%) received HSCT. VOD only occurred after HSCT, for a VOD rate of 5.4% (88 of 1624) among HSCT recipients.
The characteristics of patients with VOD were generally similar to those of the B-cell ALL population (Table I). The mean age of patients with VOD was slightly younger than the overall B-cell ALL population (44.2 vs 50.1 years, respectively), with a greater imbalance in VOD rates in the youngest (18–24 years, 18.2% VOD vs 11.2% B-cell ALL) and oldest (≥75 years, 2.3% VOD vs 7.0% B-cell ALL) age groups, which is consistent with the expectation that younger patients are more likely to receive HSCT due to better tolerance to pre-HSCT treatment and HSCT.
Table IPatient characteristics. Demographic characteristics were reported as of index date (acute lymphoblastic leukemia [ALL] index date or veno-occlusive disease [VOD] index date), and the Deyo-Charlson Comorbidity Index was measured during the 6-month period before the index date.
The inpatient mortality rates over 100 days after VOD diagnosis for patients with B-cell ALL were 26.1% (23 of 88 deaths), 37.0% (17 of 46), and 14.3% (6 of 42) for all VOD, severe VOD, and nonsevere VOD, respectively. In comparison, the overall inpatient mortality rate during the study period for patients with B-cell ALL was 20.2% (519 of 2571) (Figure 2). The mean (SD) total medical cost associated with VOD during the 100-day post-VOD diagnosis period per patient was $55,975 ($160,335), with the mean (SD) per patient cost ∼4-fold higher for severe ($86,953 [$206,906]) versus nonsevere ($22,047 [$72,847]) VOD; inpatient costs account for 98% of total medical costs, and most of the medical costs were paid by health plans (Table II). The overall mean (SD) VOD-related LOS per patient was 39.3 (33.0) days; LOS was 49.2 (36.8) days for patients with severe VOD and 28.5 (24.3) days for those with nonsevere VOD.
Figure 2Inpatient mortality among ALL patients and ALL patients with VOD. Inpatient mortality for ALL patients with VOD was calculated over 100 days post VOD index date. Inpatient mortality for ALL patients was calculated during the entire follow-up period. ALL = acute lymphoblastic leukemia.
In this retrospective analysis using 2008–2016 MarketScan data, the overall incidence of VOD in patients with B-cell ALL was low at 3.4%, and VOD was exclusively identified in patients who had received HSCT, with an incidence of 5.4% among HSCT recipients. About one half of these cases were severe VOD with MOF. Very similar results were obtained using 2009–2014 Premier Research data.
In patients undergoing HSCT and not limited to those with ALL, the estimated incidence of VOD in patients receiving HSCT was also 5.4%, with 46% of patients with VOD identified as having severe VOD. Earlier estimates of VOD incidence among patients receiving HSCT were higher. A single institution chart review (n = 845) between 1995 and 2008 found that the incidence of VOD was 8.8% with Baltimore diagnostic criteria and 13.8% with Seattle diagnostic criteria.
The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade.
Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen.
A meta-analysis of studies published between 1979 and 2007 reported a VOD incidence of 13.7% (17.3% and 9.6% based on the Seattle and Baltimore diagnostic criteria, respectively).
Although potentially biased, the decline in VOD seen with recent data might be the result of technical progress, such as the increased use of reduced-intensity conditioning (RIC) before HSCT.
The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade.
may adversely affect VOD incidence. As the mechanism of VOD along with best practices to avoid VOD need to be better understood, future studies should explore the real-world incidence of VOD associated with therapies such as inotuzumab.
The inpatient mortality rates in the present study were similar to those observed in the claims database analysis by Dvorak et al (37.0% and 39.6% for severe VOD, respectively).
estimated an overall mortality from severe VOD of 84.3%, and 15 of the 19 studies reported a mortality rate >75% when only supportive care was available. Tsirigotis et al
Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen.
reported a 100% mortality rate with severe VOD. The mortality rates of severe VOD observed in recent studies were well below the estimates in the literature, which might be due to the increasing use of defibrotide.
The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade.
Although the overall incidence of VOD was low, the inpatient mortality rate for adults with B-cell ALL VOD in the present study was higher than the overall inpatient mortality rate for patients with B-cell ALL (26.1% vs 20.2%) during the follow-up period, indicating that VOD is adding additional burden to patients with B-cell ALL.
The occurrence of VOD in patients with B-cell ALL was associated with substantial economic burden. As seen in our analysis, the VOD-related costs were notably high at $55,975 per patient ($86,953 for severe VOD; $22,047 for nonsevere VOD). In a single institution study between 2000 and 2004 of patients with hematologic malignancies who underwent an HSCT, VOD (any severity, n = 35) was associated with an incremental cost of $53,009.
A Model estimating indirect costs of premature death associated with severe hepatic veno-occlusive disease (sVOD) among hematopoietic stem cell transplant (HSCT) patients in the United States (U.S.).
In a study using the Premier Research Database between 2009 and 2014 of all patients undergoing HSCT (severe VOD, n = 134; nonsevere VOD, n = 157; no VOD, n = 5127), median adjusted total hospitalization costs (including costs unrelated to VOD) were higher for patients with either severe VOD ($140,653) or nonsevere VOD ($107,939) compared with patients not experiencing VOD ($98,951).
In their adjusted analysis, costs of the patients with nonsevere VOD and the patients with severe VOD were $8988 and $41,703 higher than the costs of non-VOD patients, respectively. For a broader perspective on the burden associated with VOD, an Excel-based model (Microsoft Corporation, Redmond, Washington) was developed to estimate the indirect costs associated with premature death resulting from severe VOD after HSCT. This model estimated that severe VOD in the HSCT population led to 361 excess deaths with indirect costs of $68 million resulting from reduced life expectancy and subsequent productivity loss.
A Model estimating indirect costs of premature death associated with severe hepatic veno-occlusive disease (sVOD) among hematopoietic stem cell transplant (HSCT) patients in the United States (U.S.).
Although the cost of VOD is high, it is not unexpected because the diagnosis of VOD almost universally results in inpatient hospitalization. Given the substantial clinical and economic burdens associated with VOD, it is important that patients at high risk for VOD be identified and treated to minimize this risk.
The present study had several limitations. First, because the identification of VOD events in this retrospective study was mainly based on clinical criteria rather than specific diagnosis codes (specific ICD-10-CM code was only available after October 2015 and thus might be underreported), the incidence of VOD may be underestimated. Second, mortality rate of VOD might be underestimated because only inpatient death can be captured in the data. In addition, this study focused on the adult patient population, and >60% of the study population were aged >45 years. Because intensive treatment is usually not well tolerated by older patients, the study patient population could be biased toward receiving reduced pre-HSCT treatment and RIC before HSCT, which might have contributed to the lower incidence and lower morality rate of VOD observed in this study compared with earlier studies. Future studies may include pediatric patients and investigate the impact of RIC on the risk of VOD. Third, the current VOD economic burden may also be underestimated in patients with B-cell ALL because a Healthcare Common Procedure Coding System code for defibrotide sodium was not available. Consequently, no patients with defibrotide use were identified, and thus the cost for defibrotide might not be included. Uncaptured inpatient defibrotide use for VOD management is suggested by the lower mortality rate of severe VOD observed in this study compared with earlier estimates. Inpatient defibrotide costs would be captured in the overall inpatient costs. Nonetheless, future studies with more recent data are needed to fully account for the economic burden of VOD in the United States. Finally, the study population consisted of patients with commercial or Medicare supplemental insurance; thus, the results may not be generalizable to all patients with VOD in the United States, especially those with insurance plans not covered in the data or those without insurance.
Conclusions
In this retrospective study of >2500 adults with B-cell ALL, VOD was a rare event associated with high inpatient mortality. The economic burden, especially for patients with severe VOD, was substantial. The mean total medical cost per patient over 100 days’ post-VOD diagnosis was $55,975 for any form of VOD. For patients with severe VOD, the cost was even higher at $86,953. Given the clinical and economic burden associated with VOD, it is important that patients at high risk for VOD be identified and treated to minimize this risk.
Acknowledgments
All authors were involved in the conception and design, interpretation of the data, and critical revision of the manuscript for intellectual content. Dr. Zhang participated in writing of the manuscript. Drs. Song, Lopez-Gonzalez, and Jariwala-Parikh were involved in data analysis. Julie Gegner, PhD, an employee of Amgen, provided writing support.
Conflicts of Interest
This study was funded by Amgen Inc. Drs. Zhang and Cong are employees and stock holders of Amgen Inc. Dr. Romanov is a former employee and stock holder of Amgen. Drs. Song, Lopez-Gonzalez, and Jariwala-Parikh are employees of Truven Health Analytics, an IBM Company. Truven Health Analytics received a research grant from Amgen in implementation of the study. Drs. Zhang, Cong and Romanov were involved in the conception and design, interpretation of the data, and critical revision of the manuscript for intellectual content. Dr. Zhang participated in writing of the manuscript. All authors gave the final approval of the manuscript to be submitted for publication. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol.
Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration.
The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade.
Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen.
Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives—a position statement from the European Society for Blood and Marrow Transplantation (EBMT).
Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study.
Idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) for untreated patients with high-risk MDS or AML evolved from MDS: a phase II study from the EORTC and GIMEMA Leukemia Groups (protocol 06013).
A Model estimating indirect costs of premature death associated with severe hepatic veno-occlusive disease (sVOD) among hematopoietic stem cell transplant (HSCT) patients in the United States (U.S.).
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