Statistical Analysis
Total cost and utilization were summarized for the cohort for the 90-day time period of interest. Cost was further characterized by the location of service provided, the presence of ICD-10 codes for the complications of CRS (D89.831-D89.835, D89.839) and/or ICANS (G92.00-G92.05). Total cost was analyzed by age group (1-9 years vs. 10-25 years) as a proxy for upfront ALL risk group and by the occurrence of CRS. Analyses were performed using R.33
Results
A cohort of 37 patients aged 1-25 years was identified with a concomitant ICD-10 code for ALL and CPT code for CAR-T cell administration (Table 1). All patients had continuous coverage enrollment from one month prior to infusion through two months post-infusion except patients who died during the time period. Thirteen patients (35%) were under 10 years of age at the time of cell infusion; median age at administration was 13 years (interquartile range [IQR] 7-19 years). Fourteen patients (37.8%) were female, and while 14 patients were reported to be White, race and ethnicity were unknown in 43% of individuals.
Over the 90 day period encompassing 30 days prior to CAR-T infusion through 60 days post-infusion, the median cost for the full cohort was $620,500 (mean, $585,398). Overall utilization and cost findings are shown in Table 2. Median cost was not significantly different between patients under vs. over age 10 ($620,279 vs $633,137, respectively). Inpatient cost accounted for approximately 71% of the total cost with a median inpatient cost of $556,492. Median outpatient cost was $70,545. There were no statistically significant differences between inpatient or outpatient total cost between the two age cohorts (Figure 1).
The median number of inpatient encounters across the cohort was 2, with patients spending a median of 21 days in the hospital. Patients had an average of 7 outpatient visits in the 30 days prior to CAR-T therapy and an average of 9 outpatient visits in the 60 days following infusion. Similar to cost, there was no significant difference between the utilization of care based on age.
Within the cohort, less than 11 patients had a diagnostic code for cytokine release syndrome at some point during the study period (n<11 cannot be identified per OptumLabs data guidelines). No patients in the dataset had a diagnostic code for ICANS. When stratified into CRS and non-CRS cohorts, there were no significant differences in total, inpatient or outpatient cost between the cohorts (Figure 2). Greater than zero but less than 11 patients had a diagnosis code indicative of death during the 60 days post-infusion.
Discussion
In this study, we examined the healthcare cost and utilization for pediatric patients receiving CAR-T cell therapy for B-ALL using a commercial claims database, the first analysis of its kind in this patient population. Patients were predominantly male and most were adolescents, which is consistent with prior studies that have shown that in the pediatric population, male sex and age >10 years are significant predictors of inferior post-relapse survival and therefore require novel therapies such as CAR-T.34
Almost all patients received the CAR-T therapy in the inpatient setting, and thus, inpatient cost was significantly higher than outpatient cost, likely reflecting the price of the tisagenlecleucel product itself in addition to the cost of lymphodepleting chemotherapy and care for post-infusion complications. Costs of emergency department care and home health-related care contributed minimally to the overall cost burden in the 90 day period of interest around CAR-T infusion.
The median total cost across the entire cohort for the period of interest was $620,500, indicating that the typical cost of care, excluding the listed drug price for tisagenlecleucel of $475,000, was approximately $145,500. This is fairly consistent with cost modeling performed for tisagenlecleucel in pediatric B-ALL patients by Lin et al. which predicted the total cost to be between $548,000 and $599,000.18 This is also consistent with other reports of cost associated with the real-world care for patients receiving CAR-T therapies in adults with relapsed or refractory lymphomas.35,36
Our study has several limitations. The landmark ELIANA trial of tisagenlecleucel study reported a CRS rate of 77% and neurotoxicity rate of 40% with this therapy.8 Prior to October 2020, no ICD-10 diagnosis codes for CRS or ICANS had been adopted by the Centers for Medicare & Medicaid Services. Therefore, other studies have utilized claims-based algorithms for CRS and neurotoxicity via expert clinical opinion and based on the clinical manifestations of these complications.35 However, given the lack of ability to validate these algorithms with electronic medical record (EMR)-based records, the interpretation of these algorithms is challenging. Less than 11 patients in our cohort had a recorded ICD-10 for cytokine release syndrome (CRS) and no patients had a diagnostic code for immune-effector cell associated neurotoxicity syndrome (ICANS). This is expected given the cohort was primarily treated prior to October 2020 when ICD-10 codes for these diagnoses were introduced, however it unfortunately impacts our ability to detect whether there was higher cost and utilization of care for patients with vs without CRS. Cost that may not have been captured in this analysis include those of leukapheresis, which often occurs greater than 30 days prior to the administration of the CAR-T product, as well as the longer term cost of B-cell aplasia and secondary hypogammaglobulinemia following CAR-T infusion, treated with immune globulin replacement therapy.
Consistent with most commercial claims databases, some demographic and clinical characteristics, such as race/ethnicity or prior therapies such as stem cell transplant, were absent or missing from the OptumLabs data.35 This limits our ability to analyze the effect of race/ethnicity on cost, a key component of health equity and opportunity in the current era of healthcare in the United States. The relatively small sample size of this study limits the power to detect differences between cohorts and the lack of clinical information or ability to validate diagnostic coding with EMR-based data limits analysis of the effect of disease characteristics, performance index or prior therapies and hinders cost-benefit analyses. Additionally, the OptumLabs Data Warehouse is limited to commercially insured individuals, thus excluding publicly insured or managed care patients from this analysis and limiting the generalizability of these results.
Conclusions
This robust real-world cost analysis shows for the first time the true cost and peri-infusion care utilization of CAR-T therapy for pediatric B-ALL. This encompasses not only the commercial cost of the cellular therapy product itself, but the care involved prior to cell product infusion and the management of its complications. The total cost and utilization of care is not significantly impacted by patient age. Mean and median total cost well exceeded $500,000 US dollars, as expected with the listed commercial price of tisagenlecleucel of $475,000. This study provides a valuable benchmark that can be used to analyze the financial toxicity of CAR-T therapy for pediatric ALL therapy on health systems, patients and families. The cost of this therapy can be reassessed over time as other novel therapeutics are introduced into ALL therapy and long-term outcome data for this therapy are established
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TABLE 1 Demographics